Neoadjuvant atezolizumab combined with pemetrexed and cisplatin, followed by surgical resection and maintenance atezolizumab, proved safe and feasible and offered hints of benefit in patients with resectable pleural mesothelioma. Results from a small multicenter study were presented by Boris Sepesi, MD, of The University of Texas MD Anderson Cancer Center, and colleagues at the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer (Abstract OA13.01). The study’s first author was Anne S. Tsao, MD, also of MD Anderson.

Dr. Sepesi called the regimen’s activity “rather encouraging,” as median overall survival was not reached in the study and median progression-free survival was 18.6 months. However, he noted, “This was a feasibility trial only of chemotherapy plus atezolizumab, and by no means was our goal to compare this to cisplatin/pemetrexed. Until the final analysis is done, I would like to refrain from speculating on the benefit of adding atezolizumab to the regimen.”

Boris Sepesi, MD

Anne S. Tsao, MD

The Challenge of Mesothelioma

“Malignant pleural mesothelioma is a deadly disease that is extremely difficult to treat,” Dr. Sepesi noted. In the curable population, neoadjuvant chemotherapy, resection, and adjuvant radiation yields a median overall survival of about 1.5 to 2 years.

But this is an immunogenic malignancy, and tumor cell expression of PD-L1 is a negative prognostic marker, he noted. “We proposed that adding an anti–PD-L1 inhibitor to neoadjuvant cisplatin/pemetrexed, followed by maintenance immunotherapy after surgical resection and adjuvant radiation, will enhance T-cell activation against microscopic disease and potentially increase overall survival outcomes.”

Study Details

The study enrolled 28 previously untreated patients (20 men and 8 women) with mesothelioma whose disease was deemed resectable by pleurectomy/decortication or extrapleural pneumonectomy. Patients underwent extended surgical staging with mediastinoscopy or endobronchial ultrasound and laparoscopy.

Patients were then slated for neoadjuvant therapy with four cycles of cisplatin (75 mg/m²) and pemetrexed (500 mg/m²) plus atezolizumab (1,200 mg) every 3 weeks. They underwent resection, and patients who had extrapleural pneumonectomy also received radiotherapy. The protocol then called for 1 year of maintenance atezolizumab (1,200 mg intravenously every 3 weeks).

The primary endpoint was safety/tolerability and feasibility of this approach. The study would be considered safe and tolerable if no patient experienced a grade 4 or 5 immune-related adverse event, and feasible if 75% of patients received at least one dose of maintenance therapy.

Study Findings

Of the 28 patients, 25 received at least two cycles of neoadjuvant therapy, 18 underwent surgery, and 15 received atezolizumab. Neoadjuvant therapy was completed by 21 patients, but 7 did not proceed to resection because of disease progression, toxicity, or death. The one treatment-related death reported in the study occurred from sepsis that was not related to immunotherapy.

Eighteen patients with stable disease or partial response proceeded to resection; 17 underwent pleurectomy/decortication and 1 underwent extrapleural pneumonectomy. One patient ultimately did not receive protocol-specified surgery because of progressive disease. There were 16 patients registered to receive maintenance atezolizumab, but 1 became ineligible because of inadequate hematologic function. Maintenance therapy is ongoing for three patients.

Most treatment-related adverse events were grade 1 or 2. One patient developed grade 4 pneumonitis and respiratory failure and died from sepsis not considered related to immunotherapy. Postoperatively, one patient experienced a fatal cardiovascular event.

“To date, no delayed grade 3 and higher treatment-related adverse events have been reported, and there was no new safety signal from this regimen or from atezolizumab maintenance,” Dr. Sepesi reported.

Suggestion of Activity

As Dr. Sepesi emphasized, this was a feasibility study only; however, he reported that after a median follow-up of about 20 months, median overall survival has not been reached, based on 9 deaths among 25 patients. Twenty of 25 patients have experience disease progression, for a median progression-free survival of 18.6 months.

These results appear comparable to historical cohorts, he noted, but he emphasized that the trial must first be completed with adequate follow-up before conclusions can be drawn about the benefit of neoadjuvant atezolizumab plus cisplatin/pemetrexed.

“At this point, it seems rather encouraging,” he commented. “But I don’t want to overstate these results until the trial is completed and the results analyzed.”

He reminded journalists in a press briefing that it takes a long time to move from early-phase studies to a phase III trial. “Mesothelioma is still an extremely difficult disease to treat. We need to reach out to patients outside of our institutions to enroll in trials in order to advance the care of these patients,” he said.

Disclosure: Dr. Sepesi has consulted for or received speakers’ fees from Bristol Myers Squibb, Lilly, Genentech, AstraZeneca, and Medscape.