Systemic and Oligo-Acquired Resistance to PD-(L)1 Blockade in Lung Cancer

Purpose: Clinical patterns and the associated optimal managesAR (P < 0.001, P ¼ 0.03, P ¼ 0.04, respectively), whereas ment of acquired resistance to PD-(L)1 blockade are poorly baseline PD-L1 and tumor burden were similar. Post-progresunderstood. sion, oligoAR was associated with improved overall survival Experimental Design: All cases of metastatic lung cancer treated (median 28 months vs. 10 months, P < 0.001) compared with with PD-(L)1 blockade at Memorial Sloan Kettering were reviewed. sAR. Within oligoAR, post-progression survival was greater In acquired resistance (complete/partial response per RECIST, among patients treated with locally-directed therapy (e.g., radifollowed by progression), clinical patterns were distinguished as ation, surgery; HR, 0.41; P ¼ 0.039). Fifty-eight percent of oligo (OligoAR ≤ 3 lesions of disease progression) or systemic patients with oligoAR treated with locally-directed therapy (sAR). We analyzed the relationships between patient character-alone are progression-free at last follow-up (median 16 months), istics, burden/location of disease, outcomes, and efficacy of theraincluding 13 patients who are progression-free more than 2 years peutic interventions. after local therapy. Results: Of 1,536 patients, 312 (20%) had an initial response Conclusions: OligoAR is a common and distinct pattern of and 143 developed AR (9% overall, 46% of responders). Oliacquired resistance to PD-(L)1 blockade compared with sAR. goAR was the most common pattern (80/143, 56%). Baseline OligoAR is associated with improved post-progression survival and tumor mutational burden, depth of response, and duration of some cases can be effectively managed with local therapies with response were significantly increased in oligoAR compared with durable benefit.