Outcomes of Platinum plus /Pemetrexed Rechallenge in Pleural Mesothelioma: The Role of Platinum-Free Interval in a Multicenter Real-World Analysis

Our plain-English summary of Outcomes of Platinum plus /Pemetrexed Rechallenge in Pleural Mesothelioma: The Role of Platinum-Free Interval in a Multicenter Real-World Analysis, by R. Shah, M. Reck, C. Grohé, et al (JTO Clinical and Research Reports, 2026).

The study

• Authors: R. Shah, M. Reck, C. Grohé, M. Faehling, D.C. Christoph, F.C. Saalfeld, E.L. Buchmeier, H.G. Kopp, P. Hoffknecht, N. Frost, F. Griesinger, J. Kuon, J. Luan, J. Roeper, M. Kimmich, T. Olchers, P. Chesi, L.V. Klotz, I. Chung, H. Bischoff, M. Thomas, P. Christopoulos
• Journal: JTO Clinical and Research Reports
• Published: 2026;7(11):101073
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Real-world (rw) practice of rechallenge with platinum plus pemetrexed (PP) in pleural mesothelioma (PM) has been recommended in international guidelines, but the evidence is scarce and based on a few very small retrospective studies.

Methods: In total, 612 patients with PM treated with first-line PP between 2010 and 2023 across 12 centers were retrospectively identified. Outcomes and treatment patterns were analyzed across second-line regimens, with a particular focus on PP rechallenge. The platinum-free interval (PFI) was evaluated using a two-tier classification (platinum-sensitive ≥6 mo and platinum-resistant <6 mo) as a selection criterion.

Results: Among 375 patients (61%) receiving second-line therapy, the rw median overall survival (rw-mOS) and rw median progression-free survival (rw-mPFS) were 11.6 months and 4.7 months, respectively. Patients with PP rechallenge (n = 78) had a median OS of 20.5 months, a median rwPFS of 6.8 months, and a disease control rate of 88%. Patients with platinum sensitivity derived greater benefit from rechallenge, with rw-mOS differing across PFI categories (platinum-sensitive: 21.4 mo versus platinum-resistant: 11.9 mo; p = 0.007). Outcomes with nivolumab plus ipilimumab (n = 29) were comparable to those observed with PP rechallenge (rw-mOS = 22.8 mo, rw-mPFS = 8.0 mo), with treatment-free interval (TFI) associated with improved median OS in the platinum-sensitive group compared with the platinum-resistant group (32 mo versus 18.1 mo, p = 0.03). Single-agent pemetrexed (n = 32) and single-agent chemotherapy were associated with substantially shorter rw-mOS of 11.6 and 8.0 months, respectively.

Conclusion: In conclusion, PP rechallenge has favorable outcomes and remains a viable alternative in patients with platinum sensitivity with PM, whereas nivolumab plus ipilimumab may be considered in both TFI categories, particularly in platinum-resistant disease, in which PP rechallenge offers limited benefit. A PFI or TFI-guided approach to second-line treatment selection is supported, although prospective validation is warranted.

© 2026 The Authors.

In plain English

This retrospective study reviewed records from the German MesoNet Cohort (12 German centers) of patients with pleural mesothelioma diagnosed between 2010 and 2023. Of 612 patients first treated with platinum plus pemetrexed, 375 (61%) received second-line treatment. Their median overall survival from its start was 11.6 months. The 78 patients given platinum plus pemetrexed again (rechallenge) had a median overall survival of 20.5 months, and 52 of 59 with response data (88%) had disease control. Rechallenged patients whose platinum-free interval (time since the last first-line platinum dose) was 6 months or longer had a median survival of 21.4 months, versus 11.9 months for the 11 with a shorter interval (p = 0.007). The 29 patients given nivolumab plus ipilimumab had a median survival of 22.8 months. Single-agent pemetrexed (32 patients) and single-agent chemotherapy had 11.6 and 8.0 months. Asbestos exposure was documented in 78% of rechallenged patients with available data. The authors concluded that rechallenge remains a viable option for platinum-sensitive patients. They cited selection bias and small subgroups as limitations and called for prospective validation.

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: Retrospective multicenter real-world cohort study
• Who was studied: Patients with histologically confirmed pleural mesothelioma in the German MesoNet Cohort, from 12 German thoracic oncology centers, diagnosed January 1, 2010 to December 31, 2023. Of 1550 cohort patients, 612 received first-line platinum plus pemetrexed. Of these, 375 received second-line therapy and 78 were rechallenged with platinum plus pemetrexed. The rechallenge group was 76.9% men, mean age 68, and 70 of 78 had epithelioid histology.
• Exposure: The exposure studied was treatment: second-line regimens after first-line platinum plus pemetrexed, with a focus on platinum plus pemetrexed rechallenge. No asbestos fiber types or doses were reported. Prior asbestos exposure was documented in 46 rechallenge patients (78.0% of those with data), and status was missing for 19 (24%).
• Main results:
  • All 375 second-line patients: real-world median overall survival 11.6 months (95% CI 9.9 to 13) and median progression-free survival 4.7 months (95% CI 3.9 to 5.2), measured from the start of second-line treatment.
  • 78 platinum plus pemetrexed rechallenge patients: median overall survival 20.5 months (95% CI 15.0 to 24.1) and median progression-free survival 6.8 months (95% CI 5.9 to 8.8).
  • Rechallenge patients with response data (59): partial response in 19 (32%) and disease control in 52 (88%).
  • Rechallenge, platinum-sensitive (interval 6 months or more) versus platinum-resistant (n = 11): median overall survival 21.4 versus 11.9 months (HR = 2.5, 95% CI 1.3 to 4.8, p = 0.007).
  • Rechallenge, multivariable analysis adjusting for subtype, age, ECOG PS and TNM stage (n = 52): the platinum-resistant group was the only independent prognostic factor for overall survival (HR = 3.31, 95% CI 1.3 to 8.0, p = 0.009).
  • 29 second-line nivolumab plus ipilimumab patients: median overall survival 22.8 months and median progression-free survival 8.0 months. Platinum-sensitive versus platinum-resistant median overall survival was 32.3 versus 18.1 months (HR = 3, 95% CI 1 to 9.2, p = 0.03).
  • 32 single-agent pemetrexed patients: median overall survival 11.6 months (95% CI 8.0 to 14.5) and median progression-free survival 3.3 months (95% CI 2.6 to 6.0). Both were reported as significantly worse than with platinum plus pemetrexed rechallenge.
  • Single-agent chemotherapy patients (143): median overall survival 8.0 months (95% CI 6.5 to 9.9).
• The authors' conclusion: The authors concluded that platinum plus pemetrexed rechallenge remains a viable alternative in platinum-sensitive patients, particularly where immunotherapy is contraindicated or unavailable. They suggested nivolumab plus ipilimumab may be considered in platinum-resistant patients, and called for prospective evaluation of interval-guided treatment selection.
• Limitations the authors state:
  • Retrospective design introduces selection bias, and treatment was not randomized.
  • Small subgroups, especially platinum-resistant patients, limit subgroup analyses.
  • Patients with sarcomatoid histology were not represented in the rechallenge group.
  • The multivariable model used a reduced sample because of missing data, so its results should be interpreted with caution.
  • The survival advantage of rechallenge over single-agent pemetrexed may be confounded by patient selection.
  • Tumor response was assessed according to local standards, which may have influenced the response analyses.

Topics

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Pleural Mesothelioma, Second-Line Therapy, Median Overall Survival, Progression-Free Survival, Nivolumab (Opdivo), Ipilimumab (Yervoy), Chemotherapy.

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