In a randomised, phase III IND227 study conducted in Canada, Italy, and France through collaborative efforts of the Canadian Cancer Trials Group (CCTG), National Cancer Institute of Naples and Intergroupe Francophone de Cancérologie Thoracique, the combination of pembrolizumab and platinum-based chemotherapy improved statistically median overall survival (OS) and median progression-free survival (PFS) regardless of PD-L1 expression compared with platinum-based chemotherapy alone in patients with previously untreated, unresectable malignant pleural mesothelioma.
The rate of serious side effects was higher in the pembrolizumab and platinum-based chemotherapy combination arm. The findings were presented by Dr. Quincy S. Chu of the Cross Cancer Institute in Edmonton, AB, Canada at 2023 ASCO Annual Meeting on 3 June in Chicago, IL, US.
The study team explained that a vast majority of patients with malignant pleural mesothelioma have unresectable disease, due to co-morbidities and/or advanced stage. In unresectable malignant pleural mesothelioma, standard first-line treatment for 20 years has been platinum plus pemetrexed, but it is moderately efficient, mostly in epithelioid histology, with a median OS of around 12 months, an improved quality-of-life (QoL), and mild side effects.
The CheckMate-743 study has recently demonstrated a significant improvement in median OS for nivolumab plus ipilimumab over platinum plus pemetrexed, particularly among patients with non-epithelioid malignant pleural mesothelioma, but 30% of patients treated with nivolumab plus ipilimumab experienced serious side effects.
The phase III IND227 study involved 440 patients, who were stratified by histologic subtype and randomly assigned 1:1 to receive platinum plus pemetrexed and pembrolizumab (222 patients) or platinum plus pemetrexed alone (218 patients). Carboplatin was allowed if cisplatin was contraindicated. The cohort was separate from the phase II portion of the study, which included 80 additional patients, including an arm of 40 patients who received pembrolizumab alone. That arm was discontinued per protocol after an early interim analysis based on early disease control rate found that it performed less well than the other arms.
The study requirements were the patients with unresectable malignant pleural mesothelioma, who are at least 18 years old with ECOG performance status 0 to 1, adequate haematological, renal, and liver function, with no active autoimmune disease, brain metastases, interstitial lung disease or other active co-morbidities. Radiological review and PD-L1 testing were centralised. The study primary endpoint was median OS, while median PFS, response rate, QoL and economic analysis were secondary endpoints.
Data cut-off was 16 September 2022. All patients were included in the analyses. Arms were well balanced. In the chemotherapy and pembrolizumab arm, 176 patients had epithelioid tumour and 46 patients had a non-epithelioid subtype. In the chemotherapy alone arm, 174 and 44 patients had epithelioid and non-epithelioid subtypes.
Approximately half of the patients in the 2 arms received carboplatin or switched from cisplatin to carboplatin. A total, 7 patients opted not to receive platinum and pemetrexed chemotherapy. Median exposure of chemotherapy was comparable between arms. Subsequent treatment with chemotherapy was similar in both arms, while 59 patients in chemotherapy alone arm received subsequently immunotherapy versus 17 patients who received initially chemotherapy and pembrolizumab.
The study investigators found by stratified log rank test that a median OS was 17.3 versus 16.1 months for chemotherapy and pembrolizumab versus chemotherapy alone arm (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.64-0.98; p = 0.0324). The magnitude of survival benefit was greater among patients with non-epithelioid subtypes, like CheckMate-743 findings, although the analyses done for the IND227 study were not prespecified. PD-L1 expression did not affect the OS benefit associated with pembrolizumab.
Median PFS was 7.13 versus 7.16 months (HR 0.80, 95% CI 0.65-0.99, p = 0.0372). The 1-year PFS rate for the chemotherapy and pembrolizumab arm was 26% and 17% for chemotherapy alone arm, and the 2-year PFS was 9% and 4%, respectively. Best overall response (BOR) was significantly higher for chemotherapy and pembrolizumab arm (63% versus 40%, p < 0.0001). The duration of BOR was 5.8 and 5.5 months for the chemotherapy and pembrolizumab arm and chemotherapy alone arm.
A rate of grade 3 or higher side effects was higher in the chemotherapy and pembrolizumab arm but is very comparable to what has been observed in non-small cell lung cancer, so thoracic oncologists are familiar to recognise and treat them, according to the presenter.
The IND227 investigators continue to analyze results for QoL and economic analyses as secondary outcomes.
Dr. Marjorie Glass Zauderer of the Memorial Sloan Kettering Cancer Center in New York, NY, US, who discussed the study results, questioned if an additional month of survival for patients in the chemotherapy and pembrolizumab arm is clinically significant. The improvement seems to be driven by a subset of patients who have long, durable OS and it is challenging to figure out who are the patients who will not get much benefit from adding pembrolizumab to the chemotherapy and prioritise them for other clinical studies.
Additional phase III studies combining chemotherapy and immunotherapy in unresectable malignant pleural mesothelioma are ongoing, including DREAM3R, which is studying the combination of cisplatin, pemetrexed, and durvalumab compared to chemotherapy alone, and BEAT-meso, which is evaluating the addition of atezolizumab to carboplatin, pemetrexed, and bevacizumab.
The IND227 study was supported by grants to Canadian Cancer Society; Merck & Co Inc.
Reference
Chu QS, Piccirillo MC, Greillier L, et al. IND227 phase III (P3) study of cisplatin/pemetrexed (CP) with or without pembrolizumab (pembro) in patients (pts) with malignant pleural mesothelioma (PM): A CCTG, NCIN, and IFCT trial. J Clin Oncol 41, 2023 (suppl 17; abstr LBA8505).
