The
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Overcoming Resistance to Targeted Therapy for Lung Cancer Ramaswamy Govindan, M.D. The discovery that certain activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain may determine responses to EGFR tyrosine kinase inhibitors in patients with advanced non–small-cell lung cancer (NSCLC) allowed more precise selection of patients who were likely to have a response.1,2 These mutations are seen in approximately 10 to 15% of metastatic NSCLC tumors, mostly in patients with adenocarcinoma who have never smoked. As compared with cytotoxic chemotherapy, EGFR tyrosine kinase inhibitors significantly improve the overall response rate and progression-free survival in previously untreated patients with EGFR-mutated NSCLC.3-5 However, despite their initial responses, progressive disease develops in the majority of these patients within several months. The most common mechanism of resistance to first-generation EGFR tyrosine kinase inhibitors (e.g., gefitinib and erlotinib) is a mutation in the “gatekeeper” residue (the ATP binding site on the kinase), where methionine replaces threonine (T790M).6 The resulting change in configuration decreases affinity for the inhibitors as compared with cellular ATP. Unfortunately, second-generation EGFR inhibitors (e.g., neratinib, afatinib, and dacomitinib) and cytotoxic chemotherapy drugs are only minimally active in this context.7 Two studies in this issue of the Journal show encouraging results with third-generation EGFR tyrosine kinase inhibitors in this patient population.7,8 AZD9291 and rociletinib (CO-1686) are oral mutant-selective EGFR tyrosine kinase inhibitors that are active against the common “sensitive” EGFR mutations — exon 19 deletion and L858R — as well as the resistant T790M mutation. Both studies involved patients with 1760
EGFR-mutated advanced NSCLC who had progressive disease after therapy with a first-generation EGFR tyrosine kinase inhibitor. In a large phase 1 study that included five expansion cohorts, the response rate with AZD9291 was 51% (95% confidence interval [CI], 45 to 58) and was higher among those with the EGFR T790M mutation (61%; 95% CI, 52 to 70) than among those without this mutation (21%; 95% CI, 12 to 34).7 The median progression-free survival was significantly longer in those with the EGFR T790M mutation (9.6 months; 95% CI, 8.3 to not reached) than in those without it (2.8 months; 95% CI, 2.1 to 4.3). Rociletinib produced similar results, with a response rate of 59% (95% CI, 45 to 73) among patients with the EGFR T790M mutation and 29% (95% CI, 8 to 51) among those without this mutation.8 The estimated median progressionfree survival was significantly longer in those with the EGFR T790M mutation (13.1 months; 95% CI, 5.4 to 13.1) than in those without it (5.6 months; 95% CI, 1.3 to not reached). As expected, owing to the selectivity of AZD9291 and rociletinib for the mutant forms of EGFR, treatment with either agent resulted in lower incidences of rash and diarrhea than have been observed with treatment with first-generation EGFR tyrosine kinase inhibitors. Hyperglycemia observed with rociletinib was easily managed with oral hypoglycemic therapy. These studies underscore the importance of repeating biopsies with molecular analysis at the time of disease progression in patients with EGFRmutated NSCLC. A variety of mechanisms contribute to disease progression after initial therapy with the first-generation EGFR tyrosine kinase inhibitors.9 Apart from the emergence of the T790M mutation, cancer cells can activate other oncogenes (e.g., MET and fibroblast growth fac-
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on April 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
editorial
tor receptor [FGFR]), undergo a phenotypic change to small-cell lung cancer, or activate survival pathways that lead eventually to treatment resistance. Finding EGFR T790M in tumor specimens after initial therapy with first-generation EGFR tyrosine kinase inhibitors now has practical relevance. In the immediate future, before the drugs are approved and widely available, these patients should be considered for ongoing clinical trials with T790M-specific EGFR tyrosine kinase inhibitors. Patients with EGFR inhibitor–resistant NSCLC whose tumor cells are activated through other oncogenes should be enrolled in appropriate clinical trials when possible. Although these results are encouraging, much work remains to be done to improve the outcomes of patients with lung cancer. Will initial therapy with AZD9291 or rociletinib delay the emergence of EGFR T790M in patients with EGFRmutated NSCLC? It is almost certain that cancer cells will continue to evolve and become resistant to these agents. Genomic analysis of the resistant lesions and expedited translation of laboratory findings to the clinic are key elements for continued success in this area. Despite advances in the treatment of patients with metastatic EGFR-mutated NSCLC, very little progress has been made in the treatment of patients with early-stage and locally advanced EGFRmutated NSCLC. A large, ambitious study — one of the three Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) sponsored by the National Cancer Institute — will evaluate the role of erlotinib in the postoperative setting after surgical resection and standard postoperative adjuvant therapy in stage I to III EGFR-mutated NSCLC (ClinicalTrials .gov number, NCT02193282). Patients with locally advanced unresectable EGFR-mutated NSCLC will be randomly assigned in another prospective study to receive primary erlotinib therapy for 3 months followed by standard definitive chemoradiation or standard definitive chemoradiation alone (NCT01822496). The use of EGFR tyrosine kinase inhibitors as front-line therapy has the potential to improve cure rates in early-stage and locally advanced NSCLC. The recent progress made in the treatment of NSCLC is heartening. Large-scale genomic studies conducted by the Cancer Genome Atlas project and others have identified a number of actionable targets.10 However, more tumor specimens
