Personalizing Treatment for NSCLC

Educational Objectives At the conclusion of this activity, participants should be able to demonstrate the ability to: Review strategies for molecular evaluation of NSCLC Discuss formulation of treatment plans for patients with NSCLC based on biomarker expression Review quality measures associated with personalizing treatment for NSCLC Discuss emerging strategies for the management of NSCLC Annual Cancer Deaths, US More Deaths Than Breast, Colon and Prostate Cancer Combined Lung Cancer : Death Rates & Smoking Consumption Per Capita Cigarette 5 45 4 35 3 25 2 15 1 5 19 191 Cigarette consumption Males Females 192 193 194 195 196 197 First Surgeons Generals Report (1964) 198 199 2 1 9 8 7 6 5 4 3 2 1 ncer Death Rates* Age-Adjusted Lung Can Year Siegel et al, 213; CA Cancer J Clin 213;63:11-3. NCI Cancer Bulletin, 25.; Vol 2 iss 7. Screening: NLST trial overview Eligibility Age 55-74 3 pack year smoking history (quit w/in preceding 15 years 1:1 randomization of CXR vs low-dose CT annually x 3 53,345 patients screened and followed for 2 years 95% of positive screens were false positives 2% relative mortality reduction-354 vs 442 lung CA deaths Number needed to screen to prevent one lung cancer death: 32 Clinicaltrials.gov; NCT47385. NLST Survival Curves Kaplan-Meier curves for all-cause mortality NLST, NEJM, 211;365:395-49. All Mortality Lung Cancer Mortality Relative reduction in all-cause mortality of 6.7%, p=.2 1877 deaths in CT group. 2 in CXR group. 213 Rockpointe 1

Case 1 Case # 1 NSCLC detected at an early stage, with an EGFR mutation A 45 yo never-smoking woman originally from India presents with increasing cough. She has no response to antibiotics. After 1 month a CXR shows a LUL mass. A CT scan confirms a 3 cm LUL mass A PET shows uptake in the mass + in the left hilum She tolerates a left upper lobectomy without complications with final pathology confirming a 2.5 cm adenocarcinoma with 3 positive hilar LNs, /14 mediastinal nodes: T2bN1M stage IIA CXR = chest x-ray; LUL = left upper lobe; CT = computed tomography; PET = positron emission tomography; LN = lymph node. Case 1: Question 1 Would you obtain testing to guide choice of adjuvant chemotherapy? If so, which biomarkers would you test for? A. Yes, ERCC1 B. Yes, ERCC1 / RRM1 C. Yes, ERCC1 / RRM1 / TS D. No Predictive Markers in NSCLC To date, these prognostic + predictive factors in early stage are retrospective analyses 15 gene signature from JBR.1 +/- chemo New gene and mirna signatures being explored Potentially ti PREDICTIVE markers in advanced d NSCLC ERCC1 low: platinum sensitive RRM1 low: gemcitabine sensitive Thymidylate synthase (TS) low: pemetrexed sensitive EGFR mutation: EGFR-TKI sensitive ALK translocation: ALK TKI sensitive NCCN v.1.214. IALT Bio - ERCC1 Old/New 761 tumors (589) of 1867 total pts on trial Old 44%: New 77% ERCC1 positive 28:HR 1.2 [.91-1.59] New: HR.96 [.74-1.25; P=.78] Old 56%: New 23% ERCC1 negative 28:HR.76 [.59-.98].98] New: HR.81 [.5-1.31 P=.39] ERCC1 Analysis Conclusions : Technical biases interfered with prior use of ERCC1 IHC as a predictive marker for platinum chemotherapy Current antibodies cannot adequately discriminate the ERCC1-22 isoform which is the only active isoform Highlights importance of assessing multiple isoforms and function in biomarker studies Functional assays required for better predictive capacity Prospective Biomarker Adjuvant Trials Trial Name Stage Therapy Marker C356 Stage I +/- Chemotherapy Multiple SWOG 72 Stage I +/- Chemotherapy (Cis/Gem) ERCC1 /RRM1 ITACA Stage I-IIIA Standard vs. Selected ERCC1/TS Chemo (Cis/Pem) TASTE Stage I-IIIA Standard vs. selected therapy (Cis vs. Erlotinib) SCAT Stage I-IIIA Standard vs. selected Platinum/Docetaxel ERCC1/ EGFR mut BRCA1/ RAP8 Olaussen KA. NEJM; 355: 983, 26; Friboulet NEJM, 368:111, 213. Clinicaltrials.gov. 213 Rockpointe 2

