Immunotherapy for Melanoma: The End of The Beginning. Jedd D. Wolchok, MD, PhD

Transcription

1 Immunotherapy for Melanoma: The End of The Beginning Jedd D. Wolchok, MD, PhD ME SL K RI M A - O ER NG E

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3 High-Dose IL-2 Therapy* Probability of continuing response CR (n = 17) PR (n = 26) CR + PR (n = 43) RR: 16% (43/270) Durable responses Duration of response, months Median 8.9 mos CR: not reached *Atkins et al. JCO, 1999 (n=270) Atkins et al, JCO, 1999

4 Ipilimumab Augments T-Cell Activation and Proliferation T-cell activation T-cell inhibition T-cell remains active T-cell T-cell T-cell CD28 CTLA-4 TCR CD28 TCR CTLA-4 TCR APC HLA CD80/ CD86 APC HLA CD80/ CD86 APC HLA CD80/ CD86 Ipilimumab blocks CTLA-4 Adapted from O Day et al. Plenary session presentation, abstract #4, ASCO 2010.

5 Kaplan-Meier Analysis of Survival Comparison HR P-value Arm A vs C Arm B vs C Arm A vs B Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C) 1 2 Years 3 4 Survival Rate Ipilimumab + gp100 Ipilimumab alone gp100 alone 1-year 44% 46% 25% 2-year 22% 24% 14%

6 Study 024: Overall Survival Proportion Alive Ipilimumab + DTIC Placebo + DTIC Years Estimated Survival Rate 1 Year 2 Year 3 Year* Ipilimumab + DTIC n= Placebo + DTIC n= *3-year survival was a post-hoc analysis 6

7 Immune-Related Adverse Events Rash (approx 20%) Colitis/enteritis (approx 15%) Elevated AST/ALT (approx 10%) Thyroiditis (2 cases) Adrenal insufficiency (1 case) Hypophysitis (4 seen in 170 patients at MSKCC) Severity is inversely related to vigilance of surveillance. If detected early, most are easily treated and reversible.

8 11/28/06 1/9/07

9 Ipilimumab Pattern of Response: Responses After the Appearance and Subsequent Disappearance of New Lesions Pre-treatment July 2006 Week 12: Progression 3 mg/kg ipilimumab Q3W X 4 New lesions Week 20: Regression Week 36: Still Regressing Source: 2008 ASCO Abstract #3020 Wolchok.

10 Four Patterns of Response to Ipilimumab Therapy were Observed 2 conventional: Response in baseline lesions Stable disease with slow, steady decline in total tumor volume 2 novel: Response after initial increase in total tumor volume Response in index plus new lesions at or after the appearance of new lesions

11 CTLA-4 Blockade Enhances Tumor-Specific Immune Responses Attenuated or Unrestrained Terminated Proliferation Proliferation IL-2 Tumor APC APC Necrotic Death Vaccines Chemotherapy Irradiation Hormone therapy Anti-angiogenesis Antibodies Targeted pathway inhibitors TCR Peptide/MHC CD28 B7-1,2 CTLA-4

12 April 2004: 33 woman w/ pt2an0 (Stage IB) melanoma arising in upper back (non-ulcerated, 2mf) October 2008: Left pulmonary nodule detected incidentally by CXR with CT scan/pet confirmation (also with additional RLL 3mm nodule) December 2008: 2 cycles of Cisplatin, Vinblastine, Temodar February 2009: August 2009: Left lower lobectomy Unresectable recurrence Postow and Callahan, NEJM, 2012

13 A B C D E A B C D E A B C D E August 2009 November 2010 January 2011 April 2011 October 2011 Unresectable Recurrence Ipilimumab Induction Maintenance Radiation Maintenance F December 2010 Radiation 8/09 A-A Stable 9/09 12/09 Slow Progression 11/10 B-B 12/10 F 1/11 C-C Response 4/11 D-D Stable 10/11 E-E

