Improving Therapy for EGFR-Mutant Lung Cancers Zosia Piotrowska, MD Instructor, Harvard Medical School Massachusetts General Hospital Cancer Center
Disclosures- Zofia Piotrowska Consulting- AstraZeneca, Ariad/Takeda, GuardantHealth • Research Funding (Institution)- Novartis •
Objectives Review the current understanding of resistance to third-generation EGFR inhibitors • and the role of cancer heterogeneity in the development of resistance. Define potential treatment strategies to overcome resistance to EGFR-targeted • therapy.
Classifying NSCLC in 2017 Mutation in > 1 gene - ROS1 Rearrangements**, 1-2% 2 - 3% RET1 Rearrangements*, 1-2% 2 - - MET exon 14 skipping*, ~5% 3 - NTRK1 Rearrangements*, <1% 4 Other - 20% MEK1 - <1% Others… MET amp* - 1% NRAS - 1% No oncogene driver Adenocarcino PIK3CA* - 1% detected - 35% ma - 50% Squamous BRAF* - 2% Cell Carcinoma - Her2* - 3% 30% EGFR (other)* - 4% ALK** - 9% KRAS* - 25% EGFR (sensitizing)** – 17% ** FDA-approved targeted 1. Kris et al, JAMA 2014 therapy available 2. Gainor and Shaw, Oncologist 2013 * Off-label or clinical trial 3. Heist et al, Oncologist 2016 targeted options 4. Farago et al, JTO 2015
The Concept of Oncogene Addiction Non-addicted case EGFR-Addicted EGFR IGFR EGFR gefitinib K-Ras P42/44 PI3K Jak/Stat MAPK PTEN PI3K MAPK Jak/Stat Slide courtesy of Lecia V Sequist Apoptosis EGFR mutant cancers are “ simple ” -one RTK controls all downstream signaling.
EGFR-mutant NSCLC: 2004 to 2017 WHAT’S NEXT? • Defining resistance to ERLOTINIB and AFATINIB- Plasma-based cobas v2 EGFR mutations described as osimertinib FDA approval for 1 st -line FDA approved as GEFITINIB- oncogenic drivers of NSCLC 1 • Combination therapies EGFRm+ NSCLC companion diagnostic FDA approval for 1 st - • Further improvement in for erlotinib (activating T790M Resistance line EGFRm+ NSCLC first-line therapy EGFR mutations) Mutation described 2 2003 2004 2005 2009 2013 2014 2015 2016 2017 2018 Ph1 studies of T790M-specific Plasma-based cobas v2 ERLOTINIB FDA approved 3 rd gen EGR TKIs start FDA approved as for NSCLC after failure of (osimertinib, rociletinib) companion diagnostic OSIMERTINIB- > 1 prior therapy FLAURA for osimertinib (T790M) FDA approval for second-line, First-line Osimertinib T790M+ EGFRm+ NSCLC 4 iPASS 3 GEFITINIB- accelerated FDA approval for NSCLC after failure of docetaxel (later lost full approval for this indication) 6 1. Lynch, et al. NEJM 2004; 2. Pao, et al. PLoS Medicine 2005; 3. Mok, et al. NEJM 2005; 4. Janne, et al. NEJM 2015.
