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New Developments in Targeted Therapy for Lung Cancer Dr. Erick G. Cruz MD Hematology Oncology BMT
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Objectives • Identify the impact of known risk factors on patients with specific subtypes of NSCLC • Classify different treatment options based on staging and tumor characteristics • Discuss the updated 2018 ASCO guidelines for stage IV NSCLC or inoperable disease • Outline therapy based on molecular profile
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Lung Cancer Remains Major Global Health Burden One of the most common cancers and leading cause of cancer deaths[1,2] New cases, 2017 (estimated): US, 224,390 Deaths, 2017 (estimated): US, 158,080 5-yr US survival rates[3] Overall: 18% Metastatic: 4% 5 new agents received FDA approval Osimertinib, necitumumab, nivolumab, pembrolizumab, alectinib, atezolizumab 1. GLOBOSCAN Cancer Fact Sheets. 2012. 2. Siegel RL, et al. CA Cancer J Clin. 2016;66:7-30. 3. National Cancer Institute. Surveillance, Epidemiology, and End Results program. Slide credit: clinicaloptions.com
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NSCLC Subtypes • Adenocarcinoma • • • Most common (40%) Originate Common in mucus secreting cells, outer part of the lung in young, non-smokers, females cell carcinoma • Squamous • Second most common (25%-30%) • Originate in the cells that line the inside Large cell carcinoma of the airways • • • • Account for 10%-15% Can appear in any part of the lung Grow and spread quickly • NSCLC not otherwise specified (NOS) American Cancer Society. What Is Non-Small Cell Lung Cancer. 2017 Chalela R, et al. J Thorac Dis. 2017 July;9(7):2142-2158 ©2017 MFMER | slide-5
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Treatment Stage I • Surgical resection • Surgical resection +/- Chemotherapy Stage II • • Surgical resection Chemo-radiotherapy Stage III • • • • Surgical resection Chemo-radiotherapy Targeted therapy Immunotherapy Stage IV American Cancer Society. What Is Non-Small Cell Lung Cancer. 2017 NCCN. Non-Small Cell Lung Cancer. 2017 ©2017 MFMER | slide-8
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Li T, et al. J Clin Oncol. 2013;31:1039-1049. NSCLC Evolution: From Single Disease to Many Molecularly Defined Subsets Slide credit: clinicaloptions.com
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Biopsy: Establish Diagnosis, Determine Histologic Subtype, Molecular Testing Adequate tissue for histologic subtyping, molecular analysis critical Choice of site to biopsy (avoid bone if possible) Determination of EGFR mutation, ALK, and ROS1 translocations indicated in all nonsquamous cancers Should other genes be evaluated? KRAS, BRAF, HER2, RET, others? Should squamous NSCLC be molecularly typed as well? Rebiopsy at time of progression from targeted therapy Helps in determining resistance in EGFR-mutated and ALK+ cases Liquid biopsy Slide credit: clinicaloptions.com NCCN. Clinical practice guidelines in oncology: non-small-cell lung cancer. v4.2016.
