medwireNews: Adding the PD-1 inhibitor sintilimab and the bevacizumab biosimilar IBI305 to chemotherapy significantly improves the progression-free survival (PFS) of people with EGFR-mutated, nonsquamous non-small-cell lung cancer (NSCLC) that has progressed after prior EGFR–tyrosine kinase inhibitor (TKI) therapy, suggests an interim analysis of a Chinese phase 3 trial.
“This finding is an important advance because such patients had a minimal benefit with PD-1 or PD-L1 monotherapy in preliminary investigations and currently have scarce treatment options and a poor prognosis,” say the study authors in The Lancet Oncology.
“However, longer follow-up is required to evaluate contributions of IBI305 and sintilimab to the observed treatment effect,” they add.
“Results from the ongoing KEYNOTE-789 (NCT03515837) and CheckMate 722 (NCT02864251) studies will also provide further data on the role of immunotherapy plus chemotherapy in this patient population.”
The double-blind ORIENT-31 trial included 444 Chinese patients with locally advanced or metastatic EGFR-mutated NSCLC who had progressed after a first- or second-generation EGFR–TKI, but not acquired a T790M resistance mutation, or had progressed after a third-generation agent.
Participants were randomly assigned to receive sintilimab 200 mg – either with IBI305 15 mg/kg or alone – alongside pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or chemotherapy alone, with all treatments given on day 1 of each 3-weekly cycle. The study drugs, except for cisplatin which was only administered for the first four cycles, could be given for up to 24 months.
After a median follow-up of 9.8 months, the primary endpoint of independently assessed PFS was significantly longer for the 148 patients who received sintilimab plus IBI305 alongside chemotherapy than for the 151 given chemotherapy alone, at a median of 6.9 versus 4.3 months. This equated to a significant 54% reduced risk for progression or death in favor of the sintilimab plus IBI305 group.
The estimated PFS rate at 6 months was 59% in the sintilimab plus IBI305 arm and 30% in the chemotherapy alone arm, while the 12-month rates were 28% and 12%, respectively.
The objective response rate, as assessed by independent review, was also higher for participants receiving sintilimab plus IBI305 alongside chemotherapy than for those treated with chemotherapy alone, at 44% versus 25%.
However, the PFS data for the sintilimab plus chemotherapy group as well as the overall survival data were immature at the time of this interim analysis.
Moving onto the safety, Shun Lu (Shanghai Jiao Tong University, China) and team say that “sintilimab plus IBI305 plus cisplatin and pemetrexed was generally well tolerated with no new safety signals.”
Grade 3–5 treatment-related adverse events (TRAEs) occurred in 51% of patients in the sintilimab plus IBI305 group and 45% of those in the chemotherapy alone group. The most common TRAE of grade 3 or 4 in both the sintilimab plus IBI305 and chemotherapy alone arms was decreased neutrophil count, observed in a respective 20% and 18% of patients.
A total of 17% of patients given sintilimab plus IBI305 alongside chemotherapy discontinued any treatment due to treatment-emergent AEs, as did 7% of those given chemotherapy alone.
Six deaths in the former group were considered possibly related to study treatment – one case each of intestinal obstruction, gastrointestinal hemorrhage, and myelosuppression and three of unknown cause – as was one death of unknown cause in the latter group.
Lu and colleagues draw attention to some of the limitations of the study, such as the low proportion of patients who received the third-generation EGFR–TKI osimertinib in the first line “due to the treatment landscape in China during the study recruitment period,” and the immature PFS and overall survival data.
But they continue: “Despite these potential limitations, our results provide strong evidence for this promising treatment strategy and can potentially change the standard of care for a difficult-to-treat patient population.”
The authors of an accompanying commentary say that “ORIENT-31 is the first prospective study to show a benefit of chemotherapy, VEGF inhibition, and anti-PD-L1 combination” in this patient population.
“However, before broad adoption of this regimen, the sintilimab plus pemetrexed and cisplatin versus chemotherapy alone data and mature survival data must be seen to allow understanding of the contribution of different components”, write Arielle Elkrief and Helena Yu, both from Memorial Sloan Kettering Cancer Center in New York, USA.
They also note that results of the FLAURA2 study, which is evaluating first-line osimertinib with or without chemotherapy in patients with EGFR-mutated NSCLC, are still awaited.
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