Neoadjuvant atezolizumab combined with pemetrexed and cisplatin, with maintenance atezolizumab, proved to be safe and feasible, offering a hint of benefit in patients with resectable pleural mesothelioma, in a small multicenter study presented at the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer.¹ The study was presented by Boris Sepesi, MD, FACS, of The University of Texas MD Anderson Cancer Center, Houston. The study’s first author and principal investigator is Anne S. Tsao, MD, also of MD Anderson.

Boris Sepesi, MD, FACS

Anne S. Tsao, MD

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 only a feasibility trial of chemotherapy plus atezolizumab, and by no means was our goal to compare this with cisplatin/pemetrexed. Until the final analysis is performed, I would like to refrain from speculating on the benefit of adding atezolizumab to the regimen.”

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 yield a median overall survival of about 1.5 to 2 years.

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

Study Details

The study enrolled 28 previously untreated patients (20 men, 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 IV) plus atezolizumab (1,200 mg IV) 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 IV 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.

Key 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 occurred from sepsis (not thought to be related to immunotherapy).

A total of 18 patients with stable disease or partial response proceeded to resection; 17 received pleurectomy/decortication and 1 had 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 of sepsis (not considered related to immunotherapy). Postoperatively, one patient experienced a fatal cardiovascular event.

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

Suggestion of Activity

As Dr. Sepesi emphasized, this was a feasibility study alone; 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. Of the 25 patients, 20 experienced disease progression, for a median progression-free survival of 18.6 months.

These results appear to be comparable to historical cohorts, noted Dr. Sepesi, 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.”

Dr. Sepesi reminded journalists in a press briefing that it takes a long time to move from early-phase studies to a phase III trial—almost 15 years to establish immunotherapy with nivolumab/ipilimumab as beneficial in unresectable mesothelioma. “Mesothelioma is still an extremely difficult disease to treat. We need to reach out to patients outside of our institutions, to enroll in trials, 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. 

REFERENCE

1. Tsao A, Qian L, Cetnar J, et al: S1619: A trial of neoadjuvant cisplatin-pemetrexed with atezolizumab in combination and maintenance for resectable pleural mesothelioma. IASLC 2021 World Conference on Lung Cancer. Abstract OA13.01. Presented September 12, 2021.