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Selection for Molecular Testing in NSCLC All pts with an adenocarcinoma component should be tested[1,2] Pure SCC diagnosis is appropriate for EGFR mutation and ALK testing in some clinical settings[1] Young, never, or light smoker Next-generation sequencing may be used to detect a broader array of mutations and gene rearrangements[3] Broad molecular testing is encouraged to detect a wider range of mutations, including BRAF V600E mutations[3] 1. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-859. 2. D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070. 3. NCCN. Clinical practice guidelines in oncology: non-small-cell lung cancer. v4.2016. Slide credit: clinicaloptions.com
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Treatment of Stage IV NSCLC ©2017 MFMER | slide-10
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Treatment of Stage IV NSCLC • Historically • Two-drug platinum-based combination • Carboplatin + paclitaxel • Median survival time • Untreated: ~ 4 – 6 months • Treated: ~ 8 – 11 months • Currently • Focusing on biomarkers Abbasi S, et al. Lung Cancer International. 2011 ©2017 MFMER | slide-11
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PD-L1 status ROS1 gene rearrangement EGFR mutation Biomarkers ALK gene rearrangement BRAF mutation PD-L1: Programmed Death-Ligand 1 EGFR: Epidermal Growth Factor Receptor ALK: Anaplastic lymphoma kinase BRAF: human gene that encodes a protein called B-Raf ROS1: proto-oncogene receptor tyrosine kinase ©2017 MFMER | slide-12
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Mutation Prevalence ROS1 gene rearrangment BRAF mutation ALK gene rearrangement 5% EGFR mutation 15% 0% 5% 10% 15% 20% Pikor LA, et al. Lung Cancer. 2013 Nov;82(2):179-89 ©2017 MFMER | slide-14 2% 3%
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Treatment Based on EGFR Mutation
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1. Pao W, et al. J Clin Oncol. 2005;23:2556-2568. 2. Wu YL, et al. J Thorac Oncol. 2007;2:430-439. Slide credit: clinicaloptions.com EGFR Mutations: Context Found in 10% to 30% of NSCLC pts[1] More common in never-smokers, adenocarcinomas, females, Asians[1,2] Predominantly located in EGFR exons 18-21[2] ~ 85% of EGFR mutations are either deletions in exon 19 or a single-point mutation in exon 21 (L858R) Specific EGFR mutation identified is important There are sensitive mutations, primary resistance mutations (often exon 20), and acquired resistance mutations (T790M)
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First-line Treatment With EGFR TKIs vs Chemotherapy in EGFR-Mutated NSCLC 1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Mitsudomi T, et al. ASCO 2012. Abstract 7521. 4. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 5. Zhou C, et al. Ann Oncol. 2015;26:1877-1883. 6. Rosell R, et al. Lancet Oncol. 2012;13:239-246. 7. Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334. 8. Yang JC, et al. Lancet Oncol. 2015;16:141-151. 9. Wu YL, et al. Lancet Oncol. 2014;15:213-222. Slide credit: clinicaloptions.com
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Improved QoL With First-line EGFR TKI for EGFR Mutation–Positive NSCLC IPASS[1]: Gefitinib vs platinum-based doublet chemotherapy showed improvement with FACT-L NEJ002[2]: Gefitinib vs platinum-based doublet chemotherapy showed improvement assessed with Care Notebook First Signal: Gefitinib vs platinum-based doublet chemotherapy showed improvement assessed with EORTC QoL C30 and Lung Cancer-13 questionnaires OPTIMAL[4]: Erlotinib vs platinum-based doublet chemotherapy showed improvement in FACT-L and LCS scores Lux-Lung-3[5]: Afatinib vs platinum-based doublet chemotherapy showed statistically significant delay in time to deterioration of cough, dyspnea; improvement in dyspnea scores, and cognitive, and physical role functions assessed by EORTC QoL C30 and Lung Cancer-13 questionnaires 1. Thongprasert S, et al. J Thorac Oncol. 2011;6:1872-1180. 2. Oizumi S, et al. Oncologist. 2012;17:863-870. 3. Han JY, et al. J Clin Oncol. 2012;30:1122-1128. 4. Chen G, et al. Ann Oncol. 2013;24:1615-1622. 5. Yang JC, J Clin Oncol. 2013;31:3342-3350. Slide credit: clinicaloptions.com
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LUX-Lung 7: First-line Afatinib vs Gefitinib in EGFR-Mutated NSCLC Grade ≥ 3 treatment-related toxicities with afatinib vs gefitinib (≥ 5% incidence) Diarrhea: 12.5% vs 1% Rash/acne: 9% vs 3% Fatigue: 6% vs 0 Increased ALT/AST: 0 vs 9% Dose reductions more common with afatinib (42% vs 2%) Discontinuations due to treatment-related toxicities of 6% in each arm Park K, et al. Lancet Oncol. 2016;17;577-589. Slide credit: clinicaloptions.com Afatinib Gefitinib HR: 0.73 (95% CI: 0.57-0.95; P = 0.017)
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Osimertinib (AZD9291): Novel EGFR TKI in EGFR-Mutated NSCLC Osimertinib FDA approved (November 2015) for advanced EGFR T790M–positive NSCLC after PD on prior EGFR TKI Approval based on AURA and AURA2 single-arm phase II studies of osimertinib in advanced/metastatic NSCLC with EGFR T790M Companion diagnostic test for EGFR mutation also approved Slide credit: clinicaloptions.com 1. Yang JC, et al. WCLC 2015. Abstract 943. 2. Mitsudomi T, et al. WCLC 2015. Abstract 1406.
