Beyond PD-1/CTLA-4: Immunotherapy Combos Explore New Ground

Targeted Therapies in OncologyMay 2016
Volume 5
Issue 4

A variety of dual immunotherapy combination regimens are currently under exploration that could build upon the success seen with the addition of the CTLA-4 inhibitor ipilimumab (Yervoy) to PD-1 blockade with nivolumab (Opdivo) for the treatment of patients with advanced melanoma.

Omid Hamid, MD

A variety of dual immunotherapy combination regimens are currently under exploration that could build upon the success seen with the addition of the CTLA-4 inhibitor ipilimumab (Yervoy) to PD-1 blockade with nivolumab (Opdi­vo) for the treatment of patients with advanced melanoma, explained Omid Hamid, MD.

“On the heels of the ipilimumab/nivolumab combination having such a high response rate, we have been looking to find other standard combinations for advanced melanoma,” says Hamid, chief of Translational Research and Immunotherapy, director of Melanoma Therapeutics, The Angeles Clinic. “That is not to say that ipilimumab/nivolumab is not a standard; it is a breakthrough in showing that we can combine these types of agents and have good outcomes; however, it makes a lot of sense to look at these other combinations.”

Numerous combinations with and without immunotherapy backbones are being investigated in phase I and II trials for advanced metastatic melanoma. Several have preliminarily demonstrated high response rates without the high level of toxicities that can sometimes be limiting with ipilimumab/ nivolumab, says Hamid.

IDO1 Inhibitors/Pembrolizumab

One option with promising combination possibilities in mela­noma is IDO1 inhibition. At the 2015 Society for Melanoma Congress, Hamid presented preliminary data on the novel IDO1 inhibitor epacadostat (INCB24360) in combination with the PD-1 antibody pembrolizumab (Keytruda).1

The data were from the melanoma cohort of an ongoing dose-escalation and dose-expansion phase Ib study, in which patients with stage IIIB/IV melanoma, as well as other cancers, received either 25, 50, 100, or 300 mg of epacadostat daily along with pembrolizumab at either 2 mg/kg every 3 weeks or 200 mg twice daily.

Of the 19 evaluable patients with melanoma, the combina­tion demonstrated an overall response rate (ORR) of 53% (n = 10) with 3 complete responses (CRs) and 7 partial responses (PRs). Four patients had stable disease.

In treatment-naïve patients (n = 16), ORR was 56% and the disease control rate was 75%. There was 1 CR in the 25-mg group (n = 2), 2 CRs and 3 PRs in the 50-mg group (n = 12), and no CRs and 4 PRs in the 100-mg group (n = 4). No re­sponses were seen in the 300-mg group (n = 1).

The regimen was generally well tolerated, with few patients experiencing dose-limiting toxicity (DLT) or grade 3 treatment-related adverse events (AEs), reporte Hamid. There were no grade 4 treatment-related AEs or deaths, and a discontinua­tion rate of 5% for treatment-related AEs.

The recommended dose for the phase II portion of this study is 100 mg of epacadostat, based on the overall efficacy and safety profile demonstrated in the phase Ib study.

Enrollment in the phase II portion of the study has been initiated, and a phase III study in patients with advanced melanoma is planned, with initiation expected in the first half of 2016, according to Hamid.

IDO inhibitors are promising because they take a different approach other than PD-1 or CTLA-4 inhibitors, said Hamid.

“The IDO inhibitor targets the tumor microenvironment; it is a new way of controlling the immune system and getting it revved up,” he says. “It is a great breakthrough in find­ing ways to reinvigorate the immune system aside from just checkpoint inhibition.”


Another exciting combination on the horizon is talimogene laherparepvec (T-VEC; Imlygic) with ipilimumab, says Hamid.

“It really is a major breakthrough to show that these 2 drugs can come together and have a high response rate with low toxicity,” he added.

A phase Ib multicenter trial evaluated the safety and ef­ficacy of T-VEC and ipilimumab in previously untreated, un­resected stage IIIB/IV melanoma.2In 17 evaluated patients, ORR was 41%, with 23.5% experiencing a CR and 17.6% experiencing a PR. Thirty-five percent of patients had stable disease and median time to response was 2.9 months. Grade 3/4 AEs occurred in 32% of patients and 2 patients had pos­sible immune-related grade 3/4 AEs.

A randomized phase III study investigating this combination is currently ongoing, said Hamid.


Combining targeted therapy with immunotherapy has the potential to harness and enhance the antitumor response fol­lowing BRAF inhibition, and may lead to durable responses and prolonged survival, said Hamid.

