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. 2022 Jul 1;28(13):2771-2778.
doi: 10.1158/1078-0432.CCR-21-2386.

Predictive Biomarkers of Overall Survival in Patients with Metastatic Renal Cell Carcinoma Treated with IFNα ± Bevacizumab: Results from CALGB 90206 (Alliance)

Andrew B Nixon #  1 , Susan Halabi #  2 , Yingmiao Liu  1 , Mark D Starr  1 , John C Brady  1 , Ivo Shterev  2   3 , Bin Luo  2 , Herbert I Hurwitz  4 , Phillip G Febbo  3 , Brian I Rini  5 , Himisha Beltran  6 , Eric J Small  7 , Michael J Morris  8 , Daniel J George  1
Affiliations

Predictive Biomarkers of Overall Survival in Patients with Metastatic Renal Cell Carcinoma Treated with IFNα ± Bevacizumab: Results from CALGB 90206 (Alliance)

Andrew B Nixon et al. Clin Cancer Res. .

Abstract

Purpose: CALGB 90206 was a phase III trial of 732 patients with metastatic renal cell carcinoma (mRCC) comparing bevacizumab plus IFNα (BEV + IFN) with IFNα alone (IFN). No difference in overall survival (OS) was observed. Baseline samples were analyzed to identify predictive biomarkers for survival benefit.

Patients and methods: A total of 32 biomarkers were assessed in 498 consenting patients randomly assigned into training (n = 279) and testing (n = 219) sets. The proportional hazards model was used to test for treatment arm and biomarker interactions of OS. The estimated coefficients from the training set were used to compute a risk score for each patient and to classify patients by risk in the testing set. The resulting model was assessed for predictive accuracy using the time-dependent area under the ROC curve (tAUROC).

Results: A statistically significant three-way interaction between IL6, hepatocyte growth factor (HGF), and bevacizumab treatment was observed in the training set and confirmed in the testing set (P < 0.0001). The model based on IL6, HGF, and bevacizumab treatment was predictive of OS (P < 0.001), with the high- and low-risk groups having a median OS of 10.2 [95% confidence interval (CI), 8.0-13.8] and 34.3 (95% CI, 28.5-40.5) months, respectively. The average tAUROC for the final model of OS based on 100 randomly split testing sets was 0.78 (first, third quartiles = 0.77, 0.79).

Conclusions: IL6 and HGF are potential predictive biomarkers of OS benefit from BEV + IFN in patients with mRCC. The model based on key biological and clinical factors demonstrated predictive efficacy for OS. These markers warrant further validation in future anti-VEGF and immunotherapy in mRCC trials. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725.

Trial registration: ClinicalTrials.gov NCT00072046.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest: A.B. Nixon has received research funding from Genentech, HTG Molecular Diagnostics, MedImmune/AstraZeneca, Medpacto, Promega Corporation, Seattle Genetics; and has received consultant/advisory compensation from AdjuVolt Therapeutics, Eli Lilly, GSK, Leap Therapeutics, Promega Corporation. H.I. Hurwitz declares ownership of Roche stock. H. Beltran has served as consultant/advisory board member for Janssen, Astellas, Astra Zeneca, Merck, Pfizer, Foundation Medicine, Blue Earth Diagnostics, Amgen, and has received research funding (inst) from Janssen, AbbVie/ Stemcentrx, Eli Lilly. E.J. Small has received consultant/advisory compensation from Janssen, Fortis, Teon Therapeutics, Ulragenyx, Beigene, Tolero; and declares ownership of Fortis Therapeutics and Harpoon Therapeutics stocks. D.L. George has received consultant/advisory compensation from Astellas, Astrazeneca, Axess Oncology, Bayer H/C Pharmaceuticals, BMS, Capio Biosciences, Constellation Pharmaceuticals, EMD Serono, Exelixis Inc., Flatiron, Ipsen, Janssen Pharmaceuticals, Merck Sharp & Dohme, Michael J Hennessey Associates, Modra Pharmaceuticals B. V., Myovant Sciences, Nektar Therapeutics, Physician Education Resource LLC, Pfizer, Propella TX, Rev Health LLC, Sanofi, UroGPO; and has received research funding from Astrazeneca, BMS, Calithera, Exelixis Inc., Janssen Pharmaceuticals, Novartis, Pfizer, Sanofi. The other authors declare no potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Patients CONSORT diagram.
Figure 2.
Figure 2.
Kaplan-Meier plots showing the univariate predictive value of IL-6 (A) and HGF (B) by treatment arm in the training set of patients.
Figure 3.
Figure 3.
Kaplan-Meier plots showing the multivariable predictive value for overall survival benefit by IL-6 and HGF in the IFN (A) and BEV+ IFN (B) arms in the training set of patients.
Figure 4.
Figure 4.
The risk score model predicting overall survival in the testing set.
See this image and copyright information in PMC

Comment in

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