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Summary of EGFR Mutation–Driven NSCLC EGFR sensitizing mutations predict higher response rate, PFS, and QoL if treated with EGFR TKI first line Several approved EGFR TKIs Only 2 have been compared head to head Specific EGFR mutation is important to know since some predict resistance to EGFR TKIs (eg. exon 20 insertions) Upon progression, postprogression biopsy is important to establish the mechanism of resistance Liquid biopsy is an option Osimertinib approved for pts with T790M+ disease Other third-generation EGFR TKIs are being investigated Response rate appears low with PD-1 immunotherapy in these patients Slide credit: clinicaloptions.com
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Treatment Algorithm Squamous cell NSCLC for Stage IV NSCLC PD-L1 status EGFR mutation NSCLC BRAF mutation ALK gene rearrangement Non- Squamous-cell NSCLC ROS gene rearrangement PD-L1 status Reck M, et al. N Engl J Med. 2017;377:849-61 ©2017 MFMER | slide-15
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ALK Gene Rearrangement Fusion oncogene arises from EML4- ALK translocation: results from an inversion in the short arm of chromosome 2 • • Occur in 3-5% in NSCLC • Associated with light/never smokers, and adenocarcinoma subtype younger age, • ALK inhibitors include: 1st 2nd • • generation: crizotinib generation: alectinib, ceritinib, brigatinib ALK: Anaplastic lymphoma kinase EML4: Echinoderm Microtubule-Associated Protein-Like 4 Camidge DR, et al. Clin Cancer Res. 2010 Nov;16(22):5581-90 Pikor LA, et al. Lung Cancer. 2013 Nov;82(2):179-89 ©2017 MFMER | slide-16
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Evolution From Chemotherapy to Targeted Therapy (ALK+, NSCLC) • Traditionally – platinum doublet • Crizotinib • • FDA approved in Progression-free • 7.7 months in 2013 survival: crizotinib group vs. 3 months in chemotherapy group Response rate: • 65% with crizotinib vs. 20% with chemotherapy • • CNS disease and resistance Shaw AT, et al. N Engl J Med. 2013;368:2385-94 ©2017 MFMER | slide-18
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Alectinib vs. Crizotinib – ALEX trial Peters S, et al. N Engl J Med. 2017 Aug;377(9):829-838 ©2017 MFMER | slide-19 Study design: International, randomized, open-label, phase 3 trial Participants: Previously untreated, advanced ALK-positive NSCLC including asymptomatic CNS disease Interventions: Patients were assigned in 1:1 ratio to either: Alectinib 600mg twice daily OR Crizotinib 250mg twice daily End points: Primary: Investigators-assessed progression-free survival Secondary: Independent review committee-assessed progression free survival, time to CNS progression, objective response rate, overall survival
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Results Peters S, et al. N Engl J Med. 2017 Aug;377(9):829-838 ©2017 MFMER | slide-20 Outcomes Alectinib n=152 (%) Crizotinib n=151 (%) p value Number of disease progressions or death 62 (41%) 102 (68%) --- 12-month progression-free survival 68.4% 48.7% <0.001 Independent review committee-assessed progression free survival 25.7 months 10.4 months <0.001 Rate of events of CNS progression 18 (12%) 68 (45%) <0.001
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Peters S, et al. N Engl J Med. 2017 Aug;377(9):829-838 ©2017 MFMER | slide-21
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Peters S, et al. N Engl J Med. 2017 Aug;377(9):829-838 ©2017 MFMER | slide-22
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Adverse Events Peters S, et al. N Engl J Med. 2017 Aug;377(9):829-838 ©2017 MFMER | slide-23 Adverse events Alectinib (%) Crizotinib (%) Any adverse event / Grade 3-5 97% / 50% 97% / 41% Anemia 20% 5% Myalgia 16% 2% Increased bilirubin 15% 1% Weight gain 10% 0% Musculoskeletal pain 7% 2% Photosensitivity reaction 5% 0% Nausea / Vomiting / Diarrhea 14% / 7% / 12% 48% / 38% / 45% Increased ALT / AST 15% / 14% 30% / 25%
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Conclusion • Longer progression-free survival - HR 0.47 • Investigator’s assessed • Independent review committee-assessed • Active against brain metastases and CNS disease • Time to CNS progression , ©2017 MFMER | slide-24
