Pembrolizumab improves OS in firstline treatment for unresectable advanced pleural mesothelioma

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Published: 4 Jun 2023
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Dr Penelope Bradbury - Princess Margaret Cancer Centre, Toronto, Canada

Dr Bradbury talks to ecancer at ASCO 2023 about results her team presented from the Phase 3 Canadian Cancer Trials Group IND.227/KEYNOTE-483 trial evaluating pembrolizumab plus chemotherapy as first-line treatment for patients with unresectable advanced pleural mesothelioma.

At the final analysis of the study, pembrolizumab improved overall survival, reducing the risk of death by 21% (HR=0.79 [95% CI, 0.64-0.98]; two-sided p value=0.0324), with a median OS of 17.3 months (95% CI, 14.4-21.3) versus 16.1 months (95% CI, 13.1-18.2) for chemotherapy alone.

Improvements were also shown in secondary end points PFS and ORR compared to chemotherapy alone.
 

We presented the results of IND.227, a randomised phase III clinical trial evaluating the addition of pembrolizumab to standard pemetrexed and cisplatin chemotherapy for patients with inoperable pleural mesothelioma in the advanced or metastatic setting. 

The trial enrolled 440 patients with inoperable pleural mesothelioma. The trial was led by the Canadian Cancer Trials Group in collaboration with our colleagues from the National Cancer Institute of Naples in Italy and the French Cooperative Thoracic Intergroup in France. The CCTG has previously published a small phase II clinical trial which was published earlier this year in a separate group of patients in The Journal of Thoracic Oncology which reported promising results. 

This phase III clinical trial enrolled patients who were 18 years or older, had performance status of 0 or 1 and met other standard eligibility criteria. Patients had to have inoperable disease, they may have had adjuvant or neoadjuvant chemotherapy but systemic therapy for advanced disease was not permitted. The trial demonstrated that the addition of pembrolizumab to pemetrexed and platinum chemotherapy significantly prolonged overall survival by reducing the risk of death by 21% with a hazard ratio of 0.79. Further, there was an improvement in the two-year overall survival from 33% on the chemotherapy arm to 39% on the pembrolizumab arm. There was also improvement in the three-year overall survival, improving from 17% on the chemotherapy arm to 25% on the pembrolizumab arm. This was despite the fact that more patients on the chemotherapy arm subsequently proceeded to have immune checkpoint inhibitors as a second-line of therapy, predominantly with nivolumab and ipilimumab which is known to have activity in this setting.

Progression free survival was also significantly longer for the pembrolizumab arm with a hazard ratio of 0.80 with a 20% reduction in the risk of progression or death with a p-value of 0.037. The objective response rate was also higher on the pembrolizumab arm with a response rate of 62% compared to just 38% on the chemotherapy arm. While the primary endpoint was overall survival, tumour shrinkage is also an important endpoint for patients, particularly for those that would be at risk for early progressive disease.

The addition of pembrolizumab to pemetrexed and cisplatin was tolerable with a manageable side effect profile. So, in summary, the addition of pembrolizumab to pemetrexed and platinum improved overall survival with a 21% reduction of risk, improved progression free survival with a 20% reduction in risk and increased overall response rate and therefore should be considered a new option for this patient population.

Chemotherapy has been the standard treatment option for patients with inoperable pleural mesothelioma for over two decades until recently when another trial evaluating nivolumab and ipilimumab demonstrated an improvement in overall survival with the immune checkpoint inhibitor combination, similar to the results on the IND.227 clinical trial. However, in the IND.227 clinical trial there was also a higher response rate, more patients on the IND.227 chemotherapy arm subsequently received immune checkpoint inhibitors and, although it was not directly compared, has a more tolerable safety profile. 

Although mesothelioma is a devastating cancer and international collaborations are needed to be able to conduct phase III clinical trials to evaluate new treatment strategies, the CCTG and its collaborators and other groups are already planning new clinical trials to evaluate new treatment options which may improve the outcome from this disease. In addition, we await the results of two other randomised phase III trials evaluating immune checkpoint inhibitors compared with chemotherapy.