Dr. Trishala Meghal

Dramatic responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were first observed in select patients with advanced lung adenocarcinoma over 10 years ago. Since that time, targeted therapy has become the preferred first-line treatment for patients with EGFR and anaplastic lymphoma kinase (ALK) mutations. In addition, patients are often treated with sequential lines of targeted therapy as the repertoire of available agents expands. Moreover, an increasing number of patients with less common oncogenic driver mutations have targeted therapy options based on reports of successful genotype-directed treatment in the literature.

Oncogene addiction

A majority of lung adenocarcinomas exhibit dependence on a single oncogenic protein or driver mutation for sustaining growth and proliferation. This phenomenon, termed oncogene addiction, renders these tumors sensitive to drugs that inhibit the activity of the altered oncogene and is the theoretical basis of targeted therapy (Weinstein. Science. 2002;297[5578]:63). While targeted therapy has been successfully integrated into the treatment of many malignancies, including breast cancers, sarcomas, and leukemias, the diversity of driver mutations in lung cancer is unique. The Lung Cancer Mutation Consortium (LCMC) analyzed samples from 1,007 patients with lung adenocarcinomas for 10 driver mutations and found an oncogenic driver in 64% of patients. Since that time, additional driver mutations have been identified. Importantly, the median survival observed in the LCMC study was significantly better in those patients who received genotype-directed therapy as compared with those who did not (Kris et al. JAMA. 2014;311[19]:1998).

EGFR-mutated lung cancer

The first successful targeted therapies for lung cancer were the EGFR TKIs erlotinib and gefitinib. EGFR is a cell surface receptor tyrosine kinase that, when activated, leads to cell survival and proliferation. Mutations are observed in 15% of lung adenocarcinoma in the United States and are more common in patients with Asian ethnicity, female gender, and lack of smoking history. The most commonly found mutations are deletions in exon 19 and point mutations in exon 21. Both mutations result in constitutive activation of the receptor and are associated with sensitivity to the small molecule inhibitors erlotinib, gefitinib, and afatinib. Recognition of the dependence of EGFR-mutated lung cancers on EGFR signaling laid the groundwork for multiple randomized trials comparing first-line EGFR TKIs to standard platinum doublet chemotherapy. In each case, EGFR TKIs produced superior response rates (RR) and progression-free survival (PFS) with lower rates of serious toxicity (Sequist et al. J Clin Oncol. 2013;31[27]:3327; Zhou et al. Lancet Oncol. 2011;12[8]:735; Mok et al. N Engl J Med. 2009;361[10]:947). Based on these results, the National Comprehensive Cancer Network (NCCN) recommends EGFR inhibitors as initial therapy in patients with advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations.

ALK-mutated lung cancer

ALK is the second most common oncogenic driver for which targeted therapy has become the standard of care in lung cancer. Most often, mutations occur as a short inversion in chromosome 2p where the ALK gene is fused with the echinoderm microtubule-associated protein like 4 (EML4) gene. The EML4-ALK fusion protein is a constitutively active kinase that drives cell growth. Crizotinib is a multitargeted small molecule inhibitor of ALK, ROS1, and MET. It was compared in phase 3 randomized controlled trials with standard second line (PROFILE 1007) and first-line chemotherapy (PROFILE 1014). Crizotinib not only improved RR and PFS but also improved lung cancer symptoms and quality of life when compared with chemotherapy (Shaw et al, N Engl J Med. 2013;368[25]:2385; Solomon et al. N Engl J Med. 2014;371[23]:2167. Based on these trials, crizotinib is the recommended first-line therapy in patients with ALK-positive NSCLC.