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1st 2018 ASCO Guidelines Non-Squamous-Cell Carcinoma – line EGFR mutation ALK gene rearrangement ROS1 gene rearrangement Wild Type Crizotinib Crizotinib PD-L1 ≥50% PD-L1 <50% Afatinib Or Erlotinib Or Geftinib Pembrolizumab Combination of platinum based chemotherapy +/- bevacizumab ©2017 MFMER | slide-25 Hanna N, et al. J Clin Oncol. 2017
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Treatment Algorithm Squamous cell NSCLC for Stage IV NSCLC PD-L1 status EGFR mutation NSCLC BRAF mutation ALK gene rearrangement Non- Squamous-cell NSCLC ROS gene rearrangement PD-L1 status Reck M, et al. N Engl J Med. 2017;377:849-61 ©2017 MFMER | slide-28
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Atezolizumab Immune Checkpoint Inhibitors Pembrolizumab Nivolumab ©2017 MFMER | slide-29
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Mechanism of Action Atezolizumab Nivolumab, Pembrolizumab PD-1: programmed cell death protein -1 PD-L: programmed cell death ligand https://s3.amazonaws.com/gotopercom/_media/_upload_image/ _upload_image/AJHO_may14_schilder_figure_3.jpg ©2017 MFMER | slide-30
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Evolution From Chemotherapy to Targeted Therapy (PD-L≥50%, NSCLC) 1st • Traditionally – platinum doublet as line • Targetable genomic alteration  targeted therapy • No targetable genomic alteration • Risk of chemotherapy toxicity vs. benefit • Median overall survival ~ 8 – 10 months • One-year survival rate ~30 – 40% Dang TO, et al. Expert Rev Anticancer Ther. 2016; 16(1): 13–20 ©2017 MFMER | slide-31
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Pembrolizumab vs. Chemo – KEYNOTE-024 Reck M, et al. N Engl J Med. 2016;375:1823-33 ©2017 MFMER | slide-32 Study design: International, randomized, open-label, phase 3 trial Participants: Stage IV advanced NSCLC with PD-L1 expression ≥ 50% and no previous treatment Interventions: Patients were assigned in 1:1 ratio to either: Pembrolizumab IV 200mg q3weeks x35 cycles OR Investigator’s choice of a platinum based chemotherapy End points: Primary: progression-free survival Secondary: overall survival, objective response rate, safety
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Results *66 patients (43.7%) in the chemotherapy group crossed over to received pembrolizumab after disease progression Reck M, et al. N Engl J Med. 2016;375:1823-33 ©2017 MFMER | slide-33 Outcomes Pembrolizumab n=154 (%) Chemotherapy n=151 (%) p value Median progression-free survival 10.3 months 6 months <0.001 Estimated rate of overall survival at 6 months 80.2% 72.4% 0.005 Response rate 44.8% 27.8% ---
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Reck M, et al. N Engl J Med. 2016;375:1823-33 ©2017 MFMER | slide-34
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Reck M, et al. N Engl J Med. 2016;375:1823-33 ©2017 MFMER | slide-35
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Adverse Events Reck M, et al. N Engl J Med. 2016;375:1823-33 ©2017 MFMER | slide-36 Adverse events Pembrolizumab (%) Chemotherapy (%) Any adverse event / Grade 3-5 73.4% / 26.6% 90% / 53.3% Immune-mediated 29.2% 4.7% Pyrexia 10.4% 5.3% Nausea / vomiting / diarrhea 9.7% / 2.6% / 14.3% 43.3% / 20% / 13.3% Anemia 5.2% 44% Neutropenia 0.6% 22.7% Thrombocytopenia 0% 11.3% Fatigue 10.4% 28.7%
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Conclusion Pembrolizumab • • Progression-free survival vs. chemotherapy • 10.3 months vs. 6 months - HR 0.5 • Overall survival at 6 months vs. chemotherapy • 80.2% vs. 72.4% - HR 0.6 1st • line agent in stage IV and PD-L1 tumor expression of ≥ 50% ©2017 MFMER | slide-37
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1st 2018 ASCO Guidelines – line Squamous-Cell Carcinoma PD-L1 ≥50% PD-L1 <50% Combination of platinum based chemotherapy Pembrolizumab Hanna N, et al. J Clin Oncol. 2017 ©2017 MFMER | slide-38