need to be studied to uncover rare oncogenic events. Comprehensive genomic analyses performed on serial biopsy specimens will enable us to more fully understand the process of clonal evolution and the molecular mechanisms that underlie metastases and treatment resistance.11 Immune checkpoint inhibitors have shown promise in the treatment of lung cancer, including EGFR-mutated NSCLC. Genome sequencing of tumor cells to identify highly antigenic neoepitopes may enable the development of customized immune therapies to augment targeted therapies and immune checkpoint blockade. With such advances on the horizon, there is every reason to be cautiously optimistic about the future of lung-cancer treatment. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Department of Medicine and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis. 1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129-39. 2. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500. 3. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. 4. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46. 5. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3327-34. 6. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005; 2(3):e73. 7. Jänne PA, Yang JC-H, Kim D-W, et al. AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer. N Engl J Med 2015; 372:1689-99. 8. Sequist LV, Soria J-C, Goldman JW, et al. Rociletinib in EGFR-mutated non–small-cell lung cancer. N Engl J Med 2015; 372:1700-9. 9. Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014;11:473-81. 10. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511: 543-50. 11. Govindan R. Cancer: attack of the clones. Science 2014;346: 169-70. DOI: 10.1056/NEJMe1500181 Copyright © 2015 Massachusetts Medical Society.
n engl j med 372;18 nejm.org april 30, 2015
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The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on April 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
n e w e ng l a n d j o u r na l
of
m e dic i n e
Edi t or i a l
Overcoming Resistance to Targeted Therapy for Lung Cancer Ramaswamy Govindan, M.D. The discovery that certain activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain may determine responses to EGFR tyrosine kinase inhibitors in patients with advanced non–small-cell lung cancer (NSCLC) allowed more precise selection of patients who were likely to have a response.1,2 These mutations are seen in approximately 10 to 15% of metastatic NSCLC tumors, mostly in patients with adenocarcinoma who have never smoked. As compared with cytotoxic chemotherapy, EGFR tyrosine kinase inhibitors significantly improve the overall response rate and progression-free survival in previously untreated patients with EGFR-mutated NSCLC.3-5 However, despite their initial responses, progressive disease develops in the majority of these patients within several months. The most common mechanism of resistance to first-generation EGFR tyrosine kinase inhibitors (e.g., gefitinib and erlotinib) is a mutation in the “gatekeeper” residue (the ATP binding site on the kinase), where methionine replaces threonine (T790M).6 The resulting change in configuration decreases affinity for the inhibitors as compared with cellular ATP. Unfortunately, second-generation EGFR inhibitors (e.g., neratinib, afatinib, and dacomitinib) and cytotoxic chemotherapy drugs are only minimally active in this context.7 Two studies in this issue of the Journal show encouraging results with third-generation EGFR tyrosine kinase inhibitors in this patient population.7,8 AZD9291 and rociletinib (CO-1686) are oral mutant-selective EGFR tyrosine kinase inhibitors that are active against the common “sensitive” EGFR mutations — exon 19 deletion and L858R — as well as the resistant T790M mutation. Both studies involved patients with 1760
EGFR-mutated advanced NSCLC who had progressive disease after therapy with a first-generation EGFR tyrosine kinase inhibitor. In a large phase 1 study that included five expansion cohorts, the response rate with AZD9291 was 51% (95% confidence interval [CI], 45 to 58) and was higher among those with the EGFR T790M mutation (61%; 95% CI, 52 to 70) than among those without this mutation (21%; 95% CI, 12 to 34).7 The median progression-free survival was significantly longer in those with the EGFR T790M mutation (9.6 months; 95% CI, 8.3 to not reached) than in those without it (2.8 months; 95% CI, 2.1 to 4.3). Rociletinib produced similar results, with a response rate of 59% (95% CI, 45 to 73) among patients with the EGFR T790M mutation and 29% (95% CI, 8 to 51) among those without this mutation.8 The estimated median progressionfree survival was significantly longer in those with the EGFR T790M mutation (13.1 months; 95% CI, 5.4 to 13.1) than in those without it (5.6 months; 95% CI, 1.3 to not reached). As expected, owing to the selectivity of AZD9291 and rociletinib for the mutant forms of EGFR, treatment with either agent resulted in lower incidences of rash and diarrhea than have been observed with treatment with first-generation EGFR tyrosine kinase inhibitors. Hyperglycemia observed with rociletinib was easily managed with oral hypoglycemic therapy. These studies underscore the importance of repeating biopsies with molecular analysis at the time of disease progression in patients with EGFRmutated NSCLC. A variety of mechanisms contribute to disease progression after initial therapy with the first-generation EGFR tyrosine kinase inhibitors.9 Apart from the emergence of the T790M mutation, cancer cells can activate other oncogenes (e.g., MET and fibroblast growth fac-
