Triplet Therapy Proves Safe in Resectable Malignant Pleural Mesothelioma

A three-agent neoadjuvant regimen met safety criteria, with 60% of eligible patients with malignant pleural mesothelioma (MPM) moving on to surgery and maintenance therapy, a researcher reported.

In a phase I study of 25 patients with stage I-III MPM, the majority successfully received neoadjuvant cisplatin-pemetrexed-atezolizumab (Tecentriq) and underwent surgical resection, while some went on maintenance atezolizumab with no treatment-related adverse events (TRAE) grade >3 reported to date, according to Boris Sepesi, MD, of the MD Anderson Cancer Center in Houston.

After about 20 months of follow-up, the median overall survival has not been reached, Sepesi said in a presentation at the virtual World Congress on Lung Cancer (WCLC). The median progression-free survival was 18.6 months.

Sepesi stressed at a WCLC press conference that this “was a feasibility trial so we cannot overstate the results. Until the final analysis is done, I would like to refrain from speculating on the benefit of adding atezolizumab to the regimen.”

WCLC press conference moderator Anne-Marie Baird, PhD, of Trinity College in Dublin, also emphasized that it was “a small study. We really need to see the final outcomes from the study before we can say a lot more that is concrete.”

Baird noted that the study only included patients who were candidates for surgery, and that is not likely the majority of real-world patients diagnosed with the disease. Sepesi conceded that selection bias was an issue for this early-stage study.

“There is also the question of whether this treatment can be applied to patients who have had previous treatments,” Baird said, suggesting that patients who are treatment naïve, but don’t have resectable disease, might also be considered for future trials of this neoadjuvant therapy.

Sepesi pointed out that MPM is an orphan disease with limited treatment options. “It is an immunogenic disease, and the PD-L1 target has been identified in mesothelioma tumor cells and associated as a negative prognostic biomarker,” he said. “We propose that adding anti-PD-L1 inhibitor to neoadjuvant cisplatin-pemetrexed and then maintenance immunotherapy after surgical resection and adjuvant radiation will enhance T-cell activation against microscopic disease and potentially increase overall survival outcomes.”

His group recruited 29 patients with resectable MPM, of which four did not meet study protocol criteria. Eventually, 25 patients received at least two cycles of the triplet treatment, and 18 of them went on to surgery, while 15 received maintenance atezolizumab. Evaluable patients were defined as those who received at least two cycles of the triplet neoadjuvant therapy, and the regimen was considered safe/tolerable if no patients experience grade 4-5 TRAE.

The authors reported one treatment-related death from sepsis, which was linked with non-immune related renal and respiratory failure. Three patients are still undergoing the 1-year of atezolizumab maintenance therapy, they said.

Sepesi explained that the regimen would be considered feasible if 75% of the patients received at least one dose of maintenance therapy and that was achieved.

He said next steps will be to stratify patients by nodal status as those outcomes are different in surgically managed mesothelioma. “As mentioned in surgical literature. median overall survival ranges between 17-25 months depending on the stage and other factors,” he said. “Previous surgical trials didn’t uniformly use neoadjuvant therapy.”

A National Cancer Institute study will assess the triplet therapy plus surgery, with or without radiation therapy, in stage I-III MPM, while the BEAT-Meso trial will look at atezolizumab plus bevacizumab (Avastin) in MPM.