Novel Immunotherapy Combinations May Be the Future of Melanoma Treatment

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Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies.
— Jeffrey Weber, MD, PhD

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The future treatment of melanoma may rely on combinations of immunotherapy agents beyond the current checkpoint inhibitors, and they are entering clinical trials, according to Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, who has spearheaded clinical trials in melanoma. At the 2016 European Society for Medical Oncology (ESMO) Congress, Dr. Weber gave attendees a taste of what’s to come in this tumor type.1

“It’s become obvious that multiple checkpoints exist that are both antagonistic and agonistic molecules controlling adaptive immunity and innate immunity,” Dr. Weber said. He counted more than 50 members of the immunoglobulin or tumor necrosis factor (TNF) receptor superfamilies that could act as controlling or regulatory molecules.

In other words, the pipeline is rife with drugs that will target far more than cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). T cells also express TIM-3, LAG-3, GITR, and other factors, which, if agonized or antagonized, could boost an immune response and yield potential clinical benefit. They include many receptor agonists, “which press on the gas pedal,” he added, and receptor antagonists, such as CTLA-4 and PD-1, which “release the brakes.” In addition to antibodies in development, up to 15 new indications could be approved for the current CTLA-4 and PD-1/programmed cell death ligand 1 (PD-L1) inhibitors, Dr. Weber predicted.

A High Bar to Surpass

The best results so far in advanced melanoma have been achieved by the combination of the anti–PD-1 agent nivolumab (Opdivo) and the anti–CTLA-4 agent ipilimumab (Yervoy). Nivolumab/ipilimumab yielded a 2-year survival rate of 63.8%, vs 53.6% for ipilimumab alone, in the CheckMate-069 trial.2

“In developing new checkpoint inhibitors, that’s the number we will have to be beat. If you want to add an inhibitory or agonistic molecule, you must at least match this, with less toxicity, and that’s a daunting challenge,” admitted Dr. Weber. “The fact that anti–PD-1 was developed early on sets a very high bar, which ironically could be a significant barrier to the successful development of other checkpoint inhibitors.”

Dr. Weber expects all new checkpoint agents to be tested in combination. Although 64% survival at 2 years is “fantastic,” he said, “at the end of the day, at least half the patients will need other therapy.” In all the tumor types for which these agents are important, “there is space for improvement,” he added.

Rationale for Novel Combinations

Immunotherapy combinations, with anti–PD-1/PD-L1 agents as backbones, will be driven by four key aims:

1. To bring T cells into tumors and overcome suppression of the immune system: For this, anti–PD-1/PD-L1 agents can be combined with anti–CTLA-4, immune-activating antibodies of cytokines, Toll-like receptor agonists, oncolytic viruses, indoleamine 2,3-dioxygenase (IDO) inhibitors, macrophage inhibitors, and targeted therapies.

2. To generate de novo T cells: This might be accomplished by vaccines, T-cell receptor–engineered adoptive-cell transfer, and chimeric antigen receptor–engineered adoptive-cell transfer.

3. To increase immune recognition: Stimulators of interferon genes (STING) agonists and interferons may help here.

4. To facilitate T-cell infiltration: This will be especially important for “cold” tumors that are deficient in T cells; the aim is to turn these “cold” tumors into “hot” ones. T-cell suppression, which occurs via multiple active and passive processes, must also be overcome.

These aims will be the mission of novel agonists, including anti-ICOS, anti-GITR, anti-OX40, anti-41BB, and anti-CD27, and novel antagonists, including anti–LAG-3, anti–TIM-3, anti-VISTA, anti-A2AR, anti-TIGIT, and IDO inhibitors.

“With T-regulatory cells, M2 macrophages, myeloid-derived suppressor cells—each a different lineage that requires a different maneuver to overcome—it’s amazing that any of this works at all,” he commented.

Sampler of Novel Combinations

Novel immunotherapies are not expected to be particularly potent as single agents, but in combination with other checkpoint inhibitors or targeted drugs, they are showing promise. More than a dozen combinations (including some triplets) are in phase II and phase III trials, including the following agents:

  • Ipilimumab plus IDO inhibitors, talimogene laherparepvec (also known as T-VEC), interferon, and nivolu­mab/histone deacetylase (HDAC) inhibitor
  • Nivolumab plus anti-CD137, TRAIL-R2 antibody, and LAG-3 antibody
  • Pembrolizumab (Keytruda) plus IDO inhibitor, talimogene laherparepvec, BRAF/MEK inhibitors, interferon, and JACK/STAT inhibitor
  • Atezolizumab (Tecentriq; anti–PD-L1) plus BRAF/MEK inhibitors
  • Durvalumab (anti–PD-L1) plus BRAF/MEK inhibitors.

“Looking at all the mouse data from almost every antibody, results are better with combinations than with single drugs alone,” he said. “Anti–PD-1/PD-L1 will be the backbone upon which all combinations will be based. The only question is whether we will have enough patients to enroll on these combination studies.”

