Novel Neoadjuvant Triplet Shows Preliminary Promise in Resectable Pleural Mesothelioma

Boris Sepesi, MD

Neoadjuvant treatment with cisplatin/pemetrexed plus atezolizumab (Tecentriq), followed by maintenance atezolizumab, demonstrated early efficacy with acceptable safety in patients with resectable pleural mesothelioma, according to data from an updated analysis of the S1619 trial presented during the International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer.

“When we speak about mesothelioma that is potentially surgically resectable, that is the patient population that we sort of consider potentially curable, although we know that recurrences occur,” explained Boris Sepesi, MD, The University of Texas MD Anderson Cancer Center. “The median survival in patients who undergo multimodality therapy that includes surgery range in different studies between 17 and 25 months… The aim of this study was really to test chemotherapy plus immunotherapy in surgically resectable mesothelioma based on the fact that these are occasionally immunogenic tumors that express PDL1 expression, which is associated with worse outcomes.”

The study sought to assess whether adding anti-PD-L1 inhibitors to neoadjuvant cisplatin-pemetrexed, followed by maintenance immunotherapy after surgical resection and adjuvant radiation would enhance T-cell activation against microscopic disease and potentially increase overall survival (OS) in patients with malignant pleural mesothelioma.

Overall, 21 patients successfully completed neoadjuvant therapy, although 7 were unable to proceed to surgical resection. Of those 7, 2 patients reported severe toxicity, 4 experienced disease progression, and 1 death occurred due to non-immune related renal and respiratory failure.

There were 18 patients with stable disease or partial response who were able to receive surgical resection, and 16 patients registered to receive maintenance atezolizumab for 1 year. Thus far, median progression-free survival is 18 months and OS has not been reached.

Participants were evaluable if they had received at least 2 cycles of the triplet neoadjuvant therapy, were chemo-naïve, had mesothelioma, and extended surgical staging. A total of 28 patients were screened between November 2017 and May 2020 with the intention of obtaining 24 eligible patients.

Patients were then administered the triple-combination regimen with the following dosage: 75 mg/m2 cisplatin, 500 mg/m2 pemetrexed, and 1200 mg IV atezolizumab every 3 weeks. As long as patients did not experience disease progression, they continued to resectable surgery. Following surgery, they were to be treated with 1 year of maintenance atezolizumab.

Within this pool of potential participants, 25 received at least 2 cycles of neoadjuvant cisplatin-pemetrexed-atezolizumab.

The median age of participants was 68 years. The majority of participants were Caucasian, and the patient pool was predominantly male. Four patients planned on receiving

extrapleural pneumonectomy (EPP) surgery, while 24 planned on receiving pleurectomy and decortication surgery (P/D).

The primary end point of the trial was to assess the safety and tolerability profiles, as well as better understand the feasibility, of neoadjuvant cisplatin-pemetrexed-atezolizumab treatment followed by surgery and maintenance atezolizumab. For the treatment to be considered safe or tolerable, there would be no reported grade 4 or 5 immune-related adverse events (irAEs). To be considered feasible, 75% of patients (18/24) needed to complete at least 1 dose of maintenance therapy.

The final analyses will separately assess patients who received EPP surgery and those who received P/D surgery for their resectable operation. Of the 18 that successfully received resection surgery, 17 received P/D and 1 received EPP. So far, 16 patients have registered to receive maintenance atezolizumab for 1 year. There are still 3 patients undergoing treatment with maintenance atelozimab therapy.

Investigators concluded that the triplet combination appeared to be reasonably tolerated in the patient population. There was only 1 patient who reported grade 4 or 5 AEs. Notably, that patient did experience multiple grade 4 AEs and 1 grade 5 AE. That patient experienced severe acute renal injury, sepsis, pneumonitis, and respiratory failure.

The most common neoadjuvant therapy-related AEs were nausea (n = 20), fatigue (n = 15), neutropenia (n = 11), anemia (n = 12), anorexia (n = 11), and vomiting (n = 7). Researchers also observed cases of hyponatremia (n = 5), creatinine increase (n = 6), constipation (n = 7), dysgeusia (n = 5), and infusion-related reactions (n = 3).

“These are some preliminary survival results which at this point seem rather encouraging although the median follow up is not the same as in some of the previous trials,” said Sepesi. “Some of these results are comparable to, [or] perhaps, slightly better to historical cohorts, but we will have to complete the trial, and complete the adequate follow-up to be able to make any conclusions from this regimen.”

“As always with mesothelioma, this trial highlights the challenging nature of the new adjuvant therapy, because of the heterogeneity of the disease, as well as how patients react as well as the difficult and complex surgical therapy,” he concluded. “However, I think this is a step forward in terms of complex treatment of mesothelioma.”

While Sepesi chose to refrain from speculating on the benefit of adding atezolizumab to the regimen, in a post-presentation discussion, he noted that future research will also need to look at patients based on nodal status (N0 vs N+) since those outcomes are different in surgically managed mesothelioma.

There are still 3 patients undergoing the therapy in this trial.

Reference

1. Tsao A, Qian L, Cetnar J, et al. A trial of neoadjuvant cisplatin-pemetrexed with atezolizumab combination and maintenance for resectable pleural mesothelioma. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021; Virtual. Absract OA13.01