Case 1: Question 2 Which of the following is NOT an appropriate choice of adjuvant chemotherapy for this patient? A. 4 cycles of cisplatin/vinorelbine B. 4 cycles cles of cisplatin/pemetrexeded C. 4 cycles of cisplatin/docetaxel D. 4 cycles of carboplatin/paclitaxel Lung Adjuvant Cisplatin Evaluation (LACE) Meta-analysis 5 trials - 4,584 patients Median follow-up: 5.1 years OS HR.89 [.82-.96], p=.5 Stage IA HR 1.4 [.95, 2.6] Stage IB HR.93 [.78, 1.1] Stage II/III HR.83 [.73,.95] Overall, about 5-1% survival benefit at 5 years with chemo therapy in stage II and greater. Strongest data with cisplatin/vinorelbine Pignon et al, JCO 28, 26(21): 3552-3559. BR.19 Overall Survival by EGFR Mutation Status and Treatment Wild type Sensitizing mutation 1 Placebo Gefitinib 1 Placebo Gefitinib EGFR Mutation Testing Per rcentage 8 6 4 2 Pe rcentage 8 6 4 2 Low N # at Risk Placebo 145 Gefitinib 136 1 126 121 2 118 15 3 Time (Years) 11 89 4 77 74 5 34 21 6 # at Risk 2 Placebo 2 Gefitinib 4 36 1 38 29 2 32 26 3 Time (Years) 3 21 4 26 17 5 6 7 6 1 HR (95% C.I.) Gefitinib/Placebo: 1.21 (.84, 1.73) Log Rank: p=.31 HR (95% C.I.) Gefitinib/Placebo: 1.58 (.83, 3.) Log Rank: p=.16 Goss ASCO 21, Abstr 75. SELECT: Disease-Free Survival RADIANT : Adjuvant NSCLC +/-Erlotinib Probability Survival P 1..9.8.7.6.5.4.3.2 6 of patients completed > of therapy 3 of patients had one or more dose reductions 94% 2-Year DFS Time from initiating adjuvant erlotinib (Years) Median follow-up time: 2.7 years.1 Censored observation..5 1. 1.5 2. 2.5 3. 3.5 4. 4.5 5. Patients at Risk 36 35 34 34 33 19 7 3 1 N=36, expanded to 1 pts ELIGIBLE: N=945 Resected I-IIIA Lobectomy Required IHC/FISH for EGFR Chemo optional R A N D O M I Z E 2:1 Erlotinib 15 mg po qd X 2 yrs Placebo po qd X 2 yrs DFS as primary endpoint 974 pts enrolled 17% w/ EGFRmut 16% KRAS mut Neal ASCO 212; Abstr 71. Richardson et al WCLC 211; O28.1. 213 Rockpointe 3

