PD-L1, tumor mutational burden (TMB) and long-term survival in patients with non-small cell lung cancer (NSCLC) and brain metastases.

person Elio Adib Brigham and Women's Hospital, Boston, MA info_outline Elio Adib, Amin Nassar, David J. Kwiatkowski, Ayal Aizer

Authors person Elio Adib Brigham and Women's Hospital, Boston, MA info_outline Elio Adib, Amin Nassar, David J. Kwiatkowski, Ayal Aizer Organizations Brigham and Women's Hospital, Boston, MA, Yale Cancer Center, New Haven, CT, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA Abstract Disclosures Research Funding No funding sources reported Background: Brain metastases (BM) affect up to 50% of patients with NSCLC and are associated with poor prognosis in patients with non-targetable genomic alterations. Radiation forms the typical mainstay of intracranial management in such patients given the historically guarded intracranial efficacy of most systemic options. Immunotherapy-based approaches have shown promise but the extent that patients with BM may display extended survival with combination radiation- and immunotherapy-based approaches remains unclear. Methods: We identified 160 patients harboring non-squamous NSCLC with 486 newly-diagnosed BM between 2015-2023 managed with brain-directed radiation (either stereotactic-based, SRT or whole brain radiation therapy, WBRT) and immune checkpoint inhibition within 3 months of radiation at Dana-Farber Cancer Institute/Brigham and Women’s Hospital (Boston, MA). PD-L1 tumor expression was categorized as <1%, 1-49%, 50-89%, and ≥90% based on immunohistochemistry. TMB was assessed via targeted next-generation sequencing. Cox-proportional hazards regression was used to assess all-cause mortality while Fine-Gray competing risks regression was used to assess other time-to-event based outcomes. Results: The median number of BM was 3 (IQR 1-7). Neurosurgical resection in advance of radiation was performed in 51/160 (32%) pts. SRT was used in 130/160 (81%) versus 30/160 (19%) patients treated with WBRT, respectively. Median follow-up time was 30.1 months (mo). Higher PD-L1 expression was associated with significantly longer overall survival (OS) with a median survival in patients with PD-L1<1%, 1-49%, 50-89% and ≥90% being 11.8, 14.4, 29.5 and 33.1 months, respectively (Table). Similarly, time to systemic death (TTSD) was longer in patients with higher PD-L1 expression, while time to neurologic death (TTND) was not different across categories. Higher TMB (≥10 vs. <10 mutations/megabase) was not associated with significantly longer OS, TTSD or TTND. Conclusions: Higher PD-L1 tumor expression was associated improved all-cause mortality, largely driven by reduction in systemic death. A significant percentage of patients with a very high PD-L1 displayed long-term survival, highlighting the potential importance of multimodality therapy in such patients, and demonstrating that clinicians should be cognizant of treatment-associated long-term toxicities in this population. Outcomes OS TTSD TTND PD-L1 groups Median (mo) p Median (mo) p Median (mo) p <1% 11.8 [8.0-17.2] Ref. 22.7 [16.8-NR] Ref. 7.2 [5.2-9.6] Ref. 1-49% 14.4 [12.6-35.3] 0.17 29.3 [19.6-NR] 0.44 7.3 [5.8-9.5] 0.087 50-89% 29.5 [17.0-NR] 0.043 NR [17.5-NR] 0.039 11.0 [6.0-20.7] 0.67 ≥90% 33.1 [17.8-NR] 0.026 61.7 [40.6-NR] 0.040 10.8 [8.5-28.3] 0.10 TMB <10 17.5 [15.0-22.3] Ref. 19.2 [16.6-49.6] Ref. 7.7 [6.0-9.0] Ref. ≥10 23.0 [17.7-36.0] 0.56 40.9 [36.0-NR] 0.17 9.7 [6.1-15.4] 0.74