Angiogenesis Inhibitor Misses Overall Survival Mark in Advanced Head and Neck Carcinoma

Charles Bankhead

Head and Neck Cancer

Chicago, IL—The addition of bevacizumab to chemotherapy for recurrent or metastatic head and neck cancer failed to improve overall survival (OS) versus chemotherapy alone, despite exceeding pretrial projections, as reported at the 2017 ASCO annual meeting.

Patients who received platinum-based chemotherapy plus the angiogenesis inhibitor had a median OS of 12.6 months versus 11 months for chemotherapy alone. Investigators had estimated that the chemotherapy arm would have a median OS of 8.5 months.

The bevacizumab arm had significantly better progression-free survival (PFS) and better OS at 2-, 3-, and 4-year landmark analyses, said Athanassios Argiris, MD, PhD, FACP, Professor, Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA.

“The better survival in the control group might be explained by many factors, including better supportive care, patient selection—particularly the bevacizumab-specific eligibility criteria—the rising HPV positivity, the chemotherapy regimens we used, and the effect of second-line therapy. Bevacizumab did improve progression-free survival and response rate. A biomarker analysis is pending,” said Dr Argiris.

“We believe that targeting of the VEGF pathway should continue to be a subject of investigation in head and neck cancer,” he added.

Recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN) has a poor prognosis, and most patients receive palliative treatment. Platinum-based chemotherapy remains the standard of care and is associated with a median OS of 6 to 9 months and a 2-year OS of <15%, said Dr Argiris.

Among targeted therapies, only cetuximab demonstrated a benefit in the first-line setting for recurrent or metastatic SCCHN. The addition of cetuximab to platinum-based chemotherapy improved OS over chemotherapy, resulting in a median OS of 10.1 months and a 2-year OS of 14% (Vermorken JB, et al. N Engl J Med. 2008;359:1116-1127).

High levels of VEGF (the target of bevacizumab) correlate with worse survival in SCCHN. A preliminary study of pemetrexed and bevacizumab as first-line treatment for recurrent or metastatic SCCHN resulted in a median OS of 11.3 months.

“We hypothesized that the addition of bevacizumab to standard platinum-based chemotherapy would improve survival in the first-line treatment of recurrent or metastatic head and neck cancer,” said Dr Argiris.

Study Design

Investigators in the randomized, phase 3 clinical trial enrolled patients with previously untreated recurrent or metastatic SCCHN. Patients received 1 of 4 platinum-based chemotherapy doublets (physician’s choice) with or without bevacizumab. Patients could discontinue chemotherapy after 6 cycles if they attained maximum response. Bevacizumab continued until disease progression or the development of unacceptable toxicity.

The primary end point was OS. The secondary objectives included toxicity, objective response rate, PFS, and correlative studies of blood and tissue samples. Investigators assumed a median OS of 8.5 months with chemotherapy alone and that the addition of bevacizumab would improve OS by 35%, to a median of 11.5 months.

The investigators enrolled 403 patients, who had a median follow-up of 23 months. In both treatment arms, 87% to 88% of patients received docetaxel paired with cisplatin or carboplatin. The 2 groups were balanced with respect to site of the primary tumor, which was the oral cavity in 20% to 22% of patients, oropharynx in 38% to 42%, and larynx in 23%.

More than 80% of the patients had previous radiotherapy, and approximately 60% had received chemotherapy outside the setting of recurrent or metastatic disease. Approximately 15% of patients had previous treatment with cetuximab.

The primary analysis showed a nonsignificant 16% reduction in the survival hazard for the bevacizumab arm (95% confidence interval, 0.67-1.05; P = .13). Landmark survival analyses favored the bevacizumab arm, and the relative difference between groups increased with each year of follow-up (26% vs 18% at 2 years, 16% vs 8% at 3 years, and 13% vs 6% at 4 years). A subgroup analysis generally favored bevacizumab for all prespecified groups.

The addition of bevacizumab to chemotherapy significantly improved median PFS from 4.4 months to 6.1 months (P = .0012). Similar to OS, the landmark PFS analyses favored bevacizumab at 2 (7% vs 2%), 3 (6% vs 0.7%), and 4 years (5% vs 0.7%). In addition, significantly more patients had objective responses with bevacizumab (36% vs 25%; P = .013).

The bevacizumab arm had more grade 3/4 neutropenia (38% vs 27%), febrile neutropenia (18% vs 9%), fatigue (18% vs 10%), diarrhea (5% vs 1%), dysphagia (5% vs 1%), oral mucositis (19% vs 4%), dehydration (16% vs 5%), hypertension (6% vs 0%), bleeding (6.7% vs 0.5%), and thromboembolic events (6% vs 1%; P <.05).