14 A Phase II Randomized Study to Evaluate the Efficacy of Combining Ipilimumab (3mg/kg) with Different Doses/Schedules of External Beam Radiotherapy Eligibility Unresectable metastatic melanoma At least 2 measurable sites by irrc and mwho One lesion in need of radiotherapy Randomize Conventional 30Gy (3Gy x 10 fractions) Starting between 1 st and 2 nd dose of ipi Complete standard ipi induction High Dose Per Fraction 24Gy (8Gy x 3 fractions) Starting between 1 st and 2 nd dose of ipi Complete standard ipi induction Primary Endpoint Disease control rate (SD, PR, CR) at week 18 by mwho Supported by Ludwig Institute for Cancer Research with correlative support from BMS Participating Sites: MSKCC, Stanford University, University of Chicago, NCI

15 Small Molecule Combinations: RAF inhibitors and Immunotherapy Boni et al Wilmott et al. 2011

16 Combination of targeted therapy and immune modulation % Tumor volume Percent tumor growth after therapy Days post tumor induction vehicle PLX anti-ctla-4 PLX + anti-ctla4 n= 4-5 mice/group

17 Paradoxical activation of the MAPK pathway: Also seen in T cells? BRAF-wild type tumor cells RAS mutant SCCs T cells TCR * RAS * * RAS RAS?? perk Poulikakos et al. Nature 2010, Hatzivassilou et al. Nature 2010, Heidorn et al. Cell 2010, perk Su et al. NEJM 2012, Oberholzer et al. JCO 2012?

18 RAF inhibitors enhance T cell activation in vitro BMS IC 50 : BRAF 4.5 nm BRAF V600E 6.0 nm CRAF 2.6 nm PLX4720 IC 50 : BRAF 160 nm BRAF V600E 13 nm CRAF 6.7* nm Callahan et al., manuscript in preparation

19 T cells from a patients treated with BMS have enhanced MAPK pathway activity Pt. 2-6 Pt. 2-3 MAPK signaling Proliferation MAPK signaling Proliferation perk ki67 perk ki67 BMS908662: Ipilimumab:

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21 Positive and Negative Signals Regulate T cell Activation Ipilimumab, tremelimumab BMS ,PF Anti- OX40 CT-011,MDX-1106, MK-3475, RG7446, AMP224

22 Clinical Activity and Safety of Anti-PD-1 (BMS , MDX-1106) in Patients with Advanced Melanoma F.S. Hodi, 1 M. Sznol, 2 D.F. McDermott, 3 R.D. Carvajal, 4 D.P. Lawrence, 5 S.L. Topalian, 6 J.M. Wigginton, 7 D. McDonald, 7 G. Kollia, 7 A. Gupta, 7 J. Sosman 8 1 Dana-Farber Cancer Institute, Boston, MA; 2 Yale Cancer Center, New Haven, CT; 3 Beth Israel Deaconess Medical Center, Boston, MA; 4 Memorial Sloan-Kettering Cancer Center, New York, NY; 5 Massachusetts General Hospital Cancer Center, Boston, MA; 6 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; 7 Bristol-Myers Squibb, Princeton, NJ; 8 Vanderbilt University Medical Center, Nashville, TN ASCO 2012; Abstract 8507

23 Role of PD-1 in Suppressing Antitumor Immunity APC B7.1 CD28 T cell Activation (cytokines, lysis, prolif., migration) MHC-Ag Tumor TCR Signal 1 PD-1 PD-L1 Inhibition (anergy, exhaustion, death) (-) (-) Tumor (-) Anti- PD-1 Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012

24 BMS Related Adverse Events Drug-Related Adverse Event All Grades Grades 3-4 Tot Pop* MEL Tot Pop MEL No. (%) of Patients, All Doses Any adverse event 207 (70) 82 (79) 41 (14) 21 (20) Fatigue 72 (24) 30 (29) 5 (2) 2 (2) Rash 36 (12) 21 (20) Diarrhea 33 (11) 18 (17) 3 (1) 2 (2) Pruritus 28 (9) 15 (14) 1 (0.3) Nausea 24 (8) 9 (9) 1 (0.3) 1 (1) Appetite 24 (8) 7 (7) Hemoglobin 19 (6) 7 (7) 1 (0.3) 1 (1) Pyrexia 16 (5) 5 (5) *AEs occurring in 5% of the total population. Common grade 3-4 AEs also included lymphopenia (3 pts) and abdominal pain and lipase increased (2 each). An additional 27 grade 3-4-related AEs were observed and one or more occurred in a single patient. ASCO 2012; Abstract 8507