Uncommon driver mutations

Multiple, less common driver mutations have also been validated as therapeutic targets. ROS1 is a receptor tyrosine kinase of the insulin receptor family that is mutated in 1% to 2% NSCLC. In a prospective study of 50 patients with ROS1 rearrangement, 72% of patients responded to crizotinib, and the duration of response far exceeded that expected with conventional chemotherapy (Shaw et al. N Engl J Med. 2014;371[21]:1963). BRAF is a downstream signaling mediator of KRAS that activates the MAP kinase pathway and is mutated in 1% to 3% of NSCLC. In a phase 2 study of patients with BRAF V600E mutations, patients treated with the BRAF inhibitor vemurafenib had a disease control rate of 56% (Peters et al. J Clin Oncol. 2013;31[20]:341). MET, a transmembrane tyrosine kinase receptor, is frequently dysregulated in tumor cells via elevated expression with or without gene amplification. There are case reports of responses to crizotinib in patients with MET amplification, and studies of crizotinib and cabozantinib in patients with MET amplification or mutation are underway. Fusions involving receptor tyrosine kinase RET gene have been identified in 1% to 2% of NSCLC, and there are case reports of responses to the RET kinase inhibitors vandetinib and cabozantinib. Mutations in HER2, an important oncogene in breast cancer, have been reported to respond to the HER2 TKI afatinib. While each of these driver mutations are individually infrequent, in aggregate, they represent a substantial fraction of lung cancer patients whose limited treatment options may be expanded to include targeted therapies.

Next generation tyrosine kinase inhibitors

With the superiority of targeted therapy over standard chemotherapy now well-established in EGFR- and ALK-mutated lung cancers, focus has shifted to developing superior TKIs. The second generation ALK inhibitor ceritinib was recently FDA-approved for patients whose disease has progressed on crizotinib. Ceritinib is approximately 20 times more potent than crizotinib and produced responses in 56% of patients with crizotinib-resistant disease. In patients whose disease has progressed on the currently available EGFR inhibitors, a secondary mutation, T790M, can be identified in approximately 60% of tumor biopsies and mediates resistance by reactivating EGFR signaling. Rociletinib (CO-1686) and AZD9291 are third generation EGFR TKIs that not only inhibit the commonly mutated forms of EGFR but also inhibit those bearing the T790M resistance mutation. Furthermore, these drugs are more mutation-specific, showing less inhibition of the wild type EGFR receptor that is responsible for the rash and GI toxicity seen with other EGFR inhibitors. These novel TKIs are first being used as second-line treatment but may supplant the currently available TKIs as initial treatment in the future.

Molecular testing

The advanced molecular characterization of lung adenocarcinoma requires interdisciplinary cooperation between the physician performing the diagnostic procedure, the pathologist, and the oncologist for acquisition of adequate tissue and its judicious use for molecular analysis. The earliest approaches to molecular diagnostic testing involved a combination of assays that each interrogated genomic changes involving a specific gene such as Sanger sequencing, immunohistochemistry, and FISH. This one gene-one test strategy was most suitable when there were few genes to test. As the number of actionable genomic alterations increases, the amount of tissue required to carry out these tests is also increasing. Multiplex testing, along with standard FISH assays, has been successful in comprehensive genotyping but fails to detect gene rearrangements. Next generation sequencing can detect several hundreds of cancer-related genes in a single test. The NCCN guidelines strongly recommend using multiplex or next generation sequencing for broader molecular profiling to detect both common and rare driver mutations. Newer technologies, such as detection of circulating tumor cells and circulating tumor DNA, are being developed to reduce the need for invasive biopsies to obtain the genetic information required to guide targeted therapy selection.

Targeted therapy offers superior efficacy and tolerability in the treatment of advanced lung adenocarcinoma. Molecular profiling to identify a treatable mutation has become a key component of the care of these patients. It is hoped that the role of targeted therapy will continue to expand to include adjuvant treatment of early stage disease, and the ALCHEMIST trial is enrolling patients to address this question. The development of more and better drugs capable of inhibiting the diverse driver mutations found in lung adenocarcinomas is enabling more patients to benefit from this advance in cancer treatment.

Drs. Meghal and Becker are with Maimonides Cancer Center, Brooklyn, New York.

