A rare, aggressive and understudied cancer affecting a small patient population of 300-400 Americans diagnosed yearly, malignant peritoneal mesothelioma (MPeM), is often confused with pleural mesothelioma, a cancer of the lung lining, commonly caused by asbestos. MPeM is cancer in the lining of the abdomen with historically poor survival and limited treatment options. Even the symptoms of MPeM are often dismissed due to the peritoneal location, and as a result, the diagnosis is late stage with less than 1 year life expectancy.
"The symptoms generally presented are a slight change of bowel habits, gastric distress, or on and off abdominal pain," said Kanwal Raghav, MD, Associate Professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center. "Most patients consider these as day-to-day symptoms that happen for other reasons such as bad food, working too hard/stress, or dehydration."
The results from a Phase II study led by Raghav and Daniel Halperin, MD, Assistant Professor of Gastrointestinal Medical Oncology, could improve treatment options for MPeM patients based on the findings of the drug combination atezolizumab and bevacizumab, which was well-tolerated and resulted in a 40 percent objective response rate in patients with advanced MPeM.
"There is a grave unmet need for patients with peritoneal mesothelioma," Raghav said. "This study establishes a much-needed treatment option and represents a singular effort to encourage research for this rare disease."
Clinical Trials for Rare Cancers
Atezolizumab is an immune checkpoint inhibitor (ICI) that targets PD-L1, while bevacizumab is a targeted therapy that slows the growth of new blood vessels by inhibiting vascular endothelial growth factor (VEGF). The study showed responses occurred in patients regardless of PD-L1 expression status and tumor mutation burden (TMB).
"PD-L1 expression has been shown to be a biomarker of response to ICI, but not in our study, which indicates a certain complex tumor-immune interaction with these two drugs," said Raghav. "TMB is also a known biomarker; however, our patients didn't have high TMB."
To define a tumor environment predictive of response to this drug treatment, Raghav and his colleagues examined pre-treatment immune cell subsets using 15 available patient samples, which revealed VEGF inhibition improves the effectiveness of ICIs by adapting the immunosuppressive tumor environment.
"Patients treated on this regimen surpassed outcomes expected with conventional therapies," 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."
Treatment strategies for MPeM are varied, but usually include optimal cytoreductive surgery, hypothermic intraoperative peritoneal perfusion with chemotherapy (HIPEC), or early postoperative intraperitoneal chemotherapy (EPIC). Patients with MPeM usually are treated following the recommendations for malignant pleural mesothelioma, and most studies on chemotherapy and immunotherapy drugs have been done for pleural mesothelioma, often excluding MPeM patients.
Identifying Genetic Predispositions
The single-center study was conducted as a multicohort basket trial for evaluation of atezolizumab and bevacizumab in a diverse set of advanced cancers.
"In this rare cancer study, each tumor cohort was a different trial in itself, with each study uniquely designed for the tumor type; ours was the second cohort within this basket trial," said Raghav.
With 20 patients in the MPeM cohort, the study showed the average patient as a 63-year-old White woman, with the reported median age of 63 years, 60 percent female, 80 percent White, 10 percent Hispanic, 5 percent Black, and 5 percent other.
"Women who present with MPeM are approached with the assumption of ovarian cancer because of the way these cancers present and are often misdiagnosed," he said. "While there are genetic predispositions, there are currently not enough studies for risk factors for such a rare cancer as MPeM. Again, this highlights the need to conduct more collaborative investigations worldwide."
The data showed that 75 percent of the patients self-reported that they had not been exposed to asbestos, a subject that needed to be addressed based on the greater attention to the risk factor of asbestos for pleural mesothelioma.
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 one year were 61 percent and 85 percent, respectively. The treatment was well-tolerated, with the most common events being hypertension and anemia.
Biomarker Analysis
"The greatest benefit that emerged from this study was the biomarker analysis," said Raghav. This determined that epithelial-mesenchymal transition (EMT) gene expression, a cancer state associated with a more aggressive biology, correlated with aggressive disease, treatment resistance, and poorer response rates.
More specifically, the integration of biopsies-before and during treatment-established the practicability, as well as the value of a translationally motivated approach to this rare cancer, he said.
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.
"When a study requires biopsies as a mandate, most patients may not want to participate," he said. "However, with rare tumor types like MPeM, that is not true."
All of the patients in this study were excited to make their contributions for biopsies in the hope of generating better outcomes for the future, Raghav noted. "This is a big step for us. These results tell us we can do these in-depth rare patient studies."
To the best of his knowledge, he believes only one other study dedicated to MPeM was conducted within the past 10 years "Our MPeM and rare cancer patients are motivated and want to participate in trials; we just need to do more."
Improving Outcomes & Awareness
The lack of trials and effective therapies associated with small patient populations like those with MPeM have historically been ignored by traditional industry, academic, and health policies, said Raghav. "One of the reasons survival of rare tumors lags behind is because of the lack of research, but we need to change that ideology and outlook," he said. "Whether 300 or 300,000, every patient's life is valuable."
Raghav said a future trial will focus on improving the outcome by identifying the reason why more patients didn't respond in this current study. Additionally, the researchers plan to study augmented therapy responses, including the use in perioperative settings with this drug combination.
"We need to make a more enthusiastic effort to overcome the current lack of information and lack of treatment options for this rare patient population," said Raghav.
Additional trials with larger numbers of patients are needed to validate these study results, determine if this drug combination could be given as frontline treatment, or improve surgical outcomes for these patients, he noted.
"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," Raghav stated. "I am thankful for the patients who are willing to participate in clinical trials and help further our knowledge of rare cancers."
Note: The research authors would like to pay tribute to senior author, Gauri Varadhachary, MD, Clinical Professor in Gastrointestinal (GI) Medical Oncology at The University of Texas MD Anderson Cancer Center, for her efforts around this research and her mentorship. Varadhachary passed away June 5, 2021.
Amy Gallagher is a contributing writer.