IMCgp100 Highly Effective for Advanced Uveal Melanoma

Richard D. Carvajal, MD, director of Experimental Therapeutics and director of the Melanoma Service at Columbia University Medical Center

Richard D. Carvajal, MD

The novel immune-based treatment IMCgp100 demonstrated a 1-year survival rate of 73% (95% CI, 46%-88%) for patients with heavily pretreated, advanced uveal melanoma, representing a promising new option on the horizon for a disease with few effective options, according to findings presented at the 2018 ARVO Annual Meeting.

At a median follow-up of 12.8 months, the median overall survival had not yet been reached. The objective response rate with IMCgp100 was 11%, with 5 additional patients showing signs of stable disease with a minor response (26%). The median progression-free survival (PFS) with the treatment was 24.3 weeks and at 1 year 62% of patients remained alive and progression free.

“Advanced uveal melanoma has a 1-year overall survival rate of approximately 40%, and no cytotoxic, targeted, or immunological therapy has been previously identified to meaningfully improve outcomes,” lead investigator Richard D. Carvajal, MD, director of Experimental Therapeutics and director of the Melanoma Service at Columbia University Medical Center, told MD Magazine.

“The 73% 1-year overall survival we observed in the heavily pretreated patients with metastatic uveal melanoma treated with IMCgp100 is quite notable,” he continued. “We are excited about the continued development of IMCgp100 for patients with this disease.”

IMCgp100 contains two functional ends, one targeting the soluble affinity enhanced T cell receptor (TCR) and the other an anti-CD3 single-chain variable fragment. The TCR end binds to the melanoma-associated antigen gp100 while the effector end activates an antitumor CD3+ T cell response.

The dose escalation study included 19 patients across 4 dose levels ranging from 54 mcg to 73 mcg. Dose limiting toxicity in the form of abnormal liver function tests were observed in 3 patients. Two of these events were seen in the 4 patients receiving the highest dose of IMCgp100, which was subsequently reduced to 68 mcg. This dose was identified as the maximum tolerated dose and will be further explored in phase 2 trials.

The median age of patients was 55 years, and the Eastern Cooperative Oncology Group performance score was 0 (74%) and 1 (26%). The median number of prior therapies was 4 (range, 0-8), which included chemotherapy for 95% of patients and prior immunotherapy for 68%. All patients had liver metastases and LDH levels were greater than the upper limit of normal for 73% of patients.

The median time to objective response was 27.8 weeks and the median response duration was 24.1 weeks. The disease control rate (responses plus stable disease) was 53% at week 16 and 32% at week 24. There were no complete responses and 26% of patients developed progressive disease as their best response, which occurred mostly in doses below 68 mcg.

Treatment-emergent adverse events (TEAEs) were experienced by all patients in the study, with 79% having a grade 3/4 event. The most common all-grade TEAEs were pruritus (90%), pyrexia (84%), fatigue (84%), hypotension (74%), chills (63%), nausea (68%), dry skin (63%), and peripheral edema (63%). The most frequent grade 3/4 TEAEs were fatigue (16%), hypotension (16%), erythema (16%), and macular rash (11%).

The skin toxicity observed in approximately two-thirds of patients persisted during the first 4 weeks of treatment and then began to taper off. There were no grade 3/4 skin toxicity events beyond 4 weeks and by week 7 skin toxicity events reached a plateau, with approximately 26% of patients having a rash beyond 100 days of treatment.

A pivotal phase 2 trial is currently enrolling participants with uveal melanoma to further test IMCgp100. In the first trial, the agent is being compared with investigator's choice of systemic therapy, which could include the immunotherapies ipilimumab or pembrolizumab. The open-label phase 2 study plans to enroll 327 participants, with an estimated primary completion date of July 2020 (NCT03070392).

In addition to this trial, a phase 2 portion of the study reported at ARVO is also now open. This expansion cohort of the study hopes to enroll 150 patients. The estimated completion date for this expansion trial is December 2018 (NCT02570308).

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