Dramatic responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were first observed in select patients with advanced lung adenocarcinoma over 10 years ago. Since that time, targeted therapy has become the preferred first-line treatment for patients with EGFR and anaplastic lymphoma kinase (ALK) mutations. In addition, patients are often treated with sequential lines of targeted therapy as the repertoire of available agents expands. Moreover, an increasing number of patients with less common oncogenic driver mutations have targeted therapy options based on reports of successful genotype-directed treatment in the literature.

Oncogene addiction

A majority of lung adenocarcinomas exhibit dependence on a single oncogenic protein or driver mutation for sustaining growth and proliferation. This phenomenon, termed oncogene addiction, renders these tumors sensitive to drugs that inhibit the activity of the altered oncogene and is the theoretical basis of targeted therapy (Weinstein. Science. 2002;297[5578]:63). While targeted therapy has been successfully integrated into the treatment of many malignancies, including breast cancers, sarcomas, and leukemias, the diversity of driver mutations in lung cancer is unique. The Lung Cancer Mutation Consortium (LCMC) analyzed samples from 1,007 patients with lung adenocarcinomas for 10 driver mutations and found an oncogenic driver in 64% of patients. Since that time, additional driver mutations have been identified. Importantly, the median survival observed in the LCMC study was significantly better in those patients who received genotype-directed therapy as compared with those who did not (Kris et al. JAMA. 2014;311[19]:1998).

EGFR-mutated lung cancer

The first successful targeted therapies for lung cancer were the EGFR TKIs erlotinib and gefitinib. EGFR is a cell surface receptor tyrosine kinase that, when activated, leads to cell survival and proliferation. Mutations are observed in 15% of lung adenocarcinoma in the United States and are more common in patients with Asian ethnicity, female gender, and lack of smoking history. The most commonly found mutations are deletions in exon 19 and point mutations in exon 21. Both mutations result in constitutive activation of the receptor and are associated with sensitivity to the small molecule inhibitors erlotinib, gefitinib, and afatinib. Recognition of the dependence of EGFR-mutated lung cancers on EGFR signaling laid the groundwork for multiple randomized trials comparing first-line EGFR TKIs to standard platinum doublet chemotherapy. In each case, EGFR TKIs produced superior response rates (RR) and progression-free survival (PFS) with lower rates of serious toxicity (Sequist et al. J Clin Oncol. 2013;31[27]:3327; Zhou et al. Lancet Oncol. 2011;12[8]:735; Mok et al. N Engl J Med. 2009;361[10]:947). Based on these results, the National Comprehensive Cancer Network (NCCN) recommends EGFR inhibitors as initial therapy in patients with advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations.

ALK-mutated lung cancer

ALK is the second most common oncogenic driver for which targeted therapy has become the standard of care in lung cancer. Most often, mutations occur as a short inversion in chromosome 2p where the ALK gene is fused with the echinoderm microtubule-associated protein like 4 (EML4) gene. The EML4-ALK fusion protein is a constitutively active kinase that drives cell growth. Crizotinib is a multitargeted small molecule inhibitor of ALK, ROS1, and MET. It was compared in phase 3 randomized controlled trials with standard second line (PROFILE 1007) and first-line chemotherapy (PROFILE 1014). Crizotinib not only improved RR and PFS but also improved lung cancer symptoms and quality of life when compared with chemotherapy (Shaw et al, N Engl J Med. 2013;368[25]:2385; Solomon et al. N Engl J Med. 2014;371[23]:2167. Based on these trials, crizotinib is the recommended first-line therapy in patients with ALK-positive NSCLC.

