# Phase I Study of Mogamulizumab in Combination with Pembrolizumab in Patients with Relapsed or Refractory Non-Hodgkin Lymphoma—A National Cancer Institute Experimental Therapeutics Clinical Trials Network (NCI-ETCTN) Trial

## TL;DR

A clinical trial tested combining two immunotherapies for non-Hodgkin lymphoma but found poor patient tolerance and no significant treatment benefits.

## Contribution

This study evaluated the safety and tolerability of combining mogamulizumab and pembrolizumab in non-Hodgkin lymphoma patients, revealing unexpected poor outcomes.

## Key findings

- The combination therapy showed poor tolerability and was associated with rapid disease progression in most patients.
- Only two of seven patients completed the first two treatment cycles, and six patients died shortly after discontinuation.
- The treatment combination was not effective in lymphoma, contrasting with results in solid tumors.

## Abstract

Lymphoma cells evade immune destruction by suppressing T cells. We hypothesized that combining two T cell enhancing immunotherapies by both blocking the PD1/PD-L1 checkpoint pathway and reducing regulatory T cell (Treg) activity could produce a stronger anti-tumor response. This Phase-I trial tested the safety of combining mogamulizumab (which targets Tregs) with pembrolizumab (a PD-1 inhibitor) in patients with relapsed or refractory non-Hodgkin lymphoma. We treated seven patients on protocol without any clinically meaningful responses and with a very poor tolerability by patients. Only two patients completed the first two treatment cycles. Three experienced rapid disease progression, and three withdrew amid clinical deterioration. Six patients died shortly after leaving the study. The seventh developed stress cardiomyopathy and discontinued treatment. In contrast to findings in solid tumors, this combination showed poor tolerability and may have been associated with hyper-progressi.

Introduction: Immune evasion through inhibition of effector T cells is a key survival mechanism of lymphoma cells. We hypothesized that reinstating effector T cell activity through concurrent inhibition of the PD1/PD-L1 axis and of Treg activity will result in a synergistic anti-tumor effect with an acceptable toxicity profile. Methods: Phase I multi-institutional NCI-ETCTN trial aimed to evaluate the safety and tolerability of the combination of mogamulizumab and pembrolizumab in relapsed or refractory non-Hodgkin lymphoma. The study used a 3 + 3 design. Treatment consisted of mogamulizumab 1 mg/kg on days 1, 8, and 15 of cycle 1, followed by 1.5 mg/kg on day 1 of each subsequent 21-day cycle in combination with pembrolizumab 200 mg on day 1 of each cycle. A de-escalation level was defined as a 50% reduction in the dose of mogamulizumab (registered in clinicaltrials.gov NCT03309878). Results: The study was discontinued early, after treating seven patients (two angioimmunoblastic T cell lymphoma, four transformed follicular lymphoma, and one diffuse large B cell lymphoma of germinal center subtype) for concerns of futility and non-tolerability. Only two patients completed the first two cycles of treatment. Three patients presented with an early progression and three withdrew consent in the setting of general deterioration with clinically suspected progression. All six patients expired shortly after withdrawal from the study. The remaining patient experienced stress cardiomyopathy during the third cycle and was taken off the study. Discussion: In striking difference to the observation in solid malignancies, the combination of mogamulizumab with pembrolizumab was associated with low tolerability and suspected hyper-progression in patients with lymphoma.