The Rapidly Changing World of EGFR Mutation-Positive Acquired Resistance

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1 The Rapidly Changing World of EGFR Mutation-Positive Acquired Resistance H. Jack West, MD Swedish Cancer Institute Seattle, WA GRACE Targeted Therapies Forum September 16, 2017 Cleveland, OH

2 EGFR Mutation-Positive Acquired Resistance: Importance of T790M Yu, Clin Cancer Res, 2013

3 T790M+ Disease Prior to First-Line Therapy?

4 Is T790M Present Prior to First Line Therapy? Using highly sensitive techniques for finding T790M (not standard), it was seen in 25-31% of patients Su, JCO 2012 Associated with significantly shorter progression-free survival, even if activating mutation also seen Similar conclusions from MSKCC series, though de novo T790M mutations seen in only ~2% of >2000 cases tested Very short PFS if T790M+ at diagnosis Yu, Ann Oncol 2014

5 Afatinib (Gilotrif)/Cetuximab (Erbitux) Combination in Acquired Resistance Gilotrif is oral EGFR tyrosine kinase inhibitor (2 nd generation) Erbitux is IV antibody to EGFR receptor Lab work activity in T790M+ cancer cells Janjigian Cancer Discov, 2014

6 Gilotrif/Erbitux for Acquired Resistance: Response Rates & Duration of Response/PFS Janjigian Cancer Discov, 2014

7 Gilotrif/Erbitux for Acquired Resistance: Side Effect Profile Summary: It can be quite challenging for many patients.

8 Tagrisso (Osimertinib) for EGFR T790M+ Patients with Acquired Resistance

9 Third Generation EGFR TKIs Can Bind to T790M-Positive NSCLC Tagrisso (FDA approved 11/15) CO-1686/rociletinib (withdrawn 5/16) T790M EGFRm WT EGFR HM61713/BI ASP8273 EGF816 Cross, Cancer Discov 2014 Finlay, J Med Chem 2014 Inhibits EGFR activating mutations Inhibits T790M Low affinity with EGFR wild type (so lower rates of skin toxicity & diarrhea)

10 Osimertinib in EGFR T790M Mutation- Positive Acquired Resistance Objective Response Rate = 61% Jänne, N Engl J Med 2015

11 Osimertinib Tagrisso: Side Side Effect Effect Profile Profile (80 mg) All Grades Grade 3+ Diarrhea 33% 1% Rash 32% 0% Nausea 18% 0% Poor Appetite 16% 1% Itching 17% 0% Fatigue Objective Response Rate 10% = 51% 0% Paronychia 12% 0% Constipation 17% 0% Jänne, N Engl J Med 2015

12 AURA3 Trial: Tagrisso vs. Chemotherapy (2:1) in T790M+ Acquired Resistance Progression-Free Survival CNS Progression-Free Survival Mok, New Engl J Med, 2017 Mok, ASCO 2017 (A#9005)

13 Options for EGFR T790M- Patients with Acquired Resistance

14 Osimertinib (Tagrisso): EGFR T790M-Positive & -Negative Patients Jänne, N Engl J Med 2015

15 Tagrisso: Progression-Free Survival by T790M Status Jänne, N Engl J Med 2015

16 Tagrisso Response Rate by T790M Status (Central Test) T790M+ T790M- 68/105 43/69 25/36 11/50 3/28 8/22 *Includes confirmed responses and responses awaiting confirmation; # TKI therapy is defined as being immediately prior if TKI was the last regimen taken prior to the study, with no subsequent therapy. Population: all dosed centrally confirmed T790M+ and T790M- patients with a baseline RECIST assessment and an evaluable response, T790M+ N=105 (from 107 T790M+ patients with response data; two patients not included as subgroup missing), T790M- N=50 Jänne, ASCO 2014, A#8009

17 What About Tagrisso First Line? Endpoint 80 mg/d 160 mg/d Total Response rate 67% 87% 77% Med PFS (mo) % alive w/o % alive w/o 18 mo Ramalingam J Clin Oncol 2017

18 What if Everyone with an Activating EGFR Mutation Received Tagrisso as First Line Treatment? (FLAURA) Advanced NSCLC Activating EGFR Mut n No Prior Systemic Therapy N = 556 R A N D Primary endpoint Progression-Free Survival Standard of Care Iressa or Tarceva Tagrisso daily Crossover to Tagrisso OK If T790M+ PFS Ramalingam, ESMO 2017 (LBA2_PR)

19 FLAURA: Progression-Free Survival by Subgroups Ramalingam, ESMO 2017 (LBA2_PR)

20 FLAURA: Overall Survival (Interim Analysis) Ramalingam, ESMO 2017 (LBA2_PR)

21 FLAURA: Tolerability/Side Effect Profile (Leading Side Effects, in >15% of Patients) Ramalingam, ESMO 2017 (LBA2_PR)

22 IPASS: Iressa (Gefitinib) vs. Carbo/Paclitaxel as First Line Rx in Asian Never- or Light Ex-Smokers Advanced NSCLC No Prior Systemic Therapy Never-/Light Former Smoker N = 1217 Primary Endpoint: Progr-Free Survival (PFS) Biomarker analysis R A N D Carbo/Paclitaxel IV every 3 weeks Iressa (Gefitinib) daily Mok, NEJM 2009

23 IPASS: Objective Response Rate by EGFR Mutation Status 71.2% Gefitinib Carboplatin / paclitaxel Overall response rate (%) 47.3% EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.60), p= EGFR M- odds ratio (95% CI) = 0.04 (0.01, 0.27), p= % 1.1% (n=132) (n=129) (n=91) (n=85) Odds ratio >1 implies greater chance of response on gefitinib

24 But What About Immunotherapy??!!

25 Opdivo AZD9291: (nivolumab) Toxicity Summary in 2 nd Line Advanced NSCLC EGFR mut+ pts have numerically better survival with chemo than Opdivo No evidence of benefit from Opdivo in EGFR mut+ patients Borghaei, NEJM 2015

26 Keytruda in 2 nd Line Advanced NSCLC: Benefit by Subgroups Overall Survival Progression-Free Survival Herbst, Lancet 2016

27 Another FDA-Approved Option: Chemo Combined with Immunotherapy Borghaei, ESMO 2017

28 KEYNOTE-021G: Efficacy Progression-Free Survival Overall Survival Response Rate FDA approved for nonsquamous NSCLC (regardless of PD-L1 level) Borghaei, ESMO 2017

29 Implications in a Post-FLAURA World Tagrisso not yet FDA approved as 1 st line therapy, but likely soon Greater overall efficacy Better tolerability Control of brain metastases/protection vs. brain progression More effective and likely soon available to ALL patients But you lose effective second line option Options after progression on Tagrisso? No studied EGFR-directed option Possible biopsy-directed options MET (MET inhibitors crizotinib, tepotinib) EGFR C797S mutation (first line EGFR inhibitor like Iressa, Tarceva) small cell transformation standard chemo (commonly platinum-etoposide) Chemotherapy +/- immunotherapy is still potentially effective

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