Melanoma Update Lynn Schuchter, MD Abramson Cancer Center University of Pennsylvania

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1 Melanoma Update 2016 Lynn Schuchter, MD Abramson Cancer Center University of Pennsylvania

2 ASCO 2016 ABSTRACT # STUDY ID AGENT OUTCOME PRESENTER 9503 KEYNOTE 001 PEMBRO 3 YR OS, PFS, ORR 9504 KEYNOTE 006 PEMBRO vs. IPI FINAL OS, PFS, ORR ROBERT SCHACHTER 9505 CHECKMATE 067 NIVO vs. IPI vs. NIVO+IPI PFS WOLCHOCK 9596 KEYNOTE 029 PEMBRO + IPI ORR LONG 9502 Combi- D Dab +T vs D (Braf Mutant) 9500 NEMO Binimetinib (Nras Mutant) 3 YR OS RR, PFS FLAHERTY DUMMER 9508 JAVELIN MERKEL 200 Avelumab (PD- L1) RR, PFS KAUFFMAN

3 ASCO 2016 ABSTRACT # STUDY ID AGENT OUTCOME PRESENTER 9503 KEYNOTE 001 PEMBRO 3 YR OS, PFS, ORR 9504 KEYNOTE 006 PEMBRO vs. IPI FINAL OS, PFS, ORR ROBERT SCHACHTER 9505 CHECKMATE 067 NIVO vs. IPI vs. NIVO+IPI PFS WOLCHOCK 9596 KEYNOTE 029 PEMBRO + IPI ORR LONG 9502 Combi- D Dab +T vs D (Braf Mutant) 3 YR OS 9500 NEMO Binimetinib (MEKi 15% RR RR, PFS Nras Mutant) 9508 JAVELIN MERKEL 200 Avelumab (PD- L1) RR, PFS FLAHERTY DUMMER KAUFFMAN

4 ASCO 2016 ABSTRACT # STUDY ID AGENT OUTCOME PRESENTER 9503 KEYNOTE 001 PEMBRO 3 YR OS, PFS, ORR 9504 KEYNOTE 006 PEMBRO vs. IPI FINAL OS, PFS, ORR ROBERT SCHACHTER 9505 CHECKMATE 067 NIVO vs. IPI vs. NIVO+IPI PFS WOLCHOCK 9596 KEYNOTE 029 PEMBRO + IPI ORR LONG 9502 Combi- D Dab +T vs D (Braf Mutant) 9500 NEMO Binimetinib (MEKi, Nras Mutant) 9508 JAVELIN MERKEL 200 Avelumab (PD- L1) 3 YR OS RR, PFS 30% RR, PFS RR FLAHERTY DUMMER KAUFFMAN

5 3-Year Overall Survival For Patients With Advanced Melanoma Treated With Pembrolizumab in KEYNOTE-001 Caroline Robert, 1 Antoni Ribas, 2 Omid Hamid, 3 Adil Daud, 4 Jedd D. Wolchok, 5 Anthony M. Joshua, 6 Wen-Jen Hwu, 7 Jeffrey S. Weber, 8 Tara C. Gangadhar, 9 Richard Joseph, 10 Roxana Dronca, 11 Amita Patnaik, 12 Hassane Zarour, 13 Richard Kefford, 14 Peter Hersey, 15 Xiaoyun Nicole Li, 16 Scott J. Diede, 16 Scot Ebbinghaus, 16 F. Stephen Hodi 17

Keynote:001- Single Agent Pembro Overall Survival, % 100 90 80 70 60 50 40 30 20 Overall Survival Pts, N Event s, n 655 358 (55%) Median (95% CI) 24.4 mo (20.2-29.0) 10 0 No.

6 Keynote:001- Single Agent Pembro Overall Survival, % Overall Survival Pts, N Event s, n (55%) Median (95% CI) 24.4 mo ( ) 10 0 No. at risk Tim e, m onths 50% 40% a Assessed per RECIST v1.1 by independent central review. b Excludes patients with ocular melanoma. Analysis cutoff date: Sep 18, 2015.

