Significant Survival Rates Seen With Novel Immunotherapy for Metastatic Uveal Melanoma

Takami Sato, MD, PhD

Takami Sato, MD, PhD

A novel immunotherapy agent has demonstrated significant survival rates for patients with metastatic uveal melanoma, according to updated results released at the 2018 ASCO Annual Meeting.¹

IMCgp100 demonstrated a 1-year overall survival (OS) rate of 74% (95% CI, 48%-88%) for patients with heavily pretreated, advanced uveal melanoma, which is almost double the historical expectations for patients with the disease. At a median follow-up of 15.9 months, the median OS had not yet been reached in the phase I/II study.

At 1 year, 66% of patients (95% CI, 39%-83%) remained alive and progression free by immune-related response criteria.

The objective response rate with IMCgp100 was 11% (90% CI, 2%-30%), with 4 additional patients showing signs of stable disease with minor responses (≥10% reduction in target lesions). The median duration of response was 30.6 weeks.

"Survival rates in uveal melanoma have remained largely unchanged for decades, and it is difficult to treat once it advances to metastatic disease," investigator Takami Sato, MD, PhD, of the Department of Medical Oncology at Kimmel Cancer Center, Thomas Jefferson University, said in a statement. "These data provide compelling evidence that IMCgp100 may offer hope to this underserved patient population."

IMCgp100 is the leading candidate in a new class of investigational therapies targeting the T-cell receptor (TCR) called immune-mobilizing monoclonal T-cell receptors. It contains 2 functional ends, 1 that targets the soluble affinity—enhanced TCR and the other an anti-CD3 single-chain variable fragment. The TCR end binds to the melanoma-associated antigen gp100, and the effector end activates an antitumor CD3-positive T-cell response. The agent received an orphan drug designation from the FDA in 2016.

Phase I of IMCgp100-102 Trial

The dose-escalation study included 19 patients across 4 dose levels ranging from 54 μg to 73 μg. The study utilized an intrapatient escalation strategy: on day 1 of the first cycle, patients received IMCgp100 at 20 μg, which was escalated to 30 μg on day 2 of cycle 2. This was followed by enrollment to 1 of 4 cohorts testing a range of doses (54 μg, 64 μg, 73 μg, and 68 μg).

Dose-limiting toxicity in the form of abnormal liver function tests (grade 3/4 ALT or AST changes) was observed in 3 patients, all of which were reversible. Two of these events were seen in the 4 patients who received the highest dose, which was subsequently reduced to 68 μg. This dose was identified as the maximum tolerated dose of IMCgp100 and will be further explored in phase II trials.

The median age of patients was 55 years, and the ECOG performance scores were 0 (74%) and 1 (26%). Participants had undergone a median number of 4 prior therapies (range, 0-8), which included chemotherapy for 95% of patients and prior immunotherapy for 68%. Prior immune therapy included ipilimumab (Yervoy; 47%), pembrolizumab (Keytruda; 32%), and nivolumab (Opdivo; 16%). All patients had liver metastases, and lactate dehydrogenase levels were greater than the upper limit of normal for 73% of patients.

In terms of responses, earlier data presented at the Association for Research in Vision and Ophthalmology (ARVO) 2018 Annual Meeting showed that the median time to objective response was 27.8 weeks and the median 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 μg.²

A pharmacokinetic (PK) analysis of the study showed consistent dose-dependent activity. The half-life for the drug was determined to be 6 to 8 hours across all doses above 20 μg.

Evidence of T-cell infiltration was seen using immunofluorescence in pharmacodynamic assessments. Immune activation was seen in the tumor after 3 weekly doses of IMCgp100, which was consistent with T cell redirection, the researchers noted.

Following treatment, there was a temporary reversible decrease in peripheral lymphocyte counts, which is indicative of lymphocyte trafficking.

Immunofluorescence analysis of biopsy samples after 3 doses of IMCgp100 showed high levels of lymphocyte trafficking into the tumor, with persistent lymphocyte infiltration. At progression, there were high levels of PD-L1 expression, gp100 antigen expression, and CD8 T cells present in the tumor.

All patients in the study experienced treatment-emergent adverse events (TEAEs), 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.

“While research is still ongoing, I am encouraged by the results from this phase I study in ocular melanoma. We are committed to progress research to benefit patients,” investigator Richard D. Carvajal, MD, said at the ARVO meeting.

An exploratory analysis that was presented at the ASCO meeting investigated the association of pharmacodynamic factors with survival and demonstrated a relationship between lymphocyte trafficking and exposure to IMCgp100.¹

Also, the investigators noted that among 42 evaluable patients across the phase I/II study, a grade &ge;2 rash observed within the first 3 weeks of dosing was associated with a prolonged OS in the patient compared with those who had a grade <2 rash or no rash at all (HR, 0.12; 95% CI, 0.03-0.45;P= .0015).

The phase II portion of the study is currently enrolling participants who have experienced disease progression after 1 or 2 prior treatment regimens, including up to 1 line of liver-directed therapy. This expansion cohort of the study hopes to enroll 150 patients with an estimated completion date of September 2019 (NCT02570308).

In addition, a pivotal phase II trial is enrolling participants with uveal melanoma to further test IMCgp100 compared with investigator&rsquo;s choice of systemic therapy, which could include the CTLA-4 inhibitor ipilimumab or the anti—PD-1 agent pembrolizumab. The open-label phase II study plans to enroll 327 participants, with an estimated primary completion date of July 2020 (NCT03070392).

References

1. Sato T, Nathan PD, Hernandez-Aya L, et al. Redirected T cell lysis in patients with metastatic uveal melanoma with gp100-directed TCR IMCgp100: Overall survival findings.J Clin Oncol.2018;36(suppl; abstr 9521).
2. Carvajal RD, Sacco J, Nathan P, et al. Safety, efficacy and biology of the gp100 TCR-based bispecific T cell redirector, IMCgp100 in advanced uveal melanoma in two phase 1 trials. Poster presented at: 2018 ARVO Annual Meeting; April 29-May 3, 2018; Honolulu, HI. Poster A0283.