Early Findings of Cobolimab in Advanced Melanoma Warrant Further Investigation

Preliminary antitumor activity and tolerability has been shown with cobolimab as a monotherapy and in combination with nivolumab (Opdivo) and dostarlimab (Jemperli) in patients with advanced or metastatic melanoma, according to findings from the phase 1 AMBER trial (NCT02817633).

Within the multi-center, open-label, cobolimab was examined in 3 parts. Part 1A examined cobolimab given intravenously (IV) as a monotherapy at 7 doses. In part 1B, cobolimab 1 mg/kg was given in addition to nivolumab 3 mg/kg IV. Finally, part 1C evaluated cobolimab at a dose of 100, 300, or 900 mg plus dostarlimab 500 mg IV.

Primary end points of the trial included safety, tolerability, and to determine the recommended phase 2 dose for cobolimab as monotherapy and in combination with other agents such as nivolumab and dostarlimab.

A total of 104 patients were enrolled in the trial with 46 in part 1A, 7 in part 1B, and 55 in part 1C. There were 4 patients from 1A of the trial who ended up crossing over to 1C. Of the enrolled patients, the most common cancers observed included non–small cell lung cancer (NSCLC) and melanoma in part 1A, NSCLC in part 1B, and NSCLC, skin, and peritoneal mesothelioma in part 1C.

Findings revealed that in regard to safety, treatment-related, treatment-emergent adverse events (TR-TEAEs) were seen in a total of 67.4% of patients in part 1A, 85.7% in 1B, and 67.3% in 1C. The most common observed events were fatigue in 1A (13.0%) and nausea (8.7%), diarrhea (57.1%), nausea and vomiting (42.9% each) in 1B, and fatigue (20.0%) and rash (14.5%) in 1C. Grade ≥ 3 TR-TEAEs occurred in 4.3% (1A), 28.6% (1B), and 14.5% (1C). No grade 5 TR-TEAEs were reported and there were no TR-TEAEs that led to dose delay. Further, serious TR-TEAEs were observed in 2.2% patients in 1A, 0% in 1B, and 12.7% in 1C. These TR-TEAEs led to discontinuation in 2.2% of patients included in part 1A, 28.6% patients in part 1B, and 9.0% of patients included in part 1C.

In 3.0% of patients in part 1A, dose-limiting toxicities (DLTs) occurred, including in grade 3 lipase increased. In part 1B, 40.0% of patients had DLTs, including grade 3 diarrhea as well as ALT and AST elevation. No patients had any signs of DLTs in part 1C.

Due to the positive results of this phase 1 study, an investigation of the recommended phase 2 dose plus docetaxel is warranted as a randomized, phase 2 study.

In an interview with Targeted Oncology^TM, Gerald Falchook, MD, director of Sarah Cannon Research Institute at HealthONE, discusses the efficacy and safety of cobolimab with or without nivolumab and dostarlimab, as evaluated in the AMBER trial.

TARGETED ONCOLOGY: What was the basis of the AMBER trial?

We presented the completed part 1 results of the first-in-human, phase 1 trial of the TIM-3 inhibitor, cobolimab in combination with PD-1 inhibitors nivolumab or dostarlimab. This was for patients with advanced or metastatic solid tumor cancers.

TIM-3 is an immune checkpoint receptor that's expressed on various types of immune cells and suppresses the anti-immune antitumor immune response. The idea was that this new drug, this TIM-3 inhibitor given in combination with the PD-1 inhibitor, would be more effective than either by itself. In the preclinical evaluation of this drug and similar drugs, we saw that blockade of PD-1 together with blockade of TIM-3 was more effective than blockade with either one by itself.

Can you explain the study’s protocol?

This is a first-in-human, phase 1 trial, and there were 3 parts. The goal was to determine the safety and recommended phase 2 dose. There are parts 1A, 1B, and 1C. In part 1 was cobolimab as a monotherapy. Escalating doses were in 1B with cobolimab in combination with nivolumab, and part 1C was in combination with dostarlimab.

A total of 104 patients were enrolled in the trial. Eligibility criteria were typical for what we designed, a first-in-human, phase 1 trial for immunotherapy agents. The most common tumor types were colorectal cancer, melanoma, lung cancer, and mesothelioma. These were patients who were already pretty heavily pretreated. Almost half the patients had received 3 or more prior lines of therapy.

Can you discuss the safety results that were concluded from the trial?

Overall, treatment was well tolerated. Both with the monotherapy and the combination, treatment-related adverse events were common, but were primarily low grade 3 or higher adverse events. We are seeing only 4% of patients in part 1A, 29% of patients in part 1Bm, and 15% of patients in part 1C.

The DLTs that we observed included the following: In part 1A, we had 1 patient with a grade 3 lipase elevation at the cobolimab 10 mg/kg dose level. In part 1B, there was 1 patient with grade 3 diarrhea, and 1 patient with both AST and ALT elevation and that was at the initial dose level of cobolimab 1 mg/kg. In part 1C, no DLTs were observed. There were also no adverse events leading to dose delays and parts 1A, B, or C. In part 1B, only 1 dose level was evaluated because of toxicity, and escalations were discontinued after the observed DLTs. Overall, the most common treatment-related adverse events in parts 1A, B, and C were fatigue, nausea, vomiting, diarrhea, and rash.

What were some of the efficacy findings of the AMBER trial?

Assessing preliminary antitumor activity was 1 of the objectives of the trial. In the part 1A, monotherapy, no objective responses were observed. In part 1B, the investigator-assessed response rate was 42.9%. That included 3 partial responses. In part 1C, the response rate was 16.4% across all dose levels, at the cobolimab 300 mg dose level. That was ultimately selected as a recommended phase 2 dose and the response rate was 25%. That included 5 partial responses. Notably, all melanoma patients treated at the 300 mg dose level achieved objective response.

What did cobolimab demonstrate in terms of pharmacokinetics [PK] and pharmacodynamics?

I think it's important to note that cobolimab demonstrated dose-proportional venir pharmacokinetics as a monotherapy both in part 1A and in combination with dostarlumab in part 1C. There were 2 patients, in each part 1A and 1C, who developed anti-drug antibodies to cobolimab. Among these patients, no hypersensitivity or infusion reactions were observed.

In the pharmacodynamic evaluation, we did observe exposure dependent receptor occupancy was achieved in increasing cobolimab doses. The normalized free-to-total TIM-3 ratio decreased with increasing cobolimab in that dose and PK exposure as expected. The optimal receptor occupancy was achieved with cobolimab at the 300 mg and 900 mg dose.

What unmet needs do you think still need to be filled in this patient population? What are the next steps for this research?

We still have a long way to go. We are talking about patients who have metastatic, incurable cancer with usually no standard of care treatments. This treatment looks promising but does require further evaluation.

The early responses that we observed support the rationale for future studies that would target both TIM-3 and PD-1 together in patients with advanced or metastatic solid tumors. In fact, several studies are already underway. We also presented efficacy results for patients with melanoma in an integrative safety analysis. In addition, enrollment to the disease-specific part 2 expansion cohorts is ongoing. Those cohorts include non–small cell lung cancer, colorectal cancer, and melanoma. In addition, there's a randomized phase 2 study evaluating this combination given with docetaxel to patients with relapsed/refractory non–small cell lung cancer.