Determinants of Long-Term Response in Patients with NSCLC Treated with PD-1 Blockade

Long-term responders were defined as patients with responses (partial response [PR] or complete response [CR]) lasting ≥24 months. Short-term responders were patients with PR or CR lasting <12 months. Researchers also compared these patients with patients who had progressive disease. PD-L1 expression was assessed by immunohistochemistry. Tumor mutation burden (TMB; defined as greater than or equal to the median of the cohort) was assessed by targeted next-generation sequencing.

Of 2382 patients, 6.3% (95% confidence interval [CI], 5.3%-7.4%) were long-term responders, with similar rates in both the Memorial Sloan Kettering Cancer Center (MSKCC) and Dana-Farber Cancer Institute (DFCI) cohorts. Short-term responses occurred in 6% of all patients. Long-term responders had a longer overall survival rate compared with short-term responders (median not reached vs 19.6 months; hazard ratio [HR], 0.07; P <.001 in the MSKCC cohort; median not reached vs 18.0 months; HR, 0.08; P <.001 in the DFCI cohort). Long-term responders had deeper responses compared with short-term responders (median best overall response, –73% vs –39%; P <.001).

Patients with long-term responses were also significantly more likely to be younger (<65 years old) with higher TMB (≥ median mutations per megabase) compared with both short-term responders and progressors. The rate of long-term response was enriched among patients with both high TMB and high PD-L1 compared with those with low TMB and low PD-L1 (16% vs 2%; P <.001).

Long-term response to PD-1 inhibition was achieved by 2% of patients with sensitizing EGFR mutations (N = 243). Loss of function variants in ARID1A (14% vs 2%), PTEN (8% vs 0%), and KEAP1 (12% vs 2%) were enriched in long-term responders compared with short-term responders (P <.05 for each). Patients with KRAS mutations and co-mutation with TP53 had a higher rate of long-term response compared with patients with KRAS mutations and co-mutation with STK11 (12% vs 2%; P = .01).

Researchers concluded that long-term response (ongoing response for ≥24 months) to PD-1 blockade is an uncommon but highly important clinical outcome in metastatic lung cancer. Younger age and high TMB correlate with long-term responders. The combination of high TMB and high PD-L1 enriches for long-term responders but not short-term responders. Features that predict long-term response may be distinct from those predicting initial response.

Reference

Luo J, Bandlamudi C, Ricciuti B, et al. Long-term responders to PD-1 blockade in patients with advanced non-small cell lung cancer. J Clin Oncol. 2020;38:suppl (abstract 9549).