Update on Melanoma. Main Themes

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therapies: HD IFN regimens: # 855 (Agarwala et al.): month of HD IFN vs observation # 856 (Chiarion-Sileni et al.

1 Update on Melanoma Antoni Ribas, M.D. Professor of Medicine, Surgery, and Medical and Molecular Pharmacology University of California Los Angeles (UCLA) and the Jonsson Comprehensive Cancer Center Main Themes IFN adjuvant therapies: HD IFN regimens: # 855 (Agarwala et al.): month of HD IFN vs observation # 856 (Chiarion-Sileni et al.): ) Intensified HD IFN vs HD IFN Peg-IFN: Abstract 856b (Eggermont et al.): Peg-IFN vs observation Anti-CTLA4: #LBA5 (Wolchok et al.): Phase III of ipilimumab + dacarbazine vs dacarbazine BRAF inhibitors: Single agent: # LBA4 (Chapman et al.): Phase III of vemurafenib vs dacarbazine #859 (Ribas et al.): Phase II of vemurafenib Combination with a MEKi: #853 (Infante et al.): GSK BRAF+MEK inhibitor

2 Adjuvant Interferon: Randomized Trials Testing Changes in the Kirkwood HD IFN Regimen Study Abstract IFN dosing No. Pts E 697 # 855 Agarwala et al. IMI # 856 Chiarion- Sileni et al. HD IFN x mo vs Observation Intensified HD IFN vs Kirkwood regimen Outcome 5 Stopped for futility Median RFS 7.3y vs 7.8y 5-y OS 82.% vs 85.% 33 No differences Median RFS 4y vs 3.3y 5-y OS595%vs532% 59.5% 53.2% EORTC 899: Peg-interferon vs Observation Abstract 856b Eggermont et al. Relapse-Free Survival (RFS) Distant Metastasis-Free Survival (DMFS) and Overall Survival (OS) NS 27 evaluation 2 evaluation P=. HR =.82 (95% CI.7,.96) (years) N Number patients risk O of at : Observation Peg-IFN alfa P=.5 HR =.87 (95% CI.76,.) (years) N Number patients risk O of at : Observation Peg-IFN alfa Evaluation: Subset analysis of siii N+Ulcerated melanoma RFS DMFS OS p=.6 HR=.72 (99% CI:.46,.3) (years) N Number patients risk O of at : Observation Peg-IFN alfa p=.2 HR=.65 (99% CI.4,.4) (years) N Number patients risk O of at : Observation Peg-IFN alfa p=.6 HR=.59 (99% CI.35,.97) (years) N Number patients risk O of at : Observation Peg-IFN alfa

3 Abstract #LBA5 Phase 3 randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) vs DTIC alone as first line treatment in patients with unresectable stage III or IV melanoma Jedd Wolchok, Luc Thomas 2, Igor Bondarenko 3, Steven O Day 4, Jeffrey Weber 5, Claus Garbe 6, Stephen Francis 7, Ramy Ibrahim 8, Axel Hoos 8, Caroline Robert 9 Memorial Sloan-Kettering Cancer Center, New York, NY; 2 Lyon University Centre Hospitalier Lyon Sud, Pierre Benite, France; 3 City Clinical Hospital, Dnepropetrovsk, Ukraine; 4 The Angeles Clinic & Research Institute, Los Angeles, CA; 5 Moffitt Cancer Center, Tampa, FL; 6 University of Tübingen, Tübingen, Germany; 7 Bristol-Myers Squibb, Brainel'Alleud, Belgium; 8 Bristol-Myers Squibb, Wallingford, CT; 9 Institut Gustave Roussy, Villejuif, France Study 24: Worldwide Sites 52 patients randomized in 24 countries: First Patient First Visit: Aug 26 Last Patient First Visit: Jan 28 Primary Endpoint Lock: Mar 2 6 3

4 Study 24: Overall Survival Alive Proportion Ipilimumab + DTIC Placebo + DTIC Ipilimumab + DTIC versus Placebo + DTIC HR (95% CI).72 (.59.87) Median OS.2 vs 9 9. months P value.9 Ipi + DTIC DTIC Years Estimated Survival Rate Year 2 Year 3 Year* Ipilimumab + DTIC n=25 Placebo + DTIC n=252 *3-year survival was a post-hoc analysis Study 24: Duration of Response r PR Proportion with CR o Ipilimumab + DTIC (n=38) Placebo + DTIC (n=26) DTIC Ipi + DTIC 2 Years Data shown for patients with a confirmed complete response (CR) or partial response (PR) 8 4

5 Study 24: Conclusions Second randomized ipilimumab phase III trial to show significant survival improvement in metastatic melanoma % difference between the ipi arm and the dacarbazine arm throughout Ipi+dacarbazine changed the toxicity profile: Less colitis/diarrhea More autoimmune hepatitis 9 Targeting Oncogenic BRAF B-Raf V6E BRAF V6E mutations drive oncogenic signaling through the MAPK pathway, which can be blocked by a new generation of targeted t inhibitors Vemurafenib GSK28436 RAF-265 GSK222 MEK P ERK P Cyclin D Cell Proliferation 5

