EGFR Mutation-Positive Acquired Resistance: Dominance of T790M
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1 Treatment of EGFR Mutation-Positive Acquired Resistance: T790M+ or T790M- H. Jack West, MD Swedish Cancer Institute, Seattle, WA EGFR Mutation-Positive Acquired Resistance: Dominance of T790M Yu, Clin Cancer Res, 2013
2 T790M+ Disease Prior to First-Line Therapy? Is T790M Present Prior to First Line Therapy? Su, JCO 2012 Using highly sensitive techniques for finding T790M (not standard), it was seen in 25-31% of patients Associated with significantly shorter progression-free survival, even if activating mutation also seen Yu, Ann Oncol 2014 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
3 Avastin with Tarceva as First Line Treatment for T790M+ Disease: The BELIEF Study Tarceva (erlotinib) 150 mg daily + Avastin (becavizumab) 15 mg/kg IV every 3 weeks 109 pts, 37 (34%) with T790M at diagnosis, detected by highly sensitive test; 72 (66%) without T790M Response rate 70.3% for T790M+, 79.2% for T790M- Median progression-free survival 16 mo in T790M+; 1 yr PFS 72.4% Median PFS 10.5 mo in T790M-, 1 yr PFS 49% Median duration of response overall 14.8 mo, not reached in T790M+, and 12 mo for T790M- Stahel, ESMO 2015, A#3BA Spanish Lung Cancer Group (SLCG) & European Thoracic Oncology Platform (ETOP) Tarceva +/- Avastin in Japanese Patients with an Activating EGFR Mutation: JO25587 Trial Advanced NSCLC EGFR Mut n (exon 19/21) No prior therapy N = 152 treated R A N D Tarceva150 mg PO daily + Avastin IV every 3 weeks until progression/prohibitive toxicity Tarceva 150 mg PO daily + until progression/prohibitive toxicity Primary endpoint: Progression-Free Survival EB E P Seto, Lancet Oncol 2014 ORR (CR/PR) 69% 64% ns DCR (CR/PR/SD) 99% 88% 0.018
4 Tarceva +/- Avastin in Japanese Patients with an Activating EGFR Mutation: Progression-Free Survival 6.3 mo Seto, Lancet Oncol 2014 Erlotinib +/- Bevacizumab in Japanese Patients with an Activating EGFR Mutation: Overall Survival (Prelim) 6.3 mo Seto, Lancet Oncol 2014
5 Toxicity Issues with Erlotinib/Bevacizumab on JO25587 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 Difference? Greater toxicity in Japanese population? Greater toxicity in EGFR mutation-positive? Longer duration of therapy à higher risk of ADRs Seto, Lancet Oncol 2014 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 à 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 Gilotrif/Erbitux for Acquired Resistance: Side Effect Profile Summary: It can be quite challenging for many patients. Janjigian Cancer Discov, 2014
7 New Options for EGFR T790M+ Patients with Acquired Resistance Chemotherapy +/- Ongoing EGFR TKI for Acquired Resistance: IMPRESS Trial Mok, WCLC 2015 Activating EGFR mutation Progression on gefitinib No prior chemotherapy N = 265 R A N D Primary endpoint: progression-free survival PFS in T790M+ Cisplatin/Pemetrexed Cisplatin/Pemetrexed + ongoing gefitinib OS in T790M+
8 Third Generation EGFR TKIs Overcome Steric Hindrance of Binding to T790M-Positive NSCLC AZD9291/osimertinib (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) Osimertinib (Tagrisso) in EGFR Mutation- Positive Acquired Resistance Objective Response Rate = 51% Jänne, N Engl J Med 2015
9 Tagrisso in EGFR T790M Mutation- Positive Acquired Resistance Objective Response Rate = 61% Jänne, N Engl J Med 2015 Tagrisso: Progression-Free Survival by T790M Status Jänne, N Engl J Med 2015
10 Tagrisso Side Effect Profile (80 mg) All Grades Grade 3+ Diarrhea 33% 1% Rash 32% 0% Nausea 18% 0% Poor Appetite 16% 1% Itching 17% 0% Fatigue 10% 0% Paronychia Objective Response Rate = 12% 51% 0% Constipation 17% 0% Jänne, N Engl J Med 2015 Tagrisso as First-Line Therapy in EGFR Mutation-Positive NSCLC? Rolling six design Escalation Expansion Cohort 1 20 mg Positive Cohort 2 40 mg Positive Negative Cohort 3 80 mg Positive Negative First-line EGFRm 80 mg Biopsy Cohort mg Positive Negative First-line EGFRm 160 mg Biopsy Cohort mg Positive T790M cohorts Tablet Cytology Ramalingam, ELCC 2016, A# LBA1_PR.
