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‘No compelling rationale’ to develop triplet regimen for recurrent, metastatic SCCHN
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The addition of pemetrexed to cisplatin and cetuximab did not extend survival in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, according to results of a phase 2 study.
Grade 3 and grade 4 toxicities associated with the triplet regimen were consistent with standard treatment, but the rate of treatment-related deaths were higher than anticipated, researchers wrote.
Jan B. Vermorken
“As such, there is no compelling rationale to further develop this combination for treatment of recurrent/metastatic SCCHN,” Jan B. Vermorken, MD, PhD, of Antwerp University Hospital in Belgium, and colleagues wrote.
Cisplatin and cetuximab (Erbitux, Eli Lilly) represent a standard systemic treatment for recurrent or metastatic SCCHN. In prior studies, pemetrexed (Alimta, Eli Lilly) demonstrated single-agent activity in this population. The addition of pemetrexed to cisplatin also has shown efficacy in other malignancies, including non–small cell lung cancer.
Vermorken and colleagues conducted the current study to determine whether the addition of pemetrexed to cisplatin and cetuximab would improve outcomes in patients with recurrent or metastatic SCCHN.
Eligibility criteria included adequate organ function and ECOG performance status of 0 or 1. Patients with locoregionally advanced disease who underwent two or more previous regimens, and patients with metastatic disease who underwent prior systemic therapy, were excluded.
Patients received an intravenous loading dose of cetuximab 400 mg/m2, followed by weekly cetuximab 250 mg/m2. Patients received pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 on day 1 of each 21-day cycle. Patients also received vitamin B12, folic acid and prophylactic medications.
Patients underwent treatment for up to six cycles. After at least four cycles, patients who demonstrated response were eligible for maintenance with pemetrexed and cetuximab, or with either agent as monotherapy, until toxicity or progression.
PFS served as the primary endpoint.
Sixty-six patients (median age, 62 years) underwent at least one cycle. Most were men (80.3%) and had ECOG performance status of 1 (71.2%). Nearly half of patients (48.5%) had distant metastases.
The triplet regimen demonstrated efficacy comparable to the standard treatment, but median PFS in the cohort (4.4 months; 95% CI, 3.6-5.4) fell short of the prespecified target of 5.5 months. Median OS was 9.7 months (95% CI, 6.5-13.1).
Researchers reported a 29.3% overall response rate with one complete response (1.7%) and 16 partial responses (27.6%). Twenty-three patients (39.7%) demonstrated stable disease, and the disease control rate was 69%.
“Our efficacy results compare favorably with those from [a previous] study evaluating pemetrexed and cisplatin without cetuximab, which demonstrated a median PFS of 3.6 months and a median OS of 7.3 months,” Vermorken and colleagues wrote. “Our results also compare favorably with efficacy results in other randomized studies using cisplatin-based chemotherapy without cetuximab, underscoring the potential benefit of cetuximab in this population.”
The response rate among the 16 patients with disease originating from the larynx was 40%. Those patients experienced longer median PFS (5.2 months vs. 4.4 months) and median OS (20.8 months vs. 8.5 months; HR=0.44; 95% CI, 0.20-0.95) than the 50 patients with disease originating from other sites.
“The results observed in the larynx subgroup are intriguing,” Vermorken and colleagues wrote. “Survival analyses are limited by sample size and a censoring rate of 43.8%, [so they] should be interpreted with caution.”
Eight patients (12.1%) died during the study period. Five of those deaths (7.6% of study population) may have been related to treatment, according to researchers. They included two deaths from respiratory failure associated with aspiration pneumonia, one from respiratory failure and septic shock, one from respiratory failure and tumor emboli, and one from an unknown cause.
Researchers reported five treatment-related deaths (7.6%). Neutropenia (33.3%) was the most common grade 3 and grade 4 drug-related toxicity, followed by fatigue (24.2%), anorexia (12.1%) and infection (10.6%).
Disclosure: The researchers report research or honoraria from, employment relationships and consultant/advisory roles with, and stock ownership in Amgen, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Genentech, GlaxoSmithKline, Merck-Serono and other pharmaceutical companies.
Perspective
Back to TopBarbara Burtness, MD
The authors report a phase 2 trial of pemetrexed with cisplatin and cetuximab in metastatic/recurrent head and neck cancers in an unselected patient population. The response rate, time to progression and OS are numerically somewhat lower than achieved in past studies with cisplatin doublets and cetuximab — and, in fact, quite similar to previously reported results with cisplatin and cetuximab alone in the ECOG study E5397. On the other hand, the treatment-related mortality seemed high. Prior studies with pemetrexed for head and neck cancers have, in general, been disappointing, including two prior negative phase 3 trials, low response rates in combination with gemcitabine (Gemzar, Eli Lilly), and a monotherapy response rate of 3% in nasopharynx cancer. Further study of pemetrexed in head and neck cancers would be difficult to defend in the absence of a powerful predictive biomarker.
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