Uncommon driver mutations

Multiple, less common driver mutations have also been validated as therapeutic targets. ROS1 is a receptor tyrosine kinase of the insulin receptor family that is mutated in 1% to 2% NSCLC. In a prospective study of 50 patients with ROS1 rearrangement, 72% of patients responded to crizotinib, and the duration of response far exceeded that expected with conventional chemotherapy (Shaw et al. N Engl J Med. 2014;371[21]:1963). BRAF is a downstream signaling mediator of KRAS that activates the MAP kinase pathway and is mutated in 1% to 3% of NSCLC. In a phase 2 study of patients with BRAF V600E mutations, patients treated with the BRAF inhibitor vemurafenib had a disease control rate of 56% (Peters et al. J Clin Oncol. 2013;31[20]:341). MET, a transmembrane tyrosine kinase receptor, is frequently dysregulated in tumor cells via elevated expression with or without gene amplification. There are case reports of responses to crizotinib in patients with MET amplification, and studies of crizotinib and cabozantinib in patients with MET amplification or mutation are underway. Fusions involving receptor tyrosine kinase RET gene have been identified in 1% to 2% of NSCLC, and there are case reports of responses to the RET kinase inhibitors vandetinib and cabozantinib. Mutations in HER2, an important oncogene in breast cancer, have been reported to respond to the HER2 TKI afatinib. While each of these driver mutations are individually infrequent, in aggregate, they represent a substantial fraction of lung cancer patients whose limited treatment options may be expanded to include targeted therapies.

Next generation tyrosine kinase inhibitors

With the superiority of targeted therapy over standard chemotherapy now well-established in EGFR- and ALK-mutated lung cancers, focus has shifted to developing superior TKIs. The second generation ALK inhibitor ceritinib was recently FDA-approved for patients whose disease has progressed on crizotinib. Ceritinib is approximately 20 times more potent than crizotinib and produced responses in 56% of patients with crizotinib-resistant disease. In patients whose disease has progressed on the currently available EGFR inhibitors, a secondary mutation, T790M, can be identified in approximately 60% of tumor biopsies and mediates resistance by reactivating EGFR signaling. Rociletinib (CO-1686) and AZD9291 are third generation EGFR TKIs that not only inhibit the commonly mutated forms of EGFR but also inhibit those bearing the T790M resistance mutation. Furthermore, these drugs are more mutation-specific, showing less inhibition of the wild type EGFR receptor that is responsible for the rash and GI toxicity seen with other EGFR inhibitors. These novel TKIs are first being used as second-line treatment but may supplant the currently available TKIs as initial treatment in the future.

Molecular testing

The advanced molecular characterization of lung adenocarcinoma requires interdisciplinary cooperation between the physician performing the diagnostic procedure, the pathologist, and the oncologist for acquisition of adequate tissue and its judicious use for molecular analysis. The earliest approaches to molecular diagnostic testing involved a combination of assays that each interrogated genomic changes involving a specific gene such as Sanger sequencing, immunohistochemistry, and FISH. This one gene-one test strategy was most suitable when there were few genes to test. As the number of actionable genomic alterations increases, the amount of tissue required to carry out these tests is also increasing. Multiplex testing, along with standard FISH assays, has been successful in comprehensive genotyping but fails to detect gene rearrangements. Next generation sequencing can detect several hundreds of cancer-related genes in a single test. The NCCN guidelines strongly recommend using multiplex or next generation sequencing for broader molecular profiling to detect both common and rare driver mutations. Newer technologies, such as detection of circulating tumor cells and circulating tumor DNA, are being developed to reduce the need for invasive biopsies to obtain the genetic information required to guide targeted therapy selection.

Targeted therapy offers superior efficacy and tolerability in the treatment of advanced lung adenocarcinoma. Molecular profiling to identify a treatable mutation has become a key component of the care of these patients. It is hoped that the role of targeted therapy will continue to expand to include adjuvant treatment of early stage disease, and the ALCHEMIST trial is enrolling patients to address this question. The development of more and better drugs capable of inhibiting the diverse driver mutations found in lung adenocarcinomas is enabling more patients to benefit from this advance in cancer treatment.

Drs. Meghal and Becker are with Maimonides Cancer Center, Brooklyn, New York.

