EGFR Inhibition Adds Toxicity, No Benefit in Head & Neck Cancer

Kate Johnson

April 14, 2014

VIENNA — Adding the investigational EGFR antibody zalutumumab (Genmab A/S) to primary chemoradiotherapy did not improve outcome in patients with head and neck squamous cell carcinoma, according to the results of the phase III Danish Head and Neck Cancer Group (DAHANCA)-19 trial.

"I truly believe that EGFR-inhibition works...but studies in broad populations like DAHANCA-19 are not the way to go anymore ― we need to go for selected populations," lead researcher Jesper Eriksen, MD, from Odense University Hospital in Denmark, told Medscape Medical News.

The trial results, which he presented here at the European Society for Radiotherapy and Oncology (ESTRO) 33, are very much in line with previous trials with other EGFR inhibitors, also showing no benefit. Both the RTOG 0552 trial with cetuximab (Erbitux, Bristol-Myers Squibb Company) and the CONCERT-1 trial with panitumumab (Vectibix, Amgen Inc) showed no benefit from adding the EGFR antibody to cisplatin-based chemoradiation in patients with head and neck cancer, perhaps all for the same reason, Dr. Eriksen suggested.

"Cisplatinum and zalutumumab (as well as other anti-EGFR agents) both work through inhibition of DNA repair and inhibition of cell proliferation...and you can't (probably) inhibit it twice," he said.

Cetuximab is approved in the United States for use in the treatment of metastatic head and neck cancer in combination with cisplatin chemotherapy (on the basis of the EXTREME trial results, which showed a survival benefit from adding the EGFR inhibitor), and also for use in locally advanced head and neck cancer in combination with radiotherapy. However, the results from the RTOG 0552 trial of cetuximab added to chemoradiation for stage 3 and 4 head and neck cancer showed no benefit from the addition of the EGFR antibody to the double modality treatment.

Danish Study Results

The DAHANCA-19 study with zalutumumab included 619 patients with biopsy-verified squamous cell carcinoma of the larynx (14%), oropharynx (70%), hypopharynx (12%), and oral cavity (4%) from all head and neck cancer centers in Denmark and Oslo, Norway.

The majority (89%) had stage 3-4 disease, and all had known HPV/p-16 status (55% were positive). Patients were relatively young (median age, 58-59 years), and about 75% had a smoking history of at least 10 pack-years.

All patients received intensity modulated radiotherapy (IMRT) and concomitant radiosensitzation with nimorazole 1200 mg/m2, while node-positive patients were offered cisplatinum 40 mg/m2 weekly.

Patients were randomly assigned to observation (n = 309) or to receive zalatumumab 8 mg/kg (n = 310) 1 week before starting and then weekly during radiotherapy.

After a median follow-up of 44 months, the study found no difference between the groups for the primary endpoint of locoregional control (71% experimental group vs 73% control patients; HR, 1.16), as well as for disease-specific survival (81% vs 84% respectively; HR, 1.12) and overall 3-year survival (68% vs 75%; HR, 1.22), with all confidence intervals crossing 1.

When the patients were distinguished on the basis of those who received chemoradiotherapy vs those who had radiotherapy alone, this pattern persisted.

As seen in many other studies, patients who were HPV/p16 positive had an overall better outcome than those who were negative (locoregional control, 82% vs 67%; HR, 0.49), but the addition of zalutumumab made no difference to the outcomes.

Compared with control patients, the zalutumumab group had significantly more toxicity, including confluent mucositis (P = .001) and grade 3-4 in-field skin reactions (P < .0001), with 94% of the experimental group developing a skin rash at some point during treatment.

There was no difference between the groups in severe late effects of radiotherapy, such as dysphagia, dryness, late edema, atrophy, or fibrosis.

Dr. Eriksen said it would likely be difficult to increase the 3-year survival rate for this patient population by adding a third modality to chemo/radiotherapy, and a much larger cohort would be needed to show such an increase.

However, he suggested a more meaningful impact of zalutumumab might be seen in patients with recurrent disease. "The EGFR pathway might be more activated in recurrent disease...at least we have seen a more pronounced expression of EGFR in metastatic/recurrent disease compared to primary disease," he said. "In the recurrent studies, survival is so much lower, and hence, fewer patients might be needed to show a small increase [in survival]," he added. "Furthermore, a very large proportion of our patients are HPV-positive, so biology behind the tumor might be different compared to the typical recurrent HNSCC, where a large proportion are HPV-negative," he commented.

"The reasons why zalutumumab added no clinical benefit to chemoradiation are unclear," agreed Roger Cohen, MD, professor of medicine at the Hospital of the University of Pennsylvania and associate director of clinical research and chief clinical research officer at the Abramson Cancer Center, in Philadelphia, when reached by Medscape Medical News for comment on the results.

Dr. Cohen, who recently wrote a review on EGFR inhibitors in the treatment of HNSCC ( Cancer Treat Rev. 2014;40:567- 577) said, "The simplest explanation for these consecutive negative results [DAHANCA 19 and RTOG 0552] is that anti-EGFR antibodies and cisplatin are both pretty good radiation sensitizers, leaving no real opportunity for additivity or synergy."

However, he pointed out that although both trials may have failed for this same reason, they had some key differences that might have led each to a different reason for failure. DAHANCA 19 used zalutumumab, a novel anti-EGFR antibody, and also included nimorazole. "Would this trial have been positive if the investigators had not included nimorazole? Was there some kind of interaction between zalutumumab and nimorazole that undermined the efficacy of zalutumumab?" he speculated, but concluded: "I don't think so."

Dr. Eriksen and Dr. Cohen reported no relevant financial relationships.

European Society for Radiotherapy and Oncology (ESTRO) 33: Abstract OC-0372. Presented April 6, 2014.

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