11 First Line Tagrisso Best Percentage Change From Baseline In Target Lesion Size (%) D D D Ramalingam, ELCC 2016, A# LBA1_PR. D D D D D D D D D D D D D D D First-line 80 mg First-line 160 mg D D D 80 mg n= mg n=30 Total N=60 Confirmed ORR 67% (95% CI: 47, 83) 87% (95% CI: 69, 96) 77% (95% CI: 64, 87) Disease control rate* 93% (95% CI: 78, 99) 100% (95% CI: 88, 100) 98% (95% CI: 89, 100) Best objective response Complete response Partial response Stable disease 6 weeks Progressive disease First Line Tagrisso: Duration of Response The DoR for patients with de novo T790M-positive tumor status was similar to the overall population (n=6, range: mo, mo) Median DoR,* months (95% CI) 80 mg n=20 NC (12.2, NC) 160 mg n= (9.7, NC) Total n=46 NC (12.5, NC) Maximum DoR, months 22.1 ongoing 18.0 ongoing 22.1 ongoing Remaining in response, % (95% CI) 12 months 18 months 79 (52, 91) 56 (31, 75) Ramalingam, ELCC 2016, A# LBA1_PR. 71 (48, 85) NC 74 (58, 85) 53 (36, 67)
12 Rociletinib in EGFR Mutation-Positive Acquired Resistance T790M+ NSCLC T790M- NSCLC ORR = 59%* *unconfirmed Sequist, New Engl J Med 2015 Rociletinib: Adverse Events at Therapeutic Dose Sequist, New Engl J Med 2015
13 Best Response in Serum T790M-Positive NSCLC Serum T790M-positive is as predictive of response as tissue T790M-positive Sequist, ASCO 2015 Rociletinib s Nosedive: Confirmed vs. Unconfirmed Responses 500 mg BID 625 mg BID N (ITT/T790M-Positive) Type of assessment INV IRR INV IRR Confirmed ORR, % % CI Median DOR, months % CI NR ODAC review April 12, against approval without TIGER-3 randomized trial results vs. placebo May 5, 2016 Clovis announces FDA gives Complete Response Letter (no approval) closes all rociletinib trials lays of 35% of employees
14 Benefit from Tagrisso after Rociletinib? 9 patients rec d osimertinib after rociletinib 6 transitioned directly 7 of 9 show PR (3) or prolonged duration of SD (4) Intracranial responses of brain mets developed on rociletinib also seen, w/o radiation Important proof of principle (& I ve seen it work myself!) Potentially relevant for patients stopping rociletinib Sequist, JAMA Onc 2015 HM61713/BI T790M+ N = 48 Duration of Response ELUXA 1: Phase II in T790M+ (N=150) Kim, ASCO 2014, A#8011
15 Conclusions on EGFR T790M+ Advanced NSCLC Third gen EGFR TKIs w/selective binding to T790M very active in EGFR T790M+ acquired resistance Relative sparing of EGFR wt à fewer side effects Toxicity profiles vary significantly among third gen EGFR TKIs Efficacy across class, but only Tagrisso FDA approved; will other agents emerge superior? Rociletinib: gone but not forgotten HM61713/BI ASP8273 EGF816 Key issues Critical need to test for T790M at time of acquired resistance Transition at earliest evidence of PD or after more significant PD? Will they move into first line for all EGFR mutation+ patients? Options for EGFR T790M- Patients with Acquired Resistance
16 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 R A N D Primary Endpoint: Progr-Free Survival (PFS) Biomarker analysis Carbo/Paclitaxel IV every 3 weeks Iressa (Gefitinib) daily Mok, NEJM 2009 IPASS: Objective Response Rate by EGFR Mutation Status Gefitinib 71.2% Carboplatin / paclitaxel EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.60), p= Overall response rate (%) 47.3% EGFR M- odds ratio (95% CI) = 0.04 (0.01, 0.27), p= % 1.1% (n=132) (n=129) (n=91) (n=85)
