Newswise — CHICAGO ― Results from three early-stage clinical trials led by researchers at The University of Texas MD Anderson Cancer Center show promising activity with novel immunotherapies and targeted therapies for patients with advanced tumors.
The findings, presented today at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, highlight advances researchers are making to develop more effective therapies for patients with treatment-refractory cancers or those harboring genetic mutations.
First-in-human study of IL-27-targeting antibody shows encouraging results against advanced solid tumors (Abstract 2501)
Results from a first-in-human study, led by Aung Naing, M.D., professor of Investigational Cancer Therapeutics, showed that blocking the IL-27 pathway with SRF388, an antibody that binds to IL-27, achieved encouraging preliminary antitumor activity with manageable toxicity and good tolerability.
“Immune checkpoint inhibitors have revolutionized the treatment landscape for cancer. However, the ability of currently available immune checkpoint inhibitors to overcome immune suppression is limited to a subgroup of patients, indicating a need for new therapeutic targets,” Naing said. “We are encouraged to see that SRF388 effectively blocks the immunosuppressive cytokine IL-27 by promoting immune system activation against the cancer, paving the way to improved treatment outcomes in cancer patients.
IL-27 is an immunoregulatory cytokine that upregulates inhibitory immune checkpoint receptors, such as PD-L1, and downregulates proinflammatory cytokines, such as IFNγ and TNFα. Dysregulation of IL-27 signaling has been implicated in the pathogenesis of various autoimmune and immune-mediated diseases and, at high levels, is associated with advanced cancers. By blocking IL-27, SRF388 has the potential to counteract IL-27-induced immunosuppression and to promote immune activation in the tumor microenvironment.
In the Phase I trial, researchers enrolled 29 patients with advanced treatment-refractory solid tumors to evaluate the safety and efficacy of SRF388, given as monotherapy every four weeks at different dose levels.
Ten patients (37%) achieved disease stabilization by eight weeks. Of those 10 patients, six (60%) exhibited durable disease control at six months. One patient with highly treatment-refractory non-small cell lung cancer experienced a confirmed partial response at eight weeks. Three of seven patients (43%) with clear cell renal cell cancer enrolled in the dose escalation experienced durable disease control for at least 20 weeks.
Naing also will present safety and efficacy results of SRF388 monotherapy in additional expansion cohorts of patients with clear cell kidney cancer and a combination with the PD-1 inhibitor pembrolizumab in patients with advanced kidney or liver cancers.
Across the monotherapy cohorts, treatment-related adverse events (TRAEs) occurred in 28% of patients and all were low grade, with fatigue (12%) being the most common. No dose-limiting toxicities or grade ≥3 TRAEs were reported in the study. No additive immune-related adverse reactions were seen in the pembrolizumab combination.
The trial is sponsored by Surface Oncology, Inc. A full list of co-authors and their disclosures can be found here.
First-in-class selective p53 reactivator demonstrates clinical activity in new study (Abstract 3003)
A first-in-human, Phase I study showed PC14586, a small molecule p53 reactivator, was safe and effective in patients with advanced solid tumors harboring the TP53 Y220C mutation. Trial results will be presented by principal investigator Ecaterina Ileana Dumbrava, M.D., associate professor of Investigational Cancer Therapeutics.
The TP53 gene provides instructions for making the p53 protein, an important transcription factor that regulates key roles in cell cycle arrest, repair and death. However, mutation to this gene can lead to inactivation of p53, enabling tumor cells to proliferate uncontrollably. Mutations in TP53 are found in more than 50% of all human cancers.
“This is an exciting study because we have discovered that p53 is no longer undruggable,” Dumbrava said. “The preliminary results of this study show how a specific TP53 mutation can be targeted with a genomically matched treatment resulting in promising antitumor efficacy. p53 Y220C is a key hot-spot TP53 mutation that occurs in ~1% of all solid tumors and it is tumor agnostic. This mutation creates a crevice or a pocket that can be targeted by a stabilizing small molecule (PC14586) to maintain p53 in a wild-type confirmation, reactivating the tumor-suppressor function.”
PC14586 is a novel, small molecule structural corrector that selectively binds to p53 Y220C mutant protein and restores its normal conformation and transcriptional activity, resulting in potent antitumor activity in preclinical studies. Researchers evaluated the safety and efficacy of PC14586 in 41 patients with advanced solid tumors harboring the TP53 Y220C mutation.
Treatment with PC14586 was safe and generally well-tolerated among patients up to 3,000 milligrams daily. Treatment-related adverse events (TRAEs) were observed in 80.5% of patients, with 22% grade 3 AEs, including increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), anemia, and decreased neutrophil and platelet count. The most common TRAEs included nausea (44%), vomiting (27%), increased AST (22%) and increased ALT (20%). Dose-limiting toxicities were reported in two patients at 1,500 milligrams twice daily with grade 3 AST/ALT increase and grade 3 acute kidney injury.
At higher doses, ranging from 1,150 to 3,000 milligrams per day, eight out of 25 evaluable patients (32%) achieved partial responses per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, including patients with metastatic or advanced cancer: ovarian (2), prostate (2), small cell lung (1), endometrial (1), breast (1) and pancreatic (1). Furthermore, 11 patients (44%) achieved stable disease. These results were durable with treatment ongoing for 6 out of 8 responders.
Enrollment of patients for confirmation of phase II recommended dose is ongoing with plans of opening the study later in the year.
The trial was supported by PMV Pharmaceuticals, Inc. A full list of co-authors and their disclosures can be found here.
Combination cobimetinib and vemurafenib safe and effective for BRAF-mutant advanced cancers (Abstract 3008)
In the Phase II Targeted Agent and Profiling Utilization Registry (TAPUR) basket study, the combination therapy of cobimetinib and vemurafenib demonstrated antitumor activity in patients with BRAF-mutant solid tumors. The data builds upon the previous TAPUR study conducted to evaluate the efficacy of commercially available targeted agents to treat advanced cancers with BRAF V600E and other mutations. Trial results will be presented by principal investigator Funda Meric-Bernstam, M.D., department chair of Investigational Cancer Therapeutics
“There is increasing awareness of the importance of genomic profiling in the care of advanced cancer patients,” Meric-Bernstam said. “Our study demonstrated that BRAF V600 mutations are drivers and that the combination of cobimetinib and vemurafenib has antitumor activity in a variety of tumor types.”
In the non-randomized, open-label trial, researchers enrolled 31 patients with solid tumors carrying BRAF mutations between December 2016 and January 2021. Of the 28 evaluable patients, 26 (93%) patients had diseases with the BRAF V600 mutation.
Two patients with BRAF V600 mutations (one breast and one ovarian cancer) achieved complete responses, while 13 patients with V600E mutations and one with a N581I mutation experienced partial responses. Stable disease of more than 16 weeks was observed in three patients, including two with V600E and one with T599_V600insT mutations. Overall, the targeted therapy combination demonstrated a disease control rate of 68%, with an objective response rate of 57%. Median progression-free survival was 23.3 weeks, with a median overall survival of 60.9 weeks. Grade 1-5 TRAEs were observed in 19 patients.
The TAPUR trial was sponsored by ASCO, in collaboration with AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Merck, Pfizer and Seagen. A full list of co-authors and their disclosures can be found here.
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About MD Anderson The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. The institution’s sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 52 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is No. 1 for cancer in U.S. News & World Report’s “Best Hospitals” rankings and has been named one of the nation’s top two hospitals for cancer since the rankings began in 1990. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).
© 2022 The University of Texas MD Anderson Cancer Center
Meeting Link: 2022 American Society of Clinical Oncology (ASCO) Annual Meeting