PURPOSE
Clinical patterns and the associated optimal management of acquired resistance to PD-(L)1 blockade are poorly understood.
EXPERIMENTAL DESIGN
All cases of metastatic lung cancer treated with PD-(L)1 blockade at Memorial Sloan Kettering were reviewed. In acquired resistance (complete/partial response per RECIST, followed by progression), clinical patterns were distinguished as oligo (OligoAR, ≤ 3 lesions of disease progression) or systemic (sAR). We analyzed the relationships between patient characteristics, burden/location of disease, outcomes, and efficacy of therapeutic interventions.
RESULTS
Of 1,536 patients, 312 (20%) had an initial response and 143 developed AR (9% overall, 46% of responders). OligoAR was the most common pattern (80/143, 56%). Baseline tumor mutational burden, depth of response, and duration of response were significantly increased in oligoAR compared to sAR (P < 0.001, P = 0.03, P = 0.04, respectively), while baseline PD-L1 and tumor burden were similar. Post-progression, oligoAR was associated with improved overall survival (median 28 vs. 10 months, P < 0.001) compared to sAR. Within oligoAR, post-progression survival was greater among patients treated with locally-directed therapy (e.g. radiation, surgery; HR 0.41, p = 0.039). 58% of patients with oligoAR treated with locally-directed therapy alone are progression-free at last follow-up (median 16 months), including 13 patients who are progression-free more than two years after local therapy.
CONCLUSIONS
OligoAR is a common and distinct pattern of acquired resistance to PD-(L)1 blockade compared to sAR. OligoAR is associated with improved post-progression survival and some cases can be effectively managed with local therapies with durable benefit.