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Targeted Therapy for Metastatic NSCLC

Targeted Therapy for Metastatic NSCLC. Gregory J. Riely October 14, 2012. Disclosures. Consulting Chugai Ariad Tragara Daiichi Novartis Abbott Foundation Medicine Celgene. Research Funding Novartis Chugai Glaxo SmithKline BMS Infinity Pfizer Merck. Lung Adenocarcinomas.

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Targeted Therapy for Metastatic NSCLC

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  1. Targeted Therapy for Metastatic NSCLC Gregory J. Riely October 14, 2012

  2. Disclosures Consulting Chugai Ariad Tragara Daiichi Novartis Abbott Foundation Medicine Celgene Research Funding Novartis Chugai Glaxo SmithKline BMS Infinity Pfizer Merck

  3. Lung Adenocarcinomas 35% Unknown 2012

  4. Epidermal Growth Factor Receptor signaling erlotinib gefitinib Pao, W. et al. JCO 23:2556-2568 2005

  5. Randomized Trial of Erlotinib in non-small cell lung cancer • Stage IIIB/IV NSCLC • PS 0–3 • 1-2 prior therapies erlotinib + supportive care placebo + supportive care Shepherd FA, et al. N Engl J Med. 2005;353:123-132.

  6. Randomized Trial of Erlotinib in non-small cell lung cancer Response Rate 9% Shepherd et al NEJM 353:123-132

  7. Why Are 1 in 10 Like This? Day 1 Day 5

  8. How could we predict who would respond to erlotinib? • Adenocarcinoma • Never Smokers • Women • Asian

  9. Epidermal Growth Factor Receptor

  10. EGFR mutations predict response to EGFR TKI

  11. EGFR TKI vs Carboplatin - Paclitaxelin Never- or Light Ex-Smokers (IPASS) • Measurable Stage IIIB or IV • Adenocarcinoma histology • No prior chemotherapy • PS 0-2 • <100 cigarettes/lifetime or <10 pack- years and stopped ≥15 years prior R A N D O M I Z E Gefitinib 250 mg/day Carboplatin AUC 5 or 6 Paclitaxel 200 mg/m2 q3wk (max 6 cycles) Mok T et al. N Engl J Med. 2009

  12. EGFR TKI vs Carboplatin-Paclitaxel Mok T et al. N Engl J Med. 2009 Mok TS, et al. N Engl J Med. 2009;361(10):947-957.

  13. Mok et al NEJM 2009, Maemondo et al NEJM 2010, Mitsudomi et al Lancet Oncol 2010, Rosell et al Lancet Oncol 2012

  14. EGFR mutation testing • Requires tissue (5-15 unstained slides) • No single “correct” way • Direct Sequencing • “Snapshot” • “Sequenom” • Next Gen Sequencing (Foundation Medicine, Hiseq, Ion Torrent, etc.) • Most important thing is to have adequate tissue and send the test

  15. In patients with stage IV EGFR mutant lung cancer, an EGFR TKI is standard in first-line Mok et al NEJM 2009, Maemondo et al NEJM 2010, Mitsudomi et al Lancet Oncol 2010, Rosell et al Lancet Oncol 2012

  16. In patients with stage IV EGFR mutant lung cancer, an EGFR TKI is standard in first-line But median PFS ~12 months Mok et al NEJM 2009, Maemondo et al NEJM 2010, Mitsudomi et al Lancet Oncol 2010, Rosell et al Lancet Oncol 2012

  17. Afatinib: an irreversible ErbB Family Blocker Li D, et al. Oncogene 2008;27:4702–11. • Afatinib is an oral, irreversible ErbB Family Blocker • Inhibition of ErbB Family receptor heterodimerization • In vitro activity against EGFR-resistant T790M mutation Adapted from Yang et al ASCO 2012 Yang JC, et al.

