First line cetuximab and cisplatin with or without paclitaxel in recurrent/metastatic head and neck cancer: A randomized phase IIb trial

Background: Cisplatin (Cis), continuous infusion 5FU and Cetuximab (Cet) (EXTREME) first-line treatment extends overall survival (OS) over Cis and 5FU of recurrent/metastatic squamous cell head and neck cancer (RM SCCHN) patients. In EXTREME, Cet has been added to a 2-drug combination, which has never shown superiority over any single drug. In this scenario, we are left with an open question about the significance of adding 1 or 2 drugs to biotherapy. In addition, a significant number of pts are excluded from EXTREME for the high incidence of ≥ G3 adverse events (AEs) (>80%), most of them attributable to 5FU. Paclitaxel (P) is active and safe, both alone and with Cis. We conducted a phase IIb trial comparing a 2-drug Cet-Cis regimen with a 3-drug combination (substituting 5FU with P) in terms of progression-free survival (PFS) and tolerability. Methods: Eligible pts had confirmed untreated R/M SCCHN. Pts were randomized to a 3 vs. a 2-drug combination (Cet + Cis w/o P) with maintenance Cet after 6 cycles. Primary endpoint was PFS; secondary end-points were overall survival (OS), response rate (RR) and toxicity. We assumed a non-inferiority margin of 1.40 as compatible with efficacy. Results: 200 pts were randomized and 191 evaluable. Pt characteristics were balanced in the 2 arms. Inferiority hypothesis was rejected (upper limit of one-sided 90% CI of PFS hazard ratio<1.4). Median PFS was 6 and 7 mos (95% CI: 5-7 and 6-8 mos) in the 2 vs. 3-drug arms, respectively (p=NS), median OS was 13 and 11 mos (95% CI: 10-16 and 9-14 mos) (p=NS), and RR was 42% vs 52% (p=NS). Grade ≥ 3 AEs were 76% and 73% for the 2 vs 3-drug regimen, respectively. Skin rash and electrolyte alterations were mainly reported in the 2-drug arm, while haematological toxicities and infections in the 3-drug arm. No toxic death and sepsis were reported and cardiac events were negligible (1%). Conclusions: A 2-drug Cet and Cis regimen proved to be non-inferior in PFS to a 3-drug combination with Cet, Cis and P. The median OS of both regimens is comparable with the 10.1 mos in EXTREME, while life-threatening toxicity rate appeared reduced. These regimens warrant further investigation as a backbone to immunotherapeutic agents. Clinical trial identification: EudraCT: 2011-002564-24 Legal entity responsible for the study: Fondazione IRCCS Istituto Nazionale Tumori Milano Funding: Merck Serono Disclosure: All authors have declared no conflicts of interest.