Mixed results

HOUSTON—Recent news from the University of Texas MD Anderson Cancer Center brought hope for some underserved patients with lung and ovarian cancer, but also included disappointment in the form of severely scaled-back expectations for the therapeutic potential of a breast cancer candidate.

 

MD Anderson partnered with Ipsen Biopharmaceuticals to explore the efficacy of IPN60090, a small-molecule inhibitor of the metabolic enzyme glutaminase (GLS1). In their report on the preclinical discovery and early-stage clinical development of the drug, they indicated positive potential benefit for at least some patients with lung and ovarian cancers. This candidate originated in MD Anderson’s Therapeutics Discovery department and was later developed in concert with Ipsen, which licensed it in 2018.

 

“This effort is a great example of our strategy within Therapeutics Discovery, taking a comprehensive approach to personalized medicine,” said Dr. Jeffrey Kovacs, co-leader of the GLS1 program and institute group leader with MD Anderson’s Translational Research to Advance Therapeutics and Innovation in Oncology program. “Our preclinical data suggest that IPN60090 may be effective in underserved groups of patients who need better treatment options, and we look forward to results from our ongoing clinical trials.”

 

The researchers found IPN60090 to be a powerful GLS1 inhibitor that was effective against some variants of lung and ovarian cancer preclinical models. They found biomarkers of response, allowing them to isolate patients with higher potential to have positive results.

 

Specifically, the identified lung cancer patients who have not had consistent benefit from immune checkpoint inhibitors showed a mutation in the KEAP1 and NFE2L2 genes, known to synchronize response to imbalance between the presence of free radicals and the body’s ability to counteract their harmful effects. The presence of this mutation induced cells to better respond to IPN60090. Likewise, in ovarian cancer, a deficit of asparagine synthetase (ASNS) forecasts a positive readiness for IPN60090.

 

“Identifying these putative predictive biomarkers of response is critical for our ongoing clinical efforts to ensure that we’re able to offer patients the most relevant therapies,” explained Dr. Timothy A. Yap, associate professor of Investigational Cancer Therapeutics and medical director of the Institute for Applied Cancer Science at MD Anderson. “These patient groups in particular, which represent distinct niches within those cancer types, are in need of more effective treatment options.”

 

IPN60090 is currently in a Phase 1 dose-escalation, dose-expansion study for these most promising candidates, who have been identified through targeted CLIA-certified assays. Preliminary data from the clinical trial indicate that IPN60090 is effectively inhibiting GLS1 activity in peripheral blood mononuclear cells from subjects. Future plans involve further investigation, combining IPN60090 with checkpoint inhibitors, chemotherapies and other targeted therapies in search of beneficial interactions.

 

Other data reported by MD Anderson were less positive, as they found their highly anticipated results for the PARP inhibitor talazoparib did not demonstrate a statistically notable benefit for overall survival (OS) in patients presenting with metastatic HER2-negative breast cancer and those with mutations in the BRACA1/2 genes.

 

Talazoparib functions by inhibiting the PARP enzyme, while also impacting the enzyme’s ability to stifle effective DNA repair. In addition to causing defects in normal DNA damage repair, PARP inhibitors also impede an innate DNA repair pathway, a manifestation which is amplified in patients with BRCA mutations.

 

Talazoparib showed significant promise in early research, published previously in the New England Journal of Medicine, as it demonstrated extended progression-free survival (PFS) in comparison to chemotherapy. Results of the EMBRACA study, the largest of its kind in patients with germline BRCA-mutated HER2-negative advanced cancer, indicated limitations to the promise of the drug.

 

While patients continued to report superior quality-of-life measures, including more than triple the time to deterioration of overall health compared to chemotherapy, the OS results were disappointing. The study recruited 431 patients, of whom 287 received talazoparib. At nearly 35 months later, 216 of the talazoparib patients had died, alongside 108 of the original 144 patients in the control group.

 

Spokespeople from MD Anderson point out that nearly half of patients in the talazoparib cohort later received another PARP inhibitor or platinum therapy, potentially impacting the OS results.

 

“Overall survival is always an important endpoint, but also a challenge for metastatic breast cancer patients as there are many treatment options available,” Dr. Jennifer Litton, professor of Breast Medical Oncology, commented in a press release. “Many of these patients also received subsequent therapies, including PARP inhibitors and platinum-based therapies, which could have potentially influenced these results. Talazoparib remains an option for patients with advanced breast cancer and a germline BRCA mutation due to its improvements in progression-free survival. Other advantages include it being an oral once-daily option, as well as the demonstrated improvements in quality of life for metastatic breast cancer patients.”