Patterns of failure in metastatic non-small cell lung cancer (mNSCLC) treated with first line pembrolizumab and use of local therapy in patients with oligoprogression.
Authors: Friedes Cole , Yegya-Raman Nikhil , Zhang Siqi , Iocolano Michelle , Cohen Roger B. , Aggarwal Charu , Thompson Jeffrey C. , Marmarelis Melina Elpi , Levin William C. , Cengel Keith A. , Ciunci Christine Agnes , Singh Aditi Puri , Davella Christopher , Davis Christiana , Langer Corey J. , Feigenberg Steven J 
Published: June 2023

e21054 Background: The patterns of failure (POF) for patients (pts) with mNSCLC treated with immunotherapy are not well established. These POF inform treatment decisions and may identify candidates for radiotherapy (RT). The primary objective of this study was to establish the POF in mNSCLC treated with first line pembrolizumab, identify the frequency of oligoprogression (OPD), and characterize the use of RT in patients with OPD. Methods: We retrospectively identified pts with mNSCLC who received first line pembrolizumab +/- chemotherapy between January 2015 – January 2021 at a single institution. We defined POF at the time of first disease progression (PD) after pembrolizumab infusion according to two classifications: 1) local, regional, or distant failure, or 2) failure in existing lesions, new lesions, or a combination. OPD was defined as PD in < 3 distinct sites of failure in any number of organs. Overall survival (OS) was measured via the Kaplan Meier method. Multivariable Cox modeling was used to correlate pt characteristics with OS. Logistic regression was used to predict pt variables associated with OPD. Results: Of the 298 pts who received first line pembrolizumab +/- chemotherapy for mNSCLC, 198 had PD at median follow up of 46.3 months. Using POF classification 1, most failures were distant (n = 87, 43.9%) or a combination of locoregional and distant (n = 68, 34.4%). For POF classification 2, failures occurred in a combination of new and existing lesions (n = 89, 45.0%), existing lesions alone (n = 66, 33.3%), or in new lesions only (n = 42, 21.7%). OPD occurred in 79 (39.9%) pts. At the time of progression, 52 pts (27.3%) had PD at 1 site, 50 pts (25.2%) had PD at 2-3 sites, 37 pts (18.7%) had PD at 4-5 sites, and 57 pts (28.8%) had PD at > 5 sites. Most PD occurred in a solitary organ (n = 93, 47.0%) or in 2-3 different organs (n = 81, 40.9%). Median OS was higher in the following groups: PD in existing lesions vs new or new + existing lesions (28.7 vs 20.2 vs 13.9 months, p < 0.001), locoregional failure vs distant or both (39.1 vs 17.4 vs 14.3 months, p < 0.001) and OPD vs polyprogression (35.1 vs. 12.2 months, p < 0.001). Among pts with OPD (n = 79), median OS was better for those who received RT to all sites of PD than for those who changed systemic therapy (66.2 vs 22.9 months, p = 0.007). Pts with oligometastatic disease at diagnosis (OR 2.94, 95% CI 1.19-7.56, p = 0.02) and PR as best response to ICI (OR 2.48, 95% CI 1.04-6.14, p = 0.04) were more likely to develop OPD. On multivariable analysis, receipt of RT at time of OPD (HR 0.35, 95% CI 0.20-0.62, p < 0.01) and higher number of ICI cycles received (HR 0.94, 95% CI 0.92-0.96, p < 0.001) were associated with improved OS. Conclusions: For pts with mNSCLC treated with pembrolizumab, PD outside of existing lesions is infrequent. OPD is common and occurs in 40% of PD. Randomized data are needed to define the benefits of RT in mNSCLC with OPD.