25 Changes in Target Lesions Over Time in Melanoma Patients ASCO 2012; Abstract 8507

26 Complete Regression of Metastatic Melanoma (BMS , 3 mg/kg) Associated With Vitiligo Pre Normal skin Boundary Post Vitiligo History: 62-year-old male had previously developed PD following IL-2, temozolomide, and multiple surgeries.

27 Preliminary Clinical Efficacy and Safety of MK-3475 (Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Melanoma Omid Hamid 1, Adil Daud 2, Caroline Robert 3, F. Stephen Hodi 4, Wen-Jen Hwu 5, Richard Kefford 6, Jedd Wolchok 7, Peter Hersey 8, Roxana Dronca 9, Richard Joseph 10, Jeffrey Weber 11, Tara Gangadhar 12, Amita Patnaik 13, Robert Iannone 14, Hassane Zarour 15, Kevin Gergich 14, Cong 1 The Angeles Clinic and Chen 14 Research Institute, 2 University of California,, S. Peter Kang 14 San Francisco, 3 Service de Dermatologie, Antoni Ribas 16 Institut Gustave Roussy, 4 Dana-Farber, Harvard Cancer Center, 5 MD Anderson Cancer Center, 6 Westmead Hospital and Melanoma Institute Australia, 7 Memorial Sloan-Kettering Center, 8 Newcastle Melanoma Center, University of Sydney, 9 Mayo Clinic, Rochester, 10 Mayo Clinic, Jacksonville, 11 Moffitt Cancer Center, 12 University of Pennsylvania School of Medicine, 13 South Texas Accelerated Research Therapeutics (START), 14 Merck, Sharp & Dolme, Whitehouse Station, NJ, USA, 15 Hillman Cancer Center, University of Pittsburgh, 16 University of California, Los Angeles

28 MK-3475 is a High-Affinity Humanized IgG4 PD-1 Blocking Antibody Mouse variable (CDR) sequences grafted onto human framework Parental Antibody Mouse IgG1 K D : ~28 pm IC50: ~800 pm EC50: ~118 pm MK-3475 Human IgG4 K D : ~29 pm IC50: ~600 pm EC50: ~70 pm Similar reactivity to human and cynomolgus PD-1, no reactivity to mouse or rat PD-1 Humanized IgG4 - no cytotoxic (ADCC/CDC) activity Contains stabilizing S228P sequence alteration

29 Adverse Events >10% Incidence All Grades and Corresponding Drug-Related and Grade 3-5 Part B: All Melanoma Patients: N=132 Adverse Events All Grades Grades 3-5 All AEs Drug Related All AEs Drug Related N (%) N (%) N (%) N (%) Any Adverse Event 125 (94.6) 95 (71.9) 36 (27.2) 12 (9.0) Fatigue 37 (28.0) 29 (21.9) 2 (1.5) 1 (0.7) Nausea 31 (23.4) 11 (8.3) 1 (0.7) 0 (0.0) Rash 29 (21.9) 24 (18.1) 2 (1.5) 2 (1.5) Diarrhea 26 (19.7) 18 (13.6) 0 (0.0) 0 (0.0) Cough 25 (18.9) 7 (5.3) 0 (0.0) 0 (0.0) Pruritus 22 (16.6) 19 (14.3) 0 (0.0) 0 (0.0) Arthralgia 18 (13.6) 15 (11.3) 0 (0.0) 0 (0.0) Headache 19 (14.3) 10 (7.5) 2 (1.5) 0 (0.0) Abdominal Pain 18 (13.6) 6 (4.5) 3 (2.2) 1 (0.7) Increased AST 16 (12.1) 10 (7.5) 1 (0.7) 1 (0.7) Pyrexia 15 (11.3) 7 (5.3) 0 (0.0) 0 (0.0) Decreased Appetite 14 (10.6) 5 (3.7) 2 (1.5) 1 (0.7) Patients who started treatment with MK-3475 before July 31, 2012 and have entered data by Sept 28, 2012

