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.

中文翻译：

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肺癌中对 PD-(L)1 阻断的全身性和寡核苷酸获得性耐药

目的：对 PD-(L)1 阻断获得性耐药的临床模式和相关最佳管理知之甚少。实验设计：回顾了纪念斯隆凯特琳医院接受 PD-(L)1 阻断治疗的所有转移性肺癌病例。在获得性耐药（根据 RECIST 完全/部分缓解，随后进展）中，临床模式被区分为寡聚（OligoAR ≤ 3 个疾病进展病变）或系统性（sAR）。我们分析了患者特征、疾病负担/位置、结果和治疗干预效果之间的关系。结果：在 1,536 名患者中，312 名 (20%) 出现初始缓解，143 名出现 AR（总体占 9%，占缓解者的 46%）。OligoAR 是最常见的模式 (80/143, 56%)。与 sAR 相比，oligoAR 的基线肿瘤突变负荷、反应深度和反应持续时间显着增加（分别为 P < 0.001、P = 0.03、P = 0.04），而基线 PD-L1 和肿瘤负荷相似。与 sAR 相比，进展后，oligoAR 与总生存期改善相关（中位 28 个月与 10 个月，P < 0.001）。在oligoAR中，接受局部定向治疗（例如放疗、手术；HR，0.41；P = 0.039）的患者的进展后生存率更高。仅接受局部定向治疗的 oligoAR 患者中有 58% 在最后一次随访（中位 16 个月）时未出现进展，其中 13 名患者在局部治疗后 2 年以上未出现进展。结论：与 sAR 相比，OligoAR 是一种常见且独特的 PD-(L)1 阻断获得性耐药模式。OligoAR 与改善进展后生存相关，某些病例可以通过局部治疗得到有效管理，并具有持久益处。