Acquired Resistance Patient Forum

1. Combinations for Treating EGFR Acquired Resistance Melissa L. Johnson, MD Acquired Resistance Patient Forum In ALK, ROS1 & EGFR Lung Cancers September 6, 2014 | Boston

2. Combination Treatments for EGFR Acquired Resistance Dx: EGFR+ lung cancer Acquired Resistance Tarceva + NEW DRUG Tarceva Gilotrif Gilotrif + NEW DRUG

3. Combination Treatments for EGFR Acquired Resistance Can we make 1st Gen TKI Better? • We have tried!! • Selected approaches to enhancing EGFR TKI in order to overcome or prevent resistance Erlotinib + Chloroquine Erlotinib + Sirolimus Erlotinib + Onartuzumab (anti-Met) Erlotiinb + Entinostat Erlotinib + R1507 (anti IGF-1) Erlotinib + Tivantinib Erlotinib + Sorafanib Erlotinib + Dasatinib Erlotinib + MK2206 (AKT) Erlotinib + MM-121 (anti-ErbB3) Erlotinib + XL184 Erlotinib + Rilotumumab (anti-HGF) • Erlotinib + Patritumumab (anti-ErbB3) • Erlotinib + AUY-922 (HSP 90 inhibitor) Slide adapted, courtesy of Thomas J. Lynch, Jr., MD

4. Combination Treatments for EGFR Acquired Resistance Dx: EGFR+ lung cancer Acquired Resistance Tarceva/Gilotrif (erlotinib/afatinib) Tarceva/Gilotrif (erlotinib/afatinib) + NEW DRUG

5. Combination Treatments for EGFR Acquired Resistance Flare associated with shorter TTP • 14 of 61 patients (23%, 95% CI 14-35%) had a disease flare (hospitalization or death) • Median time from last TKI to flare was 8 days (range 3-21 days) • 3 patients went on to trial treatment Chaft, Clin Cancer Res 2011

6. Combination Treatments for EGFR Acquired Resistance AUY922: An “Onco-Chaperone” Inhibitor AUY922 (in yellow) is a synthetic isoxazole resorcinol HSP90 inhibitor, shown here bound to the deep ATP pocket of HSP90 (in blue) Neckers and Workman Clin Cancer Res 2012 AUY922+ Erlotinib Melissa L. Johnson

7. Combination Treatments for EGFR Acquired Resistance AUY922 + Erlotinib Phase I Dose-Escalation AUY922+ Erlotinib Melissa L. Johnson

8. HSP90 Inhibitors in Lung Adenocarcinoma Preliminary Activity Patient 01-102 AUY922 25 mg/m + Erlotinib 75 mg Duration of therapy: 6 months C1D1 C1D28 AUY922+ Erlotinib Melissa L. Johnson

9. AUY922 + Erlotinib Phase II Study Design • Key Inclusion Criteria • Advanced lung adenocarcinoma • EGFR mutation OR previous response to EGFR TKI • EGFR TKI for ≥6 months and 1 full month prior to study start • Biopsy at time of acquired resistance to EGFR TKI Primary endpoint: Overall response rate ORR (CR + PR) Stage IV Adenocarcinoma +EGFR mutation Acquired Resistance Secondary endpoints: Progression-free survival, Overall survival, ORR in T790M+, Toxicity • Definition of Acquired Resistance19 • Previously treated with single-agent EGFR-TKI • Tumor harbors TKI-sensitive EGFR mutation (G719X, ex 19 del, L858R, L861Q) • EITHER RECIST-defined PR/CR OR ≥ 6 months clinical benefit (SD) with single-agent EGFR-TKI followed by systemic POD • Statistical Considerations: • stage I: 16 pts (if ≥2 responses, proceed to stage II) • stage II: 9 pts (if ≥ 5 responses overall, AUY922 and erlotinib are worthy of further study) • α=10%; β=10%; p0=10%; p1=30% Biopsy at resistance 30 day erlotinib lead-in Melissa L. Johnson 19 Jackman JCO 2009 • Key Exclusion Criteria • Brain metastasis that are symptomatic and/or requiring escalating doses of steroids • Systemic treatment within 4 weeks, RT within 2 weeks Erlotinib 150mg PO qday AUY922 70mg/m2

10. Molecular Characteristics AUY922+ Erlotinib Melissa L. Johnson

11. Best Response to AUY922 and Erlotinib N=24 Best % change in target lesions Progressive disease Stable disease Partial response EGFR T790M Partial Response (PR): 4/25 (16%)(95% CI 6-35%) Disease Control Rate (DCR): 14/25 (56%)(95% CI 37-73%) AUY922+ Erlotinib Melissa L. Johnson

12. Individual Responses According to EGFR Mutations and Time on Primary EGFR-TKI Reason withdrawn from study * Small cell transformation patient remains on study

