Systemic and Oligo-Acquired Resistance to PD-(L)1 Blockade in Lung Cancer
Adam J Schoenfeld1, Hira A Rizvi2, Danish Memon3,4
1Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
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.
Insights
Acquired resistance to PD-(L)1 blockade in lung cancer often presents as oligo-resistance (OligoAR), a distinct pattern associated with better survival. Local therapies can provide durable benefits for patients with OligoAR.
Area of Science:
- Oncology
- Immunotherapy
- Lung Cancer Research
Background:
- Acquired resistance to programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) blockade is a significant clinical challenge in metastatic lung cancer.
- Understanding the distinct clinical patterns of acquired resistance is crucial for optimizing subsequent treatment strategies.
Purpose of the Study:
- To characterize the clinical patterns of acquired resistance to PD-(L)1 blockade in metastatic lung cancer.
- To compare outcomes and evaluate the efficacy of different therapeutic interventions based on resistance patterns.
Main Methods:
- Retrospective review of metastatic lung cancer patients treated with PD-(L)1 blockade.
- Classification of acquired resistance into oligo-resistance (OligoAR) and systemic acquired resistance (sAR) based on lesion count and progression.
- Analysis of patient characteristics, disease burden, outcomes, and treatment efficacy.
Main Results:
- 20% of patients responded to PD-(L)1 blockade, with 46% of responders developing acquired resistance (AR).
- OligoAR was the predominant pattern (56%), characterized by fewer than 4 lesions of progression.
- OligoAR was associated with significantly improved overall survival (28 months vs. 10 months) and a higher response duration compared to sAR.
- Locally-directed therapies in oligoAR patients led to improved post-progression survival and durable progression-free survival in 58% of cases.
Conclusions:
- OligoAR represents a common and distinct pattern of acquired resistance to PD-(L)1 blockade, differing from systemic acquired resistance (sAR).
- OligoAR is linked to superior post-progression survival.
- Local therapies can offer durable clinical benefit for select patients with oligoAR.
