Combination Approaches in Melanoma: A Balancing Act
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1 Combination Approaches in Melanoma: A Balancing Act Antoni Ribas, MD, PhD Jonsson Comprehensive Cancer Center University of California Los Angeles Los Angeles, California
2 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):
3 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: Months
4 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):
5 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
6 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
7 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): Long GV, et al. N Engl J Med. 2014;371(20): Robert C, et al. N Engl J Med. 2014;372(1):30-39.
8 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
9 Branched Evolution Underlying Acquired BRAF Inhibitor Resistance Shi H, et al. Cancer Disc. 2014;4(1):80-93.
10 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
11 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):
12 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): ) 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 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.
13 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.
14 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: Accessed on August 17, 2016.
15 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):
16 Blockade of PD-1 or CTLA-4 Signaling Ribas A, et al. N Engl J Med. 2012;366(26):
17 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): Herbst RS, et al. Nature. 2014;515(7528):
18 Inhibiting PD 1-Mediated Adaptive Immune Resistance TCR Clonality 1 Anti PD-1 Anti PD-L1 Melanoma cell Interferons Clonality 1 Expression Score IFN Signature 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): Ribas A, et al. J Clin Oncol. 2015;33(suppl): Abstract 3001.
19 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): Interferons Le DT, et al. N Engl J Med. 2015;372(26): Hugo W, et al. Cell. 2016;165(1):35-44.
20 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): Ansell SM, et al. N Engl J Med. 2015;372(4):
21 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
22 PFS (Intent-to-Treat) NIVO + IPI (N = 314) NIVO (N = 316) IPI (N = 315) Proportion Alive and Progression-Free NIVO + IPI NIVO IPI Median PFS, months (95% CI) HR (99.5% CI) vs IPI HR (95% CI) vs NIVO 11.5 ( ) 0.42 ( )* 0.74 ( )** 6.9 ( ) 0.57 ( )* 2.9 ( ) *Stratified log-rank P< vs IPI **Exploratory endpoint No. at Risk Months NIVO + IPI NIVO IPI IPI, ipilimumab; NIVO, nivolumab Wolchok JD, et al. J Clin Oncol. 2015;33(suppl): Abstract LBA1.
23 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 (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.
24 PFS by PD-L1 Expression Level (5%) PD-L1 5%* PD-L1 <5%* 1.0 mpfs HR NIVO + IPI mpfs HR NIVO + IPI Proportion Alive and Progression-Free NIVO + IPI NIVO IPI NIVO IPI Proportion Alive and Progression-Free NIVO + IPI NIVO IPI NIVO IPI No. at Risk Months No. at Risk Months NIVO + IPI NIVO IPI NIVO + IPI NIVO IPI *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.
25 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
26 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 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
27 Best Change in Tumor Burden Long GV, et al. J Clin Oncol. 2016;34(suppl): Abstract 9568.
28 Examples of Responses in Non-Injected Tumors Baseline (Week -5) Week 0 Week 12 Patient 2 Patient 1 Long et al. SMR 2015
29 Advances in the Treatment of Metastatic Melanoma Anti CTLA-4 Anti PD-1/L1 McArthur GA, et al. J Clin Oncol. 2013;31(4):
30 EA6134: Ipi/Nivo to D/T vs D/T to Ipi/Nivo Eligibility BRAFV600+ ECOG PS 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: Accessed on August 18, 2016.
31 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: Accessed on August 18, 2016.
32 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??? Years Years Years Modified from: Ribas A, et al. Clin Cancer Res. 2012;18(2): Hodi FS, et al. N Engl J Med. 2010;363(8): Chapman PB, et al. N Engl J Med. 2011;364(26):
33 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): 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)
34 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.
35 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, % Time, weeks Change From Baseline in Sum of Longest Diameter of Target Lesion, % 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, Ribas A, et al. J Clin Oncol. 2016;34(suppl): Abstract 3014.
36 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
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