PhD

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

The relationship between the immune system and tumors is complex and dynamic, and for immunotherapy to reach its full potential it will likely need to attack on multiple fronts. Here, we discuss some of the latest and most promising developments in the immuno-oncology field designed to build on the successes and address limitations.

The anti-tumor immune response

Cancer is a disease of genomic instability, whereby genetic alterations ranging from a single nucleotide to the whole chromosome level frequently occur. Although cancers derive from a patient’s own tissues, these genetic differences can mark the cancer cell as non-self, triggering an immune response to eliminate these cells.

The first hints of this anti-tumor immunity date back more than a century and a half and sparked the concept of mobilizing the immune system to treat patients.^1-3 Although early pioneers achieved little progress in this regard, their efforts provided invaluable insights into the complex and dynamic relationship between a tumor and the immune system that are now translating into real clinical successes.

We now understand that the immune system has a dual role in both restraining and promoting cancer development and have translated this understanding into the theory of cancer immunoediting. Immunoediting has three stages: elimination, wherein the tumor is seemingly destroyed by the innate and adaptive immune response; equilibrium, in which cancer cells that were able to escape elimination are selected for growth; and escape, whereby these resistant cancer cells overwhelm the immune system and develop into a symptomatic lesion.^4,5

Immuno-oncologists have also described the cancer immunity cycle to capture the steps that are required for an effective anti-tumor immune response and defects in this cycle form the basis of the most common mechanisms used by cancer cells to subvert the anti-tumor immune response. Much like the cancer hallmarks did for molecularly targeted cancer drugs, the cancer immunity cycle serves as the intellectual framework for cancer immunotherapy.^6,7

Exploiting nature’s weapon of mass destruction

Initially, attempts at immunotherapy focused on boosting the immune response using adjuvants and cytokines. The characterization of subtle differences between tumor cells and normal cells led to the development of vaccines and cell-based therapies that exploited these tumor-associated antigens (TAAs).^1-6

Despite the approval of a therapeutic vaccine, sipuleucel-T, in 2010 for the treatment of metastatic prostate cancer, in general the success of vaccines has been limited. Marketing authorization for sipuleucel-T was recently withdrawn in Europe, and although it is still available in the United States, it is not widely used because of issues with production and administration. Other vaccines, such as GVAX, which looked particularly promising in early-stage clinical trials, failed to show clinical efficacy in subsequent testing.^8,9

Cell-based therapies, such as adoptive cellular therapy (ACT), in which immune cells are removed from the host, primed to attack cancer cells, and then reinfused back into the patient, have focused on T cells because they are the major effectors of the adaptive immune response. Clinical success with the most common approach, tumor-infiltrating lymphocyte (TIL) therapy, has so far been limited to only one type of cancer – metastatic melanoma – but ACT may be inching closer to the mainstream with the development of techniques that allow genetic manipulation of the T cells before they are infused back into the patient.

Two key techniques have been developed (Figure 1). T-cell receptor (TCR) therapy involves genetically modifying the receptor on the surface of T cells that is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APCs). The TCR can be altered to recognize a specific TAA or modified to improve its antigen recognition and binding capabilities. This type of therapy is limited by the fact that the TCRs need to be genetically matched to the patient’s immune type.

Releasing the brakes

To ensure that it is only activated at the appropriate time and not in response to the antigens expressed on the surface of the host’s own tissues or harmless materials, the immune system has developed numerous mechanisms for immunological tolerance. Cancer cells are able to exploit these mechanisms to allow them to evade the anti-tumor immune response. One of the main ways in which they do this is by manipulating the signaling pathways involved in T-cell activation, which play a vital role in tolerance.¹²

To become fully activated, T cells require a primary signal generated by an interaction between the TCR and the antigen-MHC complex on the surface of an APC, followed by secondary costimulatory signals generated by a range of different receptors present on the T-cell surface binding to their ligands on the APC.

If the second signal is inhibitory rather than stimulatory, then the T cell is deactivated instead of becoming activated. Two key coinhibitory receptors are programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) and tumor cells are able to overcome the anti-tumor immune response in part by expressing the ligands that bind these receptors to dampen the activity of tumor-infiltrating T cells and induce tolerance.¹³

The development of inhibitors of CTLA-4 and PD-1 and their respective ligands has driven some of the most dramatic successes with cancer immunotherapy, particularly with PD-1-targeting drugs which have fewer side effects. Targeting of this pathway has resulted in durable responses, revolutionizing the treatment of metastatic melanoma, with recently published long-term survival data for pembrolizumab showing that 40% of patients were alive 3 years after initiating treatment and, in a separate study, 34% of nivolumab-treated patients were still alive after 5 years.^14,15 More recently, PD-1 inhibitors have been slowly expanding into a range of other cancer types and 4 immune checkpoint inhibitors are now approved by the United States Food and Drug Administration (FDA): ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda) and atezolizumab (Tecentriq).

Six years on from the first approval in this drug class and an extensive network of coinhibitory receptors has been uncovered – so-called immune checkpoints – many of which are now also serving as therapeutic targets (Table, Figure 2).¹⁶ Lymphocyte activation gene 3 (LAG-3) is a member of the immunoglobulin superfamily of receptors that is expressed on a number of different types of immune cell. In addition to negatively regulating cytotoxic T-cell activation like PD-1 and CTLA-4, it is also thought to regulate the immunosuppressive functions of regulatory T cells and the maturation and activation of dendritic cells. T-cell immunoglobulin and mucin domain-containing 3 (TIM-3) is found on the surface of helper and cytotoxic T cells and regulates T-cell inhibition as well as macrophage activation. Inhibitors of both proteins have been developed that are being evaluated in phase 1 or 2 clinical trials in a variety of tumor types.17

Indeed, although T cells have commanded the most attention, there is growing appreciation of the potential for targeting other types of immune cell that play a role in the anti-tumor immune response or in fostering an immunosuppressive microenvironment. NK cells have been a particular focus, since they represent the body’s first line of immune defense and they appear to have analogous inhibitory and activating receptors expressed on their surface that regulate their cytotoxic activity.

The best-defined NK cell receptors are the killer cell immunoglobulin-like receptors (KIRs) that bind to the MHC class I proteins found on the surface of all cells that distinguish them as ‘self’ or ‘non-self’. KIRs can be either activating or inhibitory, depending upon their structure and the ligands to which they bind.¹⁹ To date, 2 antibodies targeting inhibitory KIRs have been developed. Though there has been some disappointment with these drugs, most recently a phase 2 trial of lirilumab in elderly patients with acute myeloid leukemia, which missed its primary endpoint, they continue to be evaluated in clinical trials.²⁰

The inhibitory immune checkpoint field has also expanded to include molecules that regulate T-cell activity in other ways. Most prominently, this includes enzymes like indoleamine-2,3 dioxygenase (IDO), which is involved in the metabolism of the essential amino acid tryptophan. IDO-induced depletion of tryptophan and generation of tryptophan metabolites is toxic to cytotoxic T cells, and IDO is also thought to directly activate regulatory T cells, thus the net effect of IDO is immunosuppression. Two IDO inhibitors are currently being developed.²¹

Stepping on the gas

Despite their unprecedented success, immune checkpoint inhibitors are not effective in all patients or in all tumor types. Their efficacy is limited in large part by the requirement for a pre-existing anti-tumor immune response. If there are no T cells within the tumor microenvironment then releasing the brakes on the immune system won’t help.

More recently, researchers have returned to the idea of stimulating an anti-tumor immune response, this time by targeting the other side of the immune checkpoint coin, the costimulatory molecules. These drugs could prove more effective as they aren’t reliant on a pre-existing anti-tumor immune response. A number of agonist antibodies designed to target these receptors have now been developed and are undergoing clinical evaluation.²²

Furthest along in development are those targeting OX40, a costimulatory molecule that is upregulated on the surface of T cells once they have been fully activated by the TCR signal and an initial costimulatory signal. OX40 is thought to be involved in a more long-term immune response and in the formation of a memory response. A mouse monoclonal antibody had a potent immune-stimulating effect accompanied by the regression of at least 1 metastatic lesion in 30% of patients treated in a phase 1 clinical trial, but was limited by the generation of anti-mouse antibodies. 7 OX40 agonists are now in clinical development, 6 fully human monoclonal antibodies and 1 OX40 ligand-Fc fusion protein, MEDI-6383.²³

Combinations are key

Many researchers are now reaching the conclusion that combination therapy is likely to be key in expanding the scope of immunotherapy into currently unresponsive patient populations. Investigating rational combinations is already becoming a burgeoning area of the immuno-oncology field, with a variety of different strategies being tested.

Now the question becomes what are the optimal combinations and the timing and sequencing of combination therapy is likely to be a paramount consideration. Developing combinations that have distinct mechanisms of action or target multiple steps in the cancer immunity cycle offers the greatest potential for therapeutic synergy since this is most likely to address potential mechanisms of resistance by blocking other paths to immune evasion for cancer cells (Figure 3).

Given the expanding network of immune-checkpoint inhibitors and agonists, the focal point of combination therapy has been combining immune checkpoint-targeting drugs with different mechanisms of action, including those that would simultaneously release the brakes and step on the gas pedal. The vast majority of ongoing clinical trials of approved checkpoint inhibitors and the drugs in development listed in the table are combination trials.

These efforts yielded the first FDA-approved combination immunotherapy regimen in 2015; nivolumab and ipilimumab for the treatment of metastatic melanoma. Approval was based on the demonstration of improved ORR, prolonged response duration, and improved progression-free survival among 142 patients treated with the combination, compared to either drug alone.²⁴

The results of a phase 1/2 trial evaluating the combination of a 4-1BB receptor agonist urelumab with nivolumab in hematologic malignancies and solid tumors found the combination to be safe and particularly effective in patients with advanced/metastatic melanoma, with an ORR of 50%.²⁵ Nivolumab was also combined with the CD27 agonist varlilumab in a phase 1/2 clinical trial of patients with solid tumors, for which data was also recently released. Among 46 patients enrolled, primarily those with colorectal and ovarian cancer the combination had an acceptable safety profile and favorable changes in intratumoral immune biomarkers were observed. The phase 2 portion of the trial is ongoing.²⁶

Meanwhile, Incyte’s IDO inhibitor epacadostat has recently been making waves in combination with pembrolizumab in patients with advanced solid tumors. It demonstrated particularly promising clinical activity in patients with metastatic melanoma, with an overall response rate (ORR) of 57%, including 2 complete responses (CRs), prompting initiation of a phase 3 trial of this combination (NCT02752074).²⁷

In November 2016, the US Food and Drug Administration expanded the approval of daratumumab for patients with multiple myeloma. The monoclonal antibody, which targets CD38, a protein that is highly expressed on the surface of multiple myeloma cells, was previously granted approval by the agency as a single agent for the treatment of patients who had received at least three previous therapies.

The current approval was for the use of daratumumab in two different combination regimens for the treatment of patients who have received one previous line of treatment. On the basis of improved progression-free survival (PFS), demonstrated in two randomized, open-label, phase 3 trials, daratumumab can now be used in combination with the immunomodulatory agent lenalidomide and dexamethasone, or the proteasome inhibitor bortezomib and dexamethasone, both standard therapies for the treatment of multiple myeloma.

In the POLLUX trial, 569 patients with relapsed/refractory multiple myeloma were randomized 1:1 to receive daratumumab in combination with lenalidomide-dexamethasone or lenalidomide-dexamethasone alone. The CASTOR trial randomized 498 patients with relapsed/refractory multiple myeloma 1:1 to daratumumab in combination with bortezomib-dexamethasone, or bortezomib-dexamethasone alone.

The eligibility and exclusion criteria for both trials were similar; patients had received at least one previous line of therapy, had documented progressive disease according to International Myeloma Working Group criteria, and had measurable disease on the basis of urine and/or serum assessments or serum-free, light-chain assay.

Patients with a neutrophil count of ≤1,000 cells/mm³, hemoglobin level of ≤7.5 g/dL, platelet count of <75,000 cells/mm³, creatinine clearance of ≤20 mL/min per 1.73m² body surface area (or <30 mL/min in the POLLUX trial), alanine aminotransferase or aspartate aminotransferase level ≥2.5 times the upper limit of normal (ULN) range, bilirubin level of ≥1.5 or more times the ULN range, disease refractory to bortezomib or lenalidomide, and unacceptable side effects from bortezomib or lenalidomide, were ineligible for these studies. In addition, patients with grade 2 or higher peripheral neuropathy or neuropathic pain, were excluded from the CASTOR study.

Randomization was stratified according to International Staging System disease stage at the time of screening (stage I, II or III, with higher stage indicating more severe disease), number of previous lines of therapy (1 vs 2, or 3 vs >3), and previous receipt of lenalidomide or bortezomib.

In the CASTOR trial, patients received up to eight 21-day cycles of bortezomib, administered subcutaneously at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1-8, and dexamethasone, administered orally or intravenously at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 for a total dose of 160 mg per cycle. Daratumumab was administered at a dose of 16 mg/kg intravenously once weekly on days 1, 8, and 15 during cycles 1 to 3, once every 3 weeks on day 1 of cycles 4-8, and once every 4 weeks thereafter.

