A phase II study published by Kanwal Raghav, MBBS, MD, and colleagues in Cancer Discovery found that combination treatment with the PD-L1 inhibitor atezolizumab and the VEGF inhibitor bevacizumab was well tolerated and resulted in a 40% objective response rate in patients with advanced malignant peritoneal mesothelioma, a rare cancer in the lining of the abdomen. Responses occurred in patients regardless of PD-L1 expression status and tumor mutational burden.

Trial results also indicated that the combination was safe and effective in patients with disease progression or intolerance to previous chemotherapy treatment.

Malignant peritoneal mesothelioma is a rare but aggressive disease with historically poor survival and limited treatment options. Because symptoms most often go unnoticed, peritoneal cancer is usually diagnosed at a late stage. If left untreated, life expectancy is often less than 1 year.

Kanwal Raghav, MBBS, MD

“There is a grave unmet need for patients with peritoneal mesothelioma,” said first study author Dr. Raghav, of the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center. “This study establishes a much-needed treatment option and represents an effort to encourage research for this rare disease.”

More About Malignant Peritoneal Mesothelioma

Researchers estimate that 300 to 500 Americans are diagnosed with malignant peritoneal mesothelioma each year. Malignant peritoneal mesothelioma usually follows the same treatment as pleural mesothelioma, a cancer of the lung lining, although there are significant differences between the diseases; malignant peritoneal mesothelioma is far rarer, understudied, has a weaker association with asbestos exposure, affects women more frequently, occurs at a younger age, and is diagnosed more often at an advanced stage.

Treatment strategies are varied, but usually include optimal cytoreductive surgery, hypothermic intraoperative peritoneal perfusion with chemotherapy (HIPEC), or early postoperative intraperitoneal chemotherapy (EPIC). Patients with malignant peritoneal mesothelioma usually are treated following the recommendations for malignant pleural mesothelioma, and most studies on chemotherapy drugs have been done for pleural mesothelioma.

The National Comprehensive Cancer Network® (NCCN®) recommends first-line platinum chemotherapy for both mesotheliomas, but after disease progression, there is no established treatment strategy or any U.S. Food and Drug Administration–approved treatments for advanced malignant peritoneal mesothelioma.

Current Study Details

This single-center study is a multicohort basket trial for evaluation of atezolizumab and bevacizumab in a variety of advanced cancers. This publication reports data for the 20 patients in the malignant peritoneal mesothelioma cohort. The median age was 63 years, 60% of participants were women, and 75% self-reported that they had not been exposed to asbestos. Trial participants were 80% White, 10% Hispanic, 5% Black, and 5% other.

Prior to enrolling in this clinical trial, patients who received standard-of-care chemotherapy progressed to next treatment at 8.3 months compared to 17.6 months with atezolizumab and bevacizumab on the study. The median response duration was 12.8 months.

Progression-free and overall survival at 1 year were 61% and 85%, respectively. The treatment was well tolerated, with the most common events being hypertension and anemia.

“Patients treated on this regimen surpassed outcomes expected with conventional therapies,” Dr. Raghav said. “This data shows that this is a reasonable treatment option and reiterates the importance of clinical trials for rare cancers to extend patient survival.”

Biomarker Analysis

Integration of biopsies before and during treatment established the practicability and the value of a translationally motivated approach in rare cancers. Using the biopsies, the researchers demonstrated that the clinical activity seen with this treatment combination did not correlate with clinically established biomarkers of response to immune checkpoint inhibition in other tumors.

The biomarker analysis determined that epithelial-mesenchymal transition (EMT) gene expression, which is a cancer state associated with a more aggressive biology, correlated with aggressive disease, treatment resistance, and poorer response rates.

To define a tumor environment predictive of response to this drug treatment, researchers examined pretreatment immune cell subsets using 15 available patient samples. They found that VEGF inhibition improved the effectiveness of immune checkpoint inhibitors by adapting the immunosuppressive tumor environment.

“I am very encouraged by the responses to this treatment, and I am hopeful that with additional research, this will provide a better treatment option for these patients,” Dr. Raghav said. “I am thankful for the patients who are willing to participate in clinical trials and help further our knowledge of rare cancers.”

Additional trials with larger numbers of patients are needed to validate these study results and to determine if this drug combination could be given as frontline treatment or improve surgical outcomes for these patients.

Disclosure: The research was supported by F. Hoffmann-La Roche/Genentech and the National Cancer Institute. For full disclosures of the study authors, visit cancerdiscovery.aacrjournals.org.