Baseline circulating soluble factors as predictors of response to nivolumab in metastatic clear cell renal cell carcinoma (mRCC): A validation study within the NIVOREN GETUG-AFU 26 translational study.

Abstract

4552 Background: The NIVOREN GETUG-AFU 26 study launched a translational research program to quantify baseline circulating soluble factors levels and correlate them with outcomes to nivolumab in mRCC pts. We previously identified on a training set (n = 80, 40 responders/40 progressors) several soluble factors significantly associated with worse overall survival (OS), progression-free survival (PFS) and response (IL-8 and VEGF), or with worse OS only (IL-6, IL-7) (Carril-Ajuria et al. ASCO GU. 2022). Our aim was to confirm these findings using an independent validation set. Methods: The remaining pts (n = 233) included in the translational-program of the NIVOREN study were included in this validation set. Based on previous results (training set), a panel of 7 different soluble factors (VEGF, VCAM-1, IL-6, IL-7, IL-8, BAFF, CXCL13) were quantified for each plasma sample using the MSD electrochemiluminescence assay. The association between baseline soluble-factors levels and response, PFS and OS was evaluated using previously identified cut-off values. Results: Two hundred thirty-three pts were included in the validation set. Baseline characteristics were similar to the overall trial population. The IMDC risk score breakdown was 17.7% good, 57.3% intermediate and 25.0% poor. With a median follow-up of 21.8 months (mo), the OS rate was 69.6% at 12 mo and median PFS was 3.0 mo. IL-8 (cut-off: 17.9 pg/ml) and IL-6 (cut-off: 8.7 pg/ml), involved in inflammation, confirmed an association with worse OS (IL8: HR = 2.57, p < 0.0001, IL-6: HR = 3.28,p < 0.0001) and worse PFS (IL-8: HR = 1.61,p = 0.0008, IL-6: HR = 1.68, p = 0.0021). VEGF (cut-off: 48.3 pg/ml) confirmed the association with worse OS (HR = 1.56, p = 0.0176), but not with PFS (p = 0.2068). IL-7, involved in T and B cells development, did not show a significant association with OS or PFS when using 8.6 pg/ml (training set) as cut-off (p = 0.0675 and p = 0.7818, respectively). IL-7 was the only cytokine to show an association with response (p = 0.044). Interestingly, circulating CXCL13 (cut-off: 106.4 pg/ml) and BAFF (cut-off: 1122.6 pg/ml), involved in B cell differentiation/survival, were significantly associated with worse OS (HR = 2.09, p = 0.0001 and HR = 2.34, p = 0.0001, respectively); BAFF showed a trend for worse PFS (HR = 1.29, p = 0.0920). Conclusions: Using the cut-off values previously identified in the training set, we confirmed a significant association between baseline blood concentration of IL-6/IL-8 and worse OS/PFS, and of VEGF with worse OS. Non-responders presented lower baseline circulating IL-7 concentrations. CXCL13 and BAFF were significantly associated with worse OS. Multivariate analyses are ongoing.

Heterogeneity of tertiary lymphoid structures in cancer

“…A pilot study of metastatic RCC showed that tremelimumab with and without cryoablation increased TLS formation in patients with clear cell histology compared with baseline (196). In another study using nivolumab in patients with metastatic RCC, a significant enrichment of TLS was observed in responders rather than non-responders, showing a trend for improved outcomes (199). Similarly, Ho et al reported the results of a single-arm phase 1b trial of neoadjuvant cabozantinib and nivolumab in patients with locally advanced HCC.…”