Vinorelbine extends PFS in relapsed malignant pleural mesothelioma
Vinorelbine combined with active supportive care conferred superior PFS compared with active supportive care alone among patients with relapsed malignant pleural mesothelioma, according to phase 2 study results.
“All patients with malignant pleural mesothelioma eventually relapse following standard chemotherapy with pemetrexed and cisplatin. However, there is no standard treatment option in this patient setting,” Dean A. Fennell, FRCP, PhD, chair of thoracic medical oncology at University of Leicester and University Hospitals of Leicester NHS Trust in the U.K., said during his presentation at the virtual ASCO Annual Meeting. “Vinorelbine exhibits useful clinical activity but has not been formally evaluated in a randomized clinical trial, despite its widespread off-label use worldwide.”
The randomized, investigator-led, phase 2 VIM trial enrolled 154 patients with malignant pleural mesothelioma across 10 U.K. sites between May 2016 and October 2018. Researchers randomly assigned the patients, all of whom progressed after first-line chemotherapy, 2:1 to vinorelbine dosed at 60 mg/m² weekly every 21 days, then escalating to 80 mg/m² from cycle two, plus active supportive care (n = 98; median age, 70.5 years; 81.6% men; 36.7% BRCA1-positive) or active supportive care alone (n = 56 median age, 70.7 years; 80.4% men; 26.8% BRCA1-positive) until disease progression, unacceptable toxicity or withdrawal of consent. Researchers noted that BRCA1 status could not be obtained for 50% of study participants.
PFS defined as the time from randomization to any progression or death served as the primary outcome. Secondary endpoints included OS, tolerability and safety.
Two patients assigned active supportive care alone crossed over to the vinorelbine group and 22 patients (39.3%) assigned active supportive care alone proceeded to another clinical trial.
Median duration of vinorelbine treatment was 2.8 months (range, 1.2-5.1).
Results of the intention-to-treat analysis showed that after 129 events occurred, median PFS was 4.2 months (90% CI, 3.5-4.8) in the vinorelbine group compared with 2.8 months (90% CI, 2.5-2.9) with active supportive care alone (HR = 0.6; 95% CI, 0.41-0.86).
Overall, 108 patients died. Median OS was 9.3 months (95% CI, 6.7-11.8) in the vinorelbine group vs. 9.1 months (95% CI, 5.7-14.1) with active supportive care alone (HR = 0.79; 95% CI, 0.53-1.17).
Researchers reported a partial response rate of 3.1% in the vinorelbine group compared with 1.8% in the active supportive care group and a stable disease rate of 62.2% vs. 46.4%. Median duration of response was 7.2 months (95% CI, 3.1-8.5) with vinorelbine compared with 4.2 months (95% CI, 4.2-4.2) with active supportive care alone.
In a subgroup analysis of PFS by BRCA1 status, researchers found that among BRCA1-positive patients, median PFS was 4.2 months (90% CI, 2.8-8) with the vinorelbine regimen compared with 2.8 months (90% CI, 1.4-2.9) with active supportive care alone (HR = 0.35; 95% CI, 0.17-0.74). For BRCA1-negative patients, median PFS was 4.4 months (90% CI, 2.8-8.3) with vinorelbine vs. 2.7 months (90% CI, 1.4-2.8) with active supportive care alone (HR = 0.22; 95% CI, 0.07-0.72).
“BRCA1 regulates spindle assembly checkpoint in malignant pleural mesothelioma and predicts vinorelbine sensitivity in preclinical models, suggesting that BRCA1-negative patients may be chemoresistant,” Fennell said. “However, there was no evidence to support BRCA1 as being predictive for outcome in this trial.”
Grade 3 to grade 4 adverse events in the overall cohort were more common with vinorelbine, including neutropenia (12.5% vs. zero), dyspnea (6.2% vs. zero) and fatigue (4.2% vs. zero).
“Vinorelbine is a safe and effective treatment and should be considered a treatment option for patients with relapsed mesothelioma,” Fennell said.
Perspective
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All patients with malignant pleural mesothelioma eventually relapse. At the time this study was conducted, there was not a clear standard of care for second-line therapy.
The activity of vinorelbine for treatment of malignant pleural mesothelioma was first reported 20 years ago, but VIM is the first randomized trial to show a benefit of vinorelbine vs. active symptom control in this disease.
Since the approval of first-line immunotherapy with nivolumab (Opdivo, Bristol Myers Squibb) and ipilimumab (Yervoy, Bristol Myers Squibb) based results of the CheckMate743 trial, the role of vinorelbine in relapsed malignant pleural mesothelioma is less clear. Although vinorelbine is an active agent with low cost and low toxicity, it falls further down in the treatment algorithm for most patients (after immunotherapy and platinum-based chemotherapy). However, a question left unanswered by this and other trials presented at ASCO this year is how reported improvements in DFS can be meaningful for patients.
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Fennell DA, et al. Abstract 8507. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.