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Michael B. Atkins, M.D. Deputy Director Georgetown-Lombardi Comprehensive Cancer Center

Immunotherapy is the Preferred Initial Treatment for Most Patients with Metastatic BRAF V600 Mutant Melanoma. Michael B. Atkins, M.D. Deputy Director Georgetown-Lombardi Comprehensive Cancer Center. The case for immunotherapy---.

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Michael B. Atkins, M.D. Deputy Director Georgetown-Lombardi Comprehensive Cancer Center

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  1. Immunotherapy is the Preferred Initial Treatment for Most Patients with Metastatic BRAFV600 Mutant Melanoma Michael B. Atkins, M.D. Deputy Director Georgetown-Lombardi Comprehensive Cancer Center

  2. The case for immunotherapy--- • Immunotherapy produces durable unmaintained tumor responses • Immunotherapy works as well against BRAFV600 mutant melanoma as WT tumors • Immunotherapy is getting better • Better drugs • Better patient selection • BRAF inhibitors work as well in patients with prior immune therapy; the converse is not so

  3. High Dose IL-2 Therapy* • RR: 16% (43 / 270) • Some large volume and visceral • Most soft tissue and lung • Durable responses • Median 8.9 mos • CR: not reached • Survival • Median 12 mos • 11% >@ 5yrs *Atkins et al JCO, 1999 (N=270)

  4. Ipilimumab activity: Plateau in survival curves of responders by WHO and irRC Criteria with PD WHO Criteria Pooled data from phase II studies CA184-008 and CA184-022:ipilimumab monotherapy 10 mg/kg (N=227) 1.0 0.8 0.6 0.4 0.2 0 mWHO CR/PR/SD = 27.8% irRC CR/PR/SD with WHO PD = 9.7% Other PD or unknown = 62.6% Proportion alive 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Wolchok, Hodi et al

  5. Overall survival for 51-patient cohort Rx’d w/ 10 mg/kg x 4 + maintenance ~26% 2 yr OS estimate also seen in 165-pt cohort from expanded access trial Kevin Heller, BMS—data presented in part at ESMO 2009, ASCO 2010, 2011 posters

  6. Relationship of MAPKinase pathway mutations and response to HD IL-2 A significantly larger proportion of patients with BRAF or NRAS mutant tumors achieved CR/PR compared to those with WT tumors. Joseph, Sullivan et al- JIT 2011

  7. Ipilimumab Therapy • Produces durable unmaintained responses; not restricted by BRAF status • Activity powerful enough to work in the CNS and overcome concurrent immunosuppression • Activity seen in patients with prior IL-2 • Activity seen in patients with elevated LDH, liver metastases, etc • Treatment more widely applicable

  8. BRAF inhibitor Therapy - Limitations • Median PFS of only 6-7 months • Median OS 13-16 months • Forrest plot suggests most of the benefit confined to patients with M1c disease Sosman et al NEJM 2012, Chapman et al ASCO 2012

  9. Overall survival (February 01, 2012 cut-off) censored at crossover 100 Vemurafenib (n=337) Median f/u 12.5 months 90 80 Hazard ratio 0.70 (95% CI: 0.57–0.87) p<0.001 (post-hoc) 70 60 Overall survival (%) 50 Dacarbazine (n=338) Median f/u 9.5 months 40 30 20 BRIM2 10 15.9 9.7 13.6 0 0 6 12 18 24 Time (months) No. at risk 338 337 173 280 111 231 79 178 50 109 24 44 4 7 0 1 244 326 Dacarbazine Vemurafenib

  10. Overall survival by baseline characteristic (February 01, 2012 cut-off) censored at crossover Number of patients Favors vemurafenib Favors dacarbazine Factor 20 0.2 0.4 0.6 1.0 2 4 6 10 Hazard ratio and 95% confidence interval

  11. BRAF inhibitor Therapy - Limitations • Median PFS of only 6-7 months • Median OS 13-16 months • Forest plot suggests most of the benefit confined to patients with M1c disease • Combination BRAF-MEK inhibition may offer some advantages… Sosman et al ASCO 2012, Chapman et al ASCO 2012

  12. BRAF inhibitor Therapy - Limitations • Median PFS of only 6-7 months • Median OS 13-16 months • Forest plot suggests most of the benefit confined to patients with M1c disease • Combination BRAF-MEK inhibition may offer some advantages, but median PFS still only 7-10 months Sosman et al ASCO 2012, Chapman et al ASCO 2012, Weber et al, ASCO 2012

  13. BRAF inhibitor Therapy - Limitations Thus, BRAF (+/- MEK) inhibitor treatment postpones but does not prevent the tragedy of metastatic melanoma Sosman et al ASCO 2012, Chapman et al ASCO 2012, Weber et al, ASCO 2012

  14. Treatment for BRAF Mutant Melanoma 1.0 0.9 0.8 0.7 0.6 Which is preferred? 0.5 Proportion Surviving 0.4 0.3 Ipilimumab 0.2 BRAFi 0.1 0.0 0 1 2 3 4 5 Years after stage IV diagnosis PRESENTED BY: Michael B. Atkins

  15. Immunotherapy is getting better

  16. Clinical Activity of BMS-936558 in Melanoma Patients • 4 melanoma patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not classified as responders for the ORR calculation 3mg/kg

  17. Changes in Target Lesions Over Time inMelanoma Patients (3mg/kg) • Of 33 patients with OR (all dose levels) • 29 were treated 1 year (before July 3, 2012) and 14 had responses of 1 year • 4 were treated <1 year and 4 had responses ranging from 1.8-5.3 months

