Immune Checkpoint Inhibition for Unresectable Malignant Pleural Mesothelioma

Our plain-English summary of Immune Checkpoint Inhibition for Unresectable Malignant Pleural Mesothelioma, by W. Cui, S. Popat (Drugs, 2021).

The study

• Authors: W. Cui, S. Popat
• Journal: Drugs
• Published: 2021;81(9):971-984
• Type of article: Review
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Immune checkpoint inhibitors (ICI) have shown important but variable efficacy in mesothelioma despite a lack of strong biological rationale. Initial trials assessed ICI monotherapy in patients with relapsed mesothelioma, with objective response rates (ORR) between 4.5 and 29%, median progression-free survival (PFS) between 2.5-6.2 months, and median overall survival (OS) between 7.7 and 18.0 months. In randomised trials of chemotherapy pre-treated patients, nivolumab was recently shown to improve PFS compared to placebo, but tremelimumab was not superior to placebo, and there was no difference in OS between pembrolizumab and chemotherapy. However, response to combination ICI appear more promising in both pre-treated and treatment-naïve mesothelioma. The randomised Phase 3 trial of upfront ipilimumab-nivolumab versus platinum-pemetrexed chemotherapy demonstrated improved OS favouring ipilimumab-nivolumab (HR 0.74, 96.6% CI 0.60-0.91; p = 0.0020), establishing this regimen as a new standard of care, especially in non-epithelioid histological subtypes. However, initially PFS was poorer in the ipilimumab-nivolumab than chemotherapy treatment arms. A single-arm Phase 2 trial of upfront platinum chemotherapy and durvalumab met its primary endpoint, with a 6-month PFS of 57% (95% CI 44-70) with chemo-immunotherapy under evaluation as an alternative upfront regimen. Several questions remain unanswered. Comparative studies of chemo-immunotherapy versus chemotherapy are underway, but these do not compare chemo-immunotherapy to combination ICI. There is a critical need to establish predictive biomarkers to improve patient selection. As ICI use moves into the front-line setting, patient selection, role for operable patients, and understanding ICI resistance mechanisms alongside role of ICI rechallenge in previous responders need further evaluation.

In plain English

This was a review of clinical trials testing immune checkpoint inhibitor drugs in mesothelioma that could not be removed surgically; asbestos was mentioned only as background. In previously treated patients, single drugs produced response rates between 4.5 and 29%. In the CONFIRM trial, nivolumab gave longer median overall survival than placebo (9.2 vs 6.6 months; HR 0.72, 95% CI 0.55–0.94). Tremelimumab was not better than placebo in the DETERMINE trial, and pembrolizumab did not improve survival compared with chemotherapy in the PROMISE-meso trial. In CheckMate-743, 605 previously untreated patients received either ipilimumab plus nivolumab or platinum-pemetrexed chemotherapy. Median overall survival was 18.1 versus 14.1 months (HR 0.74, 96.6% CI 0.60–0.91), with the largest difference in non-epithelioid tumours. Serious treatment-related side effects were more frequent with the drug combination (21% vs 8%). The authors concluded that this combination is the new first-line standard of care and that PD-L1 testing is not a reliable predictor of response. They noted that few non-epithelioid patients were included in the trials.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review ("Current Opinion") of published and presented clinical trials; no new patient data
• Who was studied: Patients with mesothelioma enrolled in the reviewed trials. These included previously treated (relapsed) patients and treatment-naïve patients, in single-arm and randomised trials ranging from 25 patients (KEYNOTE-028) to 605 patients (CheckMate-743).
• Exposure: The exposure studied was treatment, not asbestos. The reviewed trials tested immune checkpoint inhibitors (tremelimumab, ipilimumab, pembrolizumab, nivolumab, avelumab, durvalumab, and atezolizumab in an ongoing trial) alone, in combination, or with chemotherapy. The article mentions asbestos only as background to the disease.
• Main results:
  • Across the early single-drug trials in relapsed mesothelioma, objective response rates ranged from 4.5 to 29%.
  • CONFIRM (relapsed patients, nivolumab vs placebo): median overall survival was 9.2 months (95% CI 7.5–10.8) with nivolumab versus 6.6 months (95% CI 5.0–7.5) with placebo (HR 0.72, 95% CI 0.55–0.94; p = 0.02).
  • DETERMINE (571 relapsed patients): tremelimumab was not superior to placebo (median overall survival 7.7 vs 7.3 months).
  • PROMISE-meso (144 relapsed patients, pembrolizumab vs vinorelbine or gemcitabine): there was no difference in progression-free survival (median 2.5 vs 3.4 months; HR 1.06, 95% CI 0.73–1.53; p = 0.76). There was also no difference in overall survival (10.7 vs 12.4 months; HR 1.12, 95% CI 0.74–1.69; p = 0.59).
  • CheckMate-743 (605 treatment-naïve patients): median overall survival was 18.1 months with ipilimumab-nivolumab versus 14.1 months with platinum-pemetrexed chemotherapy (HR 0.74, 96.6% CI 0.60–0.91; p = 0.0020).
  • CheckMate-743, non-epithelioid subgroup: median overall survival was 18.1 months with ipilimumab-nivolumab versus 8.8 months with chemotherapy (HR 0.46, 95% CI 0.31–0.68).
  • CheckMate-743, epithelioid subgroup: overall survival was similar between the two treatment arms (HR 0.86, 95% CI 0.69–1.08).
  • CheckMate-743: progression-free survival was similar (median 6.8 months with ipilimumab-nivolumab vs 7.2 months with chemotherapy; HR 1.00, 95% CI 0.82–1.21).
  • CheckMate-743: serious treatment-related adverse events occurred in 21% of the ipilimumab-nivolumab arm versus 8% of the chemotherapy arm.
  • DREAM (55 untreated patients, cisplatin-pemetrexed plus durvalumab, single arm): 6-month progression-free survival was 57% (95% CI 44–70).
  • The authors judged that PD-L1 expression is not a reliable biomarker for predicting response to these drugs in mesothelioma.
• The authors' conclusion: The authors concluded that combination ipilimumab and nivolumab is the new first-line standard of care for advanced mesothelioma, especially non-epithelioid subtypes. They also concluded that predictive biomarkers are still needed.
• Limitations the authors state:
  • Few patients with non-epithelioid mesothelioma were included in the reviewed trials, which limits interpretation.
  • CheckMate-743 was not powered to find a survival benefit in the epithelioid subgroup, and crossover to immunotherapy in the control arm is unclear.
  • There is no agreed method for testing PD-L1 in mesothelioma.
  • In MAPS2, the two treatment arms could not be formally compared because of the trial's design.
  • In PROMISE-meso, 63% of patients crossed over to pembrolizumab, which makes overall survival harder to interpret.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Unresectable, Pleural Mesothelioma, checkpoint inhibitors, Mesothelioma, Progression-Free Survival, Median Overall Survival, Chemotherapy, Nivolumab (Opdivo).

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