Dramatic responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were first observed in select patients with advanced lung adenocarcinoma over 10 years ago. Since that time, targeted therapy has become the preferred first-line treatment for patients with EGFR and anaplastic lymphoma kinase (ALK) mutations. In addition, patients are often treated with sequential lines of targeted therapy as the repertoire of available agents expands. Moreover, an increasing number of patients with less common oncogenic driver mutations have targeted therapy options based on reports of successful genotype-directed treatment in the literature.

Oncogene addiction

A majority of lung adenocarcinomas exhibit dependence on a single oncogenic protein or driver mutation for sustaining growth and proliferation. This phenomenon, termed oncogene addiction, renders these tumors sensitive to drugs that inhibit the activity of the altered oncogene and is the theoretical basis of targeted therapy (Weinstein. Science. 2002;297[5578]:63). While targeted therapy has been successfully integrated into the treatment of many malignancies, including breast cancers, sarcomas, and leukemias, the diversity of driver mutations in lung cancer is unique. The Lung Cancer Mutation Consortium (LCMC) analyzed samples from 1,007 patients with lung adenocarcinomas for 10 driver mutations and found an oncogenic driver in 64% of patients. Since that time, additional driver mutations have been identified. Importantly, the median survival observed in the LCMC study was significantly better in those patients who received genotype-directed therapy as compared with those who did not (Kris et al. JAMA. 2014;311[19]:1998).

EGFR-mutated lung cancer

The first successful targeted therapies for lung cancer were the EGFR TKIs erlotinib and gefitinib. EGFR is a cell surface receptor tyrosine kinase that, when activated, leads to cell survival and proliferation. Mutations are observed in 15% of lung adenocarcinoma in the United States and are more common in patients with Asian ethnicity, female gender, and lack of smoking history. The most commonly found mutations are deletions in exon 19 and point mutations in exon 21. Both mutations result in constitutive activation of the receptor and are associated with sensitivity to the small molecule inhibitors erlotinib, gefitinib, and afatinib. Recognition of the dependence of EGFR-mutated lung cancers on EGFR signaling laid the groundwork for multiple randomized trials comparing first-line EGFR TKIs to standard platinum doublet chemotherapy. In each case, EGFR TKIs produced superior response rates (RR) and progression-free survival (PFS) with lower rates of serious toxicity (Sequist et al. J Clin Oncol. 2013;31[27]:3327; Zhou et al. Lancet Oncol. 2011;12[8]:735; Mok et al. N Engl J Med. 2009;361[10]:947). Based on these results, the National Comprehensive Cancer Network (NCCN) recommends EGFR inhibitors as initial therapy in patients with advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations.

ALK-mutated lung cancer

ALK is the second most common oncogenic driver for which targeted therapy has become the standard of care in lung cancer. Most often, mutations occur as a short inversion in chromosome 2p where the ALK gene is fused with the echinoderm microtubule-associated protein like 4 (EML4) gene. The EML4-ALK fusion protein is a constitutively active kinase that drives cell growth. Crizotinib is a multitargeted small molecule inhibitor of ALK, ROS1, and MET. It was compared in phase 3 randomized controlled trials with standard second line (PROFILE 1007) and first-line chemotherapy (PROFILE 1014). Crizotinib not only improved RR and PFS but also improved lung cancer symptoms and quality of life when compared with chemotherapy (Shaw et al, N Engl J Med. 2013;368[25]:2385; Solomon et al. N Engl J Med. 2014;371[23]:2167. Based on these trials, crizotinib is the recommended first-line therapy in patients with ALK-positive NSCLC.

