medwireNews: Data from the BFAST study suggest that blood-based tumor mutational burden (bTMB) at a cutoff of 16 mutations does not predict first-line atezolizumab outcomes in people with advanced non-small-cell lung cancer (NSCLC).
“Additional exploration of bTMB to identify and validate optimal cutoffs” is warranted, “as are studies to account for confounding factors such as HLA-I [loss of heterozygosity],” write Solange Peters, from Lausanne University in Switzerland, and co-researchers in Nature Medicine.
They continue: “bTMB may have utility in combination with other relevant biomarkers (for example, PD-L1 status) to identify subgroups that may be responsive to [first-line] treatment with checkpoint inhibitors in NSCLC. Further studies are needed to explore such associations.”
Peters et al explain that the proof-of-principle B-F1RST study showed “encouraging preliminary data” with the use of “bTMB as a biomarker for [first-line] atezolizumab monotherapy in locally advanced or metastatic NSCLC,” leading them to evaluate bTMB in the multicohort phase 3 BFAST trial.
They report on cohort C of the trial, which enrolled 471 patients with stage IIIB or IV NSCLC and a bTMB of at least 10 mutations as detected by the bTMB clinical trial assay (Foundation Medicine, Inc, Cambridge, Massachusetts, USA).
The primary endpoint of investigator-assessed progression-free survival (PFS) in the subset of patients with a bTMB of at least 16 mutations did not differ significantly between the 145 participants who were randomly assigned to receive atezolizumab 1200 mg every 3 weeks and the 146 who instead received four to six cycles of platinum-based chemotherapy every 3 weeks, at a median of 4.5 and 4.3 months, respectively (nonsignificant hazard ratio [HR]=0.77).
However, landmark analysis showed better PFS rates with atezolizumab than chemotherapy, at 12-month rates of 24% versus 7% and 18-month rates of 14% versus 1%.
“Therefore, the later timepoints for PFS may better represent the outcomes of the study than the HR, as shown by the shape of the Kaplan–Meier curves,” which “crossed at approximately 4 months and eventually favored atezolizumab,” say the researchers.
“This Kaplan–Meier ‘crossover gap’ in PFS has been observed in multiple other Phase 3 trials of anti-PD-L1/ PD-1 monotherapy versus chemotherapy and may reflect a subset of patients who respond better to cytotoxic chemotherapy and are refractory to an anti-PD-L1/PD-1 agent,” they continue.
The secondary endpoints were not formally tested but among patients with a bTMB of 16 mutations or more, median overall survival was longer with atezolizumab than chemotherapy, at 13.3 versus 10.3 months, and a greater proportion of atezolizumab-treated patients were estimated to be alive at 12 months (52 vs 42%) and 18 months (42 vs 28%).
The objective response rate and duration of response similarly favored the PD-L1 inhibitor over chemotherapy, at 26% versus 18% and a median of 11.9 versus 5.7 months.
Peters and colleagues also report that exploratory analyses with an alternative assay “showed improving PFS HRs at higher cutoffs, suggesting that the predictive power of bTMB may be improved by the selection of a different cutoff.”
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Nat Med 2022; doi:10.1038/s41591-022-01933-w