ALCHEMIST: Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial Stage I-III NSCLC C <6 mo post-op N=6-8 EGFR mut (N=41) (Sequencing) ALK+ (FISH) (N=336) Erlotinib x 2 yrs Placebo x 2 yrs Crizotinib x 2 yrs Placebo x 2 yrs Case 1 (continued) The 45-year-old NS woman with stage IIA NSCLC receives 4 cycles of cisplatin/pemetrexed on the control arm of E155. She tolerates it reasonably well and does well for 2 years. Unfortunately 2 years later she develops increasing dyspnea and is found to have a pleural effusion. Analysis of the effusion is consistent with recurrent adenocarcinoma. NS = never-smoking Case 1: Question 3 The patient is now 47 years old. A PET and brain MRI reveal disease limited to the left lung with extensive pleural involvement and mediastinal adenopathy. EGFR testing was repeated and she is found to have an EGFR exon 19 deletion. What would be your choice of therapy (assuming her effusion is controlled)? A. Erlotinib B. Afatinib C. Carboplatin/pemetrexed D. Carboplatin/paclitaxel/bevacizumab E. Erlotinib or Afatinib Detecting EGFR Mutations in NSCLC NSCLC patients with the somatic mutation of EGFR have been shown to be hyper-responsive to the EGFR TKIs The most common NSCLC-associated EGFR mutations are: in-frame deletion in exon 19 (E746-A75del) point mutation in exon 21 (L858R) These account for 85- of EGFR mutations Yu et al; 28 Molecular Markers Meeting; Abstract No 64. IPASS: PFS and OS by EGFR Mutation Status ession-free Survival Probability of Progre 1..8.6.4.2 PFS (28) OS (21) Gefitinib EGFR M+ Gefitinib EGFR M- C/P EGFR M+ C/P EGFR M-. 4 8 12 16 2 24 Mos of Survival Probability 1.. 8. 6 Mutation +. 4. 2 Mutation -. 4 8 12 16 2 24 28 32 36 4 44 48 52 Mos Fukuoka M, et al. J Clin Oncol. 211;29(21):2866-2874; Yang C-H, et al. European Society of Medical Oncology. 21. Abstract LBA2. Treatment Naïve EGFR mut Patients EGFR TKIs vs Chemotherapy Study Treatment N Maemondo Mitsudomi OPTIMAL EURTAC LUX-Lung 3 Gefitinib vs Carboplatin / Paclitaxel Gefitinib vs Cisplatin / Docetaxel Erlotinib vs Carboplatin / Gemcitabine Erlotinib vs plat-based chemotherapy Afatanib* vs CDDP/pemetrexed 23 177 165 174 345 Median PFS, months 1.8 vs 5.4 (P <.1) Median OS, months 3.5 vs 23.6 (P =.31) 9.2 vs 6.3 36 vs 39 (P <.1) (HR: 1.19) 13.1 vs 4.6 (P <.1) 9.7 vs 5.2 (P <.1) 11.1 vs 6.9 (P =.1) Maemondo M, et al. N Engl J Med. 21;362:238-2388; Mitsudomi T, et al. Lancet Oncol. 21;11:121-128; Mitsudomi T, et al. ASCO 212. Abstract 7521; Zhou C, et al. Lancet Oncol. 211;12:735-742; Zhou et al. ASCO 212. Abstract 752; Rosell R, et al. Lancet Oncol. 212;13:239-246; Sequist LV, et al. J Clin Oncol. 213. [epub ahead of print]. HR: 1.65 (P =.65) 19.3 vs 19.5 (P =.87) Not reported *Approved July 213 for first-line treatment of lung cancer patients with EGFR mutations. 213 Rockpointe 4

Case 1: Question 4 She starts on erlotinib and does well for 14 months before her dyspnea returns and she is found to have recurrent pleural disease. After repeating a biopsy, which of the following steps will NOT be appropriate for this patient? A. Switch to doublet chemotherapy (+/- bevacizumab) Stop erlotinib preferred under most circumstances unless a trial is available B. Add doublet chemotherapy (+/- bevacizumab) Cont erlotinib can consider but still a trial question C. Switch to a 2nd generation EGFR-TKI or trial D. Switch to crizotinib E. All of the above Repeat Biopsies for Patients with Acquired Resistance to EGFR inhibitors Observed Resistance Mechanisms N=37 T79M (total) +EGFR Amp + beta-catenin 21 4 2 + APC 1 MET amplification 2 PIK3CA 3 SCLC transformation 5 Epithelial-mesenchymal transition 2 No changes identified 8 Sequist Sci Transl Med 3:75ra26, 211 Tumor Regression by T79M Mutation Status Afatinib + Cetuximab at Recommended Dose CO-1686 Summary 42 pts (74% T79M+) treated w/ CO-1686 up to 18mg/day CO-1686 is well tolerated with no evidence of dose related diarrhea or rash Encouraging activity has been observed in heavily pretreated T79M+ EGFR mutant patients resistant to erlotinib, especially at higher doses Metastasis shrinkage has been observed at multiple organ sites, including in the CNS 3 of 4 T79M+ evaluable patients on 9mg bid achieved PRs to date Median PFS 4.7 months and median duration of response 7.7 months Horn et al, WCLC 211, Abstr O19.7. Sequist, abstr 2524 ASCO 213. Case 2: History Case # 2 A patient with an EML4-ALK transformation A 55-year-old male presented with right chest pain, dyspnea and cough. Chest CT revealed diffuse pleural-based lesions on the right hemithorax and right upper lobe lung mass 2 cm liver lesion was noted PMH significant for hypertension and stable coronary artery disease 1 pack years prior smoking history CT guided biopsy of a pleural-based mass revealed adenocarcinoma TTF-1 positive Tumor specimen was negative for EGFR mutation ECOG PS=1 213 Rockpointe 5

