Patterns of Acquired Resistance in Patients with NSCLC Who Receive PD-1 Inhibitors

Researchers at Memorial Sloan Kettering Cancer Center evaluated all patients with non–small-cell lung cancer (NSCLC) who were treated with PD-1 blockade to learn the frequency and patterns of acquired resistance to therapy. Acquired resistance was defined as initial response, either complete response or partial response, using RECIST criteria, followed by disease progression or death. Two different patterns of acquired resistance, oligo and systemic, were also defined. “Oligo” is progression in ≤2 sites of disease, whereas “systemic” is progression in ≥3 sites of disease.

Of 1201 patients with NSCLC who underwent treatment with PD-1 inhibitors, 20% achieved initial response and 78% (95% confidence interval, 72%-83%) eventually developed acquired resistance. Onset of acquired resistance was variable and decreased with longer duration of response (53% progressed within 1 year, 37% progressed within 1-2 years, and 10% after 2 years).

Patients with PD-L1 expression levels of <50% and tumor mutation burden of <8 mutations per megabase (mut/Mb) were more likely to develop acquired resistance compared with those with PD-L1 expression levels of ≥50% and tumor mutation burden of ≥8 mut/Mb (P = .02). Acquired resistance was frequently evident in lymph nodes (41%) and less often in the liver (6%).

Patterns of acquired resistance were most commonly oligo (56%) rather than systemic (28%); 16% of patients died without evidence of radiographic progression. Oligo acquired resistance occurred later, with a median onset of 12.9 months compared with 5.6 months for systemic acquired resistance. Oligo acquired resistance also correlated with higher postprogression survival (median overall survival [OS] of 55.2 months vs 9.2 months for systemic; P <.001). Postprogression OS was highest in patients with acquired resistance and a complete response or partial response compared with those with initial stable disease or progression after PD-1 blockade (median OS, 18.9 vs 12.5 vs 4.4, respectively; P <.001). Of 49 patients who were initially treated with locally directed therapy for acquired resistance, 57% remain alive and systemic therapy–free.

Researchers concluded that acquired resistance to PD-1 inhibition is common among patients with NSCLC. Risk of acquired resistance is lower in biomarker-enriched patients and as duration of response increases. Acquired resistance is commonly oligo in nature, which is amenable to locally directed therapy and can be associated with improved OS. Differences in organ-site distribution and postprogression survival suggest that acquired resistance has distinct biology compared with primary refractory disease.


Reference

  • Schoenfeld AJ, Rizvi H, Memon D, et al. Acquired resistance to PD-1 blockade in non-small cell lung cancer. J Clin Oncol. 2020;38:suppl (abstract 9621).

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