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1st 2018 ASCO Guidelines – line NSCLC EGFR mutation ALK gene rearrangement ROS1 gene rearrangement Wild Type Crizotinib Crizotinib PD-L1 ≥50% PD-L1 <50% Afatinib Or Erlotinib Or Geftinib Pembrolizumab Combination of platinum based chemotherapy +/- bevacizumab ©2017 MFMER | slide-42 Hanna N, et al. J Clin Oncol. 2017
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2nd 2018 ASCO Guidelines – line No Known mutation No prior Prior immune therapy immune therapy Unknown or PD-L1 ≥1% & No prior immune therapy negative PD-L1 <1% Combination of platinum based chemotherapy Nivolumab Or Atezolizumab Or Combination of chemotherapy Pembrolizumab Or Nivolumab Or Atezolizumab Hanna N, et al. J Clin Oncol. 2017 ©2017 MFMER | slide-43
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2nd 2018 ASCO Guidelines – line BRAF mutation ROS1 gene rearrangement EGFR mutation No prior immune therapy & PD-L1 ≥1% Previous immune therapy No T790M mutation T790M mutation Crizotinib (If no previously received) Or Platinum based therapy +/- bevacizumab Osimertinib Platinum doublet Pembrolizumab Or Nivolumab Or Atezolizumab Dabrafinib Hanna N, et al. J Clin Oncol. 2017 ©2017 MFMER | slide-44
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Summary • NSCLC • Very common disease • Leading cause of cancer death • Choice of therapy  presence/absence of biomarkers • Individualized approach • Patients’ goals and co-morbidities • Distinct improvement in outcomes for select subtype ©2017 MFMER | slide-48
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Targeted Therapy for Adenocarcinoma Tsao AS, et al. J Thorac Oncol. 2016;11:613-638. Slide credit: clinicaloptions.com EGFR Other 4% MET 3% > 1 Mutation 3% ROS1 2% BRAF 2% RET 2% NTRK1 1% PIK3CA 1% MEK1 < 1% HER2 2% KRAS 25% Unknown Oncogenic Driver 31% EGFR Sensitizing 17% ALK 7%
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Small-Cell Lung Cancer
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Assessing people with small-cell lung cancer Arrange for people with small-cell lung cancer (SCLC) to have an assessment by a thoracic oncologist within 1 week of deciding to recommend treatment. [2011] Source: https://www.nice.org.uk/guidance/ng122/resources/lung-cancer-diagnosis-and-management-pdf-66141655525573
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First-line treatment for limited-stage disease small-cell lung cancer Offer people with limited-stage disease SCLC (broadly corresponding to T1–4, N0–3, M0) 4 to 6 cycles of cisplatin-based combination chemotherapy. Consider substituting carboplatin in people with impaired renal function, poor performance status (WHO 2 or more) or significant comorbidity.[2011] Source: https://www.nice.org.uk/guidance/ng122/resources/lung-cancer-diagnosis-and-management-pdf-66141655525573
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Offer twice-daily radiotherapy with concurrent chemotherapy to people with limited-stage disease SCLC (broadly corresponding to T1–4, N0–3, M0) and a WHO performance status of 0 or 1, if they present with disease that can be encompassed in a radical thoracic radiotherapy volume. Start the radiotherapy during the first or second cycle of chemotherapy.[2019] If the person declines or is unable to have twice-daily radiotherapy, offer once daily radiotherapy. [2019] Source: https://www.nice.org.uk/guidance/ng122/resources/lung-cancer-diagnosis-and-management-pdf-66141655525573
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Offer sequential radical thoracic radiotherapy to people with limited-stage disease SCLC (broadly corresponding to T1–4, N0–3, M0) who are not well enough for concurrent chemoradiotherapy but who respond to chemotherapy. [2019] Offer prophylactic cranial irradiation at a dose of 25Gy in 10 fractions to people with limited-stage disease SCLC and WHO performance status 0 to 2, if their disease has not progressed on first-line treatment. [2011, amended 2019] [2011, amended 2019] Source: https://www.nice.org.uk/guidance/ng122/resources/lung-cancer-diagnosis-and-management-pdf-66141655525573
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