7 Complete Responders Who Stopped Pembrolizumab for Observation (N = 61) 1 year 2 years 3 years 59 (97%) of responses were maintained Time on therapy Time to last scan Last dose Complete response Partial response Time, months Total bar length represents the time to the last scan. Analysis cutoff date: Sep 18, 2015.

8 Summary and Conclusions Pembrolizumab continues to demonstrate safety and tolerability over long-term follow-up Long-term overall survival is encouraging 40% survival rate at 3 years in all patients and 45% in treatment-naive patients Responses are durable Median duration of response not reached 66% of all and 69% of treatment-naive responses were ongoing Complete responses are durable after pembrolizumab discontinuation 97% of complete responses in patients who discontinued pembrolizumab for observation were ongoing

9 Pembrolizumab Versus Ipilimumab For Advanced Melanoma: Final Overall Survival Analysis of KEYNOTE-006 Jacob Schachter, 1 Antoni Ribas, 2 Georgina V. Long, 3 Ana Arance, 4 Jean-Jacques Grob, 5 Laurent Mortier, 6 Adil Daud, 7 Matteo S. Carlino, 8 Catriona McNeil, 9 Michal Lotem, 10 James Larkin, 11 Paul Lorigan, 12 Bart Neyns, 13 Christian Blank, 14 Teresa M. Petrella, 15 Omid Hamid, 16 Honghong Zhou, 17 Scot Ebbinghaus, 17 Nageatte Ibrahim, 17 Caroline Robert 18

10 Overall Survival O S, % No. at risk Pembro Q2W Pembro Q3W Ipi 100 Arm Pembro Q2W Pembro Q3W Events, n HR (95% CI) ( ) ( ) P % 55% Ipi % 55% 80 59% 43% NR (22.1-NR) 50 NR (23.5-NR) ( ) Time, months Final analysis data cutoff date: Dec 3, 2015.

11 Incidence of Immune-Mediated AEs a Grade Incidence, % Pembro Q2W Pembro Q3W Ipi Incidence, % Pembro Q2W Pembro Q3W Ipi Any grade G rade 3-4 Led to tx d/c 0 Thyroid abnormalities b C olitis H epatitis Pneumonitis Uveitis Hypophysitis M yositis T1DM N ephritis a Not adjusted for exposure. Immune-mediated AEs are based on a list of terms specified by the sponsor and were considered regardless of attribution by the investigator. Includes hyper- and hypothyroidism and thyroiditis. Final analysis data cutoff date: Dec 3, 2015.

12 What we have learned Anti-PD-1 therapy is better than to anti- CTLA4 (Ipi) ORR 36-58% vs % CR 10-12% vs. 2-5% PFS p< (24mo 31% vs. 14%) OS p= (24mo 55% vs. 43%) Anti-PD1 has a favorable toxicity profile compared to anti-ctla4 Randomized studies (Keynote 006 & Checkmate 067 ) confirm this observation. For single agent therapy, Anti-PD1 is the preferred agent for first line therapy.

