TMB does not predict NSCLC pembrolizumab–chemotherapy response
medwireNews: Exploratory analyses from two KEYNOTE trials reported at the IASLC World Conference on Lung Cancer 2019 in Barcelona, Spain, rule out a significant correlation between tumor mutational burden (TMB) and survival of patients with non-small-cell lung cancer (NSCLC) who are treated with pembrolizumab and chemotherapy.
Marina Garassino (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy) reported the TMB results from the phase III KEYNOTE-189 study of 616 patients, which previously showed significantly better outcomes with pembrolizumab given alongside pemetrexed and carboplatin or cisplatin compared with placebo plus chemotherapy in the first-line setting.
Whole-exome sequencing from tumor tissue was feasible for 207 patients in the pembrolizumab group and 86 controls.
In all, 134 patients had a high TMB, defined as 175 or more mutations/exome, and these patients had a similar overall survival rate to their 159 counterparts with a lower TMB, with a hazard ratio for death in favor of pembrolizumab of 0.64 in both the high and low TMB groups
Progression-free survival (PFS) was also significantly better with pembrolizumab than placebo in both the high and low TMB subgroups (HR=0.32 and 0.51, respectively), as were the objective response rates (ORRs) in the high (50.0 vs 11.8%) and low (40.2 vs 19.2%) TMB groups.
Garassino therefore suggests that “tissue TMB may not help select patients who would have better outcomes with pembrolizumab plus pemetrexed and a platinum given as first-line therapy for metastatic nonsquamous NSCLC.”
Similar outcomes were also reported by Corey Langer, from the University of Pennsylvania in Philadelphia, USA, for two patient cohorts of the KEYNOTE-021 trial, which was the first to indicate that combining pembrolizumab with carboplatin was feasible as a first-line regimen for stage IIIB–IV nonsquamous NSCLC.
Langer reported that tissue TMB analysis was successfully performed on 12 of the 24 patients who received pembrolizumab 2 mg/kg or 10 mg/kg plus carboplatin, and 58 of the 123 patients who were randomly assigned to receive pembrolizumab 200 mg every 3 weeks plus carboplatin or carboplatin alone.
And TMB status was not associated with ORR in either the pembrolizumab-treated patients or patients given chemotherapy only; almost half (48%) of patients given pembrolizumab had a high TMB of at least 175 mutations/exome and their ORR was 71% versus 61% for the pembrolizumab-treated counterparts with a lower TMB.
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