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Afatinib improves progression-free survival in subtypes of head and neck squamous cell carcinoma
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Multiple biomarkers predicted subgroups of patients with head and neck squamous cell carcinoma most likely to benefit from second-line afatinib, according to findings from a phase 3 trial.
“Patients with recurrent and/or metastatic head and neck squamous cell carcinoma who have progressed on/after platinum-based therapy have poor prognosis and few effective treatment options,” Ezra E. W. Cohen, MD, associate director of the Moores Cancer Center at the University of California, San Diego, and colleagues wrote. “While some molecular biomarkers have been associated with HNSCC prognosis, none are validated to predict treatment response, particularly to EGFR-targeted therapy.”
The researchers 483 patients with recurrent or metastatic to either 40 mg per day of afatinib or 40 mg/m2 per week of methotrexate. All patients had previously at least 2 cycles of platinum therapy. Cohen and colleagues obtained tumor and serum samples from 326 patients who volunteered for biomarker analysis at the beginning of the study, and evaluated the associations between specific biomarkers and patient outcomes.
Compared with methotrexate, afatinib improved median PFS in patients with several biomarkers: p16-negative disease (2.7 vs 1.6 months; HR = 0.7; 95% CI, 0.5-0.97); EGFR-amplified (2.8 vs. 1.5 months; HR = 0.53; 95% CI, 0.33-0.85); HER3-low (2.8 vs. 1.8 months; HR = 0.57; 95% CI, 0.37-0.88) and PTEN-high tumors (1.6 vs. 1.4 months; HR = 0.55; 95% CI, 0.29-1.05).
Two combined subsets of patients also demonstrated improved PFS with afatinib: patients with p16-negative and EGFR-amplified tumors (2.7 vs. 1.5 months; HR = 0.47; 95% CI, 0.28-0.8), as well as those with p16-negative tumors who did not receive EGFR therapy (4 vs. 2.4 months; HR = 0.55; 95% CI, 0.31-0.98).
Patients whose serum tested “good” with a VeriStrat test showed an improved PFS compared with those who tested “poor” (2.7 vs. 1.5 months; HR = 0.71; 95% CI, 0.49-0.94); however, researchers did not observe any treatment interaction. Afatinib demonstrated a superior response to methotrexate in all subsets except for patients with p16-positive disease (n = 35).
“This exploratory biomarker analysis of second-line recurrent or metastatic head and neck squamous cell carcinoma...preliminarily identified subgroups of patients with tumors reflecting alterations in p16 expression (p16-negative), and ErbB- and P13K-pathway dysregulation (EGFR-amplified, HER3-low, PTEN-high), who may achieve increased benefit with afatinib versus methotrexate,” the researchers wrote. “Future studies are warranted to define assessment methodologies for these biomarkers, including relevance to the cut-offs, and provide more robust analysis of biomarker association with clinical outcomes.” – by Andy Polhamus
Disclosure : Cohen and colleagues report consulting or advisory roles with AstraZeneca, Bayer, Bristol-Myers Squibb, Esai, Merck and Novartis, as well as speaking fees from Bayer and Eisai. Please see the study for a list of all other researchers’ relevant financial disclosures.
Perspective
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This article reports an analysis of tumor biomarkers and clinical endpoints for patients with squamous cell carcinoma of the head and neck participating in the phase III LUX-Head & Neck 1 study. The primary study compared the irreversible ErbB family inhibitor, afatinib (Gilotrif, Boehringer Ingelheim), to methotrexate in the second-line systemic therapy setting, and demonstrated a modest improvement in PFS (2.6 months vs. 1.7 months, HR = 0.8, P = 0.03) with Afatinib.
Of the 483 patients randomized in the primary study, 326 patients (67%) had archival tumor tissue collected. The majority (80%) of the tissue was from the primary tumor site, followed by 14% from regional disease and 4% from distant metastatic lesions. Analysis of six prespecified biomarkers was performed on the tumor specimens, including p16, EGFR, HER-2, HER-3, PTEN, and c-MET. Overall response rate favored afatinib over methotrexate in almost all biomarker subgroups. Afatinib also improved median PFS in tumors that were p16 negative, EGFR amplified or HER-3 low disease.
Platinum-resistant recurrent and/or metastatic HNSCC remains a management challenge. The results of the LUX-Head & Neck 1 study and this subsequent biomarker analysis show that Afatinib may have greater benefit for certain subgroups, including patients with p16-negative tumors and those with EGFR amplification. Overall benefit of Afatinib, even with biomarker selection, remains modest. The role of anti-EGFR therapy in the era of checkpoint inhibition is under evaluation. The results of this study add to the understanding of the diversity of HNSCC and the importance of tumor collection for research. The results can be used for hypothesis generation to improve further treatment for this difficult disease.
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