Immunotherapy response differs by EFGR mutation subtype
medwireNews: The response to treatment with immune checkpoint inhibitors varies according to EGFR mutant subtype in patients with non-small-cell lung cancer (NSCLC), US researchers report.
Matthew Hellmann (Memorial Sloan Kettering Cancer Center, New York) and team also found that different mutant subtypes were associated with distinct tumor mutational burdens (TMBs). They say that “[t]his knowledge may be useful in selecting patients with a higher likelihood of response to these agents.”
The findings are based on a retrospective analysis of data from 171 cases of EGFR-mutant NSCLC that was treated with inhibitors of PD1, PD-L1, or CTLA-4, as well as a separate cohort of 383 cases that had sequencing data available to assess TMB.
The researchers report in the Annals of Oncology that patients with tumors harboring an EGFR L858R mutation (n=44) had a similar objective response rate (ORR) to individuals with wild-type tumors (n=212), at 16% versus 22%, as well as no increased risk for death overall.
By contrast, individuals with tumors harboring an EGFR exon 19 deletion (n=76) had a significantly lower ORR, at 7% versus 22%, and a significantly higher risk for death (hazard ratio [HR]=0.69) than those with wild-type tumors.
Both EGFR alterations, however, were associated with an increased risk for disease progression or death during immune checkpoint inhibition relative to the wild-type, at HRs of 0.59 and 0.45 for the L858R and exon 19 alterations, respectively.
Of note, PD-L1 expression was similar across EGFR mutation subtypes and did not impact response to immune checkpoint blockade.
“Overall, these data suggest that patients with EGFR [exon 19] mutant tumors, in particular, have a significantly reduced benefit upon treatment with [immune checkpoint inhibitors],” Hellmann et al remark.
They add that the reason for the difference in outcomes between overall survival and progression-free survival is unclear but “may be reflective of the variable scanning intervals represented by this multi-institutional cohort composed of both on-trial and off-trial cases.”
In line with the immunotherapy response data, the investigators found that, despite similar smoking history, tumors with the EGFR exon 19 deletion carried a significantly lower TMB than tumors with an EGFR L858R mutation, with a median TMB percentile rank of 36.5 versus 50.9.
Hellmann and colleagues suggest that the higher TMB in the EGFR L858R tumors may reflect “the generally more advanced age of patients with EGFRL858R at diagnosis compared to patients with EGFR [exon 19 deletions].”
The authors conclude: “These data serve as a foundation for further investigating which patients with EGFR mutant disease have a higher likelihood of benefitting from immunotherapies, in particular when combined with chemotherapy or anti-angiogenesis agents.”
They add: “More broadly, our data provide rationale for evaluating genomic and molecular subsets within tumors types with lower TMB to better understand which features are associated with successful outcomes with [immune checkpoint inhibitors].”
By Laura Cowen
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