Uncommon driver mutations

Multiple, less common driver mutations have also been validated as therapeutic targets. ROS1 is a receptor tyrosine kinase of the insulin receptor family that is mutated in 1% to 2% NSCLC. In a prospective study of 50 patients with ROS1 rearrangement, 72% of patients responded to crizotinib, and the duration of response far exceeded that expected with conventional chemotherapy (Shaw et al. N Engl J Med. 2014;371[21]:1963). BRAF is a downstream signaling mediator of KRAS that activates the MAP kinase pathway and is mutated in 1% to 3% of NSCLC. In a phase 2 study of patients with BRAF V600E mutations, patients treated with the BRAF inhibitor vemurafenib had a disease control rate of 56% (Peters et al. J Clin Oncol. 2013;31[20]:341). MET, a transmembrane tyrosine kinase receptor, is frequently dysregulated in tumor cells via elevated expression with or without gene amplification. There are case reports of responses to crizotinib in patients with MET amplification, and studies of crizotinib and cabozantinib in patients with MET amplification or mutation are underway. Fusions involving receptor tyrosine kinase RET gene have been identified in 1% to 2% of NSCLC, and there are case reports of responses to the RET kinase inhibitors vandetinib and cabozantinib. Mutations in HER2, an important oncogene in breast cancer, have been reported to respond to the HER2 TKI afatinib. While each of these driver mutations are individually infrequent, in aggregate, they represent a substantial fraction of lung cancer patients whose limited treatment options may be expanded to include targeted therapies.

Next generation tyrosine kinase inhibitors

With the superiority of targeted therapy over standard chemotherapy now well-established in EGFR- and ALK-mutated lung cancers, focus has shifted to developing superior TKIs. The second generation ALK inhibitor ceritinib was recently FDA-approved for patients whose disease has progressed on crizotinib. Ceritinib is approximately 20 times more potent than crizotinib and produced responses in 56% of patients with crizotinib-resistant disease. In patients whose disease has progressed on the currently available EGFR inhibitors, a secondary mutation, T790M, can be identified in approximately 60% of tumor biopsies and mediates resistance by reactivating EGFR signaling. Rociletinib (CO-1686) and AZD9291 are third generation EGFR TKIs that not only inhibit the commonly mutated forms of EGFR but also inhibit those bearing the T790M resistance mutation. Furthermore, these drugs are more mutation-specific, showing less inhibition of the wild type EGFR receptor that is responsible for the rash and GI toxicity seen with other EGFR inhibitors. These novel TKIs are first being used as second-line treatment but may supplant the currently available TKIs as initial treatment in the future.

Molecular testing

The advanced molecular characterization of lung adenocarcinoma requires interdisciplinary cooperation between the physician performing the diagnostic procedure, the pathologist, and the oncologist for acquisition of adequate tissue and its judicious use for molecular analysis. The earliest approaches to molecular diagnostic testing involved a combination of assays that each interrogated genomic changes involving a specific gene such as Sanger sequencing, immunohistochemistry, and FISH. This one gene-one test strategy was most suitable when there were few genes to test. As the number of actionable genomic alterations increases, the amount of tissue required to carry out these tests is also increasing. Multiplex testing, along with standard FISH assays, has been successful in comprehensive genotyping but fails to detect gene rearrangements. Next generation sequencing can detect several hundreds of cancer-related genes in a single test. The NCCN guidelines strongly recommend using multiplex or next generation sequencing for broader molecular profiling to detect both common and rare driver mutations. Newer technologies, such as detection of circulating tumor cells and circulating tumor DNA, are being developed to reduce the need for invasive biopsies to obtain the genetic information required to guide targeted therapy selection.

Targeted therapy offers superior efficacy and tolerability in the treatment of advanced lung adenocarcinoma. Molecular profiling to identify a treatable mutation has become a key component of the care of these patients. It is hoped that the role of targeted therapy will continue to expand to include adjuvant treatment of early stage disease, and the ALCHEMIST trial is enrolling patients to address this question. The development of more and better drugs capable of inhibiting the diverse driver mutations found in lung adenocarcinomas is enabling more patients to benefit from this advance in cancer treatment.

Drs. Meghal and Becker are with Maimonides Cancer Center, Brooklyn, New York.