No survival benefit with pembrolizumab in malignant pleural mesothelioma

Immunotherapy with pembrolizumab appears to increase response rates compared with single-agent chemotherapy in malignant pleural mesothelioma (MPM) patients who have failed a previous line of platinum-based chemotherapy, but this improved response does not translate to survival advantage, according to the results of the phase III PROMISE-meso trial presented at the 2019 Congress of the European Society for Medical Oncology (ESMO).

“These findings are disappointing but, as in previous studies, some patients benefitted from immunotherapy for long periods. If we can find out how this happens, we will have a better idea of which patients should preferentially receive this treatment over chemotherapy,” study author Dr Sanjay Popat from the Royal Marsden Hospital NHS Foundation Trust said in a statement.

“Nevertheless, whilst pembrolizumab was not superior to chemotherapy, survival was similar, and so pembrolizumab may represent an alternative,” he added.

PROMISE-meso randomized 144 patients with advanced pretreated MPM to receive pembrolizumab (200 mg every 3 weeks; n=73) or the participating centre’s choice of standard chemotherapy (gemcitabine or vinorelbine; control, n=71). Patients in the control arm were able to cross over to pembrolizumab at progression.

The median age of the cohort was 70 years. Most of the patients were male (82 percent), had poor European Organisation for Research and Treatment of Cancer prognostic score (77 percent) and had epithelioid histology (89 percent). In terms of PD-L1 expression, the tumour proportion score was ≥1 percent in 65 percent of patients.

The trial did not achieve its primary endpoint of improving progression-free survival (PFS) with pembrolizumab over single-agent chemotherapy, with a median of 2.5 months as compared with 3.4 months (hazard ratio, 1.06, 95 percent CI, 0.73–1.53; p=0.76). [ESMO 2019, abstract LBA91_PR]

At 6 months, 25.0 percent of patients in the pembrolizumab arm and 27.4 percent of those in the control arm were progression-free, and 68.5 percent and 72.9 percent were still alive, respectively. The corresponding median overall survival (OS) was 10.7 vs 11.7 months (HR, 1.05, 0.66–1.67; p=0.85). OS results were similar in an analysis accounting for the 45 chemotherapy patients who crossed over to pembrolizumab.

“If we look at the forest plot of the characteristics of patients that may have derived any differential benefit, there was no clear one group that derived any potential benefit in terms of PFS. However, when we look at the nonepitheliod subgroup of patients, this small group gave us signal of potentially having superior PFS with chemotherapy [HR, 1.76, 0.58–5.33],” Popat noted.

Objective response rate was surprisingly higher with pembrolizumab at 22 percent vs 6 percent with chemotherapy (p=0.004). However, the median duration of response was comparable at 4.6 vs 11.2 months, respectively. Popat explained that the numerical difference was due to one chemotherapy-treated patient being an outlier.

A time-to-treatment failure analysis showed no significant difference between the two treatment arms, regardless of PD-L1 status.

Treatment-related adverse events (AEs) occurred frequently with pembrolizumab and chemotherapy (overall, 69.4 percent vs 72.9 percent; higher grade AEs, 19 percent vs 24 percent; one fatality per arm). Most common AEs were fatigue (19 percent) with pembrolizumab vs nausea (27 percent) and fatigue (31 percent) with chemotherapy.

Need for better treatment

Commenting on the PROMISE-meso results, Dr Federica Grosso from Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo in Italy said, “Although we did not see better survival with immunotherapy in the ... study, the responses are encouraging and the results of the ongoing trials of checkpoint inhibitor treatment in earlier stage mesothelioma will be very important to patients and clinicians.”

Grosso pointed out that treatment for MPM is limited, with the combination of pemetrexed and platinum derivatives being the only approved regimen. Moreover, there is currently no standard effective second-line therapy. As such, patients generally die within 2 years of diagnosis.

“In studies of lung cancer, we have already learned that we can improve results with immunotherapy by combining it with chemotherapy, and the same may be true with mesothelioma,” said Popat.

“I would advise clinicians to enrol their patients into one of the large ongoing trials of first-line combination treatment so we can get answers as soon as possible about how to improve mesothelioma treatment,” he added. “Meanwhile, we need to better understand which patients benefit most from immunotherapy.”