30 Preliminary Best Overall Response of MK-3475 (Unconfirmed + Confirmed Responses) in Advanced MEL Patients (Part B: Based RECIST 1.1 and Centrally Reviewed Response Data) Complete Response (N, 95% CI) Objective Response (N, 95% CI) Disease Control Rate (N, 95% CI) All MEL N=83 5% (4; 2%-13%) 47% (39; 34% - 56%) 60% (50; 48%- 70%) IPI Naïve N=58 7% (4; 2%-18%) 50% (29; 35% -61 %) 67% (39; 51%-76%) IPI Treated N=25 0 % 40% (10; 17% -59%) All patients were dosed at 10 mg/kg Includes all patients who received first dose as of April 25, Centrally available response information as of Oct 19, 2012 Two patients were excluded due to unavailability of central read at the time of analysis. Objective response= confirmed and unconfirmed complete and partial response Disease control rate= objective response + stable disease 44% (11; 24%-68%)

31 Clinical Activity in a Melanoma Patient Baseline: 13/Apr/ /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

32 Blocking multiple T-cell co-inhibitory pathways leads to increased tumor rejection. Data shown is from B16-BL6 melanoma tumors. All mice received FVAX treatment. Curran et al. PNAS 2010

33 ipi pd- 1 ipi pd- 1 Dual CTLA-4 + PD-1 Blockade: Trial Design induction maintenance Cohort MDX1106 Ipilimumab mg/kg 3 mg/kg 2 1 mg/kg 3 mg/kg 2A 3 mg/kg 3 mg/kg 3 3 mg/kg 1 mg/kg Cohort MDX mg/kg 7 3 mg/kg

34 Patient 002 (MSKCC) 53 yo male with Stage IV (M1c) melanoma previously treated with temozolomide. He achieved a major PR (92% at 12 weeks, 99% at 18 weeks) without significant toxicity. He underwent a biopsy of a regressing subcutaneous nodule after 12 weeks on treatment, demonstrating robust immune infiltrate. He continues to have stable, near complete regression of disease after 2 years. Pre treatment 12 wks 18 wks

35 Summary Checkpoint blockade is an effective treatment with durable responses. Intense study of both predictive and pharmacodynamic biomarkers of response and toxicity will allow for more intelligent patient selection and novel target discovery. New and promising immune modulators are in clinical development. Combination therapy will be necessary for immunotherapy to achieve full potential (other immune modulators, vaccines, radiation, chemotherapy, targeted therapy, anti-angiogenic therapy).

36 Acknowledgments Jim Allison Wolchok Lab Francesca Avogadri Sadna Budhu Daniel Hirschhorn- Cymerman Nicole Malandro Taha Merghoub Judith Murphy David Schaer Stephanie Terzulli Melanoma-Sarcoma Svc Gary Schwartz Paul Chapman Richard Carvajal Ruth-Ann Roman Evelina Pogoriler Sean Houghton Lloyd Old Alan Houghton Ludwig Institute Gerd Ritter Sacha Gnjatic Erika Ritter Achim Jungbluth Ludwig Center Sasha Rudensky Jianda Yuan Zhen Yu Mu Matthew Adamow Teresa Rasalan Immunology Pgm. Eric Pamer Gregoire Altan- Bonet Fox Chase Adam Cohen Yale Mario Sznol Ruth Halaban MD Anderson Pam Sharma Support: NCI P01 CA33049 and CA59350, R01 CA056821, RC2 CA148468, Ludwig Trust, Swim Across America, Goodwin Commonwealth Fund, Melanoma Research Alliance, Breast Cancer Research Foundation