Treatment of EGFR-mutant NSCLC iPASS (Mok T, et al. NEJM 2009) GEFITINIB 250 mg QD ENDPOINTS Stage IIIB/IV disease 1 o : PFS Chemo-naïve 1:1 2 o : ORR, OS, R Adenocarcinoma Symptoms, QoL Never/light-smokers CARBOPLATIN (AUC 5/6) ECOG PS 0-2 PACLITAXEL 200mg/m2 IV q21 days (x6) *Patients were not selected based on EGFR status, but factors that enriched for EGFR + disease ** EGFR status was analyzed post- hoc
The iPASS Trial: gefitinib vs. first-line chemotherapy HR 0.48 HR 2.85 EGFR inhibitors improve PFS among EGFR-mutants, but not among those without EGFR mutations. Molecular testing is key to selecting therapy. 8 Mok et al, NEJM 2009
Study N Arms Response Med PFS HR Rate (%) (mo) IPASS 261 Gefitinib 71% 9.6 0.48 (.36, .64) NEJM ‘ 09 Carbo/taxol 47% 6.3 WJTOG 228 Gefitinib 62% 9.2 0.49 (.35, .71) 3405 Cis/docetaxel 31% 6.3 Lan Onc ‘ 10 Despite significant advances, the median PFS for all three NEJ 002 194 Gefitinib 74% 10.4 0.36 (.25, .51) EGFR TKIs (erlotinib, gefitinib, afatinib) used in the the first NEJM ‘ 09 Carbo/taxol 31% 5.5 OPTIMAL line setting remains between 9-13 months. 165 Erlotinib 83% 13.1 0.16 (.10, .26) Lan Onc ‘ 11 Carbo/gem 36% 4.6 EURTAC 174 Erlotinib 58% 9.7 0.37 (.25, .54) Lan Onc ’ 12 Cis or carbo + 15% 5.2 doce or gem LUX-Lung 3 345 Afatinib 69% 11.1 ( 13.6) 0.58 (.43,.78) JCO ‘ 13 Cis/pem 44% 6.9 ( 6.9 ) 0.47 (.34,.65) 9
Management of EGFR-mutant NSCLC Initial Diagnosis First-Line Therapy Second-Line Therapy EGFRm+ NSCLC - Exon 19 deletion Erlotinib NSCLC in mPFS - L858R ? Gefitinib - Other (G719X, 2016 9-13 mo Afatinib S768I) 10
A personalized approach to overcoming resistance to targeted therapy CLINICAL PROGRESSION TARGETED THERAPY BIOPSY MOLECULAR ANALYSIS 11
Resistance mechanisms observed upon initial resistance to EGFR TKI therapy (n=258) T790M + EGFR Amp – 15% (1 w/ PIK3CA, 2 w/ HER2 Amp) EGFR Amp - 4% T790M - 44% MET Amp – 5% (1 with PIK3CA) (2 w/ PIK3CA, 3 w/ EGFR Amp 1 w/ EGFR + HER2 Amp) SCLC Transformation – 3% (4 with PIK3CA) Overall T790M- PIK3CA - 2% positive: No Identified Mechanism 23% BRAF - 1% 59% Not tested/Insufficient- 3% Serial biopsies highlight heterogeneity in EGFR-mutant NSCLC, Presented by Zofia Piotrowska 7/13
103 patients with 2 post-resistance biopsies T790M “Gain” (11%) T790M “Loss” (24%): T790-WT T790-positive MET amp SCLC Transformation BRAF • 103 patients had 2 biopsies performed during their post-resistance course. • 56/103 (54%) had variations in the resistance mechanisms identified between biopsy 1 and 2. • 24% patients “lost” T790M between biopsy 1 and 2, while 11% “gained” T790M. • Of the 25 pts who lost T790M, 7 had a new resistance mechanism identified on the second biopsy • 1 patient had an acquired BRAF V600E mutation on biopsy two • 5 patients developed MET amplification on biopsy two • 1 patient developed SCLC transformation on biopsy two Serial biopsies highlight heterogeneity in EGFR-mutant NSCLC, Presented by Zofia Piotrowska 9/13
T790M “positive” tumors can be heterogeneous Exon 19 Deletion Clone 2 * Exon 20 T790M Exon 19 Deletion Clone 6 Exon 20 T790 WT T790M Status Total Clones Wild-type 3 of 8 (38%) Mutant 5 of 8 (62%) Piotrowska Z, et al. Cancer Discovery, July 1, 2015 5; 713. 14
