Disclosures I have no relevant exposures. Companies are smart. The - PDF document

7/31/2014 Winship Cancer Institute of Emory University Off Protocol Adjuvant TKI therapy for driver mutations in early ‐ stage NSCLC after systemic chemotherapy ‐ No! Fadlo Raja Khuri, MD Professor and Chair, Department of Hematology & Medical Oncology Deputy Director, Winship Cancer Institute of Emory University Roberto C. Goizueta Chair in Cancer Research Debates and Didactics in Hematology and Medical Oncology Sea Island, GA August 9, 2014 Disclosures • I have no relevant exposures. • Companies are smart. The prefer Ram’s opinions over mine! 1

7/31/2014 RADIANT Trial Design ASCO 2014 RADIANT: Historical Context ASCO 2014 2

7/31/2014 Disease-free Survival KM Plot ASCO 2014 Sites of Relapse (>5%) ASCO 2014 3

7/31/2014 Overall Survival KM Plot ASCO 2014 Drug Exposure ASCO 2014 4

7/31/2014 Drug Exposure: EGFR M+ ASCO 2014 Safety: EGFR M+ ASCO 2014 5

7/31/2014 Slide 22 ASCO 2014 Slide 24 ASCO 2014 6

7/31/2014 Outcomes Secondary Endpoint in EGFR mutated subgroup 7

7/31/2014 Perspective on adjuvant EGFR TKI Phase III trial of Adjuvant Gefitinib: NCI-C BR19 trial<br />Goss et al, JCO 2013; 31(27):3320-6 8

7/31/2014 BR-19: Adjuvant gefitinib in unselected population MSKCC experience<br />Janjigian et al, JTO 2011;March 6(3):569-575<br /> 9

7/31/2014 Adjuvant EGFR TKI SELECT phase II study<br />Pennell et al, ASCO 2014, abstract 7514 10

7/31/2014 SELECT results Perspective on adjuvant targeted agents FDA approved in the U.S. 11

7/31/2014 Questions to consider CTONG1104: A national, multi center, randomized, open-label, phase III trial of gefitinib versus combination of vinorelbine plus platinum as adjuvant treatment in pathological stage II- IIIA(N1-N2) NSCLC with EGFR activating mutation (ADJUVANT) 12

7/31/2014 IMPACT: WJOG6410L<br />Iressa for Mutation Positive lung cancer as Adjuvant ChemoTherapy <br />(A randomized phase III trial of adjuvant gefitinib versus cisplatin and vinorelbine in completely resected (stage II-III) NSCLC patients with mutated EGFR) ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification And Sequencing Trial) Umbrella Protocol Will Screen Patients Trial A151216 Category ALCHEMIST E5412 A081105 Target Registry/Intervention ALK+ EGFR mut with biopsy at recurrence Prevalence all comers ~5% ~10% Total Sample 378 (5% inflation) 430 (5% ineligible) 6000 – 8000 Size Primary N/A Overall Survival Overall Survival Endpoint Power N/A 80% 85% One-sided α N/A 0.05 0.05 Hazard Ratio N/A 0.67 0.67 26 Doroshow JH. Available at: deainfo.nci.nih/gov/advisory/ncab/164_1213/Doroshow.pdf. Accessed May 14, 2014. 13

7/31/2014 Decision Tree for Adjuvant Therapy for NSCLC: Utilization of Data to positively impact outcomes • Personalization of care by histology (pemetrexed and possible bevacizumab) for nonsquamous • Molecular markers – ERCC1, etc, not helpful – EGFR and ALK testing critical at the time of surgery • Support ALCHEMIST by referring and enrolling patients with EGFR and ALK mutation carrying tumors 27 Conclusions • No evidence yet that adjuvant targeted therapy even in patients whose tumors have driver mutations adds to cure. • No reason to over-interpret secondary analyses when there is no survival benefit! • Giving drugs earlier is not necessarily better unless you can impact overall survival (still the Gold Standard). • Dr. Ramalingam is the PI of ALCHEMIST and he knows the right answer here. He stated it at ASCO 2014! 14

7/31/2014 Final Conclusion • Careful planning and data interpretation always beats over-rating what data or players you have! 15