n engl j med 372;18 nejm.org april 30, 2015
The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on April 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
editorial
tor receptor [FGFR]), undergo a phenotypic change to small-cell lung cancer, or activate survival pathways that lead eventually to treatment resistance. Finding EGFR T790M in tumor specimens after initial therapy with first-generation EGFR tyrosine kinase inhibitors now has practical relevance. In the immediate future, before the drugs are approved and widely available, these patients should be considered for ongoing clinical trials with T790M-specific EGFR tyrosine kinase inhibitors. Patients with EGFR inhibitor–resistant NSCLC whose tumor cells are activated through other oncogenes should be enrolled in appropriate clinical trials when possible. Although these results are encouraging, much work remains to be done to improve the outcomes of patients with lung cancer. Will initial therapy with AZD9291 or rociletinib delay the emergence of EGFR T790M in patients with EGFRmutated NSCLC? It is almost certain that cancer cells will continue to evolve and become resistant to these agents. Genomic analysis of the resistant lesions and expedited translation of laboratory findings to the clinic are key elements for continued success in this area. Despite advances in the treatment of patients with metastatic EGFR-mutated NSCLC, very little progress has been made in the treatment of patients with early-stage and locally advanced EGFRmutated NSCLC. A large, ambitious study — one of the three Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) sponsored by the National Cancer Institute — will evaluate the role of erlotinib in the postoperative setting after surgical resection and standard postoperative adjuvant therapy in stage I to III EGFR-mutated NSCLC (ClinicalTrials .gov number, NCT02193282). Patients with locally advanced unresectable EGFR-mutated NSCLC will be randomly assigned in another prospective study to receive primary erlotinib therapy for 3 months followed by standard definitive chemoradiation or standard definitive chemoradiation alone (NCT01822496). The use of EGFR tyrosine kinase inhibitors as front-line therapy has the potential to improve cure rates in early-stage and locally advanced NSCLC. The recent progress made in the treatment of NSCLC is heartening. Large-scale genomic studies conducted by the Cancer Genome Atlas project and others have identified a number of actionable targets.10 However, more tumor specimens
need to be studied to uncover rare oncogenic events. Comprehensive genomic analyses performed on serial biopsy specimens will enable us to more fully understand the process of clonal evolution and the molecular mechanisms that underlie metastases and treatment resistance.11 Immune checkpoint inhibitors have shown promise in the treatment of lung cancer, including EGFR-mutated NSCLC. Genome sequencing of tumor cells to identify highly antigenic neoepitopes may enable the development of customized immune therapies to augment targeted therapies and immune checkpoint blockade. With such advances on the horizon, there is every reason to be cautiously optimistic about the future of lung-cancer treatment. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. From the Department of Medicine and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis. 1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non–small-cell lung cancer to gefitinib. N Engl J Med 2004; 350:2129-39. 2. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500. 3. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. 4. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46. 5. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31:3327-34. 6. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005; 2(3):e73. 7. Jänne PA, Yang JC-H, Kim D-W, et al. AZD9291 in EGFR inhibitor–resistant non–small-cell lung cancer. N Engl J Med 2015; 372:1689-99. 8. Sequist LV, Soria J-C, Goldman JW, et al. Rociletinib in EGFR-mutated non–small-cell lung cancer. N Engl J Med 2015; 372:1700-9. 9. Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol 2014;11:473-81. 10. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014;511: 543-50. 11. Govindan R. Cancer: attack of the clones. Science 2014;346: 169-70. DOI: 10.1056/NEJMe1500181 Copyright © 2015 Massachusetts Medical Society.
n engl j med 372;18 nejm.org april 30, 2015
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The New England Journal of Medicine Downloaded from nejm.org at UC SHARED JOURNAL COLLECTION on April 29, 2015. For personal use only. No other uses without permission. Copyright © 2015 Massachusetts Medical Society. All rights reserved.
