Ipilimumab and Beyond: New Therapies Imminent in Melanoma

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life.

But a landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients has offered hope, Dr. Steven O'Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O'Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane) has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O'Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer.

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O'Day said, "because I think it's so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O'Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs' manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells' antitumor activity.

"What's important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient's immune system," Dr. O'Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O'Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O'Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O'Day added.

As expected, the drug's adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O'Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O'Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O'Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O'Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O'Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O'Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It's great science, but it's not really adding to the benefit of the vast majority of patients," Dr. O'Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it's a major step forward."

Dr. O'Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life.

But a landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients has offered hope, Dr. Steven O'Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O'Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane) has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O'Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer.

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O'Day said, "because I think it's so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O'Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs' manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells' antitumor activity.

"What's important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient's immune system," Dr. O'Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O'Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O'Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O'Day added.

As expected, the drug's adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O'Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O'Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O'Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O'Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O'Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O'Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It's great science, but it's not really adding to the benefit of the vast majority of patients," Dr. O'Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it's a major step forward."

Dr. O'Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb

LAS VEGAS – Melanoma has the fastest-rising incidence of any cancer, and exacts a terrible toll among individuals who are typically in the prime of their life.

But a landmark clinical trial showing that ipilimumab (Yervoy) can prolong the lives of these patients has offered hope, Dr. Steven O'Day, a lead investigator of that trial, told attendees at the annual Community Oncology Conference.

Four new classes of therapies are improving outcomes in patients with metastatic melanoma, according to Dr. O'Day, director of the melanoma program at the Angeles Clinic and Research Institute in Santa Monica, Calif.

Targeted Chemotherapy: nab-Paclitaxel

Targeted chemotherapy with nab-paclitaxel (Abraxane) has shown activity in a phase II trial among patients with metastatic melanoma (Cancer 2010;116:155-63). Complete remissions were rare, but 38% of previously treated patients and 49% of chemotherapy-naive patients had durable partial remissions or stable disease.

"That really distinguishes it from any prior chemotherapy as a single agent," Dr. O'Day said of the nanoparticle albumin-bound taxane approved by the Food and Drug Administration for the treatment of breast cancer.

Outcomes were especially good in patients who had normal LDH (lactate dehydrogenase) levels; their overall survival exceeded 20 months regardless of prior treatment. This result was "just so out of the norm for chemo in melanoma that of course we have to take this single-agent activity seriously," he commented.

These data have led to a large international, randomized, open-label trial comparing weekly nab-paclitaxel with dacarbazine (DTIC) in 514 patients (protocol CA033). Results are likely to be reported next year.

"I predict this drug will get on the market" for melanoma, Dr. O'Day said, "because I think it's so [different from] any other chemo in terms of controlling the disease for quite a long period of time in about 50% of patients, and has a very good toxicity profile."

Antiangiogenesis Therapy: Bevacizumab

Antiangiogenesis therapy is compelling because melanoma is dense in blood vessels, and has very high levels of vascular endothelial growth factor, according to Dr. O'Day. In the randomized, phase II BEAM trial, however, adding the antiangiogenesis agent bevacizumab (Avastin) to carboplatin plus paclitaxel did not significantly improve the response rate (26% vs. 16%) or median progression-free survival (5.6 vs. 4.2 months) (Eur. J. Cancer Suppl. 2009;7:13[abstract 23LBA]).

Overall survival, which was initially superior with bevacizumab (12.3 vs. 8.6 months; P = .04), was no longer so with mature follow-up in the entire study population. But exploratory analyses suggest a benefit in the subgroup of patients having stage M1c disease (visceral metastases) plus elevated LDH levels.

"Many in the melanoma community are really pushing [the drugs' manufacturers] to go forward with a phase III trial, particularly in [patients with] high-risk visceral metastasis with high LDH, since I think this is a group that is underserved and often has a very, very short survival," he said. "And hopefully, we can get that off the ground."

Targeted Immunotherapy: Ipilimumab

The major breakthrough, of course, is ipilimumab, a monoclonal antibody that was recently approved for the treatment of metastatic melanoma. By targeting CTLA4 (cytotoxic T-lymphocyte antigen 4), which acts as a brake on T-cell activation, this antibody enhances the cells' antitumor activity.

"What's important with this paradigm shift with this treatment is that we are not targeting the tumor; we are targeting the patient's immune system," Dr. O'Day said. "So what we are trying to do is change the immune system to be able to contain the cancer, not eradicate the cancer."

The drug achieves durable responses or stable disease in 20%-30% of patients, and the responses last not weeks or months, but years. An additional 10% of patients have a durable delayed response, characterized by early tumor progression on imaging (which biopsies suggest may actually be tumor flare) followed by regression, even to complete remission in some cases.

There have been two registration trials for ipilimumab. One trial randomized patients to DTIC plus ipilimumab vs. DTIC plus placebo as first-line therapy. Full results will likely be presented at the 2011 annual meeting of the American Society of Clinical Oncology.

The other trial, conducted in the second-line setting and presented by Dr. O'Day at ASCO 2010, compared ipilimumab, the gp100 melanoma vaccine, and the combination, which was expected to show synergy. But there was a similar improvement in overall survival relative to the vaccine with ipilimumab alone (hazard ratio, 0.66; P = .0026) and with the combination (HR, 0.68; P = .0004) (J. Clin. Oncol. 2010;28[suppl., abstract 4]:18).

The study stands out as the first randomized, phase III trial to show a survival benefit in metastatic melanoma. An especially noteworthy finding has been a sustained plateau in survival curves beyond 2 years – now approaching 7 years – with no late recurrences, Dr. O'Day said. "These were ... landmark survival curves that we had never seen in stage IV melanoma."

