Management Strategies for Lung Cancer Sensitive or Resistant to EGRF Inhibitors

Transcription

1 Management Strategies for Lung Cancer Sensitive or Resistant to EGRF Inhibitors Conor E. Steuer, MD Assistant Professor The Winship Cancer Institute of Emory University July 27,

2 Lung Cancer One of the most common cancers and leading cause of cancer deaths New cases, 2016 (estimated): US, 224,390 Deaths, 2016 (estimated): US, 158,080 5-yr US survival rates Overall: 18% Metastatic: 4% Siegel RL, et al. CA Cancer J Clin. 2016;66(1):7-30. National Cancer Institute. SEER 2

3 Advances in NSCLC Therapies Chemotherapy-Histology Matters! (i.e. Alimta and Avastin for Adenocarcinomas) Checkpoint Inhibitors- Nivolumab, Pembrolizumab, Atezolizumab Targeted Therapy- FDA approved therapies for EGFR, ALK, ROS1, and possibly more coming 3

4 Epidermal Growth Factor Receptor EGFR is a glycoprotein that plays a complicated role in signal transduction and cellular processes and important in tumorigenesis Significant research was performed examining the role of EGFR in NSCLC Nyati MK, et al. Nat Rev Cancer. 2006;6(11): Shin DM, et al. Cancer Res. 1994;54(12): Brabender J, et al. Clin Cancer Res. 2001;7(7):

5 The EGFR TKIs Erlotinib and gefitinib are EGFR tyrosine kinase inhibitors that reversibly bind to the ATP binding site, inhibiting downstream signaling Moyer JD, et al. Cancer Res. 1997;57(21):

6 BR.21- Erlotinib in NSCLC Randomized, phase 3 clinical trial for NSCLC patients who had progressed on at least 1 line of therapy Patients received either erlotinib 150mg daily or placebo 731 patients underwent randomization, UNSELECTED by EGFR status Median age was 61.4 years, 49 percent had received two prior chemotherapy regimens, and 93 percent had received platinum-based chemotherapy. Shepherd FA, et al. N Engl J Med. 2005;353(2):

7 BR.21 Results Overall survival: 6.7 months (erlotinib) vs. 4.7 months (placebo) (P<0.001) FDA approval 2004 Asian ethnicity, women, adenos, lifetime nonsmokers, and tumors that expressed EGFR in 10% of cells had improved response rates Shepherd FA, et al. N Engl J Med. 2005;353(2): Pérez-Soler R, et al. J Clin Oncol. 2004;22(16):

8 EGFR mutation predicts sensitivity to EGFR TKI A) L858R mutations in exon 21 B) G719S mutant in P-loop (exon 18) C) Deletion mutants in EGFR exon 19 Paez JG, et al. Science. 2004;304(5676):

9 EGFR Mutations in NSCLC Found in 10% to 40% of NSCLC pts More common in never-smokers, adenocarcinomas, females, Asians Predominantly located in EGFR exons ~ 85% of EGFR mutations are either deletions in exon 19 or a single-point mutation in exon 21 (L858R) Specific EGFR mutation identified is important Some mutations (exon 20 insertions) are primarily resistant to EGFR inhibition Pao W, et al. J Clin Oncol. 2005;23(11): Wu YL, et al. J Thorac Oncol. 2007;2(5):

10 EGFR Mutation Prevalence Arcila ME, et al. Mol Cancer Ther. 2013;12(2):

11 The IPASS study First large, randomized phase 3 trial of an EGFR TKI in a selected NSCLC population East Asian, never- or former light-smokers with metastatic lung adenocarcinoma No prior systemic treatment 1217 pts randomized to either gefitinib or platinum-doublet chemotherapy Mok TS, et al. N Engl J Med. 2009;361(10):