17 Chemotherapy +/- Ongoing EGFR TKI for Acquired Resistance: IMPRESS Trial Activating EGFR mutation Progression on gefitinib No prior chemotherapy N = 265 R A N D Primary endpoint: progression-free survival PFS in T790M- PFS in T790M-Positive Cisplatin/Pemetrexed Cisplatin/Pemetrexed + ongoing gefitinib Disease control rate in T790M neg: 93.5% (chemo + Iressa) vs 83.1% (chemo + placebo) Mok, WCLC 2015 MISSION Trial of Sorafenib vs. Placebo: PFS based on EGFR mutation status Patients with EGFR mut (in tumor or plasma) Sorafenib N=44; Placebo N=45 HR=0.27 (95% CI 0.16,0.46) P-value<0.001 Sorafenib median PFS= 2.7 mo (83d) Placebo median PFS= 1.4 mo (42d) Patients with EGFR wild type Sorafenib N=122; Placebo N=136 HR=0.62 (95% CI 0.48,0.82) P-value<0.001 Sorafenib median PFS= 2.7 mo (82d) Placebo median PFS= 1.5 mo (46d) Biomarker*treatment interaction analysis: p-value=0.015 Mok, ESMO 2012
18 MISSION Trial of Sorafenib vs. Placebo: OS based on EGFR mutation status Patients with EGFR mut (in tumor or plasma) Sorafenib N=44; Placebo N=45 HR=0.48 (95% CI 0.3,0.76) P-value=0.002 Sorafenib median OS= 13.9 mo (423d) Placebo median OS= 6.5 mo (197d) Patients with EGFR wild type Sorafenib N=122; Placebo N=136 HR=0.92 (95% CI 0.7,1.21) P-value=0.559 Sorafenib median OS= 8.3 mo (253d) Placebo median OS= 8.4 mo (256d) Biomarker*treatment interaction analysis: p-value=0.023 Mok, ESMO 2012 Osimertinib (Tagrisso): EGFR T790M-Positive & -Negative Patients Jänne, N Engl J Med 2015
19 Tagrisso Response Rate by T790M Status (Central Test) T790M+ T790M- 68/105 43/69 25/36 11/50 3/28 8/22 Jänne, ASCO 2014, A#8009 *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 Tagrisso Progression-Free Survival by T790M Status (Central Test) Probability of progression-free survival Patients at risk T790M+ T790M- 0 T790M+ (95% CI) T790M- (95% CI) Study week Jänne, ASCO 2014, A#8009
20 Rociletinib: EGFR T790M+ vs. T790M- T790M+ NSCLC T790M- NSCLC Sequist, New Engl J Med 2015 But What About Immunotherapy??!!
21 Opdivo (nivolumab) 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 Efficacy of Keytruda (Pembrolizumab) in Advanced NSCLC: Overall and EGFR Mut+ KEYNOTE-001 Trial ORR (95% CI) PD-L1 50% (n=20) PD-L1 1% 49% (n=23) PD-L1 <1% (n=14) Overall* (n=77) Overall population 38.2% (30.2, 46.7) n= % (7.6, 17.4) n= % (4.4, 18.8) n= % (16.9, 23.8) n=550 EGFRm subgroup 20% (5.7, 43.7) n=20 8.7% (1.1, 28.0) n=23 0.0% (0.0, 23.2) n=14 7.8% (2.9, 16.2) n=77 Response rate 0% in PD-L1 negative patients In each subgroup, response rate is lower in EGFR mutationpositive patients than in overall patient population Hellman, WCLC 2015; Mini 03.05
22 Efficacy of Keytruda (Pembrolizumab) in Advanced NSCLC: Overall and EGFR Mut+ KEYNOTE-001 Trial TPS 50% (n=20) TPS 1% 49% TPS <1% OS* n/n Median, months (95% CI) n/n Median, months (95% CI) n/n Median, months (95% CI) Overall population 138/ (10.6, 18.5) 168/ (6.0, 12.7) 90/ (5.5, 12.0) EGFR WT population 62/ (11.1, NR) 152/ (9.2, 15.4) 51/ (5.8, 13.6) EGFRm subgroup 17/ (2.0, 13.7) 37/ (4.4, 12.6) 11/ (2.2, NR) Disappointing survival in EGFR mut+ pts receiving Keytruda Hellman, WCLC 2015; Mini Keytruda in 2 nd Line Advanced NSCLC: Benefit by Subgroups Overall Survival Progression-Free Survival Herbst, Lancet 2016
23 Conclusions on EGFR T790M- Advanced NSCLC Chemotherapy has significant activity Some studies show chemo efficacy far greater in EGFR mut+ pts Not just a meaningless consolation prize Still debatable whether EGFR inhibitors should continue with initiation of chemo for some patients (perhaps EGFR T790M-) Afatinib/cetuximab is a possibility, but toxicity challenging Third gen EGFR TKIs with selective binding to T790M show limited activity in EGFR T790M- acquired resistance Immunotherapy less compelling, at least as single agent Clinical trials looking at T790M-negative
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