Phase 2 Trial of Nivolumab and Ramucirumab for Relapsed Mesothelioma: HCRN-LUN15-299

Our plain-English summary of Phase 2 Trial of Nivolumab and Ramucirumab for Relapsed Mesothelioma: HCRN-LUN15-299, by A.Z. Dudek, M.X. Xi, K.A. Scilla, et al (JTO Clinical and Research Reports, 2023).

The study

• Authors: A.Z. Dudek, M.X. Xi, K.A. Scilla, H. Mamdani, B.C. Creelan, A. Saltos, T. Tanvetyanon, A. Chiappori
• Journal: JTO Clinical and Research Reports
• Published: 2023;4(12):100584
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: We hypothesized that ramucirumab could increase previously reported objective response rate (ORR) of 11% of single-agent nivolumab in the second-line therapy of unresectable mesothelioma.

Methods: This was a cooperative group, single-arm, phase 2 trial enrolling patients with unresectable mesothelioma after progression on more than or equal to one pemetrexed-containing regimen. Ramucirumab and nivolumab were given intravenously every 14 days for up to 24 months. The primary end point was ORR; secondary end points were progression-free survival (PFS) rate at 24 weeks and overall survival (OS).

Results: Between April 2018 and October 2021, 34 patients were recruited. Median age was 72 (range: 40-89) years, 12% were women, and 79% of tumors had epithelial histology. Median follow-up was 10.2 months (interquartile range 19.6 mo [4.3-23.8]). ORR was 22.6% (95% confidence interval [CI]: 9.6%-41.1%) in all population and 43% (95% CI: 10%-82%) in patients with nonepithelioid histology. Of all patients, 45.2% (95% CI: 27.3%-64.0%) had stable disease. PFS rate at 24 weeks was 32% (95% CI: 17%-51%). Median PFS was 4.2 months (95% CI: 1.9-6.4 mo). Median OS was 12.5 months (95% CI: 6.3-23.5 mo). There was no grade greater than or equal to four toxicity. Programmed death-ligand 1 expression in the tumor did not correlate with benefit from treatment. Activation of tumor-infiltrating lymphocytes in response to treatment was associated with a trend toward improvement in PFS.

Conclusions: Nivolumab and ramucirumab combination was safe and generated PFS and OS rates and ORR that compare favorably with single-agent nivolumab in a similar patient population. The primary end point of 40% ORR was not reached. Further investigation of this regimen in mesothelioma with nonepithelioid histology may be warranted. Clinical Trial Information: NCT03502746.

© 2023 The Authors.

In plain English

This single-arm phase 2 trial gave ramucirumab and nivolumab together to people with unresectable pleural or peritoneal mesothelioma that had progressed after at least one pemetrexed-containing treatment. Between April 2018 and October 2021, 34 patients were enrolled (30 men and four women; 30 pleural and four peritoneal) and given both drugs intravenously every 14 days for up to 2 years. Seven patients had partial responses. The reported objective response rate was 22.6% (95% CI 9.6% to 41.1%) overall and 43% (95% CI 10% to 82%) in patients with nonepithelioid tumors. The article does not say how many patients the overall rate was based on, and one patient withdrew before response could be assessed. The trial did not reach its goal of a 40% response rate. Median progression-free survival was 4.2 months (95% CI 1.9 to 6.4) and median overall survival was 12.5 months (95% CI 6.3 to 23.5). Grade 3 treatment-related side effects affected 33% of patients, and none had treatment-related grade 4 or 5 toxicities. Twelve percent stopped treatment because of side effects. The authors concluded the combination could be tested further in untreated, unresectable nonepithelioid mesothelioma.

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: Multicenter, single-arm, open-label phase 2 clinical trial of a drug combination (four institutions of the Hoosier Cancer Research Network)
• Who was studied: 34 patients enrolled April 2018 to October 2021, all with unresectable mesothelioma that had progressed after at least one pemetrexed-containing regimen: 30 pleural and 4 peritoneal. There were 30 men and 4 women, median age 72 (range 40 to 89). Histology was epithelioid in 27, biphasic in 4 and sarcomatoid in 3.
• Exposure: The article studies a treatment, not asbestos exposure: ramucirumab 8 mg/kg and nivolumab 240 mg given intravenously every 14 days until progression, intolerable toxicity, or up to 2 years. Asbestos exposure is not reported.
• Main results:
  • Seven patients responded, all with partial responses. The reported objective response rate was 22.6% (95% CI 9.6% to 41.1%) in what the article calls all patients, and 43% (95% CI 10% to 82%) in patients with nonepithelioid histology. The denominator for the overall rate is not stated.
  • One enrolled patient was not assessable for response because the patient withdrew one day after the first infusion.
  • The primary end point was not met: the trial did not reject a 20% response rate in favor of a 40% response rate.
  • Stable disease in 45.2% (95% CI 27.3% to 64.0%) of all patients.
  • In the overall study population, the progression-free survival rate at 24 weeks was 32% (95% CI 17% to 51%) and median progression-free survival was 4.2 months (95% CI 1.9 to 6.4 months).
  • Median overall survival in all patients was 12.5 months (95% CI 6.3 to 23.5 months).
  • Grade 3 treatment-related adverse events occurred in 33% of patients, including hypertension (9%) and hyponatremia (6%).
  • There were no treatment-related grade 4 or 5 toxicities.
  • 12% of patients (4) discontinued treatment because of adverse events.
  • Neither baseline levels nor changes in blood (soluble) PD-L1 correlated with best response, progression-free survival or overall survival.
  • In the 10 patients with paired biopsies, those whose tumors showed increasing T-lymphocyte activation had progression-free survival of 6.6 months, compared with 2.6 months in those with decreasing activation. The hazard ratio was 0.91 (95% CI 0.81 to 1.02, p equal to 0.104), which the authors described as approaching, not reaching, statistical significance.
• The authors' conclusion: The authors concluded that the nivolumab and ramucirumab combination could be further tested in patients with treatment-naive, unresectable mesothelioma of nonepithelioid histology.
• Limitations the authors state:
  • The expected effect of the combination was based on a study of only 25 patients that used a different checkpoint inhibitor (pembrolizumab).
  • The patients varied widely in their prior therapies, including prior bevacizumab use.
  • The benefit is unknown in current practice, where checkpoint inhibitors are now used as first-line treatment.

Topics

Medical terms in this study, explained in our Lexicon: Nivolumab (Opdivo), Ramucirumab, Mesothelioma, Second-Line Therapy, Unresectable, Pemetrexed (Alimta), Progression-Free Survival, Overall Survival.

Related studies

• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)
• Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial — D.A. Fennell, S. Ewings, et al. (2021)
• CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial — D.A. Fennell, E. Kirkpatrick, et al. (2018)
• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)
• Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial — M. Maio, A. Scherpereel, et al. (2017)
• Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumour or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial — B. Geoerger, H.J. Kang, et al. (2020)

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