6 Abstract #859 BRIM 2: An Open-label, Multicenter Phase II Study of Vemurafenib (PLX432, RG724) in Previously Treated Patients with BRAF V6E Mutation-positive Metastatic Melanoma A Ribas, KB Kim, L Schuchter, R Gonzalez, AC Pavlick, JS Weber, GA McArthur, TE Hutson, KT Flaherty, S Moschos, D Lawrence, P Hersey, R Kefford, B Chmielowski, I Puzanov, J Li, K Nolop, RJ Lee, AK Joe, JA Sosman Percent cha ange from baseline in diamete er of target lesion BRAF V6 mutant metastatic melanoma responses with vemurafenib (PLX432) Multi-institutional phase 2 trial 3 international sites, 32 patients Primary endpoint: Objective response rate (ORR) analyzed by an Independent Review Committee (IRC) by RECIST with response confirmation ORR 53% by IRC, 95% CI excluding 2% RR Only 4% PD ORR 57% by investigator assessments (INV) RR, including unconfirmed, 69% (INV) PR in 4 of BRAF V6K patients Disease stage Ma Mb Mc - Individual patients treated with vemurafenib ******* * 7 Confirmed CRs 6

7 Time to response and progression Time on study Time to response Progressive disease Continued response Approx timing of CT assessments Time (months) Median duration of response = 6.7 months (95% CI: 5.6, 9.8; range.3 2.7) 4 6 Overall survival %) Probability of overall survival (% No. at risk Median OS not reached 3 2 OS at 6 months 77% (95% CI: 7, 85) 2 months 58% (95% CI: 49, 67) Time (months)

Toxicities with vemurafenib Median 5 5 2 25 3 35 4 Time on vemurafenib (weeks) cusccs: Incidence: 26% Median time 8 weeks (2 36) Median number of cuscc/kas per patient (range to 7)

open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with BRAF V6E -mutated melanoma P. Chapman, A. Hauschild, C.

8 Toxicities with vemurafenib Median Time on vemurafenib (weeks) cusccs: Incidence: 26% Median time 8 weeks (2 36) Median number of cuscc/kas per patient (range to 7) Each dot represents weeks to development of first cuscc/ka lesion Other toxicities: G/2 arthralgias 59% G/2 rash 52% G/2 photosensitivity 52% Abstract #LBA4 Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with BRAF V6E -mutated melanoma P. Chapman, A. Hauschild, C. Robert, J. Larkin, J. Haanen, A. Ribas, D Hogg, S. O'Day, P. Ascierto, A. Testori, P. Lorigan, R. Dummer, J. Sosman, C. Garbe, R. Lee, K. Nolop, B. Nelson, J. Hou, K. Flaherty, G. McArthur 8

BRIM3 trial: A worldwide study 675 patients randomized : Co-primary endpoints: OS and PFS 4 centers in 2 countries enrolled patients 5 7 24 4 3 8 7 2 3 4 BRIM3

9 BRIM3 trial: A worldwide study 675 patients randomized : Co-primary endpoints: OS and PFS 4 centers in 2 countries enrolled patients BRIM3 accrual timeline. of patients accrued No Revised statistical plan Last patient enrolled Phase II data first reported N=32 Interim analysis Interim analysis data cut-off 2 2 9

10 Overall survival (2/3/ cutoff) 9 Vemurafenib (N=336) Dacarbazine (N=336) 5 4 Hazard ratio.37 3 (95% CI; ) 2 Log-rank P< No. of patients in follow up Months Overall survival (% %) Dacarbazine Vemurafenib = 63% decrease in the risk of being dead compared to chemotherapy BRIM3: OS by baseline characteristic Factor Number of patients All patients 672 Age: <65 yrs yrs 6 Sex: Female 293 Male 379 ECOG status: Disease stage: IIIc 33 Ma 74 Mb 26 Mc 439 LDH : Normal 39 Elevated 282 Favors vemurafenib Favors dacarbazine Hazard ratio and 95% confidence interval 2

11 Progression-free survival (2/3/ cutoff) 9 8 Vemurafenib (N=275) Hazard Ratio.26 (95% CI; ) Log-rank P<. 7 6 Dacarbazine 5 (N=274) 4 Median mo 2 Median.6 mo No. of patients in follow up Months Progression-free surviva al (%) Dacarbazine Vemurafenib Conclusions Vemurafenib associated with 63% decrease in hazard of death (p<.) 74% decrease in hazard of tumor progression (p< ) 74% decrease in hazard of tumor progression (p<.) Benefit seen in all subgroups, including Mc and LDH First single drug for melanoma to improve response rate, progression-free survival, and overall survival compared to active chemotherapy Vemurafenib is a promising new therapy for patients with metastatic BRAF V6E -mutated melanoma

