CheckMate 568 identifies ‘clinically meaningful’ TMB cutoff for advanced NSCLC
medwireNews: A tumor mutational burden (TMB) cutoff of 10 mutations/Mb could help identify advanced non-small-cell lung cancer (NSCLC) patients who are most likely to benefit from first-line treatment with nivolumab plus low-dose ipilimumab, report the CheckMate 568 investigators.
In the phase II trial, treatment with nivolumab 3 mg/kg every 2 weeks alongside ipilimumab 1 mg/kg every 6 weeks led to an objective response rate (ORR) of 44% among the 48 patients with a TMB of 10 mutations/Mb or more, while the ORR was 12% for the 50 participants with a lower TMB.
Median progression-free survival (PFS) was similarly improved in the higher versus lower TMB group, at a median of 7.1 and 2.6 months, respectively, and corresponding 6-month rates of 55% and 31%.
Writing in the Journal of Clinical Oncology, Neal Ready (Duke University Medical Center, Durham, North Carolina, USA) and co-investigators point out that a higher TMB was associated with efficacy regardless of PD-L1 expression.
Among patients with a TMB of 10 mutations/Mb, the ORR was 42% for patients with tumoral PD-L1 levels of at least 1% and was 47% for those with PD-L1 levels below 1%. By contrast, the corresponding ORRs were 18% and 5% in participants with a TMB below 10 mutations/Mb.
The researchers therefore summarize that the analysis supports the 10 mutations/Mb threshold “as a clinically meaningful cutoff for response and PFS with this regimen in this patient population.”
They add that the cutoff “was subsequently validated through a preplanned coprimary end point analysis in CheckMate 227,” which showed that PFS was significantly longer with first-line nivolumab plus ipilimumab than chemotherapy in patients with a TMB of 10 or more mutations/Mb, whereas there was no significant difference between the treatments among those with a lower TMB.
The CheckMate 568 trial included 288 patients with treatment-naïve, recurrent stage IIIB or stage IV NSCLC. The assessment of efficacy by TMB was introduced as a secondary endpoint during a protocol amendment and therefore sufficient tissue for TMB analysis – using the FoundationOne CDx platform (Foundation Medicine, Cambridge, Massachusetts, USA) – was available for 120 patients, with a successful result obtained for 98.
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