New Immunotherapy Combinations Gain Ground in Advanced Melanoma, but Results Preliminary

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Attention is focused among the cancer community on identifying the optimal immunotherapy combinations, with more than 800 ongoing trials of combination therapy. Two studies presented at the 2017 Annual Meeting of the American Association for Cancer Research (AACR) reported promising preliminary results for the treatment of advanced melanoma using distinct novel combinations.1,2

A phase II study combining pembrolizumab (Keytruda) with an indoleamine 2,3-dioxygenase (IDO)-pathway inhibitor called indoximod found robust responses.1 A phase Ib study of ipilimumab (Yervoy) plus Coxsackievirus A21 (CVA21; Cavatak), an intralesional therapy, showed durable responses in advanced melanoma, even among patients whose disease progressed on a prior checkpoint inhibitor.2

Indoximod Plus Pembrolizumab

This is the largest publicly available dataset on IDO inhibitors plus checkpoint inhibitors. These data support phase III development of indoximod plus pembrolizumab for the treatment of advanced melanoma.
— Yousef Zakharia, MD

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An interim analysis of a phase II clinical trial showed that indoximod combined with pembrolizumab increased the percentage of response in patients with advanced melanoma compared with previously reported response rates for single-agent pembrolizumab in advanced melanoma. In the pivotal phase III KEYNOTE-006 trial that led to the U.S. Food and Drug Administration (FDA) approval of pembrolizumab as first-line treatment of advanced melanoma, the overall response rate was 33%. In the phase II study presented at the 2017 AACR meeting, the overall response rate was 52% and the disease control rate (response plus stable disease) was 73% overall in patients with advanced melanoma (including ocular melanoma), according to the interim analysis presented by Yousef Zakharia, MD, of the University of Iowa, Iowa City.

The IDO pathway has become a target of interest in cancer therapeutics. “Tumors hijack the IDO pathway to facilitate immune escape,” Dr. Zakharia explained.

“Several IDO inhibitors in development are being studied in multiple solid tumors and hematologic malignancies,” he continued. “The majority of IDO inhibitors available in clinical trials are direct enzymatic inhibitors, like GDC 0919 and epacadostat, as opposed to indoximod ‘tryptophan mimetic,’ which acts directly on the immune cells to reverse IDO-pathway–mediated suppression. Some preclinical data suggest similar antitumor activity with both approaches,” Dr. Zakharia revealed.

Key Study Findings

The open-label, single-arm, phase II study enrolled 102 patients with stage III (13%) or IV (87%) advanced unresectable melanoma treated with indoximod plus provider choice of pembrolizumab, nivolumab (Opdivo), or ipilimumab until disease progression or unacceptable toxicity. As of January 2017 (data cutoff point), 60 patients treated with pembrolizumab and indoximod were evaluable, and their data were presented at the 2017 AACR meeting. Forty patients (67%) had cutaneous melanoma, 9 (15%) had ocular melanoma (a type with poor response to any therapy), and 11 (18%) had nonocular melanoma (mucosal or unknown primary). Patients were allowed to switch to a second checkpoint inhibitor (ipilimumab) at disease progression and continue on indoximod.

New Immunotherapies for Melanoma

  • Two new approaches exploiting checkpoint inhibitor therapy—pembrolizumab plus indoximod and ipilimumab plus Coxsackievirus A21—have produced early responses in advanced melanoma.
  • Although these findings remain preliminary, both approaches will be studied further in this patient population.

Interim results for all 60 evaluable patients showed an overall response rate in 31 patients (52%), with 6 (10%) complete responses and 25 (42%) partial responses. In the 51 patients with cutaneous or nonocular melanoma, the overall response rate was 59% (6 [12%] complete responses, 24 [47%] partial responses). The disease control rate was 73% in the overall population and 80% in the group with cutaneous/nonocular melanoma.

This is the largest publicly available dataset on IDO inhibitors plus checkpoint inhibitors,” Dr. Zakharia told listeners.

“We had impressive responses in cutaneous and nonocular melanoma, with many patients near complete response,” he noted. And the majority of the responses occurred during the first 3 months of treatment.

Adverse Effects

The combination was well tolerated. The majority of adverse events were to be expected with single-agent pembrolizumab, with few grade 3 events and no grade 4 events. Serious adverse events potentially related to indoximod were reported in four patients (grade 3 arthritis, gastritis, hearing impairment, and grade 2 interstitial nephritis), leading to treatment discontinuation in three patients. No treatment-related deaths were reported.

“These data support randomized phase III trial development of indoximod plus pembrolizumab for the treatment of advanced melanoma,” he stated.

‘Exciting Possibility’

One can prime the immune response with this kind of approach and resensitize the tumor to checkpoint inhibitor therapy. This is relevant not only for patients who have refractory tumors but also for those with earlier-stage disease….
— Louis Weiner, MD

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“This is really exciting!” emphasized Louis Weiner, MD, Director of the Georgetown-Lombardi Cancer Center, Washington, DC, and press conference moderator where these data were discussed. “Many times, combinations studied are empiric. Here is an example of taking drugs designed to work together based on an extensive body of literature accumulated over decades showing that IDO is an important pathway in cancer.”