In the POLLUX trial, patients were treated in 28-day cycles. Daratumumab was administered at the same dose as in the CASTOR trial, but on days 1, 8, 15 and 22 for 8 weeks during cycles 1 and 2, every 2 weeks on days 1 and 15 for 16 weeks during cycles 3 through 7, and every 4 weeks from then onwards. Lenalidomide was administered at a dose of 25 mg orally on days 1-21 of each cycle, and dexamethasone at a dose of 20 mg before infusion and 20 mg the following day.

The combination of daratumumab with lenalidomide-dexamethasone demonstrated a substantial improvement in PFS, compared with lenalidomide-dexamethasone alone (estimated PFS not yet reached vs 18.4 months, respectively; HR, 0.37; P < .0001), representing a 63% reduction in the risk of disease progression or death. Meanwhile, there was a 61% reduction in the risk of disease progression or death for the combination of daratumumab with bortezomib-dexamethasone in the CASTOR trial (estimated PFS not yet reached vs 7.2 months; HR: 0.39; P < .0001). The PFS benefit was observed across all prespecified subgroups in both studies.

In the CASTOR trial, over a median follow-up of 7.4 months, the overall response rate (ORR) was 82.9% for the combination arm, compared with 63.2% for the bortezomib-dexamethasone arm (P < .001), with a very good partial response (VGPR) or better rate of 59.2% compared with 29.1%, and a complete response (CR) rate of 19.2% compared with 9%. In the POLLUX trial, over a median follow-up of 13.5 months, ORR was 92.9% for the combination arm, compared with 76.4% for lenalidomide-dexamethasone, with a VGPR or better rate of 75.8% versus 44% and a CR rate of 43.1% versus 19.2%.

Overall, the safety profile for both combinations was consistent with what is usually observed with daratumumab monotherapy and lenalidomide-dexamethasone or bortezomib-dexamethasone combinations. The most frequently reported adverse events (AEs) were similar in both studies and included infusion reactions, diarrhea, and upper respiratory tract infection. In the POLLUX trial they also included nausea, fatigue, pyrexia, muscle spasm, cough, and dyspnea, whereas in the CASTOR trial patients also frequently experienced peripheral edema.

The most common grade 3/4 AEs in both trials were neutropenia (51.9% vs 37% in the POLLUX trial and 12.8 vs 4.2% in the CASTOR trial), thrombocytopenia (12.7% vs 13.5% and 45.3% vs 32.9%, respectively), and anemia (12.4% vs 19.6% and 14.4% vs 16%, respectively). The percentage of patients who discontinued treatment due to AEs was similar in both groups across the two studies; in the CASTOR trial discontinuations resulted most commonly from peripheral sensory neuropathy and pneumonia, while in the POLLUX trial, from pneumonia, pulmonary embolism and deterioration in general physical health.

The recommended dose for daratumumab in both combination regimens is 16 mg/kg intravenously, calculated on actual body weight. The dosing schedules begin with weekly administration during weeks 1-8 (when used in combination with lenalidomide-dexamethasone) and weeks 1-9 (for use with the bortezomib-dexamethasone combination), decreasing to every 2 weeks between weeks 9 and 24 or 10 and 24, respectively, and progressing to every 4 weeks from week 25 onward until disease progression and unacceptable toxicity.

Daratumumab is marketed as Darzalex by Janssen Biotech Inc. Neutropenia and thrombocytopenia have been added to the list of warnings and precautions for the prescribing information for these new indications. Complete blood cell count should be monitored periodically during treatment and daratumumab administration delayed to allow recovery of neutrophils or platelets. Supportive care with growth factors or transfusion should be considered in the event of neutropenia or thrombocytopenia, respectively.

In November 2016, the US Food and Drug Administration expanded the approval of daratumumab for patients with multiple myeloma. The monoclonal antibody, which targets CD38, a protein that is highly expressed on the surface of multiple myeloma cells, was previously granted approval by the agency as a single agent for the treatment of patients who had received at least three previous therapies.

The current approval was for the use of daratumumab in two different combination regimens for the treatment of patients who have received one previous line of treatment. On the basis of improved progression-free survival (PFS), demonstrated in two randomized, open-label, phase 3 trials, daratumumab can now be used in combination with the immunomodulatory agent lenalidomide and dexamethasone, or the proteasome inhibitor bortezomib and dexamethasone, both standard therapies for the treatment of multiple myeloma.

In the POLLUX trial, 569 patients with relapsed/refractory multiple myeloma were randomized 1:1 to receive daratumumab in combination with lenalidomide-dexamethasone or lenalidomide-dexamethasone alone. The CASTOR trial randomized 498 patients with relapsed/refractory multiple myeloma 1:1 to daratumumab in combination with bortezomib-dexamethasone, or bortezomib-dexamethasone alone.

The eligibility and exclusion criteria for both trials were similar; patients had received at least one previous line of therapy, had documented progressive disease according to International Myeloma Working Group criteria, and had measurable disease on the basis of urine and/or serum assessments or serum-free, light-chain assay.

Patients with a neutrophil count of ≤1,000 cells/mm³, hemoglobin level of ≤7.5 g/dL, platelet count of <75,000 cells/mm³, creatinine clearance of ≤20 mL/min per 1.73m² body surface area (or <30 mL/min in the POLLUX trial), alanine aminotransferase or aspartate aminotransferase level ≥2.5 times the upper limit of normal (ULN) range, bilirubin level of ≥1.5 or more times the ULN range, disease refractory to bortezomib or lenalidomide, and unacceptable side effects from bortezomib or lenalidomide, were ineligible for these studies. In addition, patients with grade 2 or higher peripheral neuropathy or neuropathic pain, were excluded from the CASTOR study.

Randomization was stratified according to International Staging System disease stage at the time of screening (stage I, II or III, with higher stage indicating more severe disease), number of previous lines of therapy (1 vs 2, or 3 vs >3), and previous receipt of lenalidomide or bortezomib.

In the CASTOR trial, patients received up to eight 21-day cycles of bortezomib, administered subcutaneously at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1-8, and dexamethasone, administered orally or intravenously at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 for a total dose of 160 mg per cycle. Daratumumab was administered at a dose of 16 mg/kg intravenously once weekly on days 1, 8, and 15 during cycles 1 to 3, once every 3 weeks on day 1 of cycles 4-8, and once every 4 weeks thereafter.

In the POLLUX trial, patients were treated in 28-day cycles. Daratumumab was administered at the same dose as in the CASTOR trial, but on days 1, 8, 15 and 22 for 8 weeks during cycles 1 and 2, every 2 weeks on days 1 and 15 for 16 weeks during cycles 3 through 7, and every 4 weeks from then onwards. Lenalidomide was administered at a dose of 25 mg orally on days 1-21 of each cycle, and dexamethasone at a dose of 20 mg before infusion and 20 mg the following day.

The combination of daratumumab with lenalidomide-dexamethasone demonstrated a substantial improvement in PFS, compared with lenalidomide-dexamethasone alone (estimated PFS not yet reached vs 18.4 months, respectively; HR, 0.37; P < .0001), representing a 63% reduction in the risk of disease progression or death. Meanwhile, there was a 61% reduction in the risk of disease progression or death for the combination of daratumumab with bortezomib-dexamethasone in the CASTOR trial (estimated PFS not yet reached vs 7.2 months; HR: 0.39; P < .0001). The PFS benefit was observed across all prespecified subgroups in both studies.

In the CASTOR trial, over a median follow-up of 7.4 months, the overall response rate (ORR) was 82.9% for the combination arm, compared with 63.2% for the bortezomib-dexamethasone arm (P < .001), with a very good partial response (VGPR) or better rate of 59.2% compared with 29.1%, and a complete response (CR) rate of 19.2% compared with 9%. In the POLLUX trial, over a median follow-up of 13.5 months, ORR was 92.9% for the combination arm, compared with 76.4% for lenalidomide-dexamethasone, with a VGPR or better rate of 75.8% versus 44% and a CR rate of 43.1% versus 19.2%.

Overall, the safety profile for both combinations was consistent with what is usually observed with daratumumab monotherapy and lenalidomide-dexamethasone or bortezomib-dexamethasone combinations. The most frequently reported adverse events (AEs) were similar in both studies and included infusion reactions, diarrhea, and upper respiratory tract infection. In the POLLUX trial they also included nausea, fatigue, pyrexia, muscle spasm, cough, and dyspnea, whereas in the CASTOR trial patients also frequently experienced peripheral edema.

The most common grade 3/4 AEs in both trials were neutropenia (51.9% vs 37% in the POLLUX trial and 12.8 vs 4.2% in the CASTOR trial), thrombocytopenia (12.7% vs 13.5% and 45.3% vs 32.9%, respectively), and anemia (12.4% vs 19.6% and 14.4% vs 16%, respectively). The percentage of patients who discontinued treatment due to AEs was similar in both groups across the two studies; in the CASTOR trial discontinuations resulted most commonly from peripheral sensory neuropathy and pneumonia, while in the POLLUX trial, from pneumonia, pulmonary embolism and deterioration in general physical health.

The recommended dose for daratumumab in both combination regimens is 16 mg/kg intravenously, calculated on actual body weight. The dosing schedules begin with weekly administration during weeks 1-8 (when used in combination with lenalidomide-dexamethasone) and weeks 1-9 (for use with the bortezomib-dexamethasone combination), decreasing to every 2 weeks between weeks 9 and 24 or 10 and 24, respectively, and progressing to every 4 weeks from week 25 onward until disease progression and unacceptable toxicity.

Daratumumab is marketed as Darzalex by Janssen Biotech Inc. Neutropenia and thrombocytopenia have been added to the list of warnings and precautions for the prescribing information for these new indications. Complete blood cell count should be monitored periodically during treatment and daratumumab administration delayed to allow recovery of neutrophils or platelets. Supportive care with growth factors or transfusion should be considered in the event of neutropenia or thrombocytopenia, respectively.

In November 2016, the US Food and Drug Administration expanded the approval of daratumumab for patients with multiple myeloma. The monoclonal antibody, which targets CD38, a protein that is highly expressed on the surface of multiple myeloma cells, was previously granted approval by the agency as a single agent for the treatment of patients who had received at least three previous therapies.

The current approval was for the use of daratumumab in two different combination regimens for the treatment of patients who have received one previous line of treatment. On the basis of improved progression-free survival (PFS), demonstrated in two randomized, open-label, phase 3 trials, daratumumab can now be used in combination with the immunomodulatory agent lenalidomide and dexamethasone, or the proteasome inhibitor bortezomib and dexamethasone, both standard therapies for the treatment of multiple myeloma.

In the POLLUX trial, 569 patients with relapsed/refractory multiple myeloma were randomized 1:1 to receive daratumumab in combination with lenalidomide-dexamethasone or lenalidomide-dexamethasone alone. The CASTOR trial randomized 498 patients with relapsed/refractory multiple myeloma 1:1 to daratumumab in combination with bortezomib-dexamethasone, or bortezomib-dexamethasone alone.

The eligibility and exclusion criteria for both trials were similar; patients had received at least one previous line of therapy, had documented progressive disease according to International Myeloma Working Group criteria, and had measurable disease on the basis of urine and/or serum assessments or serum-free, light-chain assay.

Patients with a neutrophil count of ≤1,000 cells/mm³, hemoglobin level of ≤7.5 g/dL, platelet count of <75,000 cells/mm³, creatinine clearance of ≤20 mL/min per 1.73m² body surface area (or <30 mL/min in the POLLUX trial), alanine aminotransferase or aspartate aminotransferase level ≥2.5 times the upper limit of normal (ULN) range, bilirubin level of ≥1.5 or more times the ULN range, disease refractory to bortezomib or lenalidomide, and unacceptable side effects from bortezomib or lenalidomide, were ineligible for these studies. In addition, patients with grade 2 or higher peripheral neuropathy or neuropathic pain, were excluded from the CASTOR study.

Randomization was stratified according to International Staging System disease stage at the time of screening (stage I, II or III, with higher stage indicating more severe disease), number of previous lines of therapy (1 vs 2, or 3 vs >3), and previous receipt of lenalidomide or bortezomib.

In the CASTOR trial, patients received up to eight 21-day cycles of bortezomib, administered subcutaneously at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 of cycles 1-8, and dexamethasone, administered orally or intravenously at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 for a total dose of 160 mg per cycle. Daratumumab was administered at a dose of 16 mg/kg intravenously once weekly on days 1, 8, and 15 during cycles 1 to 3, once every 3 weeks on day 1 of cycles 4-8, and once every 4 weeks thereafter.

In the POLLUX trial, patients were treated in 28-day cycles. Daratumumab was administered at the same dose as in the CASTOR trial, but on days 1, 8, 15 and 22 for 8 weeks during cycles 1 and 2, every 2 weeks on days 1 and 15 for 16 weeks during cycles 3 through 7, and every 4 weeks from then onwards. Lenalidomide was administered at a dose of 25 mg orally on days 1-21 of each cycle, and dexamethasone at a dose of 20 mg before infusion and 20 mg the following day.

The combination of daratumumab with lenalidomide-dexamethasone demonstrated a substantial improvement in PFS, compared with lenalidomide-dexamethasone alone (estimated PFS not yet reached vs 18.4 months, respectively; HR, 0.37; P < .0001), representing a 63% reduction in the risk of disease progression or death. Meanwhile, there was a 61% reduction in the risk of disease progression or death for the combination of daratumumab with bortezomib-dexamethasone in the CASTOR trial (estimated PFS not yet reached vs 7.2 months; HR: 0.39; P < .0001). The PFS benefit was observed across all prespecified subgroups in both studies.

