State of the Art Treatment of Lung Cancer Ravi Salgia, MD, PhD

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1 State of the Art Treatment of Lung Cancer Ravi Salgia, MD, PhD Professor and Chair Arthur & Rosalie Kaplan Chair Medical Oncology and Therapeutics Research

2 Nothing to disclose DISCLOSURE

3 Objectives Lung Cancer General Overview Staging Therapeutics by Stage Recent Findings Surgery Radiation Therapy Molecular Oncology Review EGFR ALK Immunotherapy Advancements

4 Lung Cancer Severity and Impact Siegel et. al. Cancer Statistics, 2018

5 NSCLC 85% of all cases of lung cancer Adenocarcinoma ~40% Squamous cell carcinoma ~25-30% Large cell carcinoma ~10-15% 5-year relative survival rates Stage I: ~66-82% Stage II: ~47-52% Stage III: ~19-36% Stage IV: ~6% Markers of NSCLC subtypes TTF-1 Napsin A CK7 p63 CK5/6 Grows more slowly Surgery possible in 35% of patients <40% chemotherapy response rate Chemotherapy indicated in Select Patients Targeted and immunotherapy available MORE AND MORE THERAPEUTIC OPTIONS TO BECOME AVAILABLE SCLC 15% of all cases of lung cancer Small cell carcinoma >90% Combined small cell carcinoma <10% Variant <5% 5-year relative survival rates Stage I: ~31% Stage II: ~19% Stage III: ~8% Stage IV: ~2% Markers of Neuroendocrine Differentiation Chromogrannin A Synaptophysin Leu-7 Bombesin or Gastrin Releasing Peptide Fast growing and aggresive Surgery possible in <10% of patients >80% chemotherapy response rate Chemotherapy indicated in All Patients Treatment limited to Platinum chemo and radiation MORE WORK NEEDS TO BE DONE IN TERMS OF BIOLOGY AND THERAPEUTICS

6 Revised 8 th edition Lung Cancer Staging T Component N0 N1 N2 N3 M1a M1b M1c T1a 1 cm IA1 IIB IIIA IIIB IVA IVA IVB T1 T1b > 1-2 cm IA2 IIB IIIA IIIB IVA IVA IVB T1c > 2-3 cm IA3 IIB IIIA IIIB IVA IVA IVB T2 T2a Central, Visceral Pleura IB IIB IIIA IIIB IVA IVA IVB T2a > 3-4 cm IB IIB IIIA IIIB IVA IVA IVB T2b > 4-5 cm IIA IIB IIIA IIIB IVA IVA IVB T3 T3 > 5-7 cm IIB IIIA IIIB IIIC IVA IVA IVB T3 Invasion IIB IIIA IIIB IIIC IVA IVA IVB T3 Satellite IIB IIIA IIIB IIIC IVA IVA IVB T4 T4 > 7 cm IIIA IIIA IIIB IIIC IVA IVA IVB T4 Ipsilateral Nodule IIIA IIIA IIIB IIIC IVA IVA IVB T4 Invasion IIIA IIIA IIIB IIIC IVA IVA IVB AJCC 8 th edition

7 Lung Cancer OS by Clinical Stage Goldstraw et al. Journal of Thoracic Oncology 2016

8 Recent Findings: Surgery

9 Recent Findings: Surgery Presented By Raymond Osarogiagbon at 2018 ASCO Annual Meeting

10 Recent Findings: Surgery Presented By Raymond Osarogiagbon at 2018 ASCO Annual Meeting

11 Recent Findings: Surgery Presented By Raymond Osarogiagbon at 2018 ASCO Annual Meeting

12 Recent Findings: Surgery Presented By Raymond Osarogiagbon at 2018 ASCO Annual Meeting

13 Recent Findings: Radiation Therapy

14 Recent Findings: Radiation Therapy

15 Recent Findings: Radiation Therapy

16 Radiation Therapy Take Home For Oligomets Consider local consolidative therapy With or without maintenance therapy Adverse Events were similar with no drastic grade 4 AEs or deaths Improved Progression-Free-Survival Patients with three or fewer metastases benefit most Phase 3 trial should be considered to assess aggressive local therapy

