In a study reported in the Journal of Clinical Oncology, Osorio et al found that responses to programmed cell death protein 1 (PD-1) inhibitor therapy tended to be consistent across metastases and occur simultaneously in metastatic lesions of non–small cell lung cancer (NSCLC) and mismatch repair–deficiency (MMRD) carcinoma. These findings suggest that peripheral clonally directed antitumor immune activity is a major contributor to response to PD-1 inhibition.
As noted by the investigators, “Response to [PD-1] blockade is often conceptualized as resulting from reinvigoration of tumor-infiltrating lymphocytes. However, recruited antitumor immunity from the periphery may also be an important contributor to response.”
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The study involved examination of 761 individual lesions from 214 patients with NSCLC and 290 lesions from 78 patients with MMRD carcinoma (37 patients with colorectal cancer, 14 patients with endometrial cancers, and 27 patients with other cancers). Absolute and percent changes of each target lesion were measured at regular computed tomography (CT) scans using Response Evaluation Criteria in Solid Tumors, version 1.1.
Systemic progression was defined as progressive disease in two or more lesions (including target, nontarget, or new lesions in each scenario) in patients with three or fewer target lesions, or progressive disease in three or more lesions in patients with four or more target lesions. Mixed progression was defined as disease progression in one lesion in patients with three or more target lesions, or progression in two or more lesions in patients with four or fewer target lesions.
Evaluation of change in size of each target lesion showed that responses correlated with the best overall response in each patient. Among 46 patients with NSCLC achieving a partial or complete response as the best overall response, 91 (85%) of their 107 individual target lesions also showed an objective response (> 30% reduction). Among 74 patients with stable disease as the best response, 118 (74%) of 159 individual target lesions had stable disease; among 94 patients with progression of disease, 130 (55%) of 235 individual target lesions had progression (> 20% growth). A similar correlation was observed for metastatic MMRD carcinoma lesions, with 93% of lesions showing a response among the 46 patients with overall partial or complete response.
In patients with response, 73% of NSCLC lesions and 76% of MMRD lesions had a synchronous response on the same computed tomography scan.
Among responders in both the NSCLC and MMRD groups, patients with depth of response equal to or greater than the median response in each cohort (−51% in NSCLC, −72% in MMRD) vs those with depth less than the median had improved progression-free survival, with hazard ratios (HRs) of 0.39 (P = .03) in the NSCLC group and 0.08 (P = .008) in the MMRD group. The hazard ratio for overall survival was 0.22 (P = .01) in the NSCLC group. All MMRD responders were alive at last follow-up, with no difference according to response depth thus being observed.
“Temporal-spatial patterns of response across individual metastases tend to be uniform, favoring the role of peripheral, clonally directed antitumor immunity as a key mediator of response to PD-1 blockade.”— Osorio et al
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In contrast to concordance of lesion response with overall response, lesion progression was frequently mixed, as exhibited by 45% of NSCLC and 53% of MMRD lesions with progression. Mixed progression was associated with improved overall survival vs systemic progression in both the NSCLC group (HR = 0.58, P = .001) and the MMRD group (HR = 0.40, P = .07).
In the NSCLC group, best responses were observed in lymph nodes, with intermediate responses in lung (P = .011 vs nodes), adrenal, and pleural (P = .002) lesions and smallest responses in bone and liver (P = .003) metastases. In the MMRD group, most lesions responded regardless of site, and no significant differences among sites were observed.
The investigators concluded: “Temporal-spatial patterns of response across individual metastases tend to be uniform, favoring the role of peripheral, clonally directed antitumor immunity as a key mediator of response to PD-1 blockade. In contrast, progression is more heterogeneous, potentially revealing the clinical importance of local features and intertumoral heterogeneity.”
Matthew D. Hellmann, MD, of the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by a Memorial Sloan Kettering Cancer Center Support Grant/Core Grant from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.