13 Anti-PD1 + Anti-CTLA4 Checkmate 067: Ipi - 3mg/kg; Nivo- 1mg/kg Keynote 029: Ipi -1mg/kg; Pembro- 2mg/kg

14 Updated Results From A Phase III Trial Of Nivolumab Combined With Ipilimumab In Treatment-naïve Patients With Advanced Melanoma (Checkmate 067) Jedd D. Wolchok, 1 Vanna Chiarion-Sileni, 2 Rene Gonzalez, 3 Piotr Rutkowski, 4 Jean-Jacques Grob, 5 C. Lance Cowey, 6 Christopher D. Lao, 7 Dirk Schadendorf, 8 Pier Francesco Ferrucci, 9 Michael Smylie, 10 Reinhard Dummer, 11 Andrew Hill, 12 John Haanen, 13 Michele Maio, 14 Grant McArthur, 15 Dana Walker, 16 Joel Jiang, 16 Christine Horak, 16 James Larkin, 17* F. Stephen Hodi 18* 1 Memorial Sloan Kettering Cancer Center, Ludwig Institute for Cancer Research and Weill Cornell Medical College, New York, NY, USA; 2 Oncology Institute of Veneto IRCCS, Padua, Italy; 3 University of Colorado Cancer Center, Denver, CO, USA; 4 Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland; 5 Hospital de la Timone, Marseille, France; 6 Texas Oncology-Baylor Charles A. Sammons Cancer Center, US Oncology Research, Dallas, TX, USA; 7 University of Michigan, Ann Arbor, MI, USA; 8 Department of Dermatology, University of Essen, Essen, Germany; 9 European Institute of Oncology, Milan, Italy; 10 Cross Cancer Institute, Edmonton, Alberta, Canada; 11 Universitäts Spital, Zurich, Switzerland; 12 Tasman Oncology Research, QLD, Australia; 13 Netherlands Cancer Institute, Amsterdam, The Netherlands; 14 University Hospital of Siena, Siena, Italy; 15 Peter MacCallum Cancer Centre, Victoria, Australia; 16 Bristol-Myers Squibb, Princeton, NJ, USA; 17 Royal Marsden Hospital, London, UK; 18 Dana-Farber Cancer Institute, Boston, MA, USA. *Contributed equally to the study CONFIDENTIAL NOT FOR FURTHER DISTRIBUTION

15 CA : Study Design CA : Study Design Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone N=314 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses NIVO 3 mg/kg Q2W Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 Stratify by: Tumor PD-L1 expression* BRAF mutation status AJCC M stage N=316 NIVO 3 mg/kg Q2W + IPI-matched placebo Treat until progression** or unacceptable toxicity N=315 IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo *Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses. **Patients could have been treated beyond progression under protocol-defined circumstances. CONFIDENTIAL NOT FOR FURTHER DISTRIBUTION 15

16 Tumor Burden Change from Baseline Database lock Sept 2015 CONFIDENTIAL NOT FOR FURTHER DISTRIBUTION 16

17 Safety Summary Patients reporting event, % Treatment-related adverse event (AE) Treatment-related AE leading to discontinuation NIVO+IPI (N=313) NIVO (N=313) IPI (N=311) Any Grade Grade 3-4 Any Grade Grade 3-4 Any Grade Grade Treatment-related death* *One reported in the NIVO group (neutropenia) and one in the IPI group (colon perforation) Database lock Sept 2015 Most common treatment-related AE that led to discontinuation in NIVO+IPI patients included colitis (8.9%), diarrhea (8.6%), elevated ALT (4.8%) and elevated AST (4.5%). CONFIDENTIAL NOT FOR FURTHER DISTRIBUTION 17

18 Pembrolizumab Plus Ipilimumab For Advanced Melanoma: Results of the KEYNOTE-029 Expansion Cohort Georgina V. Long, Victoria Atkinson, Jonathan S. Cebon, Michael B. Jameson, Bernie M. Fitzharris, Catriona M. McNeil, Andrew G. Hill, Antoni Ribas, Michael B. Atkins, John A. Thompson, Wen-Jen Hwu, F. Stephen Hodi, Alexander M. Menzies, Alexander D. Guminski, Richard Kefford, Xinxin Shu, Scot Ebbinghaus, Nageatte Ibrahim, Matteo S. Carlino Presenter: GV Long

KEYNOTE-029: Study Design Dose Run-In (Part 1A) Patients Advanced MEL, 0 prior therapies OR Advanced RCC, 1 prior therapy

points: ORR, DOR, PFS, OS Presenter: GV Long ClinicalTrials.gov, NCT02089685. 1. Atkins MA et al.

