INITIAL DATA from the ongoing, multicenter, first-in-human, phase Ia/Ib dose-escalation and -expansion study suggest that an anti–T-cell immunoglobulin domain and mucin domain–containing molecule 3 (anti–TIM-3) antibody alone or in combination with immune checkpoint blockade could counter intrinsic or acquired resistance to immunotherapy. The data were presented at the 2019 ASCO–Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Symposium.¹

“When you co-target TIM-3 and PD-L1, it appears that there is greater efficacy than PD-L1 therapy alone in preclinical models.”

— James J. Harding, MD

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The anti–TIM-3 antibody (LY3321367, also known as LY332) was well tolerated as a monotherapy and in combination with an anti–programmed cell death ligand 1 (anti–PD-L1) antibody (LY3300054, or LY330). In addition, the investigators reported preliminary antitumor activity for the monotherapy. Although a high proportion of patients had treatment-emergent antidrug antibodies, the authors noted that toxicity and pharmacokinetics were apparently not disturbed.

“Based on these data, we selected the recommended phase II dose of 1,200 mg administered intravenously every 2 weeks for 8 weeks, followed by 600 mg thereafter,” said James J. Harding, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College. “We have now opened up expansion cohorts for  monotherapy in patients with lung cancer who have previously responded and ultimately had disease progression.”

Study Rationale and Design

AS DR. HARDING EXPLAINED, TIM-3 is an immune checkpoint molecule that is expressed on multiple cell types, including T cells, natural killer cells, and macrophages. When activated, TIM-3 leads to suppressive signals to T cells and appears to be a hallmark of T-cell exhaustion in both malignancy and infection.

“It’s become apparent that when you block TIM-3 with agents like LY332, you can reinvigorate T-cell function,” said Dr. Harding. “Moreover, when you co-target TIM-3 and PD-L1, it appears that there is greater efficacy than PD-L1 therapy alone in preclinical models. Finally, there is some evidence to suggest that acquired resistance to PD-L1 or programmed cell death protein 1 (PD-1) therapy in the clinic may, in part, be mediated by TIM-3.”

Given this rationale, Dr. Harding and colleagues are exploring LY332 in the clinic in a phase Ia/Ib dose-escalation study. The primary objective of the study is to determine the safety, tolerability, and recommended phase II dose of LY332, alone and in combination with LY330. Patients with advanced solid tumors who had disease progression on standard therapy with excellent performance status and adequate organ function were eligible for enrollment. Prior anti–PD-1 or PD-L1 therapy was also allowed.

In the TIM-3 monotherapy group, there were a total of six cohorts. The first cohort started LY332 at 3 mg every 2 weeks and escalated to the final cohort of 1,200 mg biweekly for 8 weeks, followed by 600 mg, the flat dose, thereafter.

Importantly, said Dr. Harding, at the 200-mg dose, which was predicted to lead to target engagement in about 50% in the preclinical models, investigators initiated a TIM-3 and PD-L1 combination-dose escalation, in tandem, over 5 cohorts. At the 2019 ASCO-SITC symposium, however, Dr. Harding focused on the results of TIM-3 monotherapy.

Anti–TIM-3 Monotherapy Safe and Effective

AS DR. HARDING REPORTED, 23 patients were treated with TIM-3 monotherapy. Baseline characteristics of patients reflected the eligibility criteria of an all-comer histology, with a variety of tumor types treated, the most common being lung cancer.

The patient population was heavily pretreated, with more than 50% of patients having at least 3 prior lines of therapy, and a subset of 30% had received prior PD-1 or PD-L1 therapy. Patients receiving combination therapy were similarly diverse, said Dr. Harding.

Regarding treatment-related adverse events, investigators were able to escalate across all monotherapy and combination therapy cohorts. There were no dose-limiting equivalent toxicities, nor were there any treatment-related grade 3 or higher adverse events. There was 1 infusion-related reaction, which was grade 2, said Dr. Harding, but the patient recovered and continued treatment. The investigators also saw some low-grade dermatologic toxicity that was considered immune-mediated.

Dr. Harding noted that a high proportion of patients developed treatment-emergent antidrug antibodies while on monotherapy and combination therapy (approximately 60%  and 70%, respectively). Importantly, however, more than 50% of these cases were low-level titers, and only 1 patient with a higher titer had a confirmed infusion-related reaction. In addition, there was no interference with pharmacokinetics or exposure in the presence of antidrug antibodies.

Regarding the efficacy of the monotherapy, preliminary antitumor activity was observed. A single patient with small cell lung cancer had a confirmed partial response, whereas 10 patients had stable disease as the best response, for a disease control rate of 11 out of 23 patients (47%).

Based on the overall safety profile, pharmacokinetics, and efficacy data, investigators selected the recommended phase II dose of 1,200 mg every 2 weeks for 8 weeks, followed by 600 mg thereafter. Investigators have also opened up expansion cohorts for monotherapy in patients with lung cancer who have previously responded and ultimately had disease progression on prior immunotherapy. In addition, the combination regimen is being explored in five cohorts, including patients with lung, gastric, hepatocellular, head and neck, and bladder cancers. The efficacy of the combination strategy will be presented at a later time along with the ongoing recommended phase II dose cohorts. ■

DISCLOSURE: Dr. Harding has had consulting or advisory roles with Bristol-Myers Squibb, CytomX Therapeutics, and Lilly and has received research funding from Bristol-Myers Squibb, Calithera Biosciences, Incyte, Lilly, Novartis, Pfizer, and Polaris.

REFERENCE

1. Harding JJ, Patnaik A, Moreno V, et al: A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): Interim safety, efficacy, and pharmacokinetic findings in advanced cancers. 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 12. Presented March 2, 2019.