Combination Approaches in Melanoma: A Balancing Act

Combination Approaches in Melanoma: A Balancing Act Antoni Ribas, MD, PhD Jonsson Comprehensive Cancer Center University of California Los Angeles Los Angeles, California

Advances in the Treatment of Metastatic Melanoma Based on Understanding Cancer Biology Applied to Patients McArthur GA, et al. J Clin Oncol. 2013;31(4):499-506.

First-Line Therapy: Progression-Free Survival Weighted averages, first-line % Progression-Free Survival Mean survival curves created by weighted averaging of digitized Kaplan- Meier survival curves of patients with metastatic melanoma treated in selected clinical trials Ugurel S, et al. Eur J Cancer. 2016;53:125-134. Months

Advances in the Treatment of Metastatic Melanoma Based on Understanding Cancer Biology Applied to Patients McArthur GA, et al. J Clin Oncol. 2013;31(4):499-506.

Acquired Resistance to BRAF Inhibitors: PI3K/PTEN/AKT Mutations PI3K PTEN BRAF inhibitor BRAF MEK ERK AKT TORC S6K S6 Oncogenic cell proliferation and survival

Acquired Resistance to BRAF Inhibitors: PI3K/PTEN/AKT Mutations PI3K PTEN BRAF inhibitor MEK inhibitor BRAF MEK ERK AKT TORC S6K S6 Oncogenic cell proliferation and survival

BRAF + MEK Inhibitor Combination: The New Standard in BRAF V600 Mutated Melanoma Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma 1 Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma 2 Improved Overall Survival in Melanoma With Combined Dabrafenib and Trametinib 3 1. Larkin J, et al. N Engl J Med. 2014;371(20):1867-1876. 2. Long GV, et al. N Engl J Med. 2014;371(20):1877-1888. 3. Robert C, et al. N Engl J Med. 2014;372(1):30-39.

Double Oncogenic Pathway Inhibition to Treat Melanoma BRAF V600 Mutant Melanoma Wild-Type Normal Cell P P MEK1/2 ERK BRAF V600 CCND1 CDK4/6 MEKi BRAFi Improve ORR Prevent resistance (more durable responses and improved PFS) Improve OS CRAF P P RAS MEK1/2 ERK CCND1 BRAF CDK4/6 BRAFi MEKi Decrease toxicities from paradoxical MAPK activation

Branched Evolution Underlying Acquired BRAF Inhibitor Resistance Shi H, et al. Cancer Disc. 2014;4(1):80-93.

Rare Genetic Variants & Fetal Pathways Cause Acquired Resistance and Clinical Relapse Combination therapy to deplete the drug-persisters BRAF inhibitor BRAF mutation A genetic variant A developmental pathway BRAFi acquired resistance modeling according to Roger Lo, personal communication

Intermittent Dosing and Drug Sensitivity in Animal Models Tumor Volume, mm 3 Tumor Volume, mm 3 P<.0001 P =.0025 Das Thakur M, et al. Nature. 2013;494(7436):251-255.

S1320: A Randomized Phase II Trial of Intermittent Vs Continuous Dosing of Dabrafenib and Trametinib in BRAF V600E/K Mutant Melanoma Intermittent dosing of BRAFi delayed the development of acquired resistance in a mouse model (Das Thakur M, et al. Nature. 2013;494(7436):251-255.) Melanoma cells resistant to the combination of BRAFi+MEKi display increased drug addiction compared to those resistant to BRAFi alone (Moriceau, Hugo et al. Cancer Cell 2015) Features: - 10 week lead-in - 3 week holiday / 5 weeks on treatment - q 8 week assessments H 0 H 1 HR 0.67 2-sided α 20% Power 90% Patients registered 280 Patients eligible 226 PFS = 9.4 months PFS = 14.1 months Algazi AP, et al. J Clin Oncol. 2015;33(suppl): Abstract TPS9093.

