medwireNews: Adding pembrolizumab to concurrent first-line chemoradiotherapy is tolerable and shows promising efficacy in patients with locally advanced non-small-cell lung cancer (NSCLC), according to phase 1 study data published in JAMA Oncology.
“Based on the recognized efficacy of first-line PD-1/PD-L1 inhibition in advanced NSCLC, the possibility of earlier integration of these therapies into stage III NSCLC remains a relevant question,” explain Salma Jabbour (Rutgers University, New Brunswick, New Jersey, USA) and team.
They enrolled 21 patients with unresectable, stage IIIA–IIIB NSCLC from three institutional centers and treated them with one of five pembrolizumab dosing schedules with concurrent chemotherapy, comprising weekly carboplatin AUC 2 and paclitaxel 50 mg/m2, plus radiotherapy at a dose of 60 Gy given in 30 fractions.
Pembrolizumab 200 mg (full dose) or 100 mg (reduced dose), given every 3 weeks, was started on the first day of chemoradiotherapy, the 29th day, or in the case of pembrolizumab 200 mg only, any time between 2 and 6 weeks after chemoradiotherapy. The trial also included a six-patient safety expansion cohort that was given the maximum tolerated dose of pembrolizumab, which was 200 mg every 3 weeks, starting the same day as concurrent chemoradiotherapy.
During the 16-month follow-up period, grade 2 or higher immune-related adverse events (irAEs) occurred in 67% of study participants. Specifically, there were seven cases of pneumonitis, one dose-limiting grade 5, one grade 3, and five grade 2 events. Of these, the grade 5 pneumonitis – occurring 3.4 months after registration – and four of the grade 2 events occurred in patients in the safety expansion cohort.
By comparison, the grade 3 pneumonitis started 8.6 months after registration in a patient who received pembrolizumab 100 mg from day 29.
Further analysis revealed that patients who started pembrolizumab on day 1 had the highest risk for pneumonitis, regardless of whether they received the full or reduced pembrolizumab dose, compared with patients who started later.
Jabbour and colleagues say: “Although we observed an increased rate of pneumonitis, most patients had pneumonitis that responded to high-dose corticosteroid treatment.”
Other notable grade 2 or worse irAEs included one case each of type 1 diabetes and tracheoesophageal fistula, both in patients taking pembrolizumab 200 mg from day 1, one case of grade 3 interstitial nephritis in a patient initiating pembrolizumab 200 mg at 2–6 weeks after chemoradiotherapy, and four cases of grade 2 hyperthyroidism across the cohorts.
The researchers report a median progression-free survival (PFS) of 18.7 months among the 21 study participants who each received a minimum of one pembrolizumab dose, which translated into 6- and 12-month PFS rates of 81.0% and 69.7%, respectively.
Among the 19 patients who received at least two doses of pembrolizumab, the median PFS extended to 21.0 months, with respective 6- and 12-month rates of 84.2% and 78.2%.
The median time to best response was 12.6 months among these patients and the rates of complete response, partial response, and stable disease were 16%, 74%, and 5%, respectively, giving a clinical benefit rate of 95%.
Taken together, these data suggest that concurrent pembrolizumab and chemoradiotherapy “should continue to be evaluated in phase 2 and 3 clinical trials,” say Jabbour and co-investigators.
And they conclude: “Given the risk of pneumonitis, this combination should continue to be evaluated under the aegis of clinical trials in which close patient monitoring and strict adherence to careful radiation design to limit key lung parameters and biomarkers can be implemented.”
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