Durvalumab–chemotherapy ‘promising’ first-line treatment in mesothelioma
medwireNews: Patients with treatment-naïve and unresectable malignant pleural mesothelioma may respond to treatment with durvalumab given alongside cisplatin and pemetrexed, suggest results from the phase 2 PrE0505 study.
As reported by Patrick Forde (Johns Hopkins University, Baltimore, Maryland, USA) at the virtual 2020 ASCO Annual Meeting, the first 15 patients enrolled in this multicenter study did not report any dose-limiting toxicities following treatment with durvalumab 1120 mg, cisplatin 75 mg/m2, and pemetrexed 500 mg/m2 every 3 weeks.
Therefore, enrolment continued until a total of 55 participants were included. The majority (75%) of patients had epithelioid histology, while 13% had sarcomatoid, 11% biphasic, and 2% desmoplastic. The patients received a maximum of six cycles of durvalumab plus chemotherapy, followed by a year of maintenance durvalumab alone.
The median overall survival (OS) was 20.4 months. This exceeded the prespecified criteria for clinically meaningful improvement of 19.0 months, which corresponded to a 58% improvement on the median OS of 12.0 months associated with a pemetrexed–cisplatin historical control.
The 6-, 12-, and 24-month OS rates were 87.2%, 70.4%, and 44.2%, respectively, while corresponding progression-free survival (PFS) rates were 69.1%, 16.4%, and 10.9%. The median PFS was 6.7 months.
At the data cutoff point of 24 April 2020, 56.4% of patients had a partial response, 40.0% had stable disease, and 1.8% had progressive disease.
Forde described the durvalumab combination as “well tolerated,” with grade 3 or higher treatment-emergent adverse events occurring in 36 patients, and he emphasized that “many of these events are those that we see with platinum-based chemotherapy.”
Forde highlighted that among the adverse events that are “possibly related to immunotherapy,” namely, hypothyroidism (n=7), rash (n=5), pruritus (n=3), aspartate aminotransferase AST elevation (n=3), hyperthyroidism (n=3), dermatitis (n=2), neuropathy (n=2), alanine aminotransferase elevation (n=1), lipase increase (n=1), and pneumonitis (n=1), all were of grade 1–2 and none were “unexpected.”
“There was an extensive translational effort on this study,” said Forde who reported that OS and PFS did not correlate with various tumor characteristics, including tumor mutational burden (TMB) and PD-L1 expression.
But he added that they did find a higher, albeit not significant, median OS among patients with a TMB of at least 24 sequence alterations, at 27.9 months versus 14.2 months for patients with a TMB of 23 or lower.
Additional analyses described by Forde showed significant autologous T-cell expansion in three of 48 highly ranked predicted mutation-associated neoantigens in a responsive tumor. He emphasized that these “potential” T-cell responses are particularly “interesting” in patients with malignant pleural mesothelioma because this type of cancer has a low TMB.
Overall, in light of the “promising” survival outcomes, Forde highlighted the upcoming phase 3 DREAM3R (PrE0506) trial that will further examine the addition of durvalumab to cisplatin and pemetrexed in patients with malignant pleural mesothelioma.
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