Acquired Resistance to BRAF Inhibitors: PI3K/PTEN/AKT Mutations PI3K PTEN BRAF inhibitor MEK inhibitor BRAF MEK ERK AKT TORC S6K S6 Oncogenic cell proliferation and survival Shi H, et al. Cancer Discov. 2014;4(1):80-93.

S1221: Phase I Trial of BRAFi+MEKi+AKTi for BRAF Mutated Melanoma BRAF inhibitor MEK inhibitor BRAF MEK ERK PI3KPTEN AKT TORC S6K S6 AKT inhibitor Resistance to BRAF inhibitor therapy is mediated in 2/3 of the cases by reactivation of the MAPK, and in 1/3 by alternate signaling through AKT (Shi H, et al. Cancer Discov. 2014;4(1):69-79.) Combination of the BRAFi dabrafenib with the AKT inhibitor GSK795 can reverse resistance to BRAFi single agent (Lassen A, et al. Mol Cancer. 2014;13:83.) Cohort 1: Doublet therapy dabrafenib + GSK795 phase I 8 patients treated Cohort 2: Triplet dabrafenib + trametinib + GSK795 phase I 3 patients enrolled SWOG S1221 Study. Available at: https://clinicaltrials.gov/ct2/show/nct01902173. Accessed on August 17, 2016.

Advances in the Treatment of Metastatic Melanoma Based on Understanding Cancer Biology Applied to Patients Anti CTLA-4 Anti PD-1/L1 PD-L1, programmed death-ligand 1 McArthur GA, et al. J Clin Oncol. 2013;31(4):499-506.

Blockade of PD-1 or CTLA-4 Signaling Ribas A, et al. N Engl J Med. 2012;366(26):2517-2519.

Inhibiting PD 1-Mediated Adaptive Immune Resistance Pre-existing T-Cell Infiltration Anti PD-1 Anti PD-L1 Melanoma cell Interferons Tumeh P, et al. Nature. 2014;515(7528):568-571. Herbst RS, et al. Nature. 2014;515(7528):563-567.

Inhibiting PD 1-Mediated Adaptive Immune Resistance TCR Clonality 1 Anti PD-1 Anti PD-L1 Melanoma cell Interferons Clonality 1 Expression Score 2.4 2.2 2.0 1.8 1.6 1.4 1.2 IFN Signature 2 1.0 0.8 Nonresponder Responder Best Overall Response, RECISTv1.1 IFN, interferon; RECIST, Response Evaluation Criteria in Solid Tumors; TCR, t-cell receptor 1. Tumeh P, et al. Nature. 2014;515(7528):568-571. 2. Ribas A, et al. J Clin Oncol. 2015;33(suppl): Abstract 3001.

Inhibiting PD 1-Mediated Adaptive Immune Resistance Increased Mutational Load Anti PD-1 Anti PD-L1 Melanoma cell Rizvi NA, et al. Science. 2015;348(6230):124-128. Interferons Le DT, et al. N Engl J Med. 2015;372(26):2509-2520. Hugo W, et al. Cell. 2016;165(1):35-44.

Inhibiting PD 1-Mediated Adaptive Immune Resistance IPRES, Innate Anti PD-1 Resistance 1 Anti PD-1 Anti PD-L1 Melanoma cell Interferons PDJ Amplicon 2 1. Hugo W, et al. Cell. 2016;165(1):35-44. 2. Ansell SM, et al. N Engl J Med. 2015;372(4):311-319.

Management of Cancer in the Post Anti-PD-1/L1 Era Anti PD-1/Anti PD-L1 Bring T-cells into tumors: + Anti CTLA-4 + Immune activating antibodies or cytokines + TLR agonists or oncolytic viruses + IDO or macrophage inhibitors + Targeted therapies Generate T-cells: Vaccines TCR engineered ACT CAR engineered ACT