Case 2: Question 1 ALK Fusion Gene Which of the following would you do next? A. Start the patient on chemotherapy B. Order testing for ALK C. Order testing for ROS1 D. Order testing for ALK and ROS1 Potent oncogenic activity Present in approximately 4-5% of NSCLC More common in Never-smokers Adenocarcinoma Signet ring morphology Yuan et al J Hematol Oncol, 211, 4, 1-16; Shaw et al, 29, J Clin Oncol 27:4247-4253. ROS1 Rearrangements in NSCLC TPM3-ROS1 Summary of Tumor Responses in Patients with Advanced ROS1+ NSCLC (N=14*) ROS1 SDC4-ROS1 SLC34A2-ROS1 CD74-ROS1 EZR-ROS1 LRIG3-ROS1 Present in ~1% of NSCLC cases (also found in some GBMs and cholangiocarcinomas) Enriched in younger never or light smokers with adenocarcinoma histology No overlap with other oncogenic drivers Baseline (%) Decrease or Increase From B 1 8 6 4 2 2 4 6 8 15+ 16+ 18+ 4+ PD SD PR CR 12+ 8+ 22+ 18 44+ 1 2+ 35+ 48+ Bergethon et al., JCO 3(8): 863-7, 212; Takeuchi et al., Nat Med 18(3): 378-81, 212. CAP / IASLC / AMP Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK TKIs (Released on April 3, 213) IHC as a Screening Tool for ALK Detection Main Issues Addressed: Timing of molecular testing, performance of testing, should other genes be tested, and the implementation/operationalization of molecular testing Who Should Be Tested for EGFR and ALK?: 1.1a /1.1b Recommendations. EGFR (1.1a)/ALK (1.1b) molecular testing to be used to select patient for EGFR/ALK-targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics. Using Clinical Criteria is Not Optimal: Using clinical characteristics to exclude patients for EGFR mutation or ALK rearrangement testing is not recommended Lindeman et al, 213, J Thoracic Oncol, 8(7): 823-859. Cagle et al, 213, IASLC webinar. 213 Rockpointe 6

Case 2: Question 2 Crizotinib: First-in-human/Patient Trial The patient was started on treatment with carboplatin, paclitaxel and bevacizumab. Following cycle 1, ALK test came back as positive by FISH method. What is your next step? A. Continue chemotherapy B. Switch immediately to crizotinib Part 1: Dose escalation Cohort 2 (n=4) 1 mg QD Cohort 3 (n=8) 2 mg QD Cohort 4 (n=7) 2 mg BID Cohort 5 (n=6) 3 mg BID 1 DLT: grade 3 ALT elevation 2 DLTs: grade 3 fatigue Cohort 6 (n=9) 25 mg BID MTD/RP2D Part 2: Molecularly enriched cohorts (ALK and c-met) Cohort 1 (n=3) 5 mg QD Kwak et al, 21, N Eng J Med, 363(18):1693-73. Best Percent Change from Baseline in Target Lesions* m baseline % Decrease or increase from 1 8 6 4 2 2 4 6 8 1 Progressive disease Stable disease Partial response Complete response *excludes patients with early death and indeterminate response (n=16) **includes patients with early death and indeterminate response (n=116) Objective response details (all evaluable patients) N=116** ORR (95% CI) 61% (52, 7) Median response duration 48 weeks Median time to response 8 weeks Disease control rate at 8, 16 weeks 7, 67% Case 2: Question 3 CT scan after 3 cycles of therapy demonstrates disease progression. What would you do now? A. Pemetrexed B. Crizotinib C. Docetaxel D. Erlotinib Camidge et al, ASCO 211. Crizotinib is Superior to Chemotherapy Case 2 (continued) The patient was started on crizotinib therapy. He had a near CR on the CT scan after 2 months. Patient tolerated the treatment well. After 14 months, the patient was found to have three 6-8 mm lesions in the brain, consistent with metastasis. The disease was stable in the chest. Shaw et al: ESMO 212, Abstract LBA1_PR. 213 Rockpointe 7