  18. Afatinib vs Cisplatin/Pemetrexedin EGFR mutant lung cancers Stage IV lung adenocarcinoma EGFR mutation in tumor (central lab testing; Therascreen EGFR29* RGQ PCR) Randomization 2:1 Stratified by: EGFR mutation (Del19/L858R/other) Race (Asian/non-Asian) Afatinib 40 mg/day† Cisplatin + Pemetrexed 75 mg/m2 + 500 mg/m2 i.v. q21 days, up to 6 cycles Primary endpoint: PFS Yang et al ASCO 2012

  19. Afatinib vs Cisplatin/pemetrexedIntent to treat 1.0 0.8 0.6 Progression-free survival (probability) 47% 0.4 0.2 22% 0.0 0 3 6 9 12 15 18 21 24 27 Progression-free survival (months) Number at riskAfatinib 230 180 151 120 77 50 31 10 3 0Cis/Pem 115 72 41 21 11 7 3 2 0 0 Yang et al ASCO 2012 Yang JC, et al.

  20. Afatinib vs Cisplatin/pemetrexedPFS: Common mutations (Del19/L858R) 1.0 0.8 0.6 Progression-free survival (probability) 51% 0.4 0.2 21% 0.0 0 3 6 9 12 15 18 21 24 27 Progression-free survival (months) Number at riskAfatinib 204 169 143 115 75 49 30 10 3 0Cis/Pem 104 62 35 17 9 6 2 2 0 0 Yang et al ASCO 2012 Yang JC, et al.

  21. Afatinib – Summary Afatinib treatment leads to longer PFS when compared to cisplatin-pemetrexed—Likely FDA approval in early 2013 Afatinib median PFS – 11 months is similar to Gefitinib, Erlotinib Yang et al ASCO 2012 Yang JC, et al.

  22. What do we do when erlotinib fails? Dasatinib – negative HKI-272 (neratinib) – negative Erlotinib + vorinostat – negative Erlotinib + cetuximab – negative Afatinib – negative

  23. Afatinib + Cetuximab in Acquired Resistance to Erlotinib Slide courtesy of Dr. Horn. Horn L, et al. Presented at the 14th Annual World Lung Conference, July 3-7, 2011, Amsterdam: abstr#O19.07

  24. What do we do when erlotinib fails?

  25. Disease Flare Last day of TKI Off EGFR TKI Resumed TKI Day 0 Day 21 Day 42 Riely et al Clin Cancer Res. 2007

  26. Review of 61 patients with EGFR-mutant lung cancer who discontinued erlotinib as part of initiation of clinical trials evaluating other drugs 14/61 (23%) had hospitalization or death in a median of 7 days No clear predictors of patients likely to have flare Conclusion: if you plan to discontinue erlotinib, do so only after or just before initiating alternative therapy Chaft et al Clinical Cancer Research 2011

  27. Approach to Management of Patients with EGFR TKI Acquired Resistance Asymptomatic, indolent growth, multiple sites Continue erlotinib Progression of disease Chemotherapy + erlotinib OR Clinical trial Symptomatic, multiple sites Biopsy Single site (Biopsy) Local therapy, resume erlotinib

  28. In patients with stage IV EGFR mutant lung cancer, an EGFR TKI is standard in first-line Mok et al NEJM 2009, Maemondo et al NEJM 2010, Mitsudomi et al Lancet Oncol 2010, Rosell et al Lancet Oncol 2012

  29. --Erlotinib prescribing information TARCEVA monotherapy is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen

  30. Randomized Trial of Erlotinib in NSCLC • Stage IIIB/IV NSCLC • PS 0–3 • 1-2 prior therapies erlotinib + supportive care placebo + supportive care Shepherd FA, et al. N Engl J Med. 2005;353:123-132.