In the CASTOR trial, over a median follow-up of 7.4 months, the overall response rate (ORR) was 82.9% for the combination arm, compared with 63.2% for the bortezomib-dexamethasone arm (P < .001), with a very good partial response (VGPR) or better rate of 59.2% compared with 29.1%, and a complete response (CR) rate of 19.2% compared with 9%. In the POLLUX trial, over a median follow-up of 13.5 months, ORR was 92.9% for the combination arm, compared with 76.4% for lenalidomide-dexamethasone, with a VGPR or better rate of 75.8% versus 44% and a CR rate of 43.1% versus 19.2%.

Overall, the safety profile for both combinations was consistent with what is usually observed with daratumumab monotherapy and lenalidomide-dexamethasone or bortezomib-dexamethasone combinations. The most frequently reported adverse events (AEs) were similar in both studies and included infusion reactions, diarrhea, and upper respiratory tract infection. In the POLLUX trial they also included nausea, fatigue, pyrexia, muscle spasm, cough, and dyspnea, whereas in the CASTOR trial patients also frequently experienced peripheral edema.

The most common grade 3/4 AEs in both trials were neutropenia (51.9% vs 37% in the POLLUX trial and 12.8 vs 4.2% in the CASTOR trial), thrombocytopenia (12.7% vs 13.5% and 45.3% vs 32.9%, respectively), and anemia (12.4% vs 19.6% and 14.4% vs 16%, respectively). The percentage of patients who discontinued treatment due to AEs was similar in both groups across the two studies; in the CASTOR trial discontinuations resulted most commonly from peripheral sensory neuropathy and pneumonia, while in the POLLUX trial, from pneumonia, pulmonary embolism and deterioration in general physical health.

The recommended dose for daratumumab in both combination regimens is 16 mg/kg intravenously, calculated on actual body weight. The dosing schedules begin with weekly administration during weeks 1-8 (when used in combination with lenalidomide-dexamethasone) and weeks 1-9 (for use with the bortezomib-dexamethasone combination), decreasing to every 2 weeks between weeks 9 and 24 or 10 and 24, respectively, and progressing to every 4 weeks from week 25 onward until disease progression and unacceptable toxicity.

Daratumumab is marketed as Darzalex by Janssen Biotech Inc. Neutropenia and thrombocytopenia have been added to the list of warnings and precautions for the prescribing information for these new indications. Complete blood cell count should be monitored periodically during treatment and daratumumab administration delayed to allow recovery of neutrophils or platelets. Supportive care with growth factors or transfusion should be considered in the event of neutropenia or thrombocytopenia, respectively.

Failure of fear extinction is a core feature of posttraumatic stress disorder (PTSD).¹ Recently, it was confirmed that the amygdala and the orbitofrontal cortex are crucial for both fear acquisition and fear extinction.² The amygdala was found to have neurons active only during fear acquisition, and other neurons active only during fear extinction.³ In essence, the balance of activity between these 2 neuronal populations determines whether if an incoming stimulus is feared or not feared. This balance is under the influence of several cognitive domains, including memory, reward, and executive function.

In PTSD, the equilibrium is shifted heavily toward fear acquisition. The majority of patients spontaneously regain the capacity for fear extinction over time⁴ or with the help of treatment.^5,6 Nonetheless, some patients with severe PTSD seem unable to recover the ability of fear extinction and remain refractory to both standard and novel psychotherapeutic or psychopharmacologic treatments.⁷ For these patients, direct modulation of the neural activity in the amygdala may permit fear extinction. This article describes the rationale for using deep brain stimulation (DBS) and initial results from the first-ever clinical trial.

Deep Brain Stimulation

Deep brain stimulation involves inserting electrodes in precise cerebral targets and then connecting the leads to a pulse generator (similar to a pacemaker) inserted in a subclavicular pocket. The generator controls the electrical signal (amplitude, pulse width, pulse frequency) delivered to the brain target and can be adjusted with use of a noninvasive programmer. In 1997, the FDA approved DBS for patients with Parkinson disease or essential tremor. Since then, its efficacy in these movement disorders has been confirmed in several studies.^8,9

The mechanism by which the small electrical pulses of DBS influence activity is not clear. Clinically, DBS functionally inhibits the activity of local neurons.¹⁰ One theory describes “frequency jamming,” a concept similar to cardiac overdrive pacing in which the resultant high-frequency neuronal signal is meaningless and discounted by the rest of the brain.¹¹

Over the years, DBS has demonstrated a strong safety profile.¹² The risks of electrode insertion are mitigated with targeting based on high-quality magnetic resonance imaging (MRI) and computed tomography (Figure). Unlike a destructive lesion, DBS is reversible, and the implanted system can be removed in its entirety. Histologic analyses have shown only a small amount of scarring around the electrode tip.¹³ In movement disorder treatment, clinical experience has shown that stimulation-related adverse effects (AEs) are reversible with readjustment of stimulation parameters by external programmer.¹⁴

Novel Applications of DBS

The advantageous safety profile of DBS has permitted its evaluation in the treatment of other conditions thought to have malfunctioning networks at their core—such as intractable epilepsy (in resective surgery noncandidates).^15,16 Although several trials have shown promising results of using DBS for treatment-resistant depression,¹⁷ the results of pivotal sham-controlled trials have been mixed.^18,19 Obsessive-compulsive disorder, on the other hand, received the FDA humanitarian device exemption designation on the basis of positive long-term results.²⁰ In treatment-resistant depression and obsessive-compulsive disorder, functional neuroimaging has identified DBS targets.^21,22 Functional MRI or positron emission tomography (PET) images can be compared at resting state, at symptomatic state, and after treatment response. Nodes hyperactive during a symptomatic state and less active after successful treatment can be targeted with high-frequency DBS to directly reduce the hyperactivity and indirectly modulate or normalize the overall function of the circuit.²³

Given the functional MRI and O15 (oxygen-15) PET evidence of amygdala hyperactivity in patients with PTSD having core symptoms,^24-26 the authors hypothesized that high-frequency DBS targeting of the amygdala would improve PTSD-associated hyperarousal and reexperiencing symptoms in treatment-refractory patients. Indirect data supporting this hypothesis include a correlation between amygdala hyperactivity of increased intensity and symptom severity measured with the Clinician-Administered PTSD Scale (CAPS),²⁷ and a correlation between reduced pretreatment amygdala hyperactivity and successful cognitive-behavioral treatment.^28,29

Preclinical Work

Using a rodent model in which a novel object serves as a cue reminder of foot shocks (traumatic event), the authors tested the hypothesis that amygdala DBS would reduce PTSD-like symptoms.³⁰ When untreated rats were presented with the object in their cage a week after the initial exposure, they immediately buried the object under bedding to avoid being reminded of the shocks. In contrast, rats treated with DBS did not bury the object. In most cases, in fact, they played with it.

The authors also replicated their results but with the addition of rats treated with paroxetine.³¹ Using the same rodent model, they found DBS superior to paroxetine in treating PTSD-like symptoms. This study had a crossover design: DBS and sham DBS. Briefly, 20 rats received an electrode in the amygdala and were exposed to inescapable shocks in the presence of the cue object. The rats were then randomly assigned to a DBS group (10 rats) or a sham-DBS group (10 rats). After 1 week, behavioral testing showed fear extinction in the DBS group and no improvement in the sham-DBS group. Then the groups were switched: The rats originally treated with DBS received no treatment, and the rats that were originally sham-treated underwent DBS. One week later, behavioral testing showed acquisition of fear extinction in all the rats. These results suggested DBS can be effective even when delayed after establishment of fear persistence and PTSD symptoms. These results also showed that DBS effects persist even after therapy discontinuation.

Similarly, other investigators have reported that the role of the amygdala is not limited to fear acquisition; it extends to fear expression. A lesion in the amygdala can prevent fear expression even if the disruption is performed subsequent to fear-conditioning training.³² This finding is important for humans, as DBS would be initiated during the chronic phase of the disorder, after failure of less invasive treatment options, such as pharmacotherapy and psychotherapy.

Early Clinical Experience

The authors have initiated the first ever clinical trial (NCT02091843) evaluating use of DBS for PTSD and are now recruiting patients. Enrollment is limited to 6 combat veterans with disabling PTSD that has not responded to pharmacotherapy and psychotherapy. This VA-funded single-site study, being conducted at the VA Greater Los Angeles Healthcare System (VAGLAHS), was approved by the VAGLAHS Institutional Review Board and the FDA. The authors have published the 2-year trial’s protocol, which includes an active-versus-sham stimulation phase; continuous electroencephalogram monitoring; baseline and posttreatment ¹⁸FDG (fluorodeoxyglucose) PET performed during a resting state vs during investigator-guided exposure to trauma reminders; and extensive psychological and neuropsychological assessments.³³ The literature includes only 1 case report on amygdala DBS.³⁴ The authors of that report used DBS of the basolateral nucleus of the amygdala to treat a teenaged boy with severe autism and found that the therapy was safe.

As of this writing, the authors have recruited and implanted 1 patient and reported on his clinical results (including baseline PET) over the first 8 months of stimulation³⁵ and on the electrophysiologic findings over the first year.³⁶ After experiencing extremely severe combat PTSD refractory to pharmacotherapy and psychotherapy treatments for more than 20 years, the patient treated with DBS is now experiencing substantial symptom relief, and his CAPS score (primary outcome measure) has improved by about 40%. He has tolerated continuous stimulation without any serious DBS-related AEs for up to 16 months. Notably, he has not had a single severe combat nightmare in a year—in stark contrast to nightly combat nightmares during the 20-year period leading to the trial. Furthermore, he has not been having any episodes of severe dissociation, which had been a common disabling problem before the trial. He has taken a second trip out of the country, improved his relationships with family, and made strides (albeit limited) in pursuing additional social interactions.

Avoidance remains a major problem. He recently left his job after 7 years, because he prefers a more nature-oriented rather than people-oriented environment. In addition, his interest in intensive psychotherapy has increased, and he has been considering options for spending more time working on his therapy.

Over 15 months of treatment, the patient’s CAPS total and subscale scores have decreased—his symptoms have improved (Table).²¹ He has had rapid and substantial reductions in recurrence and hyperarousal symptoms but slower improvement in avoidance. Improvements in emotional reactivity would be expected to occur before any change in behavior (eg, avoidance). Patients likely must first recognize changes in emotional reactivity to events before they can engage in a cognitive process to modify learned behavioral responses to those events.

After about 9 months of treatment, all of the study patient’s symptoms were somewhat stabilized, and the authors began making gradual stimulation adjustments to the latest parameters—3.5 V, 60 µs, and 160 Hz for the right electrode and 1.5 V, 60 µs, and 160 Hz for the left electrode—using the contacts in the basolateral nucleus of the amygdala, per postoperative neuroimaging.³⁵ A thin cuts computed tomography (CT) scan of the brain was obtained postoperatively and merged to the preoperative MRI. The CT scan captured the location of the DBS electrode contacts and the MRI superimposition to determine the position of those contacts in the brain.

After 15 to 18 months, when improvement peaked at 48% symptom reduction from baseline, the patient experienced psychiatric decompensation (depression, suicide gesture) not attributable to changes in stimulation settings and not associated with exacerbation of PTSD symptoms. Treatment team members and independent psychiatric consultants attributed the decompensation to the patient’s difficulty in changing a long-standing avoidant behavior routine, owing to severe recurrence and hyperarousal symptoms in the past. His persistent inability to overcome avoidance and isolation, despite core PTSD symptom improvement, had left him feeling worthless.

The patient remains in the study but also is participating in other medication and psychotherapy trials and is making a career change. Periodic decompensations may be part of the treatment course as patients reach a more complex and volatile phase of improvement that requires more intensive cognitive reprocessing. If this proves to be the case with other patients enrolling in the study, intensive psychotherapy that addresses cognitive and emotional PTSD symptoms may be needed once there is improvement in intrusive and hyperarousal symptoms.

Conclusion

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor. Physiologically, DBS seems to inhibit specific brain regions’ dysfunctional activity stemming from a disease process. Deep brain stimulation-induced inhibition of a dysfunctional node improves clinical outcomes in movement disorders.

Given the reversibility and positive safety profile of DBS, new applications are being studied. The authors propose that DBS may benefit patients with severe treatment-refractory PTSD. Their first patient’s core PTSD symptoms have improved significantly, as expected, but as in other psychiatric DBS cases, the seriousness and chronicity of his illness may be complicating the course of recovery. The authors plan to recruit 6 patients for this early-phase safety trial.

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Failure of fear extinction is a core feature of posttraumatic stress disorder (PTSD).¹ Recently, it was confirmed that the amygdala and the orbitofrontal cortex are crucial for both fear acquisition and fear extinction.² The amygdala was found to have neurons active only during fear acquisition, and other neurons active only during fear extinction.³ In essence, the balance of activity between these 2 neuronal populations determines whether if an incoming stimulus is feared or not feared. This balance is under the influence of several cognitive domains, including memory, reward, and executive function.