17 Genomics Hensing, Mambetsariev, Salgia; 2017; in Pass et al. IASLC Thoracic Oncology 2 nd Ed.

18 Genomics Hensing, Mambetsariev, Salgia; 2017; in Pass et al. IASLC Thoracic Oncology 2 nd Ed.

19 NCCN Guideline for Metastatic NSCLC

20 Molecular Oncology: EGFR Mechanism of Action EGFR as a Pharmacological Target in EGFR-Mutant Non-Small-Cell Lung Cancer: Where Do We Stand Now?

21 Molecular Oncology: EGFR Mechanism of Resistance Management of EGFR-mutated non-small-cell lung cancer: practical implications from a clinical and pathology perspective. M. Cabanero et al. Current Oncology. 2017

22 EGFR: Front-line Treatments for NSCLC Trial TKI Chemo Mutation mpfs (TKI vs Chemo), p IPASS NEJ002 WJTOG 3405 Gefitinib Carbo- Taxol Gefitinib Carbo- Taxol PFS HR (95%CI) All 9.5 vs 6.3; p< ( ) L858R, Del vs 5.4; p< ( ) Gefitinib Cis-Doce L858R, Del vs 6.3; p< ( ) ORR% (TKI vs Chemo) 71 vs vs vs 32 NR G3 TKI tox (%) OPTIMA L Erlotinib Carbo- Gem EURTAC Erlotinib Cis/Carbo- Doce/Gem L858R, Del vs 4.6; p< ( ) L858R, Del vs 5.2; p< ( ) LUX-3 Afatinib Cis-Pem L858R, Del vs 6.9; p< ( ) LUX-6 Afatinib Cis-Gem L858R, Del vs 5.6; p< ( ) 83 vs vs vs vs Mok NEJM (2009), Mitsudomi Lancet Oncol (2010); Maemondo NEJM (2010); Zhou Lancet Oncol (2011); Rossell Lancet Oncol (2012); Sequist JCO (2013); Wu Lancet Oncol (2014); NR, not reported

23 FLAURA First-line osimertinib vs gefitinib/erlotinib Patients with locally advanced or metastatic NSCLC Key inclusion criteria 18 years* WHO performance status 0 / 1 Exon 19 deletion / L858R (enrolment by local # or central EGFR testing) No prior systemic anti-cancer / EGFR-TKI therapy Stable CNS metastases allowed Stratification by mutation status (Exon 19 deletion / L858R) and race (Asian / non-asian) Osimertinib (80 mg p.o. qd) (n=279) Randomised 1:1 EGFR-TKI SoC ; Gefitinib (250 mg p.o. qd) or Erlotinib (150 mg p.o. qd) (n=277) RECIST 1.1 assessment every 6 weeks until objective progressive disease Crossover was allowed for patients in the SoC arm, who could receive open-label osimertinib upon central confirmation of progression and T790M positivity Endpoints Primary endpoint: PFS based on investigator assessment (according to RECIST 1.1) The study had a 90% power to detect a hazard ratio of 0.71 (representing a 29% improvement in median PFS from 10 months to 14.1 months) at a two-sided alpha-level of 5% Secondary endpoints: objective response rate, duration of response, disease control rate, depth of response, overall survival, patient reported outcomes, safety FLAURA data cut-off: 12 June 2017; NCT * 20 years in Japan; # With central laboratory assessment performed for sensitivity; cobas EGFR Mutation Test (Roche Molecular Systems); Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation; Every 12 weeks after 18 months CNS, central nervous system; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival; p.o., orally; RECIST 1.1, Response Evaluation Criteria In Solid Tumors version 1.1; qd, once daily; SoC, standard-of-care; TKI, tyrosine kinase inhibitor; WHO, World Health Organization Ramalingam et al ESMO 2017 #LBA2

