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

Abstract

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 with sAR (P < 0.001, P = 0.03, P = 0.04, respectively), whereas baseline PD-L1 and tumor burden were similar. Post-progression, oligoAR was associated with improved overall survival (median 28 months vs. 10 months, P < 0.001) compared with 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). Fifty-eight percent 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 2 years after local therapy.

Conclusions: OligoAR is a common and distinct pattern of acquired resistance to PD-(L)1 blockade compared with sAR. OligoAR is associated with improved post-progression survival and some cases can be effectively managed with local therapies with durable benefit.

Figure 1.. Schema for classification of systemic and oligo-acquired resistance to PD-(L)1 blockade in lung cancer.

Acquired resistance (AR) is defined as progressive disease or death after initial objective response (complete or partial response (CR/PR) by RECIST 1.1). AR is subdivided into two groups, oligo-acquired resistance (oligoAR) and systemic AR, by the number of new and/or progressive lesions of disease progression (oligo-AR ≤ 3 lesions of disease progression, respectively).

Figure 2.. Clinical features of AR to PD-(L)1 blockade.

(A) Frequency of oligoAR and systemic AR. (B) Baseline characteristics of oligoAR and systemic AR prior to PD-(L)1 blockade. (C) Time to resistance to PD-(L)1 blockade in oligoAR vs systemic AR. (D) Overall survival post-progression on PD-(L)1 blockade in oligoAR vs systemic AR.

Figure 3.. Management and outcomes of patients with oligoAR to PD-(L)1 blockade.

(A) Post-PD-(L)1 blockade progression overall survival with or without local therapy added. (B) Survival post-PD-(L)1 blockade progression by individual patients. Arrows denote ongoing survival and X indicate death.