In PTSD, the equilibrium is shifted heavily toward fear acquisition. The majority of patients spontaneously regain the capacity for fear extinction over time⁴ or with the help of treatment.^5,6 Nonetheless, some patients with severe PTSD seem unable to recover the ability of fear extinction and remain refractory to both standard and novel psychotherapeutic or psychopharmacologic treatments.⁷ For these patients, direct modulation of the neural activity in the amygdala may permit fear extinction. This article describes the rationale for using deep brain stimulation (DBS) and initial results from the first-ever clinical trial.

Deep Brain Stimulation

Deep brain stimulation involves inserting electrodes in precise cerebral targets and then connecting the leads to a pulse generator (similar to a pacemaker) inserted in a subclavicular pocket. The generator controls the electrical signal (amplitude, pulse width, pulse frequency) delivered to the brain target and can be adjusted with use of a noninvasive programmer. In 1997, the FDA approved DBS for patients with Parkinson disease or essential tremor. Since then, its efficacy in these movement disorders has been confirmed in several studies.^8,9

The mechanism by which the small electrical pulses of DBS influence activity is not clear. Clinically, DBS functionally inhibits the activity of local neurons.¹⁰ One theory describes “frequency jamming,” a concept similar to cardiac overdrive pacing in which the resultant high-frequency neuronal signal is meaningless and discounted by the rest of the brain.¹¹

Over the years, DBS has demonstrated a strong safety profile.¹² The risks of electrode insertion are mitigated with targeting based on high-quality magnetic resonance imaging (MRI) and computed tomography (Figure). Unlike a destructive lesion, DBS is reversible, and the implanted system can be removed in its entirety. Histologic analyses have shown only a small amount of scarring around the electrode tip.¹³ In movement disorder treatment, clinical experience has shown that stimulation-related adverse effects (AEs) are reversible with readjustment of stimulation parameters by external programmer.¹⁴

Novel Applications of DBS

The advantageous safety profile of DBS has permitted its evaluation in the treatment of other conditions thought to have malfunctioning networks at their core—such as intractable epilepsy (in resective surgery noncandidates).^15,16 Although several trials have shown promising results of using DBS for treatment-resistant depression,¹⁷ the results of pivotal sham-controlled trials have been mixed.^18,19 Obsessive-compulsive disorder, on the other hand, received the FDA humanitarian device exemption designation on the basis of positive long-term results.²⁰ In treatment-resistant depression and obsessive-compulsive disorder, functional neuroimaging has identified DBS targets.^21,22 Functional MRI or positron emission tomography (PET) images can be compared at resting state, at symptomatic state, and after treatment response. Nodes hyperactive during a symptomatic state and less active after successful treatment can be targeted with high-frequency DBS to directly reduce the hyperactivity and indirectly modulate or normalize the overall function of the circuit.²³

Given the functional MRI and O15 (oxygen-15) PET evidence of amygdala hyperactivity in patients with PTSD having core symptoms,^24-26 the authors hypothesized that high-frequency DBS targeting of the amygdala would improve PTSD-associated hyperarousal and reexperiencing symptoms in treatment-refractory patients. Indirect data supporting this hypothesis include a correlation between amygdala hyperactivity of increased intensity and symptom severity measured with the Clinician-Administered PTSD Scale (CAPS),²⁷ and a correlation between reduced pretreatment amygdala hyperactivity and successful cognitive-behavioral treatment.^28,29

Preclinical Work

Using a rodent model in which a novel object serves as a cue reminder of foot shocks (traumatic event), the authors tested the hypothesis that amygdala DBS would reduce PTSD-like symptoms.³⁰ When untreated rats were presented with the object in their cage a week after the initial exposure, they immediately buried the object under bedding to avoid being reminded of the shocks. In contrast, rats treated with DBS did not bury the object. In most cases, in fact, they played with it.

The authors also replicated their results but with the addition of rats treated with paroxetine.³¹ Using the same rodent model, they found DBS superior to paroxetine in treating PTSD-like symptoms. This study had a crossover design: DBS and sham DBS. Briefly, 20 rats received an electrode in the amygdala and were exposed to inescapable shocks in the presence of the cue object. The rats were then randomly assigned to a DBS group (10 rats) or a sham-DBS group (10 rats). After 1 week, behavioral testing showed fear extinction in the DBS group and no improvement in the sham-DBS group. Then the groups were switched: The rats originally treated with DBS received no treatment, and the rats that were originally sham-treated underwent DBS. One week later, behavioral testing showed acquisition of fear extinction in all the rats. These results suggested DBS can be effective even when delayed after establishment of fear persistence and PTSD symptoms. These results also showed that DBS effects persist even after therapy discontinuation.

Similarly, other investigators have reported that the role of the amygdala is not limited to fear acquisition; it extends to fear expression. A lesion in the amygdala can prevent fear expression even if the disruption is performed subsequent to fear-conditioning training.³² This finding is important for humans, as DBS would be initiated during the chronic phase of the disorder, after failure of less invasive treatment options, such as pharmacotherapy and psychotherapy.

Early Clinical Experience

The authors have initiated the first ever clinical trial (NCT02091843) evaluating use of DBS for PTSD and are now recruiting patients. Enrollment is limited to 6 combat veterans with disabling PTSD that has not responded to pharmacotherapy and psychotherapy. This VA-funded single-site study, being conducted at the VA Greater Los Angeles Healthcare System (VAGLAHS), was approved by the VAGLAHS Institutional Review Board and the FDA. The authors have published the 2-year trial’s protocol, which includes an active-versus-sham stimulation phase; continuous electroencephalogram monitoring; baseline and posttreatment ¹⁸FDG (fluorodeoxyglucose) PET performed during a resting state vs during investigator-guided exposure to trauma reminders; and extensive psychological and neuropsychological assessments.³³ The literature includes only 1 case report on amygdala DBS.³⁴ The authors of that report used DBS of the basolateral nucleus of the amygdala to treat a teenaged boy with severe autism and found that the therapy was safe.

As of this writing, the authors have recruited and implanted 1 patient and reported on his clinical results (including baseline PET) over the first 8 months of stimulation³⁵ and on the electrophysiologic findings over the first year.³⁶ After experiencing extremely severe combat PTSD refractory to pharmacotherapy and psychotherapy treatments for more than 20 years, the patient treated with DBS is now experiencing substantial symptom relief, and his CAPS score (primary outcome measure) has improved by about 40%. He has tolerated continuous stimulation without any serious DBS-related AEs for up to 16 months. Notably, he has not had a single severe combat nightmare in a year—in stark contrast to nightly combat nightmares during the 20-year period leading to the trial. Furthermore, he has not been having any episodes of severe dissociation, which had been a common disabling problem before the trial. He has taken a second trip out of the country, improved his relationships with family, and made strides (albeit limited) in pursuing additional social interactions.

Avoidance remains a major problem. He recently left his job after 7 years, because he prefers a more nature-oriented rather than people-oriented environment. In addition, his interest in intensive psychotherapy has increased, and he has been considering options for spending more time working on his therapy.

Over 15 months of treatment, the patient’s CAPS total and subscale scores have decreased—his symptoms have improved (Table).²¹ He has had rapid and substantial reductions in recurrence and hyperarousal symptoms but slower improvement in avoidance. Improvements in emotional reactivity would be expected to occur before any change in behavior (eg, avoidance). Patients likely must first recognize changes in emotional reactivity to events before they can engage in a cognitive process to modify learned behavioral responses to those events.

After about 9 months of treatment, all of the study patient’s symptoms were somewhat stabilized, and the authors began making gradual stimulation adjustments to the latest parameters—3.5 V, 60 µs, and 160 Hz for the right electrode and 1.5 V, 60 µs, and 160 Hz for the left electrode—using the contacts in the basolateral nucleus of the amygdala, per postoperative neuroimaging.³⁵ A thin cuts computed tomography (CT) scan of the brain was obtained postoperatively and merged to the preoperative MRI. The CT scan captured the location of the DBS electrode contacts and the MRI superimposition to determine the position of those contacts in the brain.

After 15 to 18 months, when improvement peaked at 48% symptom reduction from baseline, the patient experienced psychiatric decompensation (depression, suicide gesture) not attributable to changes in stimulation settings and not associated with exacerbation of PTSD symptoms. Treatment team members and independent psychiatric consultants attributed the decompensation to the patient’s difficulty in changing a long-standing avoidant behavior routine, owing to severe recurrence and hyperarousal symptoms in the past. His persistent inability to overcome avoidance and isolation, despite core PTSD symptom improvement, had left him feeling worthless.

The patient remains in the study but also is participating in other medication and psychotherapy trials and is making a career change. Periodic decompensations may be part of the treatment course as patients reach a more complex and volatile phase of improvement that requires more intensive cognitive reprocessing. If this proves to be the case with other patients enrolling in the study, intensive psychotherapy that addresses cognitive and emotional PTSD symptoms may be needed once there is improvement in intrusive and hyperarousal symptoms.

Conclusion

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor. Physiologically, DBS seems to inhibit specific brain regions’ dysfunctional activity stemming from a disease process. Deep brain stimulation-induced inhibition of a dysfunctional node improves clinical outcomes in movement disorders.

Given the reversibility and positive safety profile of DBS, new applications are being studied. The authors propose that DBS may benefit patients with severe treatment-refractory PTSD. Their first patient’s core PTSD symptoms have improved significantly, as expected, but as in other psychiatric DBS cases, the seriousness and chronicity of his illness may be complicating the course of recovery. The authors plan to recruit 6 patients for this early-phase safety trial.

Click here to read the digital edition.

Failure of fear extinction is a core feature of posttraumatic stress disorder (PTSD).¹ Recently, it was confirmed that the amygdala and the orbitofrontal cortex are crucial for both fear acquisition and fear extinction.² The amygdala was found to have neurons active only during fear acquisition, and other neurons active only during fear extinction.³ In essence, the balance of activity between these 2 neuronal populations determines whether if an incoming stimulus is feared or not feared. This balance is under the influence of several cognitive domains, including memory, reward, and executive function.

In PTSD, the equilibrium is shifted heavily toward fear acquisition. The majority of patients spontaneously regain the capacity for fear extinction over time⁴ or with the help of treatment.^5,6 Nonetheless, some patients with severe PTSD seem unable to recover the ability of fear extinction and remain refractory to both standard and novel psychotherapeutic or psychopharmacologic treatments.⁷ For these patients, direct modulation of the neural activity in the amygdala may permit fear extinction. This article describes the rationale for using deep brain stimulation (DBS) and initial results from the first-ever clinical trial.

Deep Brain Stimulation

Deep brain stimulation involves inserting electrodes in precise cerebral targets and then connecting the leads to a pulse generator (similar to a pacemaker) inserted in a subclavicular pocket. The generator controls the electrical signal (amplitude, pulse width, pulse frequency) delivered to the brain target and can be adjusted with use of a noninvasive programmer. In 1997, the FDA approved DBS for patients with Parkinson disease or essential tremor. Since then, its efficacy in these movement disorders has been confirmed in several studies.^8,9

The mechanism by which the small electrical pulses of DBS influence activity is not clear. Clinically, DBS functionally inhibits the activity of local neurons.¹⁰ One theory describes “frequency jamming,” a concept similar to cardiac overdrive pacing in which the resultant high-frequency neuronal signal is meaningless and discounted by the rest of the brain.¹¹

Over the years, DBS has demonstrated a strong safety profile.¹² The risks of electrode insertion are mitigated with targeting based on high-quality magnetic resonance imaging (MRI) and computed tomography (Figure). Unlike a destructive lesion, DBS is reversible, and the implanted system can be removed in its entirety. Histologic analyses have shown only a small amount of scarring around the electrode tip.¹³ In movement disorder treatment, clinical experience has shown that stimulation-related adverse effects (AEs) are reversible with readjustment of stimulation parameters by external programmer.¹⁴

Novel Applications of DBS

The advantageous safety profile of DBS has permitted its evaluation in the treatment of other conditions thought to have malfunctioning networks at their core—such as intractable epilepsy (in resective surgery noncandidates).^15,16 Although several trials have shown promising results of using DBS for treatment-resistant depression,¹⁷ the results of pivotal sham-controlled trials have been mixed.^18,19 Obsessive-compulsive disorder, on the other hand, received the FDA humanitarian device exemption designation on the basis of positive long-term results.²⁰ In treatment-resistant depression and obsessive-compulsive disorder, functional neuroimaging has identified DBS targets.^21,22 Functional MRI or positron emission tomography (PET) images can be compared at resting state, at symptomatic state, and after treatment response. Nodes hyperactive during a symptomatic state and less active after successful treatment can be targeted with high-frequency DBS to directly reduce the hyperactivity and indirectly modulate or normalize the overall function of the circuit.²³

Given the functional MRI and O15 (oxygen-15) PET evidence of amygdala hyperactivity in patients with PTSD having core symptoms,^24-26 the authors hypothesized that high-frequency DBS targeting of the amygdala would improve PTSD-associated hyperarousal and reexperiencing symptoms in treatment-refractory patients. Indirect data supporting this hypothesis include a correlation between amygdala hyperactivity of increased intensity and symptom severity measured with the Clinician-Administered PTSD Scale (CAPS),²⁷ and a correlation between reduced pretreatment amygdala hyperactivity and successful cognitive-behavioral treatment.^28,29

Preclinical Work

Using a rodent model in which a novel object serves as a cue reminder of foot shocks (traumatic event), the authors tested the hypothesis that amygdala DBS would reduce PTSD-like symptoms.³⁰ When untreated rats were presented with the object in their cage a week after the initial exposure, they immediately buried the object under bedding to avoid being reminded of the shocks. In contrast, rats treated with DBS did not bury the object. In most cases, in fact, they played with it.

