Zosia Chustecka

September 27, 2014

MADRID — The oral tyrosine kinase inhibitor afatinib (Gilotrif, Boehringer Ingelheim) has shown a modest benefit in patients with recurrent and metastatic head and neck cancer in a phase 3 trial presented here at the European Society for Medical Oncology (ESMO) Congress 2014.

Dr. Jean Paul Machiels

When these patients progress after initial treatment, they typically have a "dismal prognosis," with a medial overall survival of 3 to 6 months, commented lead author Jean Paul Machiels, MD, a medical oncologist at Cliniques Universitaires Saint-Luc in Brussels. "Frequently these patients have a relapse in the head and neck area, and this is responsible for many of the symptoms that are difficult to palliate: pain, breath disorder, and swallowing difficulties."

The LUX-H&N 1 study was conducted in 483 patients with incurable recurrent or metastatic head and neck squamous cell carcinoma whose cancer had progressed despite treatment with platinum-based therapy (cisplatin or carboplatin), and many patients (60%) had also received cetuximab. Median age was 60 years, 85% of the patients were male, and 80% were smokers.

"There is no established standard of care for these patients," Dr. Machiels noted. In the study, patients were randomized 2:1 to receive afatinib 40 mg/day orally or methotrexate 40 mg/m² per week.

The results show a significant improvement in progression-free survival (2.6 months with afatinib vs 1.7 months with methotrexate; hazard ratio, 0.80; P = .03), which was the primary end point, but there was no improvement in overall survival (6.8 months with afatinib vs 6 months with methotrexate), a secondary end point in this trial.

Afatinib also significantly delayed the deterioration of global health status, and significantly delayed the worsening of pain and swallowing when compared with methotrexate (all secondary end points; P ≤ .03). "These patients had less pain over time," Dr. Machiels noted.

"This is important," commented Giuseppe Curigliano, MD, who was moderating a press briefing at which these results were highlighted. This suggests that patients on afatinib had a better quality of life for the remainder of their time. "If you can delay symptoms, this is important," he said.

However, the effect on progression-free survival was small, not quite 1 month, and the clinical significance of this is "unclear," commented Tanguy Seiwert, MD, associate director of the head and neck program at the University of Chicago, who acted as discussant for the study. "It is hard to see how, by itself, this trial could lead to clinically meaningful use for patients or approval," he added.

There is a second trial in head and neck cancer patients under way, known as LUX-H&N 2, which is looking at afatinib as adjuvant therapy in patients with locally advanced disease.

Afatinib is already marketed for the treatment of nonsmall-cell lung cancer that tests positive for EGFR; it was approved in the United States in July 2013.

Making Progress in Head and Neck Cancer

Head and neck cancer is a neglected disease area, commented Dr. Curigliano. It "does not get enough attention from the scientific community because this group of patients often has severe comorbidities and social problems, such as alcoholism and tobacco use," Dr. Machiels said.

The only new drug for this indication, cetuximab (Erbitux), was first approved back in 2004, he said. Before that, there have been no new drugs for 4 decades, noted Dr. Seiwert.

Cetuximab is a monoclonal antibody targeting EGFR, and since its success in the EXTREME study (which showed an overall survival benefit and led to its approval), there has been a concentrated effort to develop other EGFR drugs for head and neck cancer.

The LUX-H&N 1 study with afatinib is only the second positive trial that has been reported, he noted, although he added that it was positive because the primary end point was progression-free survival. Another study, with zalutumumab (Genmab), had shown a similar effect on progression-free survival but is considered negative as its primary end point was overall survival, and this was not significantly improved (neither was it with afatinib). However, zalutumumab was dropped from development.

A large fraction of head and neck cancers overexpress EGFR, but the figure is probably not quite as high as the 90% that is often quoted, he said. There is also overamplification of EGFR in about 12% to 15% of head and neck cancer patients, and this correlates, to a degree, with overexpression, but it is not useful as a prediction biomarker, he added.

In fact, that is the main problem — the response rate to cetuximab is only about 7% to 13%, but as there is no biomarker to identify the patients who are likely to respond, "we are still giving it to everybody."

Afatinib is an inhibitor of erbB3, which is a "superhighway into EGFR signaling, so it makes sense to go for that," Dr. Seiwert commented. Also, it is also an oral drug, whereas cetuximab is administered by intravenous infusion.

Signals Suggesting Better Responses

There were signals in subgroup analyses of the LUX-H&N 1 study that some patients were responding better than others to afatinib, Dr. Seiwert noted. There was a "robust effect" seen in elderly patients, and also there was a better response seen in patients who had not received prior treatment with cetuximab, compared with those that had. As many of the patients in this trial had been treated with cetuximab, "you could argue that the trial was biased against the new agent," he commented.

Also, there was a better response seen among patients considered to be negative for human papillomavirus (HPV), compared with those who were positive, although these results are "uninterpretable," he suggested, as the testing was carried out with p16 and this test has poor specificity. But this is a theme emerging from other studies also, he said — the suggestion that EGFR inhibitors work better in tumors that are HPV-negative.

The way forward calls out for predictive markers so that the patient population exposed to a new drug could be narrowed down to those who are more likely to respond, he said.

The study was funded by Boehringer Ingelheim, the manufacturer of afatinib. Dr. Machiels reports serving on the advisory boards for Boehringer Ingelheim and Novartis. Many coauthors report relationships with various pharmaceutical companies. Dr. Seiwert reports acting as a consultant to Boehringer Ingelheim, Bayer, Onyx, Joune, Novartis, and Merck, and receiving research funding from Boehringer Ingelheim and Genentech.

European Society for Medical Oncology (ESMO) Congress 2014: Abstract: 29LBA PR. Presented September 27, 2014.

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