PFS (Intent-to-Treat) NIVO + IPI (N = 314) NIVO (N = 316) IPI (N = 315) Proportion Alive and Progression-Free 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 NIVO + IPI NIVO IPI Median PFS, months (95% CI) HR (99.5% CI) vs IPI HR (95% CI) vs NIVO 11.5 (8.9 16.7) 0.42 (0.31 0.57)* 0.74 (0.60 0.92)** 6.9 (4.3 9.5) 0.57 (0.43 0.76)* 2.9 (2.8 3.4) -- -- -- *Stratified log-rank P<.00001 vs IPI **Exploratory endpoint 0.0 0 3 6 9 12 15 18 21 No. at Risk Months NIVO + IPI 314 219 173 151 65 11 1 0 NIVO 316 177 147 124 50 9 1 0 IPI 315 137 77 54 24 4 0 0 IPI, ipilimumab; NIVO, nivolumab Wolchok JD, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA1.

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 3 4 95.5 55.0 82.1 16.3 86.2 27.3 36.4 29.4 7.7 5.1 14.8 13.2 Treatment-related death* 0 0.3 0.3 *One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest). 67.5% of patients (81/120) who discontinued the NIVO + IPI combination due to treatment-related AEs developed a response Wolchok JD, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA1.

PFS by PD-L1 Expression Level (5%) PD-L1 5%* PD-L1 <5%* 1.0 mpfs HR NIVO + IPI 14.0 0.40 1.0 mpfs HR NIVO + IPI 11.2 0.42 Proportion Alive and Progression-Free 0.8 0.6 0.4 0.2 0.0 NIVO + IPI NIVO IPI NIVO 14.0 0.40 IPI 3.9 -- Proportion Alive and Progression-Free 0.8 0.6 0.4 0.2 0.0 NIVO + IPI NIVO IPI NIVO 5.3 0.60 IPI 2.8 -- 0 3 6 9 12 15 17 0 3 6 9 12 15 17 No. at Risk Months No. at Risk Months NIVO + IPI 68 53 44 39 16 1 0 NIVO 80 57 51 43 16 4 0 IPI 75 40 22 17 9 2 0 NIVO + IPI 210 142 112 96 42 9 2 NIVO 208 108 88 74 31 5 2 IPI 202 82 44 31 12 1 *Per validated PD-L1 immunohistochemical assay based on PD-L1 staining of tumor cells in a section of at least 100 evaluable tumor cells Wolchok JD, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA1.

Rationale to Combine T-VEC With PD-1 Blockade Acquired Resistance Direct tumor cell lyses Release of tumor antigen Attract DC by GM-CSF Release of progeny virus Induce IFN response Up-regulation of PD-L1? Primary Resistance DC, dendritic cells; T-VEC, talimogene laherparepvec

MASTERKEY-265 Phase Ib Study Schema N = 21 Unresectable stage III or IV melanoma Treatment naive Injectable lesions No clinically active brain mets No active herpetic skin lesions or prior complications from herpetic infection T-VEC intralesional Up to 4 ml per treatment 1 st dose 10 6 pfu/ml Then 10 8 pfu/ml q2w Week 5 Week 2 Week 0 irrc, immune-related response criteria; PFU, plaque forming units Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568. T-VEC Intralesional Pembrolizumab 200mg IV q2w DLT Window Week 6 Treatment until whichever occurs first: Progressive disease (PD) per irrc Intolerance All injectable tumors disappear (T-VEC only) 2 Years S A F E T Y F O L L O W - U P 30 (+7) days after end of treatment

Best Change in Tumor Burden Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568.

Examples of Responses in Non-Injected Tumors Baseline (Week -5) Week 0 Week 12 Patient 2 Patient 1 Long et al. SMR 2015

Advances in the Treatment of Metastatic Melanoma Anti CTLA-4 Anti PD-1/L1 McArthur GA, et al. J Clin Oncol. 2013;31(4):499-506.