Promising Early Data

Early data suggest that, for mutated patients, checkpoint inhibition plus BRAF and MEK inhibition is a powerful approach. In a study of the anti–PD-L1 antibody atezolizumab plus vemurafenib (Zelboraf) and cobimetinib (Cotellic), all patients in a 16-patient study had a reduction in target lesions; 3 patients had complete responses.3 The anti–PD-L1 antibody durvalumab plus a BRAF and MEK inhibitor produced a 69% response rate in another study, and all responses were ongoing at the time of analysis.4 In KEYNOTE 022, pembrolizumab in combination with dabrafenib (Tafinlar) and trametinib (Mekinist) produced tumor regression in almost all patients.5

Novel Combinations in Melanoma

  • The future treatment of advanced melanoma may involve combinations of agents, with anti–PD-1/PD-L1 and anti–CTLA-4 as backbones.
  • The pipeline is replete with agonistic and antagonistic molecules that target new checkpoints.

Pembrolizumab plus the IDO inhibitor epacadostat produced responses in 56% of 61 patients (63% of treatment-naive patients), and a disease control rate of 78% (and 75% of treatment-naive patients).6 Hepatotoxicity can be an issue with epacadostat, but it was not concerning in this study, he said.

One of the “more innovative” compounds targets OX40, an agonistic molecule that is expressed on activating T cells. An antibody against OX40 has shown significant and long-lasting antitumor activity in a mouse model of ovarian cancer when paired with an anti–PD-1 antibody.7 “This combination looks very impressive,” Dr. Weber commented. “You see very long survival [mean of 80 days, vs < 40 days for either agent alone], and, in fact, many of these mice were resistant to re-challenge. It’s clear that an adaptive immune response is promoted by the combination.”

An OX40 antibody (MOXR0916) was also combined with the PD-L1 inhibitor atezolizumab in a phase Ib study in solid tumors, but only 2 responses were observed among 51 patients, which he considered “disappointing.” However, this regimen will be further tested in melanoma and in other histologies with demonstrated responses to atezolizumab.

Checkpoint Inhibition Plus Talimogene Laherparepvec

The injectable oncolytic virus talimogene laherparepvec may prove to be a much better therapeutic when paired with a checkpoint inhibitor, vs its solo use, Dr. Weber said. “If you can inject enough tumors with enough volume, I think you will begin to turn cold tumors into hot tumors, and you could follow this with checkpoint inhibition,” he explained.

The combination of ipilimumab and talimogene laherparepvec doubled the response rate over ipilimumab alone, in a study in which even patients with visceral disease (not directly injected) experienced significant responses.8 “This looks very promising. Only time will tell whether we see a very good duration of response,” he commented.

Also quite promising is the combination of talimogene laherparepvec and pembrolizumab. In the phase IB ­MASTERKEY-265 trial of 21 previously untreated patients, responses were seen in 57% of patients, including complete responses in 7 patients, with no dose-limiting toxicities.9 This regimen is now in phase III trials. ■

Disclosure: Dr. Weber disclosed relation­ships with Amgen, Bristol-Myers Squibb, Boehringer Ingelheim, Merck, Merck-Serono, Novartis, Pfizer, Roche, and Sysmex.


1. Weber J: New checkpoints. 2016 ESMO Congress. Presented October 9, 2016.

2. Hodi FS, Chesney J, Pavlick AC, et al: Combined nivolumab plus ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 17:1558-1568, 2016.

3. Sullivan R, Hamid O, Patel M, et al: Preliminary clinical safety, tolerability, and activity results from a phase Ib study of atezolizumab (anti-PDL1) combined with vemurafenib in BRAFV600-mutant metastatic melanoma. 2015 Melanoma Bridge Conference. Presented December 2, 2015.

4. Ribas A, Butler M, Lutzky J, et al: Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. 2015 ASCO Annual Meeting. Abstract 3003.

5. Ribas A, Hodi FS, Lawrence DP, et al: Pembrolizumab in combination with dabrafenib and trametinib for BRAF-mutant advanced melanoma: Phase 1 KEYNOTE-022 study. 2016 ASCO Annual Meeting. Abstract 3014. Presented June 5, 2016.

6. Hamid O, Patel M, Hodi S, et al: Preliminary clinical safety, tolerability, and activity of atezolizumab (anti-PD-L1) combined with vemurafenib in BRAFV600 metastatic melanoma. 2015 ESMO Congress. Presented November 19, 2015.

7. Guo Z, Wang X, Cheng D, et al: PD-1 blockade and OX40 triggering synergistically protects against tumor growth in a murine model of ovarian cancer. PLoS One 9:e89350, 2014.

8. Puzanov I, Milhem MM, Minor D, et al: Talimogene laherparepvec in combination with ipilimumab in previously untreated unresectable stage IIIB-IV melanoma. J Clin Oncol 34:2619-2626, 2016.

9. Long GV, Dummer R, Ribas A, et al: A phase 1/3 multicenter trial of talimogene laherparepvec in combination with pembrolizumab for unresected, stage IIIB-IV melanoma (MASTERKEY-265). 2016 ASCO Annual Meeting. Abstract TPS9598.