19 KEYNOTE-029: Study Design Dose Run-In (Part 1A) Patients Advanced MEL, 0 prior therapies OR Advanced RCC, 1 prior therapy Pembro 2 mg/kg Q3W up to 24 months + Ipi 1 mg/kg Q3W x 4 doses Tolerable based on DLT rate? Stop development Combination tolerable based on DLT rate and AE profile 1,2 No Yes Dose Expansion (Part 1B) Patients Advanced MEL 0 prior therapies No prior anti CTLA-4, PD-1, or PD-L1 ECOG PS 0 or 1 Primary end point: Safety Secondary end points: ORR, DOR, PFS, OS Presenter: GV Long ClinicalTrials.gov, NCT Atkins MA et al. Presented at 2015 ASCO Annual Meeting; May 29-Jun 2, 2015; Chicago, IL. Abstr Atkins MA et al. Presented at 2016 ASCO Annual Meeting; Jun 3-Jun 7, 2016; Chicago, IL. Abstr 3009.

20 Immune-Mediated AEs: Incidence Any: 58% Grade 3-4: 25% Presenter: GV Long a Includes grade 3 rash (n = 6), grade 3 drug reaction (n = 3), grade 3 pemphigoid (n = 1), and grade 2 exfoliative dermatitis (n = 1) Data cutoff date: Mar 17, 2016.

21 Summary and Conclusions- Ipi + Pembro Pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg appears tolerable 72% received all 4 ipilimumab doses No treatment-related deaths 25% grade 3-4 immune-mediated Aes Pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg has robust antitumor activity 57% ORR (RECIST v1.1, central review) 98% of responders remained in response ORR similar across key subgroups 70% progression-free Presenter: GV Long at 6 months G. Long

22 Anti-PD1 therapy in 2016 An argument for first line therapy Combination anti-pd1 + anti-ctla4 provides: Comparable response rates and OS to targeted therapy Better PFS compared to targeted therapy Can we use lower dose of Ipi- in combination setting? Biomarkers- Provocative in suggesting a subset of patients may benefit equally from single agent anti-pd1 vs. dual checkpoint inhibitors Toxicity- remember all itises - also unusual ones- type I DM, nephritis, myositis % patients on combination require high dose steroids Long term survivorship issues Ernstoff

23 Genomic Analysis and 3-Year Efficacy and Safety Update of COMBI-d A phase 3 study of dabrafenib + trametinib vs dabrafenib monotherapy in patients with unresectable or metastatic BRAF V600E/K mutant cutaneous melanoma K.T. Flaherty, M.A. Davies, J. Grob, G.V. Long, P. Nathan, A. Ribas, C. Robert, D. Schadendorf, D.T. Frederick, M.R. Hammond, J. Jane-Valbuena, X.J. Mu, M. Squires, S.A. Jaeger, S.R. Lane, B. Mookerjee, L.A. Garraway

24 COMBI-d OS a 58% of D+T patients alive at 3 years still on D+T Progression-Free Survival Overall Survival 1.0 Dabrafenib + Trametinib (n = 211) 1.0 Dabrafenib + Trametinib (n = 211) PFS Probability y PFS, 30% OS Probability y OS, 52% 3-y OS, 44% y PFS, 16% 3-y PFS, 22% y OS, 43% 3-y OS, 32% 0.0 Dabrafenib + Placebo (n = 212) 3-y PFS, 12% 0.0 Dabrafenib + Placebo (n = 212) b 0 Number at risk D+T Months From Randomization Months From Randomization Number at risk D+T D+Pbo D+Pbo a Intent-to-treat population; b Dabrafenib + placebo includes 26 patients who crossed over to combination arm; +, censored. Presented by: Keith T. Flaherty, MD