EA6134: Ipi/Nivo to D/T vs D/T to Ipi/Nivo Eligibility BRAFV600+ ECOG PS 1.0 2.1 LDH 1.Normal 2.Elevated R A N D O M I Z E Arm 1: Ipi 3 mg/kg & Nivo 1 mg/kg, q 3 weeks x 4 + Maintenance Nivo Arm 2: Dabra 150 mg bid & Trame 2 mg qd PD PD Dabra 150 mg bid & Trame 2 mg qd Ipi 3 mg/kg & Nivo 1 mg/kg, q 3 weeks x 4 + Maintenance Nivo Open to accrual Dabra (D), dabrafenib; ECOG PS, Eastern Cooperative Oncology Group performance status; Trame (T), trametinib Available at: http://ecog-acrin.org/wp-content/uploads/2014/10/ea6134-physician-fact-sheet.pdf. Accessed on August 18, 2016.

How Can We Do Better? NIH Director s Blog* Knocking Out Melanoma: Does This Triple Combo Have What It Takes? Posted on March 31, 2015 by Dr. Francis Collins Comment on: Hu-Lieskovan S, et al. Sci Transl Med. 2015;7:279ra41. *Available at: https://directorsblog.nih.gov/2015/03/31/knocking-out-melanoma-does-this-triple-combo-have-what-it-takes/. Accessed on August 18, 2016.

Combining Immunotherapy and Targeted Therapy for Melanoma? Improved Survival With Ipilimumab in Patients with Metastatic Melanoma 1 Improved Survival With Vemurafenib in Melanoma With BRAF V600E Mutation 2 Percent Alive Immunotherapy Percent Alive Targeted therapy Percent Alive Combination??? 0 1 2 3 0 1 2 3 Years Years 0 1 2 3 Years Modified from: Ribas A, et al. Clin Cancer Res. 2012;18(2):336-341. 1. Hodi FS, et al. N Engl J Med. 2010;363(8):711-723. 2. Chapman PB, et al. N Engl J Med. 2011;364(26):2507-2516.

Hepatotoxicity With Combination of Vemurafenib and Ipilimumab Antoni Ribas, MD, PhD University of California Los Angeles, CA F. Stephen Hodi, MD Dana-Farber Cancer Institute, Boston, MA Cyril Konto, MD Bristol-Meyers Squibb, Wallingford, CT Jedd Wolchok, MD, PhD Memorial Sloan Kettering Cancer Center, New York, NY Ribas A, et al. N Engl J Med. 2013;368(14):1365-1366. Clinical trial of vemurafenib + ipilimumab stopped early due to increased frequency of grade 3 elevations in transaminases (higher than the expected rate with each agent alone)

Enhanced In Vivo Antitumor Activity With Dabrafenib, Trametinib, and Anti PD-1 Siwen Hu-Lieskovan, MD, PhD Blanca Homet Moreno, MD, PhD Ongoing clinical trials with: - Dabrafenib + trametinib + anti PD-L1 - Dabrafenib + trametinib + anti PD-1 - Vemurafenib + cobimetinib + anti PD-L1 Hu-Lieskovan S, Homet Moreno B, et al. Science Translational Med. 2015;7(279):279ra41.

KEYNOTE 022: Pembrolizumab in Combination With Dabrafenib and Trametinib Longitudinal Change From Baseline in Tumor Size a Maximum Percentage Change From Baseline in Tumor Size b Change From Baseline, % 100 75 50 25 0-25 -50-75 -100 0 10 20 30 40 50 60 70 Time, weeks Change From Baseline in Sum of Longest Diameter of Target Lesion, % 100 80 60 40 20 0-20 -40-60 -80-1 00 a Assessed in all patients who received 1 dose of study treatment (n = 13). b Only patients with measurable disease per RECIST v1.1 by investigator review at baseline and 1 post-baseline tumor assessment were included (n = 13). c In patients with confirmed response only. Data cutoff date: January 8, 2016. Ribas A, et al. J Clin Oncol. 2016;34(suppl): Abstract 3014.

Conclusions A refined understanding of melanoma biology leading to tumor regressions with targeted therapies BRAF + MEK inhibitors for BRAF mutated melanoma Durable responses (and potential cures) in a subset of patients with metastatic melanoma treated with different modes of immunotherapy Anti CTLA-4 Anti PD-1/L1 Anti PD-1/L1 combinations