Induction chemotherapy followed by chemoradiotherapy with cisplatin or cetuximab for unresectable locally advanced head and neck cancer (TTCC-2007-01 trial): Analysis of genomic biomarkers by next-generation sequencing after long-term outcomes.

Abstract

6054 Background: Induction chemotherapy (ICT) may provide survival benefit in some patients (pts) with unresectable locally advanced squamous head and neck carcinoma (LA-SCCHN). Objective: Study the benefit of ICT followed by radiotherapy plus cetuximab versus (vs) cisplatin (RT/CET vs RT/CDDP) by profiling predictor biomarkers of response from pts of TTCC-2007-01 trial (NCT00716391). Methods: Design TTCC-2007-01: studied the non-inferiority of RT/CET (70Gy + 400mg/250mg/m2 weekly) vs RT/CDDP (70Gy + 100mg/m2 d1-22-43) after ICT (docetaxel 75mg/m2 + platinum 75mg/m2 + 5-FU 750mg/m2 d1-5) in unresectable LA-SCCHN (Oral Oncology, 2022 Nov:134:106087). A cohort of samples were analyzed after DNA extraction and processed using OncoScan platform and TruSight Panel (next-generation sequencing). Survival analysis was performed using Kaplan-Meier (log-rank or Breslow test, survival in months ‘m’) and Cox regression (HR 95% CI). Statistical significance was p<0.05 (SPSSv28). Results: In total, 70 pts (male 90% / female 10%) were analyzed in RT/CDDP arm (mean age 55 [45-68]) versus 72 pts (male 88,9% / female 11.1%) in RT/CET arm (mean age 60 [32-70]). The most frequent localizations in RT/CDDP arm were oropharynx (44.3%) and hypopharynx (21.4%). In RT/CET were oropharynx (37,5%) and hypopharynx (23,6%). In RT/CDDP arm HPV was positive in 17.1% of tumors versus 13,1% in RT/CET. In RT/CDDP arm the median overall survival (OS) was 65m [25.6-105.4] vs 36.8m [14.3-59.2] in the RT/CET arm. The progression-free survival (PFS) was 33.2m [16.2-50-1] in the RT/CDDP arm vs 18.3m [9.1-28.6] in the RT/CET arm. TP53 was the most frequent mutation without differences in OS in either arm. However, mutations were associated with unfavorable PFS in the RT/CDDP arm (22.6 vs 66.2; p=0.025 Breslow), with no difference in RT/CET arm (20.1 vs 15.2; p=0.885 Breslow). HPV+ tumors were associated with better OS (83.9 vs 33.2; p=0.027 Breslow) in RT/CDDP arm. There was no difference in the RT/CET arm (28.1 vs 23.9; p>0.05). In the RT/CDDP arm the chromosomal biomarker that was associated with worse OS was 18q12.2- (22.7 vs 85.6; HR 3.3 [1.6-6.6]). Focal alterations 3p14.2- had superior OS (83.9 vs 22.9m; HR 0.1 [0.04-0.30]). In the RT/CET arm the 6p25.3+ biomarker was associated with superior OS (not reached vs 26.6m; HR 0.42 [0.2-0.8]). In terms of PFS in RT/CDDP arm, gains in 2p were associated with worse PFS (12.0 vs 41.7m; HR 2.9 [1.4-6.2]). 6p25.3+ alterations had better PFS in the RT/CET arm (38.8 vs 11.5; HR 0.40 [0.2-0.8]). Conclusions: ICT plus RT/CDDP was shown most beneficial in pts with TP53 wild type, HPV+ and 3p14.2-. In contrast, ICT plus RT/CET is not influenced by TP53 or HPV. 6p25.3+ is a robust biomarker of response in RT/CET arm in terms of OS and PFS. Correct pts selection may allow for further standardization of ICT in LA-SCCHN.