After decades of off-label use, vinorelbine finally has a randomized clinical trial supporting its efficacy as a second-line treatment of mesothelioma, an investigator reported at the annual meeting of the American Society of Clinical Oncology.
However, the development of other treatment regimens, and notably immuno-oncology approaches, are pushing this classic chemotherapy option to later lines of therapy in patients with malignant pleural mesothelioma (MPM), a speaker said at the meeting.
Adding vinorelbine to active symptom control statistically improved progression-free survival (PFS), among patients with MPM who had prior platinum-based therapy, according to results of the randomized Vinorelbine in Mesothelioma (VIM) trial.
Median PFS reached 4.2 months in the vinorelbine arm, versus 2.8 months for active symptom control alone, study results show.
That finding , coupled with safety results, supports the off-label use of vinorelbine as a treatment option for patients with relapsed MPM, according to investigator Dean Anthony Fennell, FRCP, PhD, of the University of Leicester (England).
“Vinorelbine appears to be a safe and effective treatment and could be considered as a treatment option for patients with relapsed mesothelioma,” Prof. Fennell said in his presentation at ASCO (Abstract 8507).
Changing status
While that welcome pronouncement was a long time coming, there are now other promising treatment approaches that relegate vinorelbine to a “lower priority” in the treatment algorithm, said discussant Anna K. Nowak, MBBS, FRACP, PhD, of the University of Western Australia, Nedlands.
In October 2020, the U.S. Food and Drug Administration approved the combination of ipilimumab and nivolumab for the first-line treatment of unresectable malignant pleural mesothelioma, on the basis of results from CHECKMATE-743, a randomized, open-label trial.
“Certainly, we know now that first-line ipilimumab and nivolumab is of very substantial benefit to these patients, and we still have clinical trials open in this space as well,” Prof. Nowak said in her discussion at ASCO.
There is “no doubt” that many patients with mesothelioma should at some point receive an IO agent, particularly now with recently reported randomized clinical trial evidence of an overall survival benefit, she added.
“This really pushes vinorelbine out to be a third- or fourth-line treatment,” she added, “and we know that there are usually diminishing returns from using chemotherapies further down the treatment algorithm.”
Trial details
The VIM trial described at ASCO by Prof. Fennell was a randomized, controlled phase 2 including 154 patients with MPM that had progressed after first-line chemotherapy.
“Vinorelbine has shown useful clinical activity in single-arm phase two studies, however, the specific efficacy of vinorelbine has not been evaluated in an appropriately controlled randomized trial,” Prof. Fennell said in this presentation.
Patients in the trial were randomized 2:1 to either vinorelbine plus active supportive care or active supportive care alone. Vinorelbine was given initially at 60 mg/m2 weekly every 21 days, escalated to 80 mg/m2 from cycle 2.
The median age of patients in VIM was approximately 71 years, and about 80% were male.
More partial responses were seen in the vinorelbine arm, at 3.1% of patients, compared with 1.8% for active supportive care, according to Prof. Fennell. Likewise, the rate of stable disease was higher in the vinorelbine arm, at 62.2%, versus 46.4% in the control arm.
The primary outcome of the study, PFS, was significantly improved in the vinorelbine arm, according to Dr. Fennell. The median PFS was 4.2 months in the vinorelbine arm and 2.8 months in the supportive care arm (P = .002), translating into a hazard ratio of 0.60 (95% confidence interval, 0.41-0.86), Prof. Fennell reported.
The most common grade 3-4 adverse event was neutropenia, occurring in 12.5% of the vinorelbine-treated patients and no patients managed with supportive care alone, according to the report. Other grade 3-4 adverse events occurred in fewer than 10% of patients and included dyspnea, lower respiratory infection, lymphopenia, and fatigue, among others.
Overall survival (OS) was not statistically different between vinorelbine and supportive care arms, with median OS of 9.3 months and 9.1 months, respectively.
However, a number of patients in the control arm went on to receive subsequent therapy, including 15 (or about 27%) who went into CONFIRM, a randomized phase 3 trial that, as recently reported, met its coprimary endpoints of improve OS and PFS with nivolumab vs. placebo in relapsed malignant mesothelioma.
Investigators also sought to test the hypothesis that BRCA1-negative patients might be chemoresistant, based in part on preclinical models demonstrating that BRCA1 predicted sensitivity to vinorelbine. However, there was no difference in PFS by BRCA1 expression in the VIM study, according to Prof. Fennell.
Taken together, findings of the VIM trial suggest vinorelbine is a “modestly active” agent with low cost and acceptable toxicity, according to Prof. Nowak.
“It is incumbent on us to have clear discussions with our patients on the risks and benefits of trying this as a subsequent-line therapy, in the context of this evidence that was generated as a second-line therapy,” she said in her discussant remarks on the study.
“I would say that it is a lower priority in our algorithm than cisplatin and pemetrexed, or of course, immuno-oncology agents,” she added.
Dr. Fennell reported disclosures related to AstraZeneca, Astex Therapeutics, Bayer, and multiple other pharmaceutical companies. Dr. Nowak reported disclosures with AstraZeneca, Atara Biotherapeutics, Boehringer Ingelheim, and multiple other pharmaceutical companies.