1. Acquired Resistance Patient Forum September 6, 2014 | Boston In ALK, ROS1 & EGFR Lung Cancers Life After Erlotinib: What Next? Jared Weiss Vice President, Cancergrace Assistant Professor of Medicine, UNC Lineberger Comprehensive Cancer Center

2. Yesterday’s victory is today’s challenge EGFR mutation positive 132 71 311130 129377210 108 103 04812162024 Gefitinib C/P 0.0 0.2 0.4 0.6 0.8 1.0 Probability of progression-free survival Patients at risk : Months Gefitinib (n=132) Carboplatin/paclitaxel (n=129) 2009 Perspective: 10 months PFS without chemo! 2014 Perspective: Only 10 months? Now what?

3. Crizotinib for ALK: Like erlotinib for EGFR, better than chemo, but again, now what should be done? Mok, ASCO 2014

4. Option 1: Learn from the politicians

5. When this is a good idea West, ASCO 2013 Time Amount of Cancer

6. Now it’s time for a new idea West, ASCO 2013 Amount of Cancer Time

7. 45 Baseline: Start TKI3m: Response14m: RECIST PD 30m18m24m Oxnard, ASCO 2012 and Santa Monica Lung 2014 35m37m: Stop TKI39m: First dyspnea

8. EGFR TKI beyond RECIST 42 pts with EGFR-mutant lung cancer receiving 1 st -line erlotinib on 3 clinical trials 45% of pts could delay change of therapy >3 months after RECIST progression 21% delayed treatment change >12 months S R R R R R R R R S S S Oxnard et al, ASCO, 2012 and Santa Monica Lung 2014

9. Crizotinib past progression Acquired Resistance Patient Forum | Sept. 6, 2014 | Boston 9 Ou, Annals of Oncology 2014

10. Option 2: Weeding the garden

11. When weeding is a good idea Oligo-PD PD-Subtype CNS-PD (Sanctuary) Slightly adapted from Gandara, CLC 2013 Systemic-PD

12. Why radiation can be a good way to weed 1.Das, AACR 2006. 2.Das, AACR 2007. Mak, The Oncologist, 2011 In vitroIn vivo

13. It has been tried: MSKCC experience, all EGFR (n=18) Yu, JTO 2013

14. U Colorado Experience: Mixed EGFR (n=27) and ALK (n=38) Weickhardt, JTO 2012

15. Ongoing Trial: LCCC1123: Prospective Phase II Inclusion: *EGFR mutant *Progression on TKI *PS 0-1 *No prior XRT to sites of PD *<5 sites of PD *All sites of PD amenable to SRS or other local treatment SRS or Surgery based on priority system to defined limit: 1) Sites of PD on TKI 2) Areas of residual FDG avidity on TKI Site-specific rules for local ablation Re-initiation of erlotinib until progression Primary endpoint: PFS after SRS Secondary endpoints: LCR of ablated lesions, mOS from initiation of SRS, QOL as measured by FACT-L, attributable toxicity, serum-based biocorrelates (Veristrast) PI: Jared Weiss Collaborators: Cleveland Clinic UPMC U. Colorado UCSF Swedish FCCC Yale U. ECU UNC

16. Last day of TKI Off EGFR TKIResumed TKI Day 0Day 21Day 42 Flare Reaction: The Danger of Coming off of EGFR TKI at progression Chaft…Riely CCR 2011

17. Case studies describe the same phenomenon with ALK Pop JTO 2012 Disease well controlled Flare 15 days After stopping crizotinib

18. Third option: Keep the TKI going with the new chemo Goldberg et al, Oncologist, 2013 Chemo aloneChemo + erlotinib 18% RR 41% RR

19. But, no advantage for PFS or OS Acquired Resistance Patient Forum | Sept. 6, 2014 | Boston 19 Platinum-based combination chemotherapy One drug chemotherapy Goldberg, Oncologist 2013

20. And, there is a toxicity cost Acquired Resistance Patient Forum | Sept. 6, 2014 | Boston 20 Herbst, JCO 2005 (TRIBUTE data)

21. Chemotherapy +/- Ongoing EGFR TKI for Acquired Resistance: IMPRESS Trial Primary endpoint: progression-free survival Activating EGFR mutation Progression on gefitinib No prior chemotherapy N = 250 RANDRAND Cisplatin/Pemetrexed IMPRESS TRIAL PI: Tony Mok & Jean-Charles Soria Cisplatin/Pemetrexed + ongoing gefitinib

22. Chemotherapy +/- Ongoing EGFR TKI for Acquired Resistance: Vanderbilt Trial Carboplatin / pemetrexed PD Caboplatin / pemetrexed with erlotinib EGFR-mutant lung cancer with acquired resistance to erlotinib R PI: Leora Horn, VICC

23. When chemo used, it’s worth coming back to TKI later Acquired Resistance Patient Forum | Sept. 6, 2014 | Boston 23 Hata, ASCO 2012 Heon, ASCO 2012

24. Systemic options other than chemo: Combination trials and 3 rd generation TKIs 3 rd generation TKIs: CO1686, AZD9291, HM61713, EGFR816, ASP8273: Look promising, but most requires repeat biopsy (more on this in next talk from Dr. Sequist). More on 3 rd gen TKI from Dr. Pasi Janne in afternoon breakout session Combination trials: Afatinib/cetuximab farthest along; AUY922/erlotinib, MET inhibitor/EGFR TKI, others. More on combo trials from Dr. Melissa Johnson at afternoon breakout session) Other trials: Any active agent can be considered including immunotherapy. Acquired Resistance Patient Forum | Sept. 6, 2014 | Boston 24

25. Options, summarized Kick the can down the road Local ablation of spots that are growing then restart TKI Chemo + TKI Chemo alone (but, must start quickly after stopping TKI and reconsider TKI later) Combination Therapies 3 rd Generation TKIs Other clinical trials