medwireNews: Adding nintedanib to pemetrexed plus cisplatin does not improve progression-free survival (PFS) for patients with advanced malignant pleural mesothelioma, say researchers who conducted a phase III trial on the basis of earlier positive findings.
Specifically, results from the phase II part of the LUME-Meso study showed that the angiogenesis inhibitor nintedanib significantly prolonged PFS by a median of 3.7 months versus placebo, particularly among patients with epithelioid histology.
This led the investigators to carry out the confirmatory trial in which chemotherapy-naïve patients with unresectable epithelioid malignant pleural mesothelioma were randomly assigned to receive up to six 21-day cycles of pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1, with either nintedanib 200 mg twice daily (n=229) or matched placebo (n=229) on days 2–21 of each cycle.
After completion of chemotherapy, 63% of patients in the nintedanib group and 61% of those in the placebo group received daily maintenance therapy with their assigned treatment.
However, after 250 cases of disease progression or death during a median follow-up period of 9.2–9.7 months, there was no significant difference in median investigator-assessed PFS between the patients who received nintedanib and those who received placebo, at 6.8 versus 7.0 months. The was also no difference in PFS between the treatments when the data were assessed by independent central review (6.8 months in both groups).
In addition, there were no significant between-group differences in secondary efficacy outcomes, including interim analysis of overall survival, objective response, Lung Cancer Symptom Scale-Meso scores, and average symptom burden index scores.
The trial was therefore stopped, as per the protocol, due to a lack of efficacy, the researchers note.
Writing in The Lancet Respiratory Medicine, Giorgio Scagliotti (University of Turin, Italy) and co-authors say it is unclear why the phase III part of the trial did not confirm the phase II findings, but the data do “not support further exploration of nintedanib in combination with pemetrexed and cisplatin as a first-line treatment in malignant pleural mesothelioma.”
And they conclude that their results “are a reminder that conducting well controlled trials of appropriate size and duration remains essential to confirm the efficacy and safety of a new treatment option.”
In an accompanying commentary, Michele Maio and Luana Calabrò, both from the University Hospital of Siena in Italy, say that “[t]his latest failure of an anti-angiogenetic drug in patients with mesothelioma fosters consistent doubts and scepticism and raises the questions of whether we should drop the anti-angiogenetic approach after so many trial failures; whether angiogenesis should still be considered an adequate therapeutic target in this disease and whether it should still be investigated in unselected patients; or whether identification and careful selection is needed of subgroups of patients who are the best candidates for this therapeutic approach on the basis of their pro-angiogenic tumour features.”
Instead they suggest that immune checkpoint inhibitors and their use in novel combinations or sequences could be “the beginning of a new era in mesothelioma therapy.” However, they point out that this this “remains to be established” in future trials such as the soon to be published CheckMate743 study, which compares the co-targeting of CTLA-4 and PD-1 with the cisplatin plus pemetrexed regimen.
By Laura Cowen
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