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Characteristics of Patients Who Achieve Long-Term Response with PD-1 Blockade

Conference Correspondent  - ASCO 2020 - Lung Cancer

To learn more about the frequency, characteristics, and predictors of long-term response to PD-1 inhibitors, patients from 2 institutions (Memorial Sloan Kettering Cancer Center [MSKCC] and Dana-Farber Cancer Institute [DFCI]) who were diagnosed with advanced non–small-cell lung cancer (NSCLC) and treated with anti–PD-1 or PD-L1 therapy were examined. Responses were assessed by RECIST. Long-term responders had responses (partial response [PR] or complete response [CR]) lasting ≥24 months. Short-term responders had PR or CR lasting <12 months. Comparisons were also made with patients who had progressive disease. PD-L1 expression was assessed by immunohistochemistry. Tumor mutation burden (TMB) was assessed by targeted next-generation sequencing. High TMB was defined as greater than or equal to the median of the cohort.  

Of 2382 patients, 6.3% (95% confidence interval [CI], 5.3%-7.4%) were long-term responders, with similar rates in both the MSKCC and DFCI cohorts. Short-term responses occurred in 6% of all patients. Overall survival was longer in long-term responders 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).

Two percent of patients with sensitizing EGFR mutations (N = 243) achieved long-term response to PD-1 inhibition. 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). Among patients with KRAS mutations, the rate of long-term response was higher in those with co-mutation with TP53 compared with STK11 (12% vs 2%; P = .01).

Researchers concluded that long-term response, defined as ongoing response for ≥24 months, to PD-1 blockade is an uncommon but profound 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).
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Last modified: May 30, 2020