Clinical trials evaluate novel immune checkpoint inhibitor combinations
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In the clinical trials plenary Novel Immune Checkpoint Inhibitor Combinations at the American Association for Cancer Research Annual Meeting 2024 on Sunday, April 7, four experts discussed findings from clinical trials testing novel combinations of immune checkpoint inhibitors.
The session was chaired by Colin D. Weekes, MD, PhD, director of medical oncology research for pancreatic cancer at Massachusetts General Hospital, and Solange Peters, MD, PhD, director of oncology at Lausanne University Hospital (CHUV), Switzerland.
This session is available on demand for registered Annual Meeting participants through July 10, 2024, on the virtual meeting platform.
Cadonilimab plus chemotherapy for locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma
Jiafu Ji, MD, PhD, a professor at Peking University Cancer Hospital and Institute in Beijing, presented results from the interim analysis of COMPASSION-15.
In the first-line treatment of advanced G/GEJ adenocarcinoma, inhibitors of programmed cell death protein 1 (PD-1) plus chemo is the standard of care. However, survival benefits are limited to patients with high programmed death ligand 1 (PD-L1) expression. In the phase Ib/II COMPASSION-3 trial, the PD-1/cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) bispecific antibody cadonilimab plus chemotherapy showed benefit regardless of PD-L1 expression.
“Our phase Ib/II study showed cadonilimab had a promising result for our patients … so we conducted a phase III randomized clinical trial,” Ji said.
The COMPASSION-15 study is a phase III trial evaluating the efficacy and safety of cadonilimab plus chemotherapy for the first-line treatment of G/GEJ adenocarcinoma with low PD-L1 expression.
Compared to chemotherapy alone, cadonilimab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in overall survival regardless of PD-L1 expression. Cadonilimab also improved progression-free survival, objective response rate, and duration of response. Cadonilimab had a manageable safety profile, and no new safety signals were observed.
Copanlisib plus nivolumab for microsatellite stable (MSS) colorectal cancer (CRC)
Eric S. Christenson, MD, assistant professor of oncology at Johns Hopkins Hospital, presented results from a clinical trial evaluating the phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in combination with nivolumab in MSS CRC patients.
“PIK3Cα mutations are present in about 15 to 32 percent of patients with CRC, with MSS CRC generally having very low response rates to anti-PD-1 monotherapy of less than 5 percent,” Christenson said. PI3K inhibitors and third-line therapeutic options in CRC also provide limited benefit. However, preclinical work suggested that combining PD-1 and PI3K inhibitors may improve patient survival. This hypothesis was tested in a phase I/II trial.
Copanlisib, in combination with nivolumab, produced durable responses in patients with MSS CRC. Indicators of enhanced immune activation were observed after treatment with copanlisib plus nivolumab, including an increase in effector CD8+ T cells and pro-immune cytokines, including tumor necrosis factor α, interleukin-5, and interleukin-15.
Treatment was generally well tolerated. The most common grade 3/4 treatment-related adverse events were hyperglycemia and hypertension.
Mirvetuximab soravtansine (IMGN853) plus pembrolizumab in patients with microsatellite stable recurrent or persistent endometrial cancer
Rebecca L. Porter, MD, PhD, medical oncologist at Dana-Farber Cancer Institute, presented results from a phase II, two-stage study of mirvetuximab soravtansine (MIRV) plus pembrolizumab in patients with MSS recurrent or persistent endometrial cancer. Endometrial cancer is the most common gynecologic malignancy in the U.S. and has a rising incidence and mortality.
MIRV is a first-in-class antibody-drug conjugate approved for treatment-refractory ovarian cancer that consists of a folate receptor alpha (FRα)-binding antibody, a cleavable linker, and the tubulin-disrupting maytansinoid DM4. In a phase I study, MIRV demonstrated modest activity in patients with endometrial cancer.
“The current study is aiming to improve the response to mirvetuximab by combining it with immune checkpoint blockade,” Porter said. “There is strong preclinical data to suggest that antibody-drug conjugates—both from their cytotoxic payload and their antibody component—may augment the cancer immunity cycle in a variety of ways.”
Treatment with MIRV plus pembrolizumab demonstrated clinical activity in patients with FRα-positive, recurrent, mismatch repair-proficient (pMMR)/MSS endometrial cancer, meeting the prespecified criteria of being worthy of further evaluation in this patient population. While two patients had a prolonged duration of response, other patients progressed after their initial response. Thus, investigations into subpopulations most likely to benefit from MIRV plus pembrolizumab are needed. The safety profile of MIRV plus pembrolizumab was acceptable, and there were no unexpected toxicities.
Phase III trial of atezolizumab (atezo) vs placebo in high-risk locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN)
Deborah J. Wong, MD, PhD, associate clinical professor of medicine at UCLA Medical Center, presented results from IMvoke010, a phase III, double-blind, randomized trial of atezo after completion of definitive local therapy in patients with high-risk LA SCCHN.
Treatment for high-risk LA SCCHN involves a combination of surgery, chemotherapy, and radiation. Following the completion of definitive local therapy, the standard of care is for patients to be monitored for potential local recurrence or distant metastases. “Unfortunately, despite the intensive nature of such therapy, treatment outcomes are quite poor,” Wong said.
Given that atezo has demonstrated antitumor activity in advanced recurrent or metastatic SCCHN, it was hypothesized that it may offer clinical benefit in an earlier setting.
Treatment with atezo did not demonstrate a statistically significant improvement in event-free survival. Further, overall survival did not differ between patients treated with atezo versus placebo. Atezo was generally well tolerated, with no new safety signals.
