First-line pembrolizumab plus chemotherapy versus bevacizumab plus chemotherapy in response and survival outcomes in PD-L1-negative advanced non-squamous NSCLC: a retrospective comparative cohort study.

BACKGROUND: Direct real-world comparisons of pembrolizumab plus chemotherapy and bevacizumab plus chemotherapy in programmed cell death ligand 1 (PD-L1)-negative advanced non-squamous non-small cell lung cancer (NSCLC) are limited. We compared response, survival, safety, and blood biomarkers between these regimens. METHODS: This single-center retrospective cohort included 160 patients treated at Shanghai Chest Hospital from May 2017 to October 2023: 76 received pembrolizumab plus platinum-pemetrexed chemotherapy and 84 received bevacizumab plus the same chemotherapy backbone. Eligibility required advanced non-squamous NSCLC, PD-L1 tumor proportion score <1%, no actionable driver alteration, Eastern Cooperative Oncology Group performance status 0-1, at least two treatment cycles, and complete data. Laboratory time points were defined as T0 (within 1 week before treatment) and T2 (after two treatment cycles); objective response rate (ORR) and disease control rate (DCR) were assessed after two treatment cycles. Cutoffs were selected using X-tile. Treatment-group Cox models adjusted for age, sex, smoking, stage, metastatic sites, baseline lactate dehydrogenase (LDH), and prognostic nutritional index (PNI); regimen-specific models included variables with univariable P<0.10. RESULTS: The pembrolizumab cohort was older and included more men and patients with lung metastases. At the two-cycle response assessment, ORR (35.5% vs. 33.3%, P=0.77) and DCR (92.1% vs. 90.5%, P=0.72) did not differ significantly; median progression-free survival was also not significantly different [PFS; 8.8 vs. 9.9 months; adjusted hazard ratio (HR) 1.15, 95% confidence interval (CI): 0.80-1.68; P=0.45]. Median overall survival (OS) was 23.2 versus 20.8 months, in the pembrolizumab group and the bevacizumab group, respectively (P=0.04); adjusted mortality was lower with pembrolizumab plus chemotherapy (HR 0.58, 95% CI: 0.39-0.88; P=0.01). Documented grade ≥3 treatment-related adverse events occurred in 34.2% versus 44.0% in the pembrolizumab group and the bevacizumab group, respectively (P=0.20). In the pembrolizumab cohort, higher baseline LDH (>155 U/L) and ΔLDH (>501 U/L) were independently associated with shorter PFS, whereas higher PNI at T2 (>41.5) was associated with longer PFS; higher PNI at T0 (>47) and T2 (>39.5) were independently associated with longer OS. In the bevacizumab cohort, higher baseline LDH (>255 U/L for PFS; >250 U/L for OS) was independently associated with worse outcomes, whereas higher PNI at T2 (>47) was associated with longer PFS and higher PNI at T0 (>48) and T2 (>44) were associated with longer OS. CONCLUSIONS: In this retrospective non-randomized cohort, pembrolizumab plus chemotherapy and bevacizumab plus chemotherapy showed no statistically significant differences in response or PFS, whereas pembrolizumab plus chemotherapy was associated with longer adjusted OS. LDH and PNI provided complementary prognostic information, particularly early on-treatment PNI, supporting further evaluation of these routinely available markers for dynamic risk assessment. Prospective multicenter studies are needed to confirm the treatment association and biomarker thresholds.