PD-L1 expression in pulmonary sarcomatoid carcinoma and response to immunotherapy.
Authors: Hong Lingzhi , Di Federico Alessandro , Aminu Muhammad , Ricciuti Biagio , Alessi Joao Victor Machado , Rinsurongkawong Waree , Elamin Yasir Y , Sepesi Boris , Lewis Jeff , Gibbons Don Lynn , Vaporciyan Ara A. , Lee J. Jack , Le Xiuning , Heymach John , Wu Jia , Awad Mark M. , Zhang Jianjun , Vokes Natalie I 
Published: June 2024

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Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of poorly differentiated non-small cell lung cancer (NSCLC) with poor prognosis. Outcomes to immune checkpoint inhibitors (ICIs) in patients with PSC have been incompletely examined, nor have they been compared to other NSCLC histologies. Methods: This retrospective study included two cohorts from MDACC and DFCI with metastatic NSCLC treated with ICI alone or with chemotherapy. Patients were categorized by histology as PSC, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). We compared clinical and demographic characteristics between groups. Clinical progression-free survival (PFS), overall survival (OS), and best of response (BOR) were evaluated. BOR was further divided into responders (including partial and complete response) and non-responders (including stable and progressive disease). Results: A total of 1,515 patients from MDACC were included: 65 (4.3%) PSC, 1,138 (75.1%) LUAD, and 312 (20.6%) LUSC. PSC patients were more likely to be older and present with metastatic disease at diagnosis. PD-L1 expression was higher in PSC, with 71.7% having PD-L1 ≥50%. 19 out of 50 PSC patients (38%) treated with ICIs were responders, compared to 26.4% in LUAD and 21.8% in LUSC. In ICI-treated patients, median PFS (p=0.033) was 5.83 months (95%CI:2.9-22.67) in PSC, 7.5 (95%CI:6.97-8.17) in LUAD, and 6.13 (95%CI:5.23-7.23) in LUSC; median OS (p<0.001) was 33.4 (months, 95%CI:15.4-NA) in PSC, 27.6 (95%CI:25.3-30.3) in LUAD, and 18.2 (95%CI:14.6-21.9) in LUSC. Subgroup analysis showed no significant difference among histologies for patients with PD-L1 high expression in either PFS (p=0.16) or OS (p=0.23). In PSC patients, chemotherapy treatment alone had worse outcomes than treatment with ICIs; when added to ICIs, however, there was no difference between ICI-mono and ICI-chemotherapy. The DFCI cohort included 1,405 patients treated with ICI-mono or ICI-chemotherapy: 41 (2.9%) PSC, 1,296 (92.2%) LUAD, and 68 (4.8%) LUSC. As above, PSC patients had higher PD-L1 expression (65.9% PD-L1≥50%) and higher response rate (45.6%). In PSC patients, median PFS was 5.4 (months, 95%CI:3.5-14.37) and median OS was 11.7 (months, 95%CI:7.7-35.9), without significant difference compared to LUAD and LUSC. Across cohorts, PSC tumors were enriched for KRAS, MET, and TP53 mutations. There was no significant difference across histologies in tumor mutational burden or tumor-infiltrating lymphocytes (TIL) in the DFCI cohort, where this data was available. Conclusions: PSC is associated with higher PD-L1 expression and higher proportion of responders when treated with immunotherapy, with similar PFS and OS compared to LUAD and LUSC. Further investigation of the immune profile in PSC is needed to explore predictive factors of immunotherapy to optimize patient selection in clinical practice.