“We still need to interpret these data with caution. If the data are verified, the results will suggest a strategy for enhancing activity of immune checkpoint inhibitors in advanced melanoma and potentially other diseases. This would represent a real advance and is an exciting possibility,” Dr. Weiner stated.

CVA21 Plus Ipilimumab

Preliminary results of a phase Ib study (MITCI) of the combination of intralesional CVA21 plus ipilimumab were encouraging in a small subset of 25 patients evaluable for safety and 22 patients evaluable for response. The overall response rate was 50% (4 complete responses and 7 partial responses), with a median duration of response not yet reached, a number of responses beyond 6 months, and several patients still in ongoing response.

Brendan D. Curti, MD

Brendan D. Curti, MD

“We are excited about these preliminary responses in some patients whose melanoma has progressed after immune checkpoint inhibitor therapy and some who have not yet received immunotherapy. The preliminary overall response rate of 50% is very positive, because previous reports indicate an 11% response rate for ipilimumab alone and an approximately 28% overall response rate for CVA21 alone,” said lead author Brendan D. Curti, MD, Director of the Clinical Biotherapy Program and Co-Director of the Melanoma Program at the Earle A. Chiles Research Institute of Providence Cancer Center in Portland, Oregon.

“While preliminary, this approach may represent a viable treatment option for an unmet need in advanced melanoma patients refractory to prior anti–programmed cell death protein 1 and [cytotoxic T-lymphocyte–associated protein 4] therapies,” he stated.

One of the exciting observations by Dr. Curti and coauthors is that pretreatment biopsies of patients’ tumors revealed few T cells and a “cold” tumor, whereas 1 week after intralesional injection of CVA21, a pronounced infiltration of T cells was seen, and the tumor becomes a “hot” tumor, he explained.

Early Phase II Trial Results

Planned enrollment of the phase II trial includes 70 patients. Patients received intralesional injections of CVA21 on days 1, 3, 5, 8, and 22 and then every 3 weeks until day 358. Ipilimumab was started after the first 3 weeks and then given every 3 weeks out of 4 until day 85. After completion of ipilimumab, patients can continue to receive CVA21 injections, for a total of 19 doses.

In the first 25 patients evaluable for safety, no grade 3 or higher toxicity was associated with injection of CVA21. The main adverse events were mild to moderate injection-site reactions. Two grade 3 adverse events were reported with ipilimumab: transaminitis and fatigue. “This is a small patient group, but we see fewer adverse events than we see with ipilimumab monotherapy,” noted Dr. Curti.

In an intent-to-treat analysis of 22 patients for best overall response (3 of whom had prior ipilimumab), the overall response rate was 50%, with complete responses seen in 4 patients (18%) and partial responses seen in 7 patients (32%). In patients who had prior checkpoint inhibitor therapy, the best overall response rate was 36%, he said. In those with no prior checkpoint inhibitor therapy, the best overall response rate was 64%.

Objective responses were also seen in noninjected sites. The overall response rate was 46% (6 of 13 noninjected visceral lesions) and 67% (6 of 9 noninjected visceral lesions) in patients with and without prior checkpoint inhibitor therapy, respectively. The study will be expanded to include more patients, including those treated with prior checkpoint inhibitor therapy.

“We hypothesize that the virus priming the immune system is important to the synergy we have observed. The immune response with intralesional therapy is local,” he revealed.

Dr. Curti noted that CVA21 is also being studied when given intravenously. “It is conceivable the virus could circulate systemically to other [metastatic] sites,” he said.

Take Home Message

“The take home point of this study is that one can prime the immune response with this kind of approach and resensitize the tumor to checkpoint inhibitor therapy. This is relevant not only for patients who have refractory tumors but also for those with earlier-stage disease, but this is still pretty early for this approach, and more study is needed,” Dr. Weiner commented at a press conference. ■

Disclosure: Dr. Zakharia reported no conflicts of interest. Dr. Weiner is on the scientific advisory board for Celldex Pharmaceuticals, Cytomx, Jounce Pharmaceuticals, and Merrimack Pharmaceuticals; is a consultant for AbbVie, Genentech, Merck, and Novartis; and has investments in Targeted Diagnostics and Therapeutics, Inc. Dr. -Curti’s institution has received research funding fromViralytics and Bristol-Myers Squibb.


1. Zakharia Y, McWilliams R, Shaheen M, et al: Interim analysis of the phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma. 2017 AACR Annual Meeting. Abstract CT117. Presented April 4, 2017.

2. Curti B, Richards J, Hallmeyer S, et al: The MITCI (phase 1b) study: A novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients with or without previous immune checkpoint therapy treatment. 2017 AACR Annual Meeting. Abstract CT114. Presented April 4, 2017.