Baseline tumor size as prognostic index in patients with cancer receiving experimental targeted agents

Background: Several studies showed that high baseline tumor size (BTS) is associated with worse outcomes in cancer patients treated with immunotherapy (IO). However, the prognostic impact of BTS for patients receiving targeted therapies (TT) remains uncertain. Methods: We collected clinical data for patients with solid tumors consecutively treated within early phase trials at our institution from 01/2014 to 04/2021. Treatments were categorized as IO-based (if any IO-agent was included) or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST 1.1 baseline target lesions. Progression-free survival (PFS), overall survival (OS) and objective-response rate (ORR) were compared between patients with high BTS (> median) and low BTS (≤median). Results: 444 patients were eligible for the analysis (220 IO, 151 TT biomarker-matched, 73 TT biomarker-unmatched). Median age was 56 years (interquartile range, IQR 48-64) and median BTS was 69 mm (IQR 40-100). Most represented tumor types were breast (49%), lung (9%), melanoma (5%) stomach, colorectal, head and neck and ovarian (4% each). Patients with low BTS were more often female (p < 0.001), had a better performance status (PS, p = 0.008), lower LDH (p < 0.001), lower neutrophile/lymphocyte ratio (NLR, p < 0.001) and higher albumin (p = 0.003). OS was significantly longer for patients with low BTS (16.6 vs 8.2 months, p < 0.001), including when restricting at those receiving IO (12 vs 7.5 months, p = 0.005). Among patients receiving TT, those with lower BTS experienced longer PFS (4.7 vs 3.1 months, p = 0.002) and OS (20.5 vs 9.9 months, p < 0.001) as compared with those with high BTS. However, BTS was only prognostic among patients receiving biomarker-matched TT, with improved PFS (6.2 vs 3.3 months, p < 0.001) and OS (21.2 vs 6.7 months, p < 0.001) in the low-BTS subgroup, despite a similar ORR (28% vs 22%, p = 0.57). BTS was instead not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs 4.4 months, p = 0.30), OS (19.3 vs 11.8 months, p = 0.20) and ORR (33% vs 28%, p = 0.78) in the two BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (p = 0.03) and OS (p < 0.001) but not with ORR (p = 0.11), regardless of tumor site, treatment category, PS, NLR, sites of metastases and number of prior lines. Conclusions: Patients receiving biomarker-matched TT experience longer PFS and OS if having a lower BTS, whereas response rate is not affected by this variable. This difference may reflect the faster emergence of molecular mechanisms of resistance among patients with higher baseline burden. Lower BTS is also confirmed to be associated with longer survival among patients receiving experimental IO. BTS has instead no prognostic value among patients receiving unmatched TT.