The anti—PD-L1 agent atezolizumab has demonstrated prom­ising response rates in melanoma, bladder cancer, non–small cell lung cancer, and renal cell carcinoma. In patients with advanced melanoma, single-agent atezolizumab had an ORR of 33%.

In a phase Ib dose-escalation and cohort expansion study, atezolizumab was investigated along with the BRAF inhibitor vemurafenib (Zelboraf) in 17 patients withBRAFV600-mutant metastatic melanoma who were previously untreated with a BRAF inhibitor or immunotherapy.3

The study included 3 cohorts. In cohort 1, patients received the combination concurrently. In cohort 2, patients received a 56-day run-in of vemurafenib followed by vemurafenib and atezolizumab given simultaneously, while patients in cohort 3 received a 28- day run-in of vemurafenib followed by vemurafenib and atezoli­zumab simultaneously.

The ORR in the overall study population was 76% (95% CI, 50.1-93.2) with 10 PRs and 3 CRs. In cohort 1 (n = 3) the ORR was 33% with 1 CR, in cohort 2 (n = 8) the ORR was 75%, with 5 PRs and 1 CR, and in cohort 3 (n = 6) the ORR was 100% with 1 CR and 5 PRs.

All treatment-related AEs were manageable and generally re­solved. No treatment-related grade 4 AEs occurred, and no grade 5 AEs occurred. The tolerability improved with the staggered start versus the concurrent start doses, according to Hamid.

“The combination is tolerable and has minimal toxicities,” he said. “That is showing us that, now, you can add these targeted agents with anti—PD-1/PD-L1 agents and it is safe.”

Bispecific Antibodies/CTLA-4

While many combinations include a PD-1/PD-L1 backbone, that doesn’t work for all patients, said Hamid. In certain situ­ations, CTLA-4, which recruits the immune system to attack a tumor, might be an ideal companion.

“We’ve been all caught up with PD-1 therapies and PD-1/ CTLA-4 combinations, and what we are now finding is that there are people who don’t benefit from those combinations,” he said. “Although these are great breakthroughs, now we have patients who have gone through this and now need something else.”

One alternative may be bispecific antibodies. The lead agent currently under exploration, IMCgp100, for melanoma in this space consists of T-cell receptor specific to gp100 fused to anti—CD3 antibody single-chain variable fragment.

“These bispecifics are a new way of manipulating the im­mune system that has not shown the same toxicities as check­point inhibitors,” he said. “If you have had a patient who has not had significant activity on checkpoint inhibitors, you can still offer this as a therapy. That is amazing.”

The bispecific antibody IMCgp100 has shown promise as a single agent, in combination with both the PD-L1 inhibitor dur­valumab (MEDI4736) and the CTLA-4 inhibitor tremelimumab. Also, all 3 agents can be given together, said Hamid.

“IMCgp100 is basically what I call a matchmaker,” Hamid not­ed. “It has 2 ‘suction cups.’ One suction cup targets CD3, which is the T cell. The second suction cup targets the tumor cell.”

A phase Ib/II, multicenter, 4-arm study of IMCgp100 as a single agent, and in combination with durvalumab, tremeli­mumab, and with both durvalumab and tremelimumab for patients with advanced metastatic melanoma is currently ongoing and recruiting patients.

Finding the Perfect Combination

Although there are numerous options on the horizon, find­ing the “winning” combination treatment for patients with advanced melanoma isn’t necessary right now, explained Hamid.

“I don’t see this as a mad dash to identify one combination as the combination for everyone,” he said. “I think it is a process where we are looking at these combinations; we are evaluating how feasible they are, how tolerable they are, and what their effi­cacy is. Then, we are obtaining tissue and blood from each patient in order to identify the right biomarkers. We need to do a lot of investigation into biomarkers that would allow us to say which pa­tients will respond to which combinations better than others.”


  1. Hamid O, Gajewski TF, Smith DC, et al. Preliminary data from a phase 1/2 study of epacadostat (INCB024360) with pembrolizumab in patients with advanced/metastatic melanoma. Presented at the 2015 Society for Melanoma Research Congress; November 18-21, 2015; San Francisco, CA.
  2. Puzanov I, Milhem M, Hans R, et al. Primary analysis of a phase 1b multicenter trial to evalu¬ate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.J Clin Oncol.2014;32:5s (suppl; abstr 9029).
  3. Hamid O, Patel M, Hodi S, et al. Preliminary clinical safety, tolerability and activity of atezolizumab (anti-PDL1) combined with vemurafenib inBRAFV600 metastatic melanoma. Presented at the Society for Melanoma Research 2015 Congress; November 18-21, 2015; San Francisco, CA.
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