  18. MK-3475 (Unconfirmed + Confirmed Responses) in Advanced MEL Patients Hamid SMR 11/11/12

  19. Clinical Activity in a Melanoma Patient-1 Baseline: 13/Apr/2012 27/July/2012 Courtesy of A. Ribas M.D. • 72 yrs old male with melanoma after progressing on bio-chemotherapy, HD IL-2, and ipilimumab • Patient was on oxygen support due to progressive lung disease burden and pleural effusion • After 3 months of MK-3475, the patient is off the oxygen support and continues to respond

  20. Clinical Activity in a Melanoma Patient-1 Baseline: 13/Apr/2012 27/July/2012

  21. MK-3475 Characteristics of Responses (irRC): Time to Respond & Duration for 43 Patients with Objective Response • Median duration of treatment, • 7.6 months + (3.3-11+) • one patients discontinued due to PD and four patients discontinued due to AEs On Treatment Duration in Weeks

  22. Immunotherapy for Melanoma ??? 1.0 0.9 0.8 0.7 0.6 Anti PD1 + x 0.5 Proportion Surviving Anti-PD1 0.4 0.3 Ipilimumab 0.2 IL-2 0.1 0.0 0 1 2 3 4 5 Years after stage IV diagnosis PRESENTED BY: Michael B. Atkins

  23. Checkpoint blockade vs oncogene-mutation targeted therapy for melanoma Annual pt-years of remission Adapted from Drew Pardoll

  24. Treatment Selection Opportunities

  25. Correlation of PD-L1 expression in pretreatment tumor biopsies with clinical outcomes in Anti-PD-1 Therapy Melanoma 42 pts include 18 MEL, 10 NSCLC, 7 CRC, 5 RCC, and 2 CRPC. 17/17 16*/25 Proportion of patients RCC * 9/25 † p=0.006 † analysis not pre-planned and based on subset of subjects'. 0/17 *2 pts still under evaluation NSCLC Topalian S, et al. NEJM 2012;366:2443-2454.

  26. Sequencing of Treatment

  27. BRIM2- ORR by pre-defined subgroups 80 70 60 50 Overall response rate (%) 40 30 20 Overall ORR of 53% (IRC) 10 RR (size proportional to the number of patients in the subgroup) 95% Confidence intervals 0 Alltreatedpatients <65 65 F M 0 1 M1a/M1b M1c 1 >1 Yes No Normal 1.0–1.5xULN >1.5xULN Age Sex ECOG PS # priortherapies Previous IL-2 Stage LDH at enrollment Baseline characteristics Ribas et al ASCO 2011

  28. BRAF inhibition +/- prior immunotherapy Ackerman/Sullivan-BIDMC/MGH-SITC 2012 MAPKi PFS IT initially PFS 6.7 mo (CI 4.3-9.1 mo) MAPKi initially PFS 5.6 mo (CI 4.7-6.8 mo) p-value 0.43, log rank MAPKi OS IT initially OS 19.6 mo (CI 10.0- mo) MAPKi initially OS 13.4 mo (CI 10.1-17 mo) p-value 0.40, log rank OS (probability) Time (mo)

  29. Immunotherapy following MAPKI: DFHCC/MIA Retrospective Data • 193 patients discontinued MAPKi therapy (176 with disease progression) • Median OS 2.9 mos (CI 1.8-4.4 mos) from last dose of MAPKi • Single agent ipilimumab treatment (n=34 pts) No tumor responses (2 SD) Median PFS 2.7 mos, median OS 5 mos 50% of patients received < 4 doses All Pts alive > 1 year- are back on MAPK inhibitors inhibitors • Summary: • Patients progressing on BRAFi appear unlikely to respond to ipilimumab • Those alive either had slow growing disease and short period of RAFi treatment due to toxicity or are back on a RAFi Ackerman/Sullivan-BIDMC/MGH-SITC 2012

  30. Ipilimumab following BRAF inhibitor Therapy PFS 2.7 mo (CI 1.8-3.1 mo) Ackerman/Sullivan-BIDMC/MGH-SITC 2012 OS 5.0 mo (CI 3.0-8.8 mo) OS (probability) long term survivors all treated with additional MAPKi Time (mo)

  31. Treatment Selection in Patients with BRAF Mutant Melanoma: Conclusions • Current data suggests that for many patients with BRAFV600E melanoma (asymptomatic, immune infiltrate), starting with immunotherapy offers them a chance for longterm benefit without compromising their benefit from subsequent BRAFi therapy

  32. Two shots on goal are better than one

  33. E1612: Ipi vs Vemurafenib PD Arm 1: Ipi 3 or 10mg/kg q 3wks x 4 +/- maint q12 wks Vemurafenib 960mg BID • ECOG PS • 0 • 1 • Stage • St III or M1a/b • M1c • Prior therapy • No prior Rx • Prior Rx R A N D O M I Z E Ipi 3 or 10mg/kg q 3wks x 4 +/- maint q12 wks Arm 2: Vemurafenib 960mg BID PD ECOG and SWOG protocol – Atkins, Chmielowski Tumor measurements q12 wks

  34. Treatment Selection in Patients with BRAF Mutant Melanoma: Conclusions • Current data suggests that for many patients with BRAFV600E melanoma (asymptomatic, immune infiltrate), starting with immunotherapy offers them a chance for longterm benefit without compromising their benefit from subsequent BRAFi therapy • Newer immunotherapies are approaching the efficacy (RR and PFS) of BRAFi with more durability

  35. Immunotherapy may be the better of the two shots

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