Combination Therapy With Mogamulizumab Demonstrates Tolerable and Manageable AEs

Dmitriy Zamarin, MD, PhD

Results from a two-part, phase I dose-escalation and -expansion trial involving mogamulizumab (Poteligeo) in combination with durvalumab (Imfinzi) or tremelimumab for the treatment of patients with advanced solid tumors demonstrated mild-to-moderate adverse events (AEs) that were tolerable and manageable, according to Dmitriy Zamarin, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center, during his presentation at the 33rd Annual Meeting of the Society for Immunotherapy of Cancer (SITC 2018).¹

Mogamulizumab targets CC chemokine receptor type 4 (CCR4), a lymphocyte receptor expressed on a limited number of cells, including normal human circulating regulatory T cells (Tregs) and on T cell malignancies. It has been shown to deplete Tregs from peripheral blood in patients with solid tumors. Dr. Zamarin reported a reduction in the number of peripheral blood CCR4+ effector Tregs (eTregs). Mogamulizumab was recently approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome, two types of T cell lymphoma.

“Mogamulizumab clearly removed CCR4+ eTregs but it was also removing other cell populations, including natural killer cells, Th2, Th17, and Th22 were also observed,” Dr. Zamarin said.

The dose-escalation phase of the trial involved administering mogamulizumab and anti-PD-L1 durvalumab (treatment A) to 21 patients with locally advanced or metastatic solid tumors across four cohorts. Treatment B, which was the combination of mogamulizumab and anti-CTLA-4 tremelimumab, was provided to 19 patients. Dr. Zamarin reported that both combinations resulted in mild-to-moderate AEs, and no difference in safety profiles were observed for either combination.

The cohort expansion portion of the study involved patients with locally advanced or metastatic non—small cell lung cancer (NSCLC), pancreatic cancer, or head and neck cancer. However, the researchers were only able to report on patients with pancreatic cancer and presented safety data from that subset. These patients also received either treatment A (n = 12) or treatment B (n = 13).

Dr. Zamarin noted that patient baseline characteristics were similar between the two treatment cohorts within the dose-escalation study, but that both populations were heavily pretreated. In addition, “many of the cancer types that we saw were not typically expected to respond to immune checkpoint blockade, such as colorectal cancer, prostate cancer, and sarcoma.” Median age for the dose-escalation study was 63 years (treatment A) and 57 years (treatment B). The median age for the dose-expansion study was 68 years (treatment A) and 64.5 years (treatment B).

The most common treatment-emergent adverse events (TEAEs) reported for any grade in the subset of patients undergoing treatment A in the escalation study was maculo-papular rash reported by seven patients (36.8 percent). This was followed by fatigue (n = six), pruritus (n = five), and infusion-related reactions (n = four). For treatment B, the most common TEAEs (any grade) were infusion-related reactions (n = seven), maculo-papular rash (n = five), fatigue (n = three), and pruritus (n = three).

Dr. Zamarin reported that for patients undergoing treatment A, six patients (28.6 percent) in all dose cohorts of the dose-escalation and four patients (33 percent) in the pancreatic cancer dose-expansion cohort had any TEAE grade ≥ three related to either drug. Four patients (19 percent) in all dose cohorts of the dose-escalation and three patients (25 percent) in the pancreatic cancer dose-expansion cohort had a serious adverse event (SAE) related to either drug. For treatment B, nine patients (47.4 percent) in all cohorts of the dose-escalation study and four patients (33.3 percent) of the pancreatic cancer dose-expansion cohort had any TEAE grade ≥ three related to either drug. Five patients (26.3 percent) in all dose cohorts of the dose-escalation and one patient (8.3 percent) in the pancreatic cancer dose-expansion cohort had an SAE related to either drug.

No patients in either treatment arm achieved a complete response. In treatment A of the escalation trial, five patients had stable disease (SD). Two patients had SD in the pancreatic expansion trial. For treatment B, seven patients reported SD, while three patients reported SD in the pancreatic expansion trial.

For treatment A in the escalation trial, 12 patients (63.2 percent) reported progressive disease (PD) and 10 patients had PD in the pancreatic expansion trial. For treatment B, seven patients reported PD in the escalation trial and three patients with pancreatic cancer reported PD in the expansion trial.

“Combining mogamulizumab with either durvalumab or tremelimumab in solid tumors was tolerable, with manageable AEs that were generally mild to moderate,” said Dr. Zamarin. “Compared with historic monotherapy with these individual agents, we saw no differences in the safety profiles of the three agents.”

Reference:

Zamarin D, Hamid O, Nayak-Kapoor A, et al. Phase 1 study using mogamulizumab (KW-0761) to deplete regulatory T cells in combination with checkpoint inhibitors durvalumab (MEDI4736) or tremelimumab in patients with advanced solid tumors. In: Proceedings from the 2018 SITC Annual Meeting; November 7-11, 2018; Washington, D.C. Abstract 105.