Targeting T790M- Osimertinib 15
AURA3 - Osimertinib vs. Platinum-Pemetrexed Mok TS, et al, NEJM 2016 16
Resistance mechanisms observed upon initial resistance to EGFR TKI therapy (n=258) T790M + EGFR Amp – 15% (1 w/ PIK3CA, 2 w/ HER2 Amp) EGFR Amp - 4% T790M - 44% MET Amp – 5% (1 with PIK3CA) (2 w/ PIK3CA, 3 w/ EGFR Amp 1 w/ EGFR + HER2 Amp) SCLC Transformation – 3% (4 with PIK3CA) Overall T790M- PIK3CA - 2% positive: No Identified Mechanism 23% BRAF - 1% 59% Not tested/Insufficient- 3% Serial biopsies highlight heterogeneity in EGFR-mutant NSCLC, Presented by Zofia Piotrowska 7/13
Overcoming non-T790M resistance MET amplification (~5%): • – Erlotinib + Crizotinib – Clinical trials • Osimertinib + Savolitinib (AZD6094) – TATTON (NCT02143466) • EGF816 + Capmatinib (INC280) - NCT02335944 Gainor J, et al, JTO 2016 18
Overcoming non-T790M resistance Histologic transformation to SCLC • – SCLC Transformed cancers lose expression of/dependence upon EGFR – Genetic loss of Rb1, which appears to be necessary but not sufficient to cause the transformation – Patients can respond to Platinum + Etoposide chemotherapy Niederst, Nat Comm 2015 19
Management of EGFR-mutant NSCLC Third-Line Initial Diagnosis First-Line Therapy Second-Line Therapy Therapy EGFRm+ NSCLC T790M+ : Osimertinib NSCLC - Exon 19 deletion Erlotinib - L858R MET amp : EGFR + MET TKI in ? Gefitinib - Other (G719X, SCLC: Platinum/Etoposide Afatinib 2016 S768I) Other: Carboplatin/Pemetrexed 20
Resistance to 3 rd generation EGFR TKIs Heterogeneity Plays an Important Role in Development of Resistance Others: BRAF V600E mutations FGFR3 Piotrowska, et al. Cancer Discov 2015, Yu, et al. JAMA Oncol 2015, KRAS Thress, et al. Nat Med 2015 Piotrowska, Sequist, JAMA Onc 2016 21
Heterogeneity may play an increasing role in resistance Overlapping resistance mechanisms to rociletinib detected in ctDNA Chabon, et al Nat Comm 2016 22
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EGFR C797S mediates resistance to osimertinib Niederst, et al. Clinical Cancer Research 2015 Piotrowska Z, et al. WCLC 2017
Potential Strategies to Overcome EGFR C797S Brigatinib (EGFR/ALK Tyrosine Kinase Inhibitor) + EGFR mAb EAI045 (Allosteric EGFR Inhibitor) + EGFR mAb Uchibori, et al. Nature Communications 2017. Jia Y, et al. Nature 2016
Management of EGFR-mutant NSCLC Initial Diagnosis First-Line Therapy Second-Line Therapy Third-Line Therapy EGFRm+ NSCLC T790M+ : Osimertinib NSCLC Erlotinib Chemotherapy - Exon 19 deletion in Gefitinib Clinical Trials - L858R MET amp : EGFR + MET TKI - Other (G719X, SCLC: Platinum/Etoposide Afatinib Afatinib/Cetuximab 2016 S768I) Other: Carboplatin/Pemetrexed 26
Management of EGFR-mutant NSCLC Initial Diagnosis First-Line Therapy Second-Line Therapy Third-Line Therapy EGFRm+ NSCLC T790M+ : Osimertinib Erlotinib Chemotherapy - Exon 19 deletion 2016 Gefitinib Clinical Trials - L858R MET amp : EGFR + MET TKI - Other (G719X, SCLC: Platinum/Etoposide Afatinib Afatinib/Cetuximab S768I) Other: Carboplatin/Pemetrexed EGFRm+ NSCLC - Exon 19 deletion Osimertinib ? - L858R - Other (G719X, S768I) 27
Improving front-line therapy for EGFR-mutant NSCLC Ramalingam S, et al. ESMO 2017.
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