25 COMBI-d: Normal LDH a and < 3 Disease Sites b PFS OS 1.0 Dabrafenib + Trametinib (n = 76) 1.0 Dabrafenib + Trametinib (n = 76) PFS Probability y PFS, 38% OS Probability y OS, 61% 2-y OS, 68 % 3-y OS, 62% 3-y OS, 45% Dabrafenib + Placebo (n = 96) 3-y PFS, 15% 0.0 Dabrafenib + Placebo (n = 96) Number at risk D+T Months From Randomization Number at risk D+T Months From Randomization D+Pbo D+Pbo a Baseline LDH ULN; b Any organ at baseline with 1 metastasis could be counted as a single disease site; +, censored. Presented by: Keith T. Flaherty, MD

26 Conclusions- D + T vs D Dabrafenib + trametinib continued to show significant benefit over dabrafenib monotherapy despite cross-over 3-year OS, 44% vs 32% 3-year PFS, 22% vs 12% Best 3-year outcome with dabrafenib + trametinib was observed in patients with normal LDH and < 3 disease sites 3-year OS, 62% 3-year PFS, 38% Longest OS follow-up among randomized phase 3 trials evaluating BRAFi + MEKi in patients with BRAF-mutant metastatic melanoma Presented by: Keith T. Flaherty, MD

27 Responses to Anti-PD1 + Anti-CTLA4 (With COMBI -D Study comparison) Checkmate 067 N+I N I ORR % CR % MEDIAN DURATION OF RESPONSE (M) NR ONGOING RESPONSE IN RESPONDER % Keynote 029 P + I ORR % 57 CR % 15 COMBI-d D+T D CR % ORR % Presented by:

28 KID IN A CANDY STORY WHAT LOLLIES SHOULD WE CHOOSE? G. Long

29 BRAF/MEKi Anti-PD-1 Presented by Georgina V. Long

30 Overall Survival Metastatic Melanoma 25 35% 46% 47% 56% 70% 71% 71% Pembro b 74% Dab + Tram c 75% Vem + Cobi 73% Nivo+Ipi (Ph II) % Nivo a 15% 24% 29% Ipi 45% Dab 53% Dab + Tram c 2-year OS 48% Vem + Cobi 49% Pembro (Ph I) 64% Nivo + Ipi (Ph II) 55% Pembro 3-year OS 22% Ipi 42% Nivo (Ph I) 38% Dab+Tram(Ph II) 44% Dab + Tram 40/45% Pembro (Ph I) 5-year OS 18% Ipi 34% Nivo (Ph I) Slide courtesy Georgina V Long

31 Treatment Selection

32 Selection of Treatment BRAF Wild Type Immunotherapy- First Line or Single Agent Anti-PD-1 Combination Anti-PD-1 and Ipilumumab Clinical Trials

33 Selection of Treatment BRAF Wild Type Critical to obtain mutation testing beyond BRAF NRAS, Kit, now NF-1 or Single Agent Anti-PD-1 Antibody Combination Anti-PD-1 Antibody and Ipilumumab Clinical Trials

34 Selection of Treatment BRAF Mutant? Optimal sequence

35 What we have learned Anti-PD-1 therapy appropriate first line therapy- BRAF wild type or BRAF mutant Anti-PD-1 + Anti CTLA4 (Ipi) looks better than single agent anti-pd-1 These treatments are new standards for advanced melanoma therapy Toxicity of combination immunotherapy is severe, lower dose ipi strategy very interesting. BRAF and MEK inhibitors- active- still need to sort out when to use. Key to perform somatic mutation testing beyond BRAF Many clinical trial options

Immunoterapia e melanoma maligno metastatico: siamo partiti da li. Vanna Chiarion Sileni Istituto Oncologico Veneto

Immunoterapia e melanoma maligno metastatico: siamo partiti da li Vanna Chiarion Sileni Istituto Oncologico Veneto Vanna.chiarion@iov.veneto.it Metastatic Melanoma Available Treatment: 197 217 Zelboraf