The authors also replicated their results but with the addition of rats treated with paroxetine.³¹ Using the same rodent model, they found DBS superior to paroxetine in treating PTSD-like symptoms. This study had a crossover design: DBS and sham DBS. Briefly, 20 rats received an electrode in the amygdala and were exposed to inescapable shocks in the presence of the cue object. The rats were then randomly assigned to a DBS group (10 rats) or a sham-DBS group (10 rats). After 1 week, behavioral testing showed fear extinction in the DBS group and no improvement in the sham-DBS group. Then the groups were switched: The rats originally treated with DBS received no treatment, and the rats that were originally sham-treated underwent DBS. One week later, behavioral testing showed acquisition of fear extinction in all the rats. These results suggested DBS can be effective even when delayed after establishment of fear persistence and PTSD symptoms. These results also showed that DBS effects persist even after therapy discontinuation.

Similarly, other investigators have reported that the role of the amygdala is not limited to fear acquisition; it extends to fear expression. A lesion in the amygdala can prevent fear expression even if the disruption is performed subsequent to fear-conditioning training.³² This finding is important for humans, as DBS would be initiated during the chronic phase of the disorder, after failure of less invasive treatment options, such as pharmacotherapy and psychotherapy.

Early Clinical Experience

The authors have initiated the first ever clinical trial (NCT02091843) evaluating use of DBS for PTSD and are now recruiting patients. Enrollment is limited to 6 combat veterans with disabling PTSD that has not responded to pharmacotherapy and psychotherapy. This VA-funded single-site study, being conducted at the VA Greater Los Angeles Healthcare System (VAGLAHS), was approved by the VAGLAHS Institutional Review Board and the FDA. The authors have published the 2-year trial’s protocol, which includes an active-versus-sham stimulation phase; continuous electroencephalogram monitoring; baseline and posttreatment ¹⁸FDG (fluorodeoxyglucose) PET performed during a resting state vs during investigator-guided exposure to trauma reminders; and extensive psychological and neuropsychological assessments.³³ The literature includes only 1 case report on amygdala DBS.³⁴ The authors of that report used DBS of the basolateral nucleus of the amygdala to treat a teenaged boy with severe autism and found that the therapy was safe.

As of this writing, the authors have recruited and implanted 1 patient and reported on his clinical results (including baseline PET) over the first 8 months of stimulation³⁵ and on the electrophysiologic findings over the first year.³⁶ After experiencing extremely severe combat PTSD refractory to pharmacotherapy and psychotherapy treatments for more than 20 years, the patient treated with DBS is now experiencing substantial symptom relief, and his CAPS score (primary outcome measure) has improved by about 40%. He has tolerated continuous stimulation without any serious DBS-related AEs for up to 16 months. Notably, he has not had a single severe combat nightmare in a year—in stark contrast to nightly combat nightmares during the 20-year period leading to the trial. Furthermore, he has not been having any episodes of severe dissociation, which had been a common disabling problem before the trial. He has taken a second trip out of the country, improved his relationships with family, and made strides (albeit limited) in pursuing additional social interactions.

Avoidance remains a major problem. He recently left his job after 7 years, because he prefers a more nature-oriented rather than people-oriented environment. In addition, his interest in intensive psychotherapy has increased, and he has been considering options for spending more time working on his therapy.

Over 15 months of treatment, the patient’s CAPS total and subscale scores have decreased—his symptoms have improved (Table).²¹ He has had rapid and substantial reductions in recurrence and hyperarousal symptoms but slower improvement in avoidance. Improvements in emotional reactivity would be expected to occur before any change in behavior (eg, avoidance). Patients likely must first recognize changes in emotional reactivity to events before they can engage in a cognitive process to modify learned behavioral responses to those events.

After about 9 months of treatment, all of the study patient’s symptoms were somewhat stabilized, and the authors began making gradual stimulation adjustments to the latest parameters—3.5 V, 60 µs, and 160 Hz for the right electrode and 1.5 V, 60 µs, and 160 Hz for the left electrode—using the contacts in the basolateral nucleus of the amygdala, per postoperative neuroimaging.³⁵ A thin cuts computed tomography (CT) scan of the brain was obtained postoperatively and merged to the preoperative MRI. The CT scan captured the location of the DBS electrode contacts and the MRI superimposition to determine the position of those contacts in the brain.

After 15 to 18 months, when improvement peaked at 48% symptom reduction from baseline, the patient experienced psychiatric decompensation (depression, suicide gesture) not attributable to changes in stimulation settings and not associated with exacerbation of PTSD symptoms. Treatment team members and independent psychiatric consultants attributed the decompensation to the patient’s difficulty in changing a long-standing avoidant behavior routine, owing to severe recurrence and hyperarousal symptoms in the past. His persistent inability to overcome avoidance and isolation, despite core PTSD symptom improvement, had left him feeling worthless.

The patient remains in the study but also is participating in other medication and psychotherapy trials and is making a career change. Periodic decompensations may be part of the treatment course as patients reach a more complex and volatile phase of improvement that requires more intensive cognitive reprocessing. If this proves to be the case with other patients enrolling in the study, intensive psychotherapy that addresses cognitive and emotional PTSD symptoms may be needed once there is improvement in intrusive and hyperarousal symptoms.

Conclusion

Deep brain stimulation has been successful in treating Parkinson disease and essential tremor. Physiologically, DBS seems to inhibit specific brain regions’ dysfunctional activity stemming from a disease process. Deep brain stimulation-induced inhibition of a dysfunctional node improves clinical outcomes in movement disorders.

Given the reversibility and positive safety profile of DBS, new applications are being studied. The authors propose that DBS may benefit patients with severe treatment-refractory PTSD. Their first patient’s core PTSD symptoms have improved significantly, as expected, but as in other psychiatric DBS cases, the seriousness and chronicity of his illness may be complicating the course of recovery. The authors plan to recruit 6 patients for this early-phase safety trial.

Click here to read the digital edition.

BACKGROUND: Identifying hospitals that are both early and consistent adopters of high-value care can help shed light on the culture and practices at those institutions that are necessary to promote high-value care nationwide. The use of troponin testing to diagnose acute myocardial infarction (AMI), and not testing for myoglobin or creatine kinase-MB (CK-MB), is a high-value recommendation of the Choosing Wisely® campaign.

OBJECTIVE: To examine the variation in cardiac biomarker testing and the effect of the Choosing Wisely® troponin-only testing recommendation for the diagnosis of AMI.

DESIGN: A retrospective, observational study using administrative ordering data from Vizient’s Clinical Database/Resource Manager.

PATIENTS: Hospitalized patients with a principal discharge diagnosis of AMI.

INTERVENTION: The Choosing Wisely® recommendation to order troponin-only testing to diagnose AMI was released during the first quarter of 2015.

RESULTS: In 19 hospitals, troponin-only testing was consistently ordered to diagnose AMI before the Choosing Wisely® recommendation and throughout the study period. In 34 hospitals, both troponin testing and myoglobin/CK-MB testing were ordered to diagnose AMI even after the Choosing Wisely® recommendation. In 26 hospitals with low rates of troponin-only testing before the Choosing Wisely® recommendation, the release of the recommendation was associated with a statistically significant increase in the rate of troponin-only testing to diagnose AMI.

CONCLUSION: In institutions with low rates of troponin-only testing prior to the Choosing Wisely® recommendation, the recommendation was associated with a significant increase in the rate of troponin-only testing.

Read the entire article in the Dec. 2017 issue of the Journal of Hospital Medicine.

Also in JHM this month

Hospital perceptions of Medicare’s Sepsis Quality Reporting Initiative

AUTHORS: Ian J. Barbash, MD, MS; Kimberly J. Rak, PhD; Courtney C. Kuza, MPH; and Jeremy M. Kahn, MD, MS

Health literacy and hospital length of stay: An inpatient cohort study

AUTHORS: Ethan G. Jaffee, MD; Vineet M. Arora, MD, MAPP; Madeleine I. Matthiesen, MD; David O. Meltzer, MD, PhD, MHM; and Valerie G. Press, MD, FAAP, FACP, MPH

How exemplary teaching physicians interact with hospitalized patients

AUTHORS: Sanjay Saint, MD, MPH, FHM; Molly Harrod, PhD; Karen E. Fowler, MPH; and Nathan Houchens, MD, FACP, FHM

A randomized cohort controlled trial to compare intern sign-out training interventions

AUTHORS: Soo-Hoon Lee, PhD; Christopher Terndrup, MD; Phillip H. Phan, PhD; Sandra E. Zaeh, MD; Kwame Atsina, MD; Nicole Minkove, MD; Alexander Billioux, MD; DPhil, Souvik Chatterjee, MD; Idoreyin Montague, MD; Bennett Clark, MD; Andrew Hughes, MD; and Sanjay V. Desai, MD

BACKGROUND: Identifying hospitals that are both early and consistent adopters of high-value care can help shed light on the culture and practices at those institutions that are necessary to promote high-value care nationwide. The use of troponin testing to diagnose acute myocardial infarction (AMI), and not testing for myoglobin or creatine kinase-MB (CK-MB), is a high-value recommendation of the Choosing Wisely® campaign.

OBJECTIVE: To examine the variation in cardiac biomarker testing and the effect of the Choosing Wisely® troponin-only testing recommendation for the diagnosis of AMI.

DESIGN: A retrospective, observational study using administrative ordering data from Vizient’s Clinical Database/Resource Manager.

PATIENTS: Hospitalized patients with a principal discharge diagnosis of AMI.

INTERVENTION: The Choosing Wisely® recommendation to order troponin-only testing to diagnose AMI was released during the first quarter of 2015.

RESULTS: In 19 hospitals, troponin-only testing was consistently ordered to diagnose AMI before the Choosing Wisely® recommendation and throughout the study period. In 34 hospitals, both troponin testing and myoglobin/CK-MB testing were ordered to diagnose AMI even after the Choosing Wisely® recommendation. In 26 hospitals with low rates of troponin-only testing before the Choosing Wisely® recommendation, the release of the recommendation was associated with a statistically significant increase in the rate of troponin-only testing to diagnose AMI.

CONCLUSION: In institutions with low rates of troponin-only testing prior to the Choosing Wisely® recommendation, the recommendation was associated with a significant increase in the rate of troponin-only testing.

Read the entire article in the Dec. 2017 issue of the Journal of Hospital Medicine.

Also in JHM this month

Hospital perceptions of Medicare’s Sepsis Quality Reporting Initiative

AUTHORS: Ian J. Barbash, MD, MS; Kimberly J. Rak, PhD; Courtney C. Kuza, MPH; and Jeremy M. Kahn, MD, MS

Health literacy and hospital length of stay: An inpatient cohort study

AUTHORS: Ethan G. Jaffee, MD; Vineet M. Arora, MD, MAPP; Madeleine I. Matthiesen, MD; David O. Meltzer, MD, PhD, MHM; and Valerie G. Press, MD, FAAP, FACP, MPH

How exemplary teaching physicians interact with hospitalized patients

AUTHORS: Sanjay Saint, MD, MPH, FHM; Molly Harrod, PhD; Karen E. Fowler, MPH; and Nathan Houchens, MD, FACP, FHM

A randomized cohort controlled trial to compare intern sign-out training interventions

AUTHORS: Soo-Hoon Lee, PhD; Christopher Terndrup, MD; Phillip H. Phan, PhD; Sandra E. Zaeh, MD; Kwame Atsina, MD; Nicole Minkove, MD; Alexander Billioux, MD; DPhil, Souvik Chatterjee, MD; Idoreyin Montague, MD; Bennett Clark, MD; Andrew Hughes, MD; and Sanjay V. Desai, MD

BACKGROUND: Identifying hospitals that are both early and consistent adopters of high-value care can help shed light on the culture and practices at those institutions that are necessary to promote high-value care nationwide. The use of troponin testing to diagnose acute myocardial infarction (AMI), and not testing for myoglobin or creatine kinase-MB (CK-MB), is a high-value recommendation of the Choosing Wisely® campaign.

OBJECTIVE: To examine the variation in cardiac biomarker testing and the effect of the Choosing Wisely® troponin-only testing recommendation for the diagnosis of AMI.

DESIGN: A retrospective, observational study using administrative ordering data from Vizient’s Clinical Database/Resource Manager.

PATIENTS: Hospitalized patients with a principal discharge diagnosis of AMI.

INTERVENTION: The Choosing Wisely® recommendation to order troponin-only testing to diagnose AMI was released during the first quarter of 2015.

RESULTS: In 19 hospitals, troponin-only testing was consistently ordered to diagnose AMI before the Choosing Wisely® recommendation and throughout the study period. In 34 hospitals, both troponin testing and myoglobin/CK-MB testing were ordered to diagnose AMI even after the Choosing Wisely® recommendation. In 26 hospitals with low rates of troponin-only testing before the Choosing Wisely® recommendation, the release of the recommendation was associated with a statistically significant increase in the rate of troponin-only testing to diagnose AMI.

