medwireNews: Adding pembrolizumab to first-line chemotherapy significantly improves the overall survival (OS) of people with advanced pleural mesothelioma, indicate findings published in The Lancet.
At a median follow-up of 16.6 months, the risk for death was a significant 21% lower for patients who did versus did not receive pembrolizumab alongside platinum-doublet chemotherapy, but the median OS improvement was “only slightly longer” than a month, at 17.3 and 16.1 months, respectively, report the researchers.
They note, however, that “[d]elayed efficacy outcomes with immunotherapy have been observed in other trials and are biologically plausible.”
Indeed, an exploratory restricted mean survival time at 54 months gave OS durations of 23.4 and 20.0 months in the pembrolizumab plus chemotherapy and chemotherapy alone groups, respectively.
The phase 3 component of the IND227 trial comprised 440 patients with untreated advanced pleural mesothelioma recruited from 51 hospitals in Canada, Italy, and France. Participants received chemotherapy consisting of up to six cycles of cisplatin 75 mg/m2 or carboplatin AUC 5–6 mg/mL per min plus pemetrexed 500 mg/m2 every 3 weeks either with or without pembrolizumab 200 mg every 3 weeks for up to 2 years.
Lesley Seymour (Canadian Cancer Trials Group, Kingston, Ontario) and colleagues report that the addition of pembrolizumab was associated with a significant 20% reduction in the risk for progression or death, but the median progression-free survival times were almost identical in the pembrolizumab and chemotherapy alone groups, at 7.13 and 7.16 months, respectively.
The objective response rate was significantly higher among patients who received pembrolizumab plus chemotherapy than those given chemotherapy alone, at 62% versus 38%, but the median duration of response was similar, at a respective 5.8 and 5.5 months.
A higher proportion of participants in the pembrolizumab than control group experienced grade 3–4 toxicity, at 27% versus 15%. The most common events of this severity in the pembrolizumab arm were fatigue (7 vs 6%) and nausea (5 vs 1%).
The rate of discontinuation of any trial therapy due to toxicity was also higher in the pembrolizumab than control arm, at 37% versus 20%.
The authors of an accompanying commentary – YC Gary Lee, from the University of Western Australia in Perth – observes that “[t]his unfavourable profile is at least partly explained by the longer duration of exposure to immunotherapy with pembrolizumab (up to 2 years) than that to chemotherapy (six cycles).”
And Seymour et al highlight that quality of life analyses using the EORTC Quality of Life questionnaire C30 and lung cancer module LC13 “did not demonstrate a detriment to the addition of pembrolizumab despite the increased toxic effects.”
The time to deterioration of three key symptoms – cough, dyspnea, and chest pain – did not differ significantly between the groups, while pembrolizumab addition was associated with improvement in pain and less deterioration in global health status.
Lee notes, however, that the survival benefit with the addition of pembrolizumab to chemotherapy was “largely driven by the non-epithelioid subgroup,” at a median OS duration of 12.3 months versus 8.2 months with chemotherapy alone. By contrast, the improvement in the epithelioid subgroup was “modest,” with respective OS times of 19.8 and 18.2 months.
He continues: “Based on the IND227 trial, pembrolizumab-platinum-pemetrexed might be an alternative to dual immunotherapy for selected patients with non-epithelioid pleural mesothelioma but a head-to-head comparison is required.
“For epithelioid pleural mesothelioma, the trial did not provide sufficient evidence to justify addition of pembrolizumab especially in view of potential toxic effects.”
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Lancet 2023; doi:10.1016/S0140-6736(23)01613-6
Lancet 2023; doi:10.1016/S0140-6736(23)01883-4