Advances for Non Small cell Lung Cancer

1. New and Improved Targeted Therapies for NSCLCs William N. William Jr. Assistant Professor Chief, Head and Neck Section Department of Thoracic / Head and Neck Medical Oncology M. D. Anderson Cancer Center

2. Outline • Adenocarcinomas • Squamous Cell Carcinomas

4. Shepherd et al. N Engl J Med. 2005;353:123. Adenocarcinomas Targeted agents for driver molecular alterations

6. Selective EGFR TKIs Sequist et al., ASCO 2014 CO-1686

7. Selective EGFR TKIs Janne et al., ASCO 2014 AZD-9298

8. Selective EGFR TKIs Lynch et al., ASCO 2014

9. Selective EGFR TKIs: Conclusions • High response rates and extended PFS after failure of first-generation EGFR TKIs • Higher response rates in T790M+ • Toxicity patterns consistent with selectivity to mutant receptors

11. Crizotinib

12. Crizotinib

13. PROFILE 1007 Crizotinib versus Docetaxel or Pemetrexed – PROFILE 1007 Shaw A et al. NEJM 2013

16. PROFILE 1007 Crizotinib versus Pemetrexed / Platinum – PROFILE 1014 Mok T et al. ASCO 2014

17. Ceritinib in ALK+ Patients Shaw A et al. NEJM 2014 Response rates: • 56% crizotinib-treated patients • 62% crizotinib-naïve patients Response rates: • 86% ALK-dependant resistance • 59% non ALK-dependant resistance

19. ALK Inhibitors: Conclusions • Crizotinib improves PFS over pemetrexed/platinum in treatment-naïve ALK+ patients • Crizotinib improves response rates, PFS and QoL over pemetrexed or docetaxel in previously treated ALK+ patients. No improvements on premature analysis of OS, in the setting of high crossover rate (64%) • Pemetrexed has better response rates and PFS compared to docetaxel in ALK+ patients • Second generation ALK inhibitors have high response rates in crizotinib-naïve and crizotinib-treated patients, including responses in the brains • Best strategy as regards to sequencing of ALK inhibitors and chemotherapy to be determined

21. Crizotinib in ROS1-rearranged NSCLCs Ou et al. ASCO 2013

23. Dabrafenib in NSCLCs with V600E BRAF Mutation [TITLE] Presented By David Planchard, MD, PhD at 2013 ASCO Annual Meeting

24. Dabrafenib in NSCLCs with V600E BRAF Mutation [TITLE] Presented By David Planchard, MD, PhD at 2013 ASCO Annual Meeting

25. Dasatinib in NSCLCs with BRAF Inactivating Mutation Sen et al. Sci Transl Med 2012

27. Docetaxel plus Selumetinib vs. Placebo in NSCLCs with KRAS Mutations Response rates PFS OS Janni et al. ASCO 2012

28. Docetaxel vs. Trametinib in NSCLCs with KRAS Mutations Blumenschein et al. ASCO 2013

30. HER-2 Targeted Therapies in NSCLCs with HER2 Mutations Patient First-Line Treatment Second-Line Treatment Third-Line Treatment Fourth-Line Treatment Treatment Best Disease Response Treatment Best Disease Response Treatment Best Disease Response Treatment Best Disease Response 11 VIN-TRAS PR CAR-PAC-TRAS 15 SD 19 TXT-MASA PD 24 VIN-TRAS PR CAR-PAC-TRAS 26 PR 27 VIN-TRAS PR 28 VIN-TRAS SD 30 LAP PD 31 NVB-TRAS PR 32 LAP PD TRAS-VIN PR AFA SD CAR-TRAS SD 37 VIN-TRAS PD 41 DOC-TRAS PR 43 VIN-TRAS PR AFA PR 44 VIN-TRAS PR AFA SD 45 VIN-TRAS SD PAC-TRAS SD 47 TRAS PR Mazières et al. JCO 2013

35. Cabozantinib in NSCLCs with RET Fusions

37. Shepherd et al. N Engl J Med. 2005;353:123. Adenocarcinomas Crizotinib for MET-amplified NSCLCs Camidge et al., ASCO 2014

38. Targeted agents for driver molecular alterations Shepherd et al. N Engl J Med. 2005;353:123. Adenocarcinomas Selumetinib / Trametinib Erlotinib / Gefitinib / Afatinib / selective EGFR TKIs Crizotinib / Ceritinib / Alectinib Cabozantinib Vemurafenib / Dabrafenib Trastuzumab ...

39. Targeted Agents for Driver Molecular Alterations • Crizotinib is active in ROS-1 positive tumors • Dabrafenib is active in patients with a BRAF V600E activating mutation • Dasatinib may be active in patients with a BRAF inactivating mutation • MEK inhibitors with modest activity in difficult to treat, KRAS positive patients • Preliminary evidence of activity of HER-2 targeting with trastuzumab, afatinib, but not lapatinib, in HER-2 mutant tumors • Cabozantinib may be active in RET positive tumors • Metmab + erlotinib may improve PFS and OS comapred to erlotinib in MET positive patients. Phase III results pending.

41. Squamous Cell Carcinomas Targeted agents for driver molecular alterations Shepherd et al. N Engl J Med. 2005;353:123. Paik et al. ASCO 2013

42. Take Home Messages • Treatment with agents targeting driver alterations may result in promising activity for molecularly-defined subgroups of patients • Targetable mutations more frequently identified in adenocarcinomas, compared to squamous cell carcinomas • Precision medicine for NSCLC treatment is here to stay

Advances for Non Small cell Lung Cancer

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Advances for Non Small cell Lung Cancer