  31. What value do EGFR TKI have in patients without EGFR mutations?

  32. Erlotinib vs Docetaxel in EGFR wild type lung cancers TAILOR CROSS OVER NOT ALLOWED DOCETAXEL 75 mg/m2 iv day 1,21 OR 35 mg/m2 iv day 1,8,15,28 • Advanced/recurrent • Previousplatinumbaseddoublet • EGFR wild-type • KRAS determined • ECOG PS 0-2 R 1:1 ERLOTINIB 150 mg po, daily • STRATIFICATION • minimizationapproach • centre • recurrent/progressed • type of priorchemotherapyregimen (pem vs gem vs vnb) • ECOG-PS (0-1 vs 2) • adequacy of tissue sample (optimal vs suboptimal) Garassino et al ASCO 2012

  33. Erlotinib vs Docetaxel in EGFR wild type patients Progression-free survival 1.0 0.9 HR 0.69 (95%CI 0.52-0.93) p=0.014 0.8 0.7 0.6 0.5 Progression free survival 0.4 0.3 0.2 Docetaxel 0.1 Erlotinib 0 0 1 2 3 4 5 6 7 Garassino et al ASCO 2012

  34. TAILOR does not support the use of an EGFR TKI (erlotinib) in comparison to standard chemotherapy (docetaxel) in advanced NSCLC patients with wild-type EGFR Garassino et al ASCO 2012

  35. Erlotinib as First-Line Therapy is Detrimental in Patients Not Selected by EGFR mutation status Gridelli C, et al. J ClinOncol. 2012 Aug 20;30(24):3002-11.

  36. Lung Adenocarcinomas 35% Unknown 2012

  37. ALK Rearrangements in Lung Adenocarcinoma

  38. EML4–ALK Is an Oncogenic Driver Vector EML4 ALK EML4–ALK K589M NPM–ALK v-Ras 3T3 Nude mice tumour/ injection 0/8 0/8 0/8 8/8 0/8 8/8 2/2 • Expression plasmids for WT, EML4, ALK, EML4-ALK, EML4-ALK K589M, • and NPM-ALK were introduced into 3T3 fibroblasts. • Subcutaneous injection of the transfected 3T3 cells into nude mice revealed • those that formed tumors 1Soda M, et al. Nature. 2007;448:561–67.

  39. Frequency of ALK Rearrangements

  40. Histology/IHC FISH/Cytogenetics PCR Sequencing How do we test for ALK rearrangments?

  41. Histology/IHC FISH/Cytogenetics PCR Sequencing How do we test for ALK rearrangments?

  42. Phase 1 (expansion) of Crizotinib in “ALK +” Lung Cancers Kwak EL, et al. NEJM2010;363:1693-1703.

  43. FDA approved for treatment of patients with ALK-positive NSCLC August 26, 2011 Approved for treatment of patients with ALK-positive NSCLC

  44. Phase 3 Trial of CrizotinibProfile 1007 crizotinib (PF-02341066) 250 mg bid Inclusion Criteria: -locally advanced or metastatic NSCLC -EML4/ALK translocation -1 prior platinum-based therapy -ECOG PS 0-2 n=318 1 1 pemetrexed (500 mg/m2 ) or docetaxel (75 mg/m2) 1˚ Endpoint: PFS (Independent Review RECIST) 2˚ Endpoints: RR (independent review), DR, DCR at 6 and 12 weeks, OS, Toxicity

  45. Crizotinib in 2nd-Line Treatment of ALK Positive Lung Cancers Shaw et al, ESMO 2012

  46. What do we do when crizotinib fails? Novartis LDK-378 Ariad AP26113 Chugai AF802 Others…

  47. LDK378 is a second-generation ALK inhibitor • Potent activity in enzymatic and cell based assays • LDK378 treatment results in tumor regression in EML4-ALK expressing xenografts Mehra et al ASCO 2012

  48. LDK378 shows antitumor activity in ALK+ NSCLC • Response rate 81% (21/26) in NSCLC patients treated at ≥400 mg who progressed following crizotinib • Responses include confirmed + unconfirmed per RECIST 1.0 (6 patients with PR awaiting confirmatory scans) Mehra et al ASCO 2012

  49. Responses to LDK378 were seen at the 400 mg dose level After 6 weeks on LDK378 Baseline Mehra et al ASCO 2012

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