The long-term survivors still have visible tumors on radiographic imaging, and some of the tumors even show metabolic activity on PET imaging. But the tumors are completely stable.

Of note, the patients in this ipilimumab trial had poor risk features, such as visceral metastases and elevated LDH levels, he said. "So this was a community-representative patient, [who] really had not been looked at much in sort of more sophisticated interleukin-2–based protocols."

And from a health economics perspective, the treatment is advantageous in that these benefits were achieved with four doses of the drug given over 12 weeks, without any maintenance treatment, Dr. O'Day added.

As expected, the drug's adverse-effect profile is autoimmune in nature. "But it correlates with an antitumor response," he said. "So we want to see some autoimmunity because it means we are breaking tolerance."

About 30% of patients develop colitis, manifesting as watery, nonbloody diarrhea. He recommended early, aggressive management of this adverse effect with fluids, hydration, and high-dose steroids followed by a taper.

"A fascinating thing is that [in patients having a tumor response to ipilimumab], T cells targeting the tumor are resistant to apoptosis from the steroids, whereas the autoimmune T cells are not," Dr. O'Day noted. "So we can turn the autoimmunity off on a dime, and yet it’s incredibly rare, if the patient’s responding at that point, to lose control of the tumor."

Another important autoimmune adverse effect is hypophysitis, which occurs in about 10% of patients and manifests as profound fatigue or behavior change, headache, and/or visual changes such as photophobia or double vision. This adverse effect can be managed with replacement therapy to address the hormone deficits, according to Dr. O'Day. Most patients recover, but some will require lifelong therapy for persistent hormone deficits.

Targeted MAP Kinase Therapy: BRAF Inhibitors

The fourth class of agents targets components of the MAP (mitogen-activated protein) kinase–signaling pathway. Thus far among these agents, inhibitors of BRAF hold promise for the greatest number of patients, as about half of cutaneous melanomas have BRAF mutations.

Studies in which the less-selective BRAF inhibitor sorafenib (Nexavar) was combined with chemotherapy, as both first- and second-line therapy, have had negative results. But two new, highly selective investigational BRAF inhibitors – PLX4032 (manufactured by Plexxikon and Roche) and GSK2118436 (manufactured by GlaxoSmithKline) – are making an impact clinically. The former was found to achieve a response rate of 70% in patients with BRAF-mutated melanoma (Eur. J. Cancer Suppl. 2009;7:5[abstract 6BA]).

"We had never seen anything like this in melanoma," Dr. O'Day commented.

Responses were both dramatic and early. "These were patients literally on their deathbeds with performance statuses of 3," he elaborated. "Within a few days they felt better, and then in ... PET scans at 15 days, you can see just absolutely dramatic responses," often accompanied by marked tumor shrinkage and even lysis.

An interim analysis of a trial comparing a PLX4032 with DTIC as first-line therapy found that the novel drug met its progression-free and overall survival end points, according to a press release. Therefore, the trial is being stopped and patients who were initially assigned to DTIC will be offered the BRAF inhibitor.

"Now, the durability of responses has not been as good as hoped, so obviously, resistance develops," Dr. O'Day commented. Patients have had responses lasting more than a year, but the median is more like 6-9 months; also, some relapses have been fulminant.

"Clearly, blocking this one pathway may not be enough," he said. One mechanism of resistance appears to be the up-regulation of MEK. "So now we are just starting combination studies with BRAF and MEK [inhibitors] together," with the hope that the combination will be more durable, he said.

Adverse effects of BRAF inhibitors are manageable and include photosensitivity, arthralgia, fatigue, and a rash, according to Dr. O'Day. The rashes tend "to be keratotic, and they can actually develop acanthomas and little, well-differentiated squamous cell cancers. So [patients’] skin has to be watched carefully."

Putting It All Together

"The treatment decisions for me as a melanoma doctor in the clinic now are becoming very exciting," Dr. O'Day said. "I think there is going to need to be a real art to the sequence and combinations."

For rare patients with indolent stage IV melanoma, curative resection remains an option, he said. And young patients with good performance status may want to try high-dose interleukin-2, which leads to cure in about 5% of cases: "But it’s toxic [and] expensive, and we have failed to provide good predictive factors for this, so we really struggle with knowing who and when to treat" with IL-2.

Biochemotherapy – the combination of IL-2 and interferon with chemotherapy – has some benefit in patients with rapidly progressive melanoma and high LDH levels.

Although adoptive T-cell therapy can produce dramatic remissions in some patients, it has not proved very practical because of factors such as labor intensiveness. "It's great science, but it's not really adding to the benefit of the vast majority of patients," Dr. O'Day said.

Ipilimumab expands on these options, with short-term therapy offering the possibility of long-term disease control for about a third of patients. Ongoing trials will continue to provide data on the investigational agents that target MAP kinase signaling.

Additionally, combining new drugs from different classes has tremendous potential for improving melanoma outcomes, he noted. "The obvious next step is to combine – in BRAF-mutated cases – a BRAF drug that is breaking tumors up [90% of the time or more] with an immune drug that can then come in and, with the tumor exposed and the antigens released from necrosis and apoptosis, it makes sense that there should be great synergy there," he said.

Moreover, this could be done on an outpatient basis, in contrast to existing combination therapies, which have required inpatient stays because of toxicity and route of admission, he noted. "So it's a major step forward."

Dr. O'Day reported receiving research support from and being a consultant to Bristol-Myers Squibb, GlaxoSmithKline, and Roche, and being on the speakers bureau for Bristol-Myers Squibb