24 Primary Endpoint: PFS by Investigator Assessment FLAURA data cut-off: 12 June 2017 Tick marks indicate censored data; CI, confidence interval; DCO, data cut-off; HR, hazard ratio; SoC, standard-of-care; PFS, progression-free survival

25 Overall Survival Interim Analysis FLAURA data cut-off: 12 June 2017; Tick marks indicate censored data CI, confidence interval; DCO, data cut-off; HR, hazard ratio; SoC, standard-of-care Ramalingam et al ESMO 2017 #LBA2

26 All Causality Adverse Events ( 15% of patients) FLAURA data cut-off: 12 June Grade 3 QTc prolongation based on collected digital ECGs values were recorded for 3 patients in the osimertinib arm and 2 patients in the SoC arm *In the SoC arm there was one patient with Grade missing and one patient with Grade 5 diarrhoea AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; SoC, standard-of-care Ramalingam et al ESMO 2017 #LBA2

27 Frontline EGFR Treatment PFS Recondo G et al. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat Rev Clin Oncol Aug 14.

28 Molecular Oncology: ALK

29 ALK rearranged NSCLC Setting Drug Generation FDA approval EMA approval Key trials First line Alectinib Second awaited J-ALEX/ALEX First line Crizotinib First PROFILE 1014 First line Ceritinib Second awaited ASCEND 1,3,4 Post crizotinib Ceritinib Second ASCEND 1,2,5 Post crizotinib Brigatinib Second awaited ALTA Post crizotinib Alectinib Second awaited Phase 2 NA, Intl Post chemo Crizotinib First PROFILE 1005,1007

30 ALEX Study Design Shaw et al ASCO 2017 #LBA 9008

31 PFS-investigator assessed and baseline CNS mets Shaw et al ASCO 2017 #LBA 9008

32 ALEX: Alectinib moves to first-line ALEX places alectinib as the optimal 1 st line ALK TKI choice With CNS metastases enhanced efficacy Without CNS metastases neuroprotective Questions the role of radiotherapy for CNS disease at presentation OS is immature but no current signal of superiority with alectinib PD on crizotinib is salvageable BUT close attention to CNS for failure required (41% at 1yr) 1 st -line Phase 3 Trials Ongoing Sponsor Trial Drug Comparator Target Reporting date Trial ID Takeda ALTA-1L brigatinib crizotinib 270 April 2019 NCT Pfizer CROWN lorlatinib crizotinib 280 Dec 2019 NCT Xcovery exalt3 ensartinib crizotinib 402 April 2020 NCT

33 Front-line ALK Treatment PFS Recondo G et al. Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI? Nat Rev Clin Oncol Aug 14.

34 NSCLC Targets and Therapies Tsao AS, et al. JTO, 2016

35 Mechanism of action of PD-1 and PD-L1 inhibitors Jun Gong, Chehrazi-Raffle, Reddi and Salgia; Journal of ImmunoTherapy of Cancer 2018

36 Timeline of FDA approvals for PD-1 and PD-L1 inhibitors Jun Gong, Chehrazi-Raffle, Reddi and Salgia; Journal of ImmunoTherapy of Cancer 2018

37 NCCN Guideline Chemotherapy+Immunotherapy

38 Advances in NSCLC immunotherapy Russo et al. Crit Reviews in Onc/Heme 2018

39 Summary Lung cancer is a heterogenous group of cancers Early stage is treated with surgery and potentially adjuvant chemotherapy Localized unresectable disease is treated with chemotherapy/radiation therapy followed by durvalumab Metastatic NSCLC treatment has come a long way Chemotherapy/Immunotherapy Targeted Therapy EGFR ALK Others ROS1, BRAF, MET, RET