Case 2: Question 4 The patient received SBRT to brain lesions and was continued on crizotinib. He did well for another 5 months after which he had progression in the liver and the lungs. What is your next step? A. Switch to pemetrexed B. Obtain a tumor biopsy C. Continue crizotinib Resistance Mutation ALK Mutation 28% ALK+/Unknown Mechanism* 18% Unknown Oncogene/ ALK- EGFR mut/alk- ALK Mutation/CNG KRAS mut/alk- KRAS mut/alk+* ALK CNG Alternate Oncogene (& KIT) ALK Copy Number Gain (CNG) Doebele et al., 212, Clin Can Res 18(5); 1 11. Case 3: History Case # 3 A patient with Squamous Cell NSCLC A 72-year-old male with 4 pack years of smoking history presented with increasing dyspnea and cough. CT scan revealed a right upper lobe lung mass (5 cm), extensive mediastinal adenopathy, and bilateral pulmonary nodules. Transbronchial biopsy of right paratracheal lymph node was consistent with squamous cell cancer. P63 positive Co-morbid illness: COPD, Hypertension, DM ECOG PS=1 You recommend smoking cessation and no further testing Therapeutic Targets in Squamous Cell Carcinoma Case 3: Question 2 Which of the following regimens would you NOT recommend? A. Platinum agent-gemcitabine B. Platinum agent-pemetrexed C. Platinum agent-nab-paclitaxel D. Platinum agent-paclitaxel Source: Hammerman P, Targeted Therapies Meetings, Santa Monica, 212 213 Rockpointe 8

Pemetrexed/Cisplatin vs Gemcitabine/Cisplatin in First-Line Advanced NSCLC Nab-paclitaxel: Efficacy by histology 5% 4% 3% 2% Squamous Non-Squamous 41% 37% 37% 3% 2 26% 24% 25% nab-p/c P/C 1% Scagliotti, et al. J Clin Oncol. 28;26(21):3543-3551. % Independent Radiologic Review Investigator Assessment Socinski et al, ASCO 21, Abstr LBA7511. Independent Radiologic Review Investigator Assessment Case 3 (continued) Case 3: Question 3 The patient was treated with carboplatin and paclitaxel for 4 cycles. He had stable disease, but developed peripheral neuropathy. He has no interest in further chemotherapy, but wishes to try promising novel agents. Which of the following agents are promising in squamous cell lung cancer? A. PARP inhibitors B. PD-1 targeted therapy C. Heat shock protein 9 inhibitors Role of PD-1 in Suppressing Antitumor Immunity APC MHC-Ag Tumor B7.1 CD28 T cell TCR Signal 1 Inhibition (anergy, exhaustion, death) Keir ME et al, Annu Rev Immunol 28; Pardoll DM, Nat Rev Cancer 212 Activation (cytokines, lysis, prolif., migration) (-) PD-1 PD-L1 (-) Tumor (-) Anti-PD- 1 Clinical Activity of BMS-936558 in NSCLC Patients Pop ALL NSCLC NSCLC Dose (mg/kg) Pts n ORR n (%) Duration of Response (mo) SD 24 wk n (%) PFSR at 24 wk (%) 1-1 76 14 (18) 1.9+ to 3.8+ 5 (7) 26 1 18 1 (6) 9.2+ 1 (6) 16 3 19 6 (32) 1.9+ to 3.8+ 2 (11) 41 1 39 7 (18) 3.7 to 14.8+ 2 (5) 24 ORR was assessed using modified RECIST v1. 3 NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not classified as responders for the ORR calculation Gettinger et al, EMSO 212, Abstract 265. 213 Rockpointe 9

Quality Measures for NSCLC: ASCO-QOPI Adjuvant chemotherapy recommended and received for patients with AJCC stage II or IIIA NSCLC Adjuvant cisplatin based chemotherapy received within 6 days after curative resection by patients with AJCC stage II or IIIA NSCLC** Performance status documented for patients with initial AJCC stage IV or distant metastatic NSCLC* Platinum doublet first line chemotherapy or targeted therapy (with documented DNA mutation) received by patients with initial AJCC stage IV or distant metastatic NSCLC with performance status of 1 without prior history of chemotherapy* Positive mutation for patients with stage IV NSCLC who received first line EGFR tyrosine kinase inhibitor or other targeted therapy Patient Information Brochures from National Lung Cancer Partnership A copy has been provided with your syllabus Excellent tool to provide patients Can be shipped to your office (minimal charge for postage) Available online with additional resources at: http://www.nationallungcancerpa rtnership.org/shop/freeresources/patient-familycaregiver-kit-1.html 213 Rockpointe 1