Acquired resistance to PD-1 blockade in NSCLC.

9621 Background: Although durability is the trademark characteristic of response to PD-1 blockade, acquired resistance can occur. The frequency, patterns, and survival outcomes of patients with acquired resistance to PD-1 blockade are unknown. Methods: All patients with NSCLC treated with PD-1 blockade at MSKCC were examined. Acquired resistance was defined as initial CR/PR (by RECIST) followed by progression/death. Oligo vs systemic patterns of acquired resistance were defined as progression in ≤ 2 sites of disease or ≥ 3 sites of disease, respectively. Results: Of 1201 patients treated with PD-1 blockade, 243 (20%) achieved initial response and 189 (78%, 95% CI 72-83%) eventually developed acquired resistance (AR). Onset of AR was variable and decreased with longer duration of response (53% within 1 year, 37% 1-2 years, 10% > 2 years). Patients with PD-L1 expression < 50% and TMB < 8mut/Mb were more likely to develop resistance compared those with PD-L1 expression ≥50% and TMB ≥8mut/Mb (OR 5.5, p = 0.02). Unlike organ sites of primary refractory disease, AR commonly occurred in lymph nodes (41%) and infrequently in the liver (6%). Patterns of AR were most commonly oligo rather than systemic (79/141 [56%], 39/141 [28%]); some patients died without radiographic progression (23/141 [16%]). Oligo-AR occurred later (median onset 13 vs 5.6 mo) and associated with improved post-progression survival (median OS 55.2 vs 9.2 mo, HR 6.0, p < 0.001) compared to systemic-AR. Post-progression survival was highest in patients with AR compared to those with initial SD or PD to PD-1 blockade (median 18.9 vs 12.5 vs 4.4, p < 0.001). Of 49 patients treated initially with locally-directed therapy for AR, 28 (57%) remain alive and systemic therapy-free. Conclusions: Acquired resistance to PD-1 blockade is common in NSCLC. Risk of acquired resistance is lower in biomarker-enriched patients and with increased duration of response. Patterns of acquired resistance is commonly oligo in nature, which is amenable to locally-directed therapy and can be associated with improved survival. Differences in organ-site distribution and post-progression survival suggest distinct biology associated with acquired resistance vs primary refractory disease.