CONCLUSION: In institutions with low rates of troponin-only testing prior to the Choosing Wisely® recommendation, the recommendation was associated with a significant increase in the rate of troponin-only testing.

Read the entire article in the Dec. 2017 issue of the Journal of Hospital Medicine.

Also in JHM this month

Hospital perceptions of Medicare’s Sepsis Quality Reporting Initiative

AUTHORS: Ian J. Barbash, MD, MS; Kimberly J. Rak, PhD; Courtney C. Kuza, MPH; and Jeremy M. Kahn, MD, MS

Health literacy and hospital length of stay: An inpatient cohort study

AUTHORS: Ethan G. Jaffee, MD; Vineet M. Arora, MD, MAPP; Madeleine I. Matthiesen, MD; David O. Meltzer, MD, PhD, MHM; and Valerie G. Press, MD, FAAP, FACP, MPH

How exemplary teaching physicians interact with hospitalized patients

AUTHORS: Sanjay Saint, MD, MPH, FHM; Molly Harrod, PhD; Karen E. Fowler, MPH; and Nathan Houchens, MD, FACP, FHM

A randomized cohort controlled trial to compare intern sign-out training interventions

AUTHORS: Soo-Hoon Lee, PhD; Christopher Terndrup, MD; Phillip H. Phan, PhD; Sandra E. Zaeh, MD; Kwame Atsina, MD; Nicole Minkove, MD; Alexander Billioux, MD; DPhil, Souvik Chatterjee, MD; Idoreyin Montague, MD; Bennett Clark, MD; Andrew Hughes, MD; and Sanjay V. Desai, MD

This spring, the US Food and Drug Administration approved a second cyclin-dependent kinase (CDK) inhibitor for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer in combination with aromatase inhibitors (AIs).¹ The drug, ribociclib, joins palbociclib as the second drug in this class, which targets key regulators of the mammalian cell cycle and can help to overcome resistance to endocrine therapy–like AIs, a standard front-line treatment option in this group of patients. Palbociclib (Ibrance) was approved last year in combination with the AI letrozole, which was recently expanded to include its use in combination with all AIs, the same indication for which ribociclib received approval.

The ribociclib approval was based on the results of a phase 3, randomized, double-blind, placebo-controlled, international clinical trial called MONALEESA-2.² The trial, conducted in 29 countries, compared the effects of ribociclib plus letrozole with letrozole plus placebo in 668 postmenopausal women with locally confirmed, HR-positive, HER2-negative, recurrent or metastatic breast cancer.

Patients had not received previous systemic therapy for advanced disease, had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (range, 1-5; 0, fully active and 5, dead), and had adequate bone marrow and organ function.

Patients were excluded if they had received previous CDK4/6 therapy, any previous systemic chemotherapy, endocrine therapy for advanced disease, previous neoadjuvant or adjuvant therapy with any nonsteroidal AI (unless they had been disease free for more than 12 months), and had inflammatory breast cancer, central nervous system metastases, history of cardiac disease or dysfunction, or impaired gastrointestinal function that alters drug absorption.

Patients were treated with ribociclib at a dose of 600 mg daily on a 3-weeks-on, 1-week-off schedule in 28-day cycles or placebo, which were combined with letrozole at a dose of 2.5 mg a day on a continuous schedule. Randomization was stratified according to the presence or absence of liver or lung metastases and treatment was continued until disease progression, unacceptable toxicity, death or discontinuation of treatment. Dose reductions of ribociclib were allowed, to manage adverse events (AEs), but treatment crossover was not permitted.

Tumor assessments were performed at screening, every 8 weeks during the first 18 months, every 12 weeks thereafter until disease progression, and at the end of treatment, and were assessed by an independent review committee. The baseline characteristics of the patient population were well balanced; patients had a median age of 62 years, all were HR positive except 1 patient who was HER2 positive.

The trial was ended prematurely after an initial interim analysis demonstrated a significant benefit in favor of ribociclib in the primary endpoint, progression-free survival (PFS). Over a median duration of follow-up of 15.3 months, the median PFS was not yet reached in the ribociclib arm, compared with 14.7 months in the placebo arm (hazard ratio, 0.556; P < .0001). In a subsequent analysis with 11 months of additional follow-up, the median PFS was 25.3 months in the combination arm, compared with 16 months in the placebo arm, which translated into a 44% reduction in the risk of disease progression or death. The PFS benefit with ribociclib was observed across all preplanned subgroup analyses. The objective response rates were 52.7% in the ribociclib arm, compared with 37.1% in the placebo arm, but overall survival data were immature.

The frequency and severity of AEs were increased in the combination arm; most common were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. The most common grade 3 or 4 AEs experienced with ribociclib were neutropenia, leukopenia, abnormal liver function tests, lymphopenia, and vomiting.

Ribociclib is accompanied by warnings and precautions about QT interval prolongation, hepatobiliary toxicity, and neutropenia. Clinicians are advised to monitor electrocardiograms and electrolytes before the start of ribociclib therapy and to begin treatment only in patients with QTcF values <450 ms and in whom electrolyte abnormalities have been corrected. ECG should be repeated at around day 14 of the first cycle, the beginning of the second cycle, and as deemed clinically necessary.

Liver function tests should be performed before starting treatment, every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated. For aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels greater than 3-5 times the upper limit of normal (ULN, grade 2), ribociclib should be interrupted until recovery to baseline or lower. For levels >5-20 times the ULN (grade 3) or recurring grade 2 increases, treatment should be interrupted until recovery to baseline or lower and then resumed at the next lowest dose level. Treatment with ribociclib should be discontinued in the event of recurring grade 3 elevations or for AST/ALT elevations >3 times ULN in combination with total bilirubin >2 times ULN.

Complete blood counts should be performed before starting treatment and monitored every 2 weeks for the first 2 cycles, at the beginning of each of the 4 subsequent cycles, and as clinically needed. If absolute neutrophil counts are 500-1,000 mm³ (grade 3), treatment should be discontinued until recovery to grade 2 or lower. If grade 3 neutropenia recurs or for grade 3 febrile neutropenia or grade 4 neutropenia, treatment should resume at a lower dose level upon recovery to grade 2 or lower.

Pregnant women and those of reproductive age should be warned of the risk of fetal harm and the need for effective contraception during treatment and for at least 3 weeks after the last dose. Ribociclib is marketed as Kisqali by Novartis.

This spring, the US Food and Drug Administration approved a second cyclin-dependent kinase (CDK) inhibitor for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer in combination with aromatase inhibitors (AIs).¹ The drug, ribociclib, joins palbociclib as the second drug in this class, which targets key regulators of the mammalian cell cycle and can help to overcome resistance to endocrine therapy–like AIs, a standard front-line treatment option in this group of patients. Palbociclib (Ibrance) was approved last year in combination with the AI letrozole, which was recently expanded to include its use in combination with all AIs, the same indication for which ribociclib received approval.

The ribociclib approval was based on the results of a phase 3, randomized, double-blind, placebo-controlled, international clinical trial called MONALEESA-2.² The trial, conducted in 29 countries, compared the effects of ribociclib plus letrozole with letrozole plus placebo in 668 postmenopausal women with locally confirmed, HR-positive, HER2-negative, recurrent or metastatic breast cancer.

Patients had not received previous systemic therapy for advanced disease, had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (range, 1-5; 0, fully active and 5, dead), and had adequate bone marrow and organ function.

Patients were excluded if they had received previous CDK4/6 therapy, any previous systemic chemotherapy, endocrine therapy for advanced disease, previous neoadjuvant or adjuvant therapy with any nonsteroidal AI (unless they had been disease free for more than 12 months), and had inflammatory breast cancer, central nervous system metastases, history of cardiac disease or dysfunction, or impaired gastrointestinal function that alters drug absorption.

Patients were treated with ribociclib at a dose of 600 mg daily on a 3-weeks-on, 1-week-off schedule in 28-day cycles or placebo, which were combined with letrozole at a dose of 2.5 mg a day on a continuous schedule. Randomization was stratified according to the presence or absence of liver or lung metastases and treatment was continued until disease progression, unacceptable toxicity, death or discontinuation of treatment. Dose reductions of ribociclib were allowed, to manage adverse events (AEs), but treatment crossover was not permitted.

Tumor assessments were performed at screening, every 8 weeks during the first 18 months, every 12 weeks thereafter until disease progression, and at the end of treatment, and were assessed by an independent review committee. The baseline characteristics of the patient population were well balanced; patients had a median age of 62 years, all were HR positive except 1 patient who was HER2 positive.

The trial was ended prematurely after an initial interim analysis demonstrated a significant benefit in favor of ribociclib in the primary endpoint, progression-free survival (PFS). Over a median duration of follow-up of 15.3 months, the median PFS was not yet reached in the ribociclib arm, compared with 14.7 months in the placebo arm (hazard ratio, 0.556; P < .0001). In a subsequent analysis with 11 months of additional follow-up, the median PFS was 25.3 months in the combination arm, compared with 16 months in the placebo arm, which translated into a 44% reduction in the risk of disease progression or death. The PFS benefit with ribociclib was observed across all preplanned subgroup analyses. The objective response rates were 52.7% in the ribociclib arm, compared with 37.1% in the placebo arm, but overall survival data were immature.

The frequency and severity of AEs were increased in the combination arm; most common were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. The most common grade 3 or 4 AEs experienced with ribociclib were neutropenia, leukopenia, abnormal liver function tests, lymphopenia, and vomiting.

Ribociclib is accompanied by warnings and precautions about QT interval prolongation, hepatobiliary toxicity, and neutropenia. Clinicians are advised to monitor electrocardiograms and electrolytes before the start of ribociclib therapy and to begin treatment only in patients with QTcF values <450 ms and in whom electrolyte abnormalities have been corrected. ECG should be repeated at around day 14 of the first cycle, the beginning of the second cycle, and as deemed clinically necessary.

Liver function tests should be performed before starting treatment, every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated. For aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels greater than 3-5 times the upper limit of normal (ULN, grade 2), ribociclib should be interrupted until recovery to baseline or lower. For levels >5-20 times the ULN (grade 3) or recurring grade 2 increases, treatment should be interrupted until recovery to baseline or lower and then resumed at the next lowest dose level. Treatment with ribociclib should be discontinued in the event of recurring grade 3 elevations or for AST/ALT elevations >3 times ULN in combination with total bilirubin >2 times ULN.

Complete blood counts should be performed before starting treatment and monitored every 2 weeks for the first 2 cycles, at the beginning of each of the 4 subsequent cycles, and as clinically needed. If absolute neutrophil counts are 500-1,000 mm³ (grade 3), treatment should be discontinued until recovery to grade 2 or lower. If grade 3 neutropenia recurs or for grade 3 febrile neutropenia or grade 4 neutropenia, treatment should resume at a lower dose level upon recovery to grade 2 or lower.

Pregnant women and those of reproductive age should be warned of the risk of fetal harm and the need for effective contraception during treatment and for at least 3 weeks after the last dose. Ribociclib is marketed as Kisqali by Novartis.

This spring, the US Food and Drug Administration approved a second cyclin-dependent kinase (CDK) inhibitor for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced/metastatic breast cancer in combination with aromatase inhibitors (AIs).¹ The drug, ribociclib, joins palbociclib as the second drug in this class, which targets key regulators of the mammalian cell cycle and can help to overcome resistance to endocrine therapy–like AIs, a standard front-line treatment option in this group of patients. Palbociclib (Ibrance) was approved last year in combination with the AI letrozole, which was recently expanded to include its use in combination with all AIs, the same indication for which ribociclib received approval.

The ribociclib approval was based on the results of a phase 3, randomized, double-blind, placebo-controlled, international clinical trial called MONALEESA-2.² The trial, conducted in 29 countries, compared the effects of ribociclib plus letrozole with letrozole plus placebo in 668 postmenopausal women with locally confirmed, HR-positive, HER2-negative, recurrent or metastatic breast cancer.

Patients had not received previous systemic therapy for advanced disease, had measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), had an Eastern Cooperative Oncology Group performance status of 0 or 1 (range, 1-5; 0, fully active and 5, dead), and had adequate bone marrow and organ function.

Patients were excluded if they had received previous CDK4/6 therapy, any previous systemic chemotherapy, endocrine therapy for advanced disease, previous neoadjuvant or adjuvant therapy with any nonsteroidal AI (unless they had been disease free for more than 12 months), and had inflammatory breast cancer, central nervous system metastases, history of cardiac disease or dysfunction, or impaired gastrointestinal function that alters drug absorption.

Patients were treated with ribociclib at a dose of 600 mg daily on a 3-weeks-on, 1-week-off schedule in 28-day cycles or placebo, which were combined with letrozole at a dose of 2.5 mg a day on a continuous schedule. Randomization was stratified according to the presence or absence of liver or lung metastases and treatment was continued until disease progression, unacceptable toxicity, death or discontinuation of treatment. Dose reductions of ribociclib were allowed, to manage adverse events (AEs), but treatment crossover was not permitted.

