The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: There is a significant need to find biomarkers of response to radiotherapy and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC) and biomarkers that predict altered immunity, thereby enabling personalized treatment.

Objectives: To examine whether the Kirsten rat sarcoma viral oncogene homolog (KRAS)-variant, a germline mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiotherapy and cisplatin treatment and to evaluate the interaction of the KRAS-variant with p16 status and blood-based transforming growth factor β1 (TGF-β1).

Design, setting, and participants: A total of 891 patients with advanced HNSCC from a phase 3 trial of cisplatin plus radiotherapy with or without cetuximab (NRG Oncology RTOG 0522) were included in this study, and 413 patients with available samples were genotyped for the KRAS-variant. Genomic DNA was tested for the KRAS-variant in a CLIA-certified laboratory. Correlation of the KRAS-variant, p16 positivity, outcome, and TGF-β1 levels was evaluated. Hazard ratios (HRs) were estimated with the Cox proportional hazards model.

Main outcomes and measures: The correlation of KRAS-variant status with cetuximab response and outcome, p16 status, and plasma TGF-β1 levels was tested.

Results: Of 891 patients eligible for protocol analyses (786 male [88.2%], 105 [11.2%] female, 810 white [90.9%], 81 nonwhite [9.1%]), 413 had biological samples for KRAS-variant testing, and 376 had plasma samples for TGF-β1 measurement. Seventy patients (16.9%) had the KRAS-variant. Overall, for patients with the KRAS-variant, cetuximab improved both progression-free survival (PFS) for the first year (HR, 0.31; 95% CI, 0.10-0.94; P = .04) and overall survival (OS) in years 1 to 2 (HR, 0.19; 95% CI, 0.04-0.86; P = .03). There was a significant interaction of the KRAS-variant with p16 status for PFS in patients treated without cetuximab. The p16-positive patients with the KRAS-variant treated without cetuximab had worse PFS than patients without the KRAS-variant (HR, 2.59; 95% CI, 0.91-7.33; P = .07). There was a significant 3-way interaction among the KRAS-variant, p16 status, and treatment for OS (HR, for KRAS-variant, cetuximab and p16 positive, 0.22; 95% CI, 0.03-1.66; HR for KRAS-variant, cetuximab and p16 negative, 1.43; 95% CI, 0.48-4.26; HR for KRAS-variant, no cetuximab and p16 positive, 2.48; 95% CI, 0.64-9.65; and HR for KRAS-variant, no cetuximab and p16 negative, 0.61; 95% CI, 0.23-1.59; P = .02). Patients with the KRAS-variant had significantly elevated TGF-β1 plasma levels (median, 23 376.49 vs 18 476.52 pg/mL; P = .03) and worse treatment-related toxic effects.

Conclusions and relevance: Patients with the KRAS-variant with HNSCC significantly benefit from the addition of cetuximab to radiotherapy and cisplatin, and there is a significant interaction between the KRAS-variant and p16 status. Elevated TGF-β1 levels in patients with the KRAS-variant suggests that cetuximab may help these patients by overcoming TGF-β1-induced suppression of antitumor immunity.

Trial registration: clinicaltrials.gov Identifier: NCT00265941.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Weidhaas reports being a coinventor of the discovery of the KRAS-variant, which has been patented by Yale University, and licensed to a company that she cofounded, MiraDx. Dr Ferris reported serving on advisory boards for Amgen, AZ-Medimmune, BMS, Lilly, and Merck. Dr Chung reported serving on the Scientific Advisory Board for BMS and Lilly Oncology. No other disclosures were reported.

Figures

Figure 1.. Progression-Free Survival and Overall Survival for Patients With Head and Neck Squamous Cell Carcinoma by KRAS-Variant Status and Assigned Treatment

A, Progression-free survival (PFS). In total, 179 of 413 patients (43.3%) experienced a PFS failure: 19 of 38 (50.0%) in the non–cetuximab-treated KRAS-variant group, 13 of 32 (40.6%) in the cetuximab-treated KRAS-variant group, 74 of 169 (43.8%) in the non–cetuximab-treated nonvariant group, and 73 of 174 (42.0%) in the cetuximab-treated nonvariant group. B, Overall survival. In total, 134 of 413 patients (32.4%) have died: 14 of 38 (36.8%) in the non–cetuximab-treated KRAS-variant group, 8 of 32 (25.0%) in the cetuximab-treated KRAS-variant group, 58 of 169 (34.3%) in the non–cetuximab-treated nonvariant group, and 54 of 174 (31.0%) in the cetuximab-treated nonvariant group.

Figure 2.. Progression-Free Survival and Overall Survival by KRAS Genotype and p16 Status for Patients Treated Without or With Cetuximab Treatment

A, Progression-free survival. There is a significant 2-way interaction between KRAS-variant status and p16 in patients treated without cetuximab (P = .04). B, Overall survival. There is a significant 3-way interaction among cetuximab treatment, KRAS-variant status, and p16 status (P = .02).