12 Progression Free Survival Mok TS, et al. N Engl J Med. 2009;361(10):

13 1st and 2nd generation EGFR TKI trials Regimen ORR Median PFS Median OS Study Year TKI (N) Chemo (N) Mok et al. 18, Gefitinib (132) Carbo-Taxol (129) TKI (%) Chem o (%) TKI (months) Chemo (months) TKI (months) Chemo (months ) Mitsudomi 2010 Gefitinib et al. 21, 55 (86) Maemondo 2010 Gefitinib et al. 20 (114) Zhou et 2011 Erlotinib al. 56, 57 (83) Rosell et 2012 Erlotinib al. 19 (86) Sequist et al. 22, Afatanib (230) Wu et al. 58, 2014 Afatanib 59 (242) Cis- Taxotere (86) Carbo-Taxol (114) Carbo-Gem (82) Platinum Doublet (87) Cis-Pem (115) Cis-Gem (122) Steuer CE, et al. Mol Aspects Med. 2015;45:

14 Improved QoL With First-line EGFR TKI vs. Chemotherapy IPASS: Gefitinib vs platinum-based doublet chemotherapy showed improvement with FACT-L NEJ002: Gefitinib vs platinum-based doublet chemotherapy showed improvement assessed with Care Notebook First Signal: Gefitinib vs platinum-based doublet chemotherapy showed improvement assessed with EORTC QoL C30 and Lung Cancer-13 questionnaires OPTIMAL: Erlotinib vs platinum-based doublet chemotherapy showed improvement in FACT-L and LCS scores Lux-Lung-3: Afatinib vs platinum-based doublet chemotherapy showed statistically significant delay in time to deterioration of cough, dyspnea; improvement in dyspnea scores, and cognitive, and physical role functions assessed by EORTC QoL C30 and Lung Cancer-13 questionnaires Slide credit: clinicaloptions.com Thongprasert S, et al. J Thorac Oncol. 2011;6(10): Oizumi S, et al. Oncologist. 2012;17(6): Han JY, et al. J Clin Oncol. 2012;31(10): Chen G, et al. Ann Oncol. 2013;24(6): Yang JC, et al. J Clin Oncol. 2013;31(127):

15 Adverse Events Landi L, et al. Transl Lung Cancer Res. 2013;2(!):

16 Does the specific TKI matter? LUX-Lung 7- afatinib vs. gefitinib first line in metastatic EGFRm patients Grade 3 AE(afatinib vs gefitinib) Diarrhea: 12.5% vs 1% Rash/acne: 9% vs 3% Fatigue: 6% vs 0 Increased ALT/AST: 0 vs 9% Dose reductions more common with afatinib (42% vs 2%) Drug discontinuation same (6%) in each arm Median PFS 11m (a) vs 10.9m (g) No sig. OS difference Park K, et al. Lancet Oncol. 2016;17(5):

17 Dacomitinib Mok T, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA

18 Dacomitinib Mok T, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA

19 Dacomitinib Mok T, et al. J Clin Oncol. 2017;35(suppl): Abstract LBA9007. Dose Modification Dacomitinib 66% vs. Gefitinib 8% 19

20 Does the specific mutation matter? Exon 19 del Exon 21 L858R Exon 21 insertions treated with EGFR TKI Yang JC, et al. J Clin Oncol. 2013;31(127): Naidoo J, et al. Cancer. 2015;121(18):

21 Adjuvant Erlotinib-RADIANT Patients with completely resected IB to IIIA NSCLC were treated with either placebo or erlotinib for 2 years. Primary endpoint- DFS EGFRm patients were a subgroup analysis NO difference in PFS or OS Kelly K, et al. J Clin Oncol. 2015;33(34):

22 ADJUVANT study design (NCT ) Wu Y-L, et al. J Clin Oncol. 2017;35(suppl): Abstract

23 Primary endpoint: DFS (ITT population) Wu Y-L, et al. J Clin Oncol. 2017;35(suppl): Abstract No PET required for n2 disease About 20% of patients refused chemotherapy No OS data 23

24 Progression on EGFR TKI? What to do if: Slow, asymptomatic progression of disease? Oligometastatic progression, esp. CNS? REAL progression 24