Tumor assessments were performed at screening, every 8 weeks during the first 18 months, every 12 weeks thereafter until disease progression, and at the end of treatment, and were assessed by an independent review committee. The baseline characteristics of the patient population were well balanced; patients had a median age of 62 years, all were HR positive except 1 patient who was HER2 positive.

The trial was ended prematurely after an initial interim analysis demonstrated a significant benefit in favor of ribociclib in the primary endpoint, progression-free survival (PFS). Over a median duration of follow-up of 15.3 months, the median PFS was not yet reached in the ribociclib arm, compared with 14.7 months in the placebo arm (hazard ratio, 0.556; P < .0001). In a subsequent analysis with 11 months of additional follow-up, the median PFS was 25.3 months in the combination arm, compared with 16 months in the placebo arm, which translated into a 44% reduction in the risk of disease progression or death. The PFS benefit with ribociclib was observed across all preplanned subgroup analyses. The objective response rates were 52.7% in the ribociclib arm, compared with 37.1% in the placebo arm, but overall survival data were immature.

The frequency and severity of AEs were increased in the combination arm; most common were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. The most common grade 3 or 4 AEs experienced with ribociclib were neutropenia, leukopenia, abnormal liver function tests, lymphopenia, and vomiting.

Ribociclib is accompanied by warnings and precautions about QT interval prolongation, hepatobiliary toxicity, and neutropenia. Clinicians are advised to monitor electrocardiograms and electrolytes before the start of ribociclib therapy and to begin treatment only in patients with QTcF values <450 ms and in whom electrolyte abnormalities have been corrected. ECG should be repeated at around day 14 of the first cycle, the beginning of the second cycle, and as deemed clinically necessary.

Liver function tests should be performed before starting treatment, every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles, and as clinically indicated. For aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels greater than 3-5 times the upper limit of normal (ULN, grade 2), ribociclib should be interrupted until recovery to baseline or lower. For levels >5-20 times the ULN (grade 3) or recurring grade 2 increases, treatment should be interrupted until recovery to baseline or lower and then resumed at the next lowest dose level. Treatment with ribociclib should be discontinued in the event of recurring grade 3 elevations or for AST/ALT elevations >3 times ULN in combination with total bilirubin >2 times ULN.

Complete blood counts should be performed before starting treatment and monitored every 2 weeks for the first 2 cycles, at the beginning of each of the 4 subsequent cycles, and as clinically needed. If absolute neutrophil counts are 500-1,000 mm³ (grade 3), treatment should be discontinued until recovery to grade 2 or lower. If grade 3 neutropenia recurs or for grade 3 febrile neutropenia or grade 4 neutropenia, treatment should resume at a lower dose level upon recovery to grade 2 or lower.

Pregnant women and those of reproductive age should be warned of the risk of fetal harm and the need for effective contraception during treatment and for at least 3 weeks after the last dose. Ribociclib is marketed as Kisqali by Novartis.

When the US Food and Drug Administration approved olaratumab as a first-line treatment for patients with soft tissue sarcoma (STS) in the fall of 2016, it marked the first approval since the chemotherapy drug doxorubicin became standard of care more than 40 years ago.¹ Though rare, STS, which comprises a host of different histologic subtypes, has proven difficult to treat. Like pazopanib, which was approved in 2012 for the treatment of STS in the second-line setting, olaratumab targets the platelet-derived growth factor receptor alpha (PDGFRα), a tyrosine kinase receptor involved in cell signaling pathways that promotes key hallmark abilities in both cancer cells and the cells of the tumor microenvironment. Olaratumab, however, is a much more specific inhibitor of PDGFRα compared with pazopanib.

Accelerated approval was granted for the treatment of patients with STS that is not amenable to curative treatment with radiotherapy or surgery and with a subtype that cannot be treated effectively with an anthracycline-containing regimen. The approval was based on the phase 2 JGDG study, a randomized, active-controlled clinical trial in which 133 patients were randomized 1:1 to receive olaratumab plus doxorubicin, or doxorubicin alone.²

Eligible patients included those aged 18 years and over, with histologically confirmed diagnosis of locally advanced or metastatic STS not previously treated with an anthracycline, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (range, 1-5; 0, fully active and 5, dead), and with available tumor tissue for determination of PDGFRα expression by immunohistochemistry. Patients were enrolled at 16 clinical sites in 16 cities and 15 states in the United States from October 2010 to January 2013.

Patients were excluded if they had histologically or cytologically confirmed Kaposi sarcoma; untreated central nervous system metastases; received prior treatment with doxorubicin or other anthracyclines and anthracenediones, or any drug targeting PDGF or the PDGFRs; received concurrent treatment with other anticancer therapy within 4 weeks before study entry; unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction within 6 months before study entry; HIV infection; or if they were pregnant or lactating.

Olaratumab was administered at 15 mg/kg as an intravenous infusion on days 1 and 8 of each 21-day cycle, and doxorubicin at 75 mg/m² as an intravenous infusion on day 1 of each cycle, for a maximum of 8 cycles. Patients were permitted to receive dexarozoxane on cycles 5-8 and crossover was permitted. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 6 weeks, and survival assessed every 2 months, until study completion. PDGFR expression was assessed by immunohistochemistry at a central academic laboratory before randomization.

The primary endpoint of the study was progression-free survival (PFS) and the combination of olaratumab–doxorubicin significantly extended PFS in this patient population: median PFS was 6.6 months in the combination arm, compared with 4.1 months in the doxorubicin-alone arm (hazard ratio [HR], 0.672; P = .0615). The objective response rate (ORR) and median overall survival (OS), which were secondary endpoints in the trial, were also significantly improved with combination therapy compared with doxorubicin alone (ORR, 18.2% vs 11.9%, respectively; median OS, 26.5 months vs 14.7 months). The benefits of combination therapy were observed across prespecified subgroups, including histological tumor type, number of previous treatments, and PDGFRα expression level.

The most common adverse events (AEs) in the patients taking olaratumab were nausea, fatigue, neutropenia, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache. Grade 3/4 AEs were also higher for the combination than for doxorubicin alone. The most common AE leading to discontinuation of olaratumab was infusion-related reactions, which occurred in 13% of patients.

According to the prescribing information, the recommended dose for olaratumab is 15 mg/kg as an intravenous infusion over 60 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity, in combination with doxorubicin for the first 8 cycles. Patients should be premedicated with dexamethasone and diphenhydramine, to help protect against infusion-related reactions.

Olaratumab, marketed as Lartruvo by Lilly Oncology, has warnings and precautions relating to infusion-related reactions and embryofetal toxicity. Patients should be monitored for signs and symptoms of the former during and after infusion and olaratumab should be administered in a setting with available resuscitation equipment. Olaratumab should be permanently discontinued in the event of grade 3/4 infusion-related reactions. Olaratumab can cause fetal harm and female patients should be advised of the potential risk to a fetus and the need for effective contraception during treatment and for 3 months after the last dose.

When the US Food and Drug Administration approved olaratumab as a first-line treatment for patients with soft tissue sarcoma (STS) in the fall of 2016, it marked the first approval since the chemotherapy drug doxorubicin became standard of care more than 40 years ago.¹ Though rare, STS, which comprises a host of different histologic subtypes, has proven difficult to treat. Like pazopanib, which was approved in 2012 for the treatment of STS in the second-line setting, olaratumab targets the platelet-derived growth factor receptor alpha (PDGFRα), a tyrosine kinase receptor involved in cell signaling pathways that promotes key hallmark abilities in both cancer cells and the cells of the tumor microenvironment. Olaratumab, however, is a much more specific inhibitor of PDGFRα compared with pazopanib.

Accelerated approval was granted for the treatment of patients with STS that is not amenable to curative treatment with radiotherapy or surgery and with a subtype that cannot be treated effectively with an anthracycline-containing regimen. The approval was based on the phase 2 JGDG study, a randomized, active-controlled clinical trial in which 133 patients were randomized 1:1 to receive olaratumab plus doxorubicin, or doxorubicin alone.²

Eligible patients included those aged 18 years and over, with histologically confirmed diagnosis of locally advanced or metastatic STS not previously treated with an anthracycline, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (range, 1-5; 0, fully active and 5, dead), and with available tumor tissue for determination of PDGFRα expression by immunohistochemistry. Patients were enrolled at 16 clinical sites in 16 cities and 15 states in the United States from October 2010 to January 2013.

Patients were excluded if they had histologically or cytologically confirmed Kaposi sarcoma; untreated central nervous system metastases; received prior treatment with doxorubicin or other anthracyclines and anthracenediones, or any drug targeting PDGF or the PDGFRs; received concurrent treatment with other anticancer therapy within 4 weeks before study entry; unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction within 6 months before study entry; HIV infection; or if they were pregnant or lactating.

Olaratumab was administered at 15 mg/kg as an intravenous infusion on days 1 and 8 of each 21-day cycle, and doxorubicin at 75 mg/m² as an intravenous infusion on day 1 of each cycle, for a maximum of 8 cycles. Patients were permitted to receive dexarozoxane on cycles 5-8 and crossover was permitted. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 6 weeks, and survival assessed every 2 months, until study completion. PDGFR expression was assessed by immunohistochemistry at a central academic laboratory before randomization.

The primary endpoint of the study was progression-free survival (PFS) and the combination of olaratumab–doxorubicin significantly extended PFS in this patient population: median PFS was 6.6 months in the combination arm, compared with 4.1 months in the doxorubicin-alone arm (hazard ratio [HR], 0.672; P = .0615). The objective response rate (ORR) and median overall survival (OS), which were secondary endpoints in the trial, were also significantly improved with combination therapy compared with doxorubicin alone (ORR, 18.2% vs 11.9%, respectively; median OS, 26.5 months vs 14.7 months). The benefits of combination therapy were observed across prespecified subgroups, including histological tumor type, number of previous treatments, and PDGFRα expression level.

The most common adverse events (AEs) in the patients taking olaratumab were nausea, fatigue, neutropenia, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache. Grade 3/4 AEs were also higher for the combination than for doxorubicin alone. The most common AE leading to discontinuation of olaratumab was infusion-related reactions, which occurred in 13% of patients.

According to the prescribing information, the recommended dose for olaratumab is 15 mg/kg as an intravenous infusion over 60 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity, in combination with doxorubicin for the first 8 cycles. Patients should be premedicated with dexamethasone and diphenhydramine, to help protect against infusion-related reactions.

Olaratumab, marketed as Lartruvo by Lilly Oncology, has warnings and precautions relating to infusion-related reactions and embryofetal toxicity. Patients should be monitored for signs and symptoms of the former during and after infusion and olaratumab should be administered in a setting with available resuscitation equipment. Olaratumab should be permanently discontinued in the event of grade 3/4 infusion-related reactions. Olaratumab can cause fetal harm and female patients should be advised of the potential risk to a fetus and the need for effective contraception during treatment and for 3 months after the last dose.

When the US Food and Drug Administration approved olaratumab as a first-line treatment for patients with soft tissue sarcoma (STS) in the fall of 2016, it marked the first approval since the chemotherapy drug doxorubicin became standard of care more than 40 years ago.¹ Though rare, STS, which comprises a host of different histologic subtypes, has proven difficult to treat. Like pazopanib, which was approved in 2012 for the treatment of STS in the second-line setting, olaratumab targets the platelet-derived growth factor receptor alpha (PDGFRα), a tyrosine kinase receptor involved in cell signaling pathways that promotes key hallmark abilities in both cancer cells and the cells of the tumor microenvironment. Olaratumab, however, is a much more specific inhibitor of PDGFRα compared with pazopanib.

Accelerated approval was granted for the treatment of patients with STS that is not amenable to curative treatment with radiotherapy or surgery and with a subtype that cannot be treated effectively with an anthracycline-containing regimen. The approval was based on the phase 2 JGDG study, a randomized, active-controlled clinical trial in which 133 patients were randomized 1:1 to receive olaratumab plus doxorubicin, or doxorubicin alone.²

Eligible patients included those aged 18 years and over, with histologically confirmed diagnosis of locally advanced or metastatic STS not previously treated with an anthracycline, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (range, 1-5; 0, fully active and 5, dead), and with available tumor tissue for determination of PDGFRα expression by immunohistochemistry. Patients were enrolled at 16 clinical sites in 16 cities and 15 states in the United States from October 2010 to January 2013.

Patients were excluded if they had histologically or cytologically confirmed Kaposi sarcoma; untreated central nervous system metastases; received prior treatment with doxorubicin or other anthracyclines and anthracenediones, or any drug targeting PDGF or the PDGFRs; received concurrent treatment with other anticancer therapy within 4 weeks before study entry; unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction within 6 months before study entry; HIV infection; or if they were pregnant or lactating.

Olaratumab was administered at 15 mg/kg as an intravenous infusion on days 1 and 8 of each 21-day cycle, and doxorubicin at 75 mg/m² as an intravenous infusion on day 1 of each cycle, for a maximum of 8 cycles. Patients were permitted to receive dexarozoxane on cycles 5-8 and crossover was permitted. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 6 weeks, and survival assessed every 2 months, until study completion. PDGFR expression was assessed by immunohistochemistry at a central academic laboratory before randomization.