13. Combination Treatments for EGFR Acquired Resistance Afatinib + Cetuximab

14. Combination Treatments for EGFR Acquired Resistance Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor-Resistant EGFR Mutant Lung Cancer with and without T790M Pathology confirmed NSCLC with EGFR mutation1 OR SD 6 months on erlotinib/gefitinib OR Partial or complete response to erlotinib/gefitinib Dose escalation schema 3–6 patients per cohort Afatinibp.o. daily + escalating doses of i.v. cetuximab q 2 weeks Dose levels starting at: afatinib 40 mg +cetuximab 250 mg/m2 Predefined maximum dose: afatinib 40 mg + cetuximab 500 mg/m2 Stop erlotinib/ gefitinib for ≥72 hours3 Disease progression2 MTD cohort expanded up to 80 EGFRmutation-positive patients4: 40 T790M+ and 40 T790M– ECOG PS 0-2 Age ≥ 18 years Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

15. Combination Treatments for EGFR Acquired Resistance Tumor Regression by T790M Mutation Statusat Recommended Dose Horn at al. IASLC 2011

16. Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

17. Combination Treatments for EGFR Acquired Resistance Cetux/Afatanib Toxicity Janjigian, et al. Cancer Discovery 4(9): 1-10, 2014

18. Combination Treatments for EGFR Acquired Resistance Preliminary Efficacy Comparison

19. Toxicity Comparison

20. Combination Treatments for EGFR Acquired Resistance T+A vs T (#8005) Unselected Patient Population • BeTa in second line setting • ATLAS as maintenance • Both with compelling results in enriched populations of never smokers, East Asians • Possible EGFR regulation of VEGF in EGFR mutant cell lines (Heymach)

21. Combination Treatments for EGFR Acquired Resistance JO25567Study Design • Chemotherapy-naïve • Stage IIIB/IV NSCLC or postoperative recurrence • Non-squamous • Activating EGFR mutations* • Exon 19deletion • Exon 21 L858R • Age ≥20 years • PS 0–1 • No brain metastasis EB combination Erlotinib 150mg qd + bevacizumab 15mg/kgq3w (n = 75) • Primary endpoint: PFS (RECIST v1.1, independent review) • Secondary endpoints: OS, tumor response, QoL, safety • Exploratory endpoint:biomarker assessment PD R Emonotherapy Erlotinib 150mg qd (n = 75) 1:1 PD Stratification factors: sex, smoking status, clinical stage, EGFRmutation type *T790M excluded Abstract 8005: Presented by TerufumiKato

22. Combination Treatments for EGFR Acquired Resistance Primary endpoint: PFS by independent review 1.0 0.8 *log-ranktest, two-sided EB 0.6 E PFS probability 0.4 0.2 9.7 16.0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Time (months) Number at risk EB 75 72 69 64 60 53 49 38 30 20 13 8 4 4 0 E 77 66 57 44 39 29 24 21 18 12 10 5 2 1 0 Abstract 8005: Presented by TerufumiKato

23. Combination Treatments for EGFR Acquired Resistance PFS by EGFR Mutation Type EB EB Exon 19 deletion Exon 21 L858R E E 1.0 1.0 0.8 0.8 0.6 0.6 PFS probability PFS probability 0.4 0.4 0.2 0.2 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Time (months) Time (months) Number at risk Number at risk EB 40 39 38 36 33 29 27 24 19 12 8 5 2 2 0 EB 35 33 31 28 27 24 22 14 11 8 5 3 2 2 0 E 40 35 29 26 22 16 12 9 9 5 3 1 0 0 0 E 37 31 28 18 17 13 12 12 9 7 7 4 2 1 0 Abstract 8005: Presented by TerufumiKato

24. Combination Treatments for EGFR Acquired Resistance Toxicity with Tarceva + AvastinJO25587 • No unforeseen toxicities or Rx-related deaths • Grade >3 toxicity 91% vs. 53% (esp. HTN, proteinuria) • 41% discontinued bevacizumab for adverse effects • Primarily proteinuria (15%) or hemorrhagic (12%) • Bevacizumab discontinuation rate 10-15% in BeTa, ATLAS trials

25. EGFR + NSCLC Trials-PFS (months) Combination Treatments for EGFR Acquired Resistance Med PFS (mo) JO25587- Tarceva5 JO25587- T/A5 LUX- Lung-33 LUX- Lung-64 EURTAC1 OPTIMAL2 1. Rosell et al. Lancet Oncol. 2012;13:239;11. Zhou et al. Lancet Oncol. 2011;12:735; 3. Sequistet al. J ClinOncol. 2013;31:3327; 4. Wu et al. Lancet Oncol. 2014;15:213; 5. Kato, Proc ASCO 2014, A#8005

26. Combination Treatments for EGFR Acquired Resistance What’s next? Akbay et al. Cancer Discovery 3:1355-1363, 2013

27. Combination Treatments for EGFR Acquired Resistance Summary • TWICE the opportunity for success, but TWICE the side effects • Upfront or after the development of • Acquired Resistance? • Future Directions: Tarceva + PDL-1 inhibitor?