25 Slow/Oligo Progression 10 patients who progressed on erlotinib or gefitinib, then had the TKI discontinued, had scans 3 weeks later: median 10% growth of tumor, 70% of patients had increased symptoms After restarting TKI, decrease in tumor size in 80% of pts Approximately 20% of patients undergoing wash-out of EGFR TKI experience a tumor flare In one study, 18 patients with oligometastatic progression who got local treatment had a median time to treatment change of 22 months Riely GJ, et al. Clin Cancer Res. 2007;13(17): Chaft JE, et al. Clin Cancer Res. 2011;17(19): Yu HA, et al. J Throac Oncol. 2013;8(3):

26 EGFR Tumor Flare Riely GJ, et al. Clin Cancer Res. 2007;13(17):

27 Cisplatin/Pemetrexed ± Gefitinib in EGFRm pts who progressed on TKI Outcome Gefitinib (n = 133) Placebo (n = 132) Median PFS, mos Median OS, mos HR 0.86 (P =.27) 1.62 (P =.03) Soria JC, et al. Lancet Oncol. 2015;16(8):

28 Resistance to EGFR-directed therapy Camidge DR, et al. Nat Rev Clin Oncol. 2014;11(8):

29 T790M Represents the resistance mechanism to EGFR TKI therapy for approximately 50-60% of patients Average time to 1st and 2nd gen EGFR TKI resistance is 9-13 months The substitution of threonine to a bulky methionine at amino acid position 790 (T790M) in exon 20 of the EGFR gene creates steric hinderance in the ATP binding domain of EGFR Remon J, et al. Ann Oncol. 2017;28(4):

30 What to do if tissue biopsy is not feasible? Liquid Biopsy for ctdna Retrospective study demonstrated similar t790m detection for liquid as tissue biopsies (50%) In patients with both liquid and tissue samples (n=25), 20% were only positive in blood testing In a prospective trial of osimertinib, T790M-positivity in plasma achieved an ORR of 62.5% and 6-months PFS 66.7% (similar to tissue) Sandaresan TK, et al. Clin Cancer Res. 2016;22(5): Remon J, et al. Ann Oncol. 2017;28(4):

31 Osimertinib Only FDA approved 3 rd generation EGFR TKI Targets both the original EGFRm and T790M EGFR EGFR EGFR EGFR (L858R/T790M) (L858R) (L861Q) (wildtype) Osimertinib Afatinib 3 <1 <1 3 Gefitinib 155 <1 <1 3 Cross DA, et al. Cancer Discov. 2014;4(9):

32 Osimertinib AURA ph I AURA Extension (T790M+) AURA2 (T790M+) AURA3 (T790M+) Osimertinib vs. CT N 253 (T790M +: 138) ORR 51% T790M+: 61% T790M-: 21% PFS 8.2 months (mo.) T790M+: 9.6 mo. T790M-: 2.8 mo % 70% 71% vs. 31%, p< mo 9.9 mo 10.1 vs. 4.4 mo., HR 0.30; 95% CI, , p< Remon J, et al. Ann Oncol. 2017;28(4): Goss G, et al. Lancet Oncol. 2016;17(12):

33 Osimertinib Mok TS, et al. N Engl J Med. 2017;376(20):

34 Resistance to Osimertinib Despite its efficacy, patients inevitably progress In a study of T790M EGFRm cell lines, the C797S mutation disrupted covalent bonding between osimertinib and the cysteine residue at the ATP-binding domain of EGFR Confirmed in patient samples. Other resistance mecanisms: BRAF V600E, KRAS Q61K, FGFR3 fusion, transformations to small cell lung cancer Mechanism of resistance to Osimertinib in frontline EGFRm (T790M-) unclear at this time Oxnard GR, et al. Presented at: American Association of Cancer Research Annual Meeting. April 4-5, Washington, DC. Abstract

35 Resistance to Osimertinib Piotrowska Z, et al. J Clin Oncol. 2017;35(suppl): Abstract

36 FLAURA Study Patients with EGFRm+ locally advanced or metastatic NSCLC who are treatment-naïve and eligible to receive first-line treatment with approved EGFR- TKI. AZD mg orally once daily (n=325) EGFR-TKI orally once daily (n=325) Progression 36

37 Immunotherapy in EGFR Gainor JF, et al. Clin Cancer Res. 2016;22(18): Lee CK, et al. J Thorac Oncol. 2017;12(2):

38 Thank you! 38