The primary endpoint of the study was progression-free survival (PFS) and the combination of olaratumab–doxorubicin significantly extended PFS in this patient population: median PFS was 6.6 months in the combination arm, compared with 4.1 months in the doxorubicin-alone arm (hazard ratio [HR], 0.672; P = .0615). The objective response rate (ORR) and median overall survival (OS), which were secondary endpoints in the trial, were also significantly improved with combination therapy compared with doxorubicin alone (ORR, 18.2% vs 11.9%, respectively; median OS, 26.5 months vs 14.7 months). The benefits of combination therapy were observed across prespecified subgroups, including histological tumor type, number of previous treatments, and PDGFRα expression level.

The most common adverse events (AEs) in the patients taking olaratumab were nausea, fatigue, neutropenia, musculoskeletal pain, mucositis, alopecia, vomiting, diarrhea, decreased appetite, abdominal pain, neuropathy, and headache. Grade 3/4 AEs were also higher for the combination than for doxorubicin alone. The most common AE leading to discontinuation of olaratumab was infusion-related reactions, which occurred in 13% of patients.

According to the prescribing information, the recommended dose for olaratumab is 15 mg/kg as an intravenous infusion over 60 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity, in combination with doxorubicin for the first 8 cycles. Patients should be premedicated with dexamethasone and diphenhydramine, to help protect against infusion-related reactions.

Olaratumab, marketed as Lartruvo by Lilly Oncology, has warnings and precautions relating to infusion-related reactions and embryofetal toxicity. Patients should be monitored for signs and symptoms of the former during and after infusion and olaratumab should be administered in a setting with available resuscitation equipment. Olaratumab should be permanently discontinued in the event of grade 3/4 infusion-related reactions. Olaratumab can cause fetal harm and female patients should be advised of the potential risk to a fetus and the need for effective contraception during treatment and for 3 months after the last dose.

Rucaparib was granted accelerated approval by the US Food and Drug Administration for the treatment of patients with BRCA1/2 mutant advanced ovarian cancer in January this year, making it the second drug in its class for this indication. It is a poly(ADP-ribose) polymerase inhibitor that works by blocking the repair of damaged DNA in cancer cells and triggering cell death.

Study 10 included only patients with platinum-sensitive disease and eligible patients were aged 18 years or older, with a known deleterious BRCA mutation, evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors (version 1.1), sufficient archival tumor tissue, histologically confirmed high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer and relapsed disease confirmed by radiologic assessment. Meanwhile, ARIEL2 had similar eligibility criteria, except that patients with platinum-sensitive, resistant, and refractory disease were included.

Both studies excluded patients with active second malignancies, and for those with a history of prior cancer that had been curatively treated, no evidence of current disease was required and chemotherapy should have been completed more than 6 months or bone marrow transplant more than 2 years before the first dose of rucaparib. Patients who had previously been treated with a PARP inhibitor, with symptomatic and/or untreated central nervous system metastases, or who had been hospitalized for bowel obstruction within the previous 3 months, were also ineligible.

Across the 2 trials, the median age of trial participants was 59 years, 78% were white, and all had an Eastern Cooperative Oncology Group performance status of 0 (fully active, able to carry on all pre-disease performance without restriction) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature). Both trials used a surrogate endpoint for approval, measuring the percentage of patients who experienced complete or partial tumor shrinkage, the overall response rate (ORR), while taking rucaparib.

In Study 10, the ORR was 60%, including a complete response (CR) rate of 10% and a partial response (PR) rate of 50%, over a median duration of response (DoR) of 7.9 months, while in ARIEL2, the ORR was 50%, including a CR of 8% and a PR of 42%, over a median DoR of 11.6 months. The pooled analysis demonstrated an ORR of 54%, CR of 9% and PR of 45%, over a median DoR of 9.2 months. In separate data reported in the prescribing information, the ORR as assessed by independent radiology review was 42%, with a median DoR of 6.7 months, while ORR according to investigator assessment was 66%. In all analyses, the response rate was similar for patients having BRCA1 versus BRCA2 gene mutations.

Safety analyses were performed in 377 patients across the 2 studies who received 600 mg rucaparib twice daily. The most common adverse events (AEs) of any grade included nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. The most common serious AEs (grade 3 or 4) were anemia (25%), fatigue/asthenia (11%), and increased alanine aminotransferase or aspartate aminotransferase levels (11%). Overall, 8% of patients discontinued treatment because of AEs.

The recommended dose according to the prescribing information is 600 mg, in the form of two 300-mg tablets taken orally twice daily with or without food. Physicians prescribing rucaparib should be aware of the potential for myelodysplastic syndrome or acute myeloid leukemia and for embryofetal toxicity. Complete blood count should be monitored at baseline and monthly thereafter and treatment should not be initiated until after patients have made a complete recovery from any hematologic toxicities caused by prior chemotherapy.

If hematologic toxicities occur while taking rucaparib, treatment should be interrupted and blood counts monitored until recovery and failure to recover to grade 1 or higher after 4 weeks should prompt referral to a hematologist for further investigation, while confirmed diagnosis of myelodysplastic syndromes or acute myeloid leukemia should lead to discontinuation of rucaparib. Pregnant women and those of reproductive potential should be advised of the potential risk to a fetus or the need for effective contraception during treatment and for 6 months after the last dose of rucaparib.

Rucaparib is indicated only for the treatment of patients with confirmed BRCA1/2 mutations, so the drug was approved in conjunction with a companion diagnostic. FoundationFocus CDxBRCA is the first next-generation sequencing-based test to receive FDA approval and detects the presence of deleterious BRCA gene mutations in tumor tissue samples. Rucaparib is marketed as Rubraca by Clovis Oncology Inc, and the companion diagnostic by Foundation Medicine Inc.

Rucaparib was granted accelerated approval by the US Food and Drug Administration for the treatment of patients with BRCA1/2 mutant advanced ovarian cancer in January this year, making it the second drug in its class for this indication. It is a poly(ADP-ribose) polymerase inhibitor that works by blocking the repair of damaged DNA in cancer cells and triggering cell death.

Study 10 included only patients with platinum-sensitive disease and eligible patients were aged 18 years or older, with a known deleterious BRCA mutation, evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors (version 1.1), sufficient archival tumor tissue, histologically confirmed high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer and relapsed disease confirmed by radiologic assessment. Meanwhile, ARIEL2 had similar eligibility criteria, except that patients with platinum-sensitive, resistant, and refractory disease were included.

Both studies excluded patients with active second malignancies, and for those with a history of prior cancer that had been curatively treated, no evidence of current disease was required and chemotherapy should have been completed more than 6 months or bone marrow transplant more than 2 years before the first dose of rucaparib. Patients who had previously been treated with a PARP inhibitor, with symptomatic and/or untreated central nervous system metastases, or who had been hospitalized for bowel obstruction within the previous 3 months, were also ineligible.

Across the 2 trials, the median age of trial participants was 59 years, 78% were white, and all had an Eastern Cooperative Oncology Group performance status of 0 (fully active, able to carry on all pre-disease performance without restriction) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature). Both trials used a surrogate endpoint for approval, measuring the percentage of patients who experienced complete or partial tumor shrinkage, the overall response rate (ORR), while taking rucaparib.

In Study 10, the ORR was 60%, including a complete response (CR) rate of 10% and a partial response (PR) rate of 50%, over a median duration of response (DoR) of 7.9 months, while in ARIEL2, the ORR was 50%, including a CR of 8% and a PR of 42%, over a median DoR of 11.6 months. The pooled analysis demonstrated an ORR of 54%, CR of 9% and PR of 45%, over a median DoR of 9.2 months. In separate data reported in the prescribing information, the ORR as assessed by independent radiology review was 42%, with a median DoR of 6.7 months, while ORR according to investigator assessment was 66%. In all analyses, the response rate was similar for patients having BRCA1 versus BRCA2 gene mutations.

Safety analyses were performed in 377 patients across the 2 studies who received 600 mg rucaparib twice daily. The most common adverse events (AEs) of any grade included nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. The most common serious AEs (grade 3 or 4) were anemia (25%), fatigue/asthenia (11%), and increased alanine aminotransferase or aspartate aminotransferase levels (11%). Overall, 8% of patients discontinued treatment because of AEs.

The recommended dose according to the prescribing information is 600 mg, in the form of two 300-mg tablets taken orally twice daily with or without food. Physicians prescribing rucaparib should be aware of the potential for myelodysplastic syndrome or acute myeloid leukemia and for embryofetal toxicity. Complete blood count should be monitored at baseline and monthly thereafter and treatment should not be initiated until after patients have made a complete recovery from any hematologic toxicities caused by prior chemotherapy.

If hematologic toxicities occur while taking rucaparib, treatment should be interrupted and blood counts monitored until recovery and failure to recover to grade 1 or higher after 4 weeks should prompt referral to a hematologist for further investigation, while confirmed diagnosis of myelodysplastic syndromes or acute myeloid leukemia should lead to discontinuation of rucaparib. Pregnant women and those of reproductive potential should be advised of the potential risk to a fetus or the need for effective contraception during treatment and for 6 months after the last dose of rucaparib.

Rucaparib is indicated only for the treatment of patients with confirmed BRCA1/2 mutations, so the drug was approved in conjunction with a companion diagnostic. FoundationFocus CDxBRCA is the first next-generation sequencing-based test to receive FDA approval and detects the presence of deleterious BRCA gene mutations in tumor tissue samples. Rucaparib is marketed as Rubraca by Clovis Oncology Inc, and the companion diagnostic by Foundation Medicine Inc.

Rucaparib was granted accelerated approval by the US Food and Drug Administration for the treatment of patients with BRCA1/2 mutant advanced ovarian cancer in January this year, making it the second drug in its class for this indication. It is a poly(ADP-ribose) polymerase inhibitor that works by blocking the repair of damaged DNA in cancer cells and triggering cell death.

Study 10 included only patients with platinum-sensitive disease and eligible patients were aged 18 years or older, with a known deleterious BRCA mutation, evidence of measurable disease as defined by Response Evaluation Criteria in Solid Tumors (version 1.1), sufficient archival tumor tissue, histologically confirmed high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer and relapsed disease confirmed by radiologic assessment. Meanwhile, ARIEL2 had similar eligibility criteria, except that patients with platinum-sensitive, resistant, and refractory disease were included.

Both studies excluded patients with active second malignancies, and for those with a history of prior cancer that had been curatively treated, no evidence of current disease was required and chemotherapy should have been completed more than 6 months or bone marrow transplant more than 2 years before the first dose of rucaparib. Patients who had previously been treated with a PARP inhibitor, with symptomatic and/or untreated central nervous system metastases, or who had been hospitalized for bowel obstruction within the previous 3 months, were also ineligible.

Across the 2 trials, the median age of trial participants was 59 years, 78% were white, and all had an Eastern Cooperative Oncology Group performance status of 0 (fully active, able to carry on all pre-disease performance without restriction) or 1 (restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature). Both trials used a surrogate endpoint for approval, measuring the percentage of patients who experienced complete or partial tumor shrinkage, the overall response rate (ORR), while taking rucaparib.

In Study 10, the ORR was 60%, including a complete response (CR) rate of 10% and a partial response (PR) rate of 50%, over a median duration of response (DoR) of 7.9 months, while in ARIEL2, the ORR was 50%, including a CR of 8% and a PR of 42%, over a median DoR of 11.6 months. The pooled analysis demonstrated an ORR of 54%, CR of 9% and PR of 45%, over a median DoR of 9.2 months. In separate data reported in the prescribing information, the ORR as assessed by independent radiology review was 42%, with a median DoR of 6.7 months, while ORR according to investigator assessment was 66%. In all analyses, the response rate was similar for patients having BRCA1 versus BRCA2 gene mutations.

Safety analyses were performed in 377 patients across the 2 studies who received 600 mg rucaparib twice daily. The most common adverse events (AEs) of any grade included nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. The most common serious AEs (grade 3 or 4) were anemia (25%), fatigue/asthenia (11%), and increased alanine aminotransferase or aspartate aminotransferase levels (11%). Overall, 8% of patients discontinued treatment because of AEs.

The recommended dose according to the prescribing information is 600 mg, in the form of two 300-mg tablets taken orally twice daily with or without food. Physicians prescribing rucaparib should be aware of the potential for myelodysplastic syndrome or acute myeloid leukemia and for embryofetal toxicity. Complete blood count should be monitored at baseline and monthly thereafter and treatment should not be initiated until after patients have made a complete recovery from any hematologic toxicities caused by prior chemotherapy.

If hematologic toxicities occur while taking rucaparib, treatment should be interrupted and blood counts monitored until recovery and failure to recover to grade 1 or higher after 4 weeks should prompt referral to a hematologist for further investigation, while confirmed diagnosis of myelodysplastic syndromes or acute myeloid leukemia should lead to discontinuation of rucaparib. Pregnant women and those of reproductive potential should be advised of the potential risk to a fetus or the need for effective contraception during treatment and for 6 months after the last dose of rucaparib.

Rucaparib is indicated only for the treatment of patients with confirmed BRCA1/2 mutations, so the drug was approved in conjunction with a companion diagnostic. FoundationFocus CDxBRCA is the first next-generation sequencing-based test to receive FDA approval and detects the presence of deleterious BRCA gene mutations in tumor tissue samples. Rucaparib is marketed as Rubraca by Clovis Oncology Inc, and the companion diagnostic by Foundation Medicine Inc.