Standard first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is the EXTREME regimen of cetuximab, platinum chemotherapy (cisplatin or carboplatin), and 5-FU. While this regimen improves overall survival (OS) compared to chemotherapy alone (10.1 months vs 7.4 months, HR 0.80, P = .04), it is highly toxic and use is limited to fit patients who can tolerate the associated adverse events (AEs). In particular, 5-FU in this combination is difficult to administer and has been associated with severe AEs including cardiotoxicity. Thus, in clinical practice other combinations including taxane, platinum, and cetuximab are sometimes used even though these are not evidence-based approaches. There is a need to better characterize the benefit of these more tolerable regimens that can be used as an alternative to the EXTREME regimen in R/M SCCHN.
A randomized, phase IIB noninferiority Italian study (B490) compared the safety and efficacy of cetuximab plus cisplatin with or without paclitaxel as first-line treatment in 201 fit patients with R/M SCCHN. Inclusion criteria for the study were same as for the EXTREME trial, except that patients who previously received cetuximab for locally advanced disease were allowed to enroll (6%). The study met its primary endpoint of noninferior progression-free survival (PFS) for the two treatment arms. Median PFS for patients receiving the two drug regimen was 6 months, compared to 7 months for patients receiving the three drug regimen (HR 0.99, P = .906). There were no significant differences in overall response rate (ORR: 41.8% vs 51.7%; OR 0.69, P = .181) or OS (13 months vs 11 months; HR 0.77, P = .117) between the two arms.
While there were similar rates of grade ≥3 AEs between the two treatment arms (76% vs 72.5%), the two drug regimen was associated with significant reduction in grade 4 AEs (14% vs 33%; P = .015). There were no cases of treatment-related sepsis or death, and cardiac toxicity was negligible (1%).
In their discussion, the investigators highlighted that although cross-trial comparisons are challenging, these results indicate that substituting 5-FU in the EXTREME regimen with paclitaxel results not only in similar OS, but also in an increase of ORR by about 15% as well as a more favorable toxicity profile (including reduced cardiac toxicity). In addition, information about the noninferiority of both cetuximab/cisplatin and cetuximab/cisplatin/paclitaxel is valuable, as both regimens are already used for select patients based on better tolerability. The authors believe these regimens could be appropriate backbones for emerging immunotherapy combinations.