12 Mechanisms of Resistance to Vemurafenib Nazarian et al. Nature 2 NRAS Q6 PDGFRb or IGFR Johannessen et al. Nature 2 COT CRAF BRAF inh BRAF V6E Poulikakos AACR 2 PI3K PI3Ki or AKTi Nazarian et al. Nature 2 Villanueva et al. Cancer Cell 2 MEK-dependent progression MEK MEKi P ERK P Wagle et al. JCO 2 AKT MEK-independent progression Survival Abstract #CRA853 Phase I/II Study of the Oral MEK /2 Inhibitor GSK222 Dosed in Combination with the Oral BRAF Inhibitor GSK28436 Jeffrey Infante, Gerald Falchook 2, Donald Lawrence 3, Jeff Weber 4, Richard Kefford 5, Johanna Bendell, Razelle Kurzrock 2, Geoffrey Shapiro 3, Ragini Kudchadkar 4, Georgina Long 5, Howard Burris, Kevin Kim 2, Arthur Clements 5, Peng Sun 6, Bingming Yi 6, Alicia Allred 6, Daniele Ouellet 6, Kiran Patel 6, Peter Lebowitz 6, Keith Flaherty 3 Sarah Cannon Research Institute, Nashville, TN, USA; 2 MD Anderson Cancer Center, Houston, TX, USA; 3 MGH/DFCI, Boston, MA, USA; 4 Moffitt Cancer Center, Tampa, FL, USA; 5 Melanoma Institute of Australia and Westmead Hospital, University of Sydney, Australia; 6 GlaxoSmithKline Research and Development, Philadelphia, PA and RTP, NC, USA 2

Rationale for Combination of BRAFi (GSK436) + MEKi (GSK22) in BRAF Mutant Tumors RAS BRAF MEK BRAFi (GSK436) MEKi (GSK22) Tumor Type % BRAF Mutant Melanoma 5% Colorectal 5% NSCLC 3-5% Cholangioca 5%

Potentially decrease incidence of BRAFi-induced hyper-proliferative skin lesions Data presented at ASCO 2 GSK BRAFi+MEKi phase : A new paradigm in combination targeted therapy drug development

13 Rationale for Combination of BRAFi (GSK436) + MEKi (GSK22) in BRAF Mutant Tumors RAS BRAF MEK BRAFi (GSK436) MEKi (GSK22) Tumor Type % BRAF Mutant Melanoma 5% Colorectal 5% NSCLC 3-5% Cholangioca 5% Thyroid 5% Goals of Combination. Synergy in combination perk Proliferation, Survival, Invasion, Metastasis 2. Prevent/overcome potential monotherapy resistance 3. Potentially decrease incidence of BRAFi-induced hyper-proliferative skin lesions Data presented at ASCO 2 GSK BRAFi+MEKi phase : A new paradigm in combination targeted therapy drug development Maximum % reduction from baseline mea asurement 83% of responses ongoing (-2 mo f/y) % incidence of cuscc GSK mg BID/GSK22 mg QD GSK436 5 mg BID/GSK22 mg QD GSK436 5 mg BID/GSK22.5 mg QD GSK436 5 mg BID/GSK22 2 mg QD ASCO 2, abstract #853: Infante, J. R., G. S. Falchook, D. P. Lawrence, J. S. Weber, R. F. Kefford, J. C. Bendell, R. Kurzrock, G. Shapiro, R. R. Kudchadkar, G. V. Long, H. A. Burris, K. B. Kim, A. Clements, S. Peng, B. Yi, A. J. Allred, D. Ouellet, K. Patel, P. F. Lebowitz, and K. T. Flaherty. 3

of melanoma FDA approvals of new agents for the treatment of melanoma 975 996 998 2

14 Treatment Duration for Melanoma Patients without Prior BRAFi (n=77) 83% of patients are ongoing Treatment duration (weeks) Conclusion: 2, a year with major advances in the treatment of melanoma FDA approvals of new agents for the treatment of melanoma Dacarbazine Pegylated interferon IFN IL-2 Ipilimumab Peginterferon BRAFi? Ipilimumab Vemurafenib GSK28436+GSK2 4

a randomized trial in patients with advanced metastatic melanoma BRAF inhibitors for BRAF V6 mutant metastatic melanoma have high response rates and

15 Conclusions Adjuvant HD IFN following the Kirkwood regimen continues to be the standard therapy for high risk melanoma. Peg-IFN may yprovide advantages in stage III with microscopic nodal metastases Ipilimumab has improved survival twice against standard of care therapies in a randomized trial in patients with advanced metastatic melanoma BRAF inhibitors for BRAF V6 mutant metastatic melanoma have high response rates and improve survival: Vemurafenib: Confirmed response rate of 53% and improved survival over dacarbazine GSK28436 combined with the MEK inhibitor GSK222 may improve efficacy while decreasing toxicities 5

Targeted Therapies in Melanoma

Mutations and Targets Targeted Therapies in Melanoma ckit NRAS