Keytruda Doubles Efficacy of Only Targeted Therapy for Head and Neck Cancer

The immunotherapy Keytruda (pembrolizumab), in a recent study, proved twice as effective for the treatment of head and neck cancer as Erbitux (cetuximab), the only targeted therapy indicated as a therapy for the disease.

The multisite study offers the largest experience to date of how immunotherapy can be deployed in patients with head and neck cancer, and could change the way the disease is treated. The findings were announced May 29 during the annual meeting of the American Society of Clinical Oncology, a gathering of nearly 30,000 oncology professionals taking place in Chicago.

Keytruda is an antibody designed to disable the protein PD-1 so it cannot do its job of keeping the immune system in check; this allows T cells to become more active in recognizing and fighting cancer cells. In the study, investigators found that the drug produced broad and durable responses in patients with advanced head and neck cancer.

Fifty-six percent of patients in the study experienced some tumor shrinkage with Keytruda, and 86 percent of those patients continued to respond to treatment at data cutoff on March 23, 2015. Keytruda produced an overall response rate (ORR) of 25 percent, and it proved active in both HPV (human papillomavirus)-positive and HPV-negative patients.

“The efficacy was remarkable — pembrolizumab seems to be roughly twice as effective, when measured by response, as our only targeted therapy, cetuximab,” said Tanguy Seiwart, an assistant professor of medicine and associate leader of the head and neck cancer program at the University of Chicago, who presented the results in a press briefing during the ASCO meeting. “We have high hopes that immunotherapy will change the way we treat head and neck cancer.”

Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) has a poor prognosis with a median overall survival (OS) of 13 months in patients treated in the first-line setting, and six months in previously treated patients. Previously treated patients made up the majority of the population of the study, which built on earlier findings from the KEYNOTE-012 study (NCT01848834). In that study, Keytruda — administered at 10 mg/kg every two weeks — had a 20 percent response rate in patients with advanced HNSCC whose tumors were positive for the protein PD-L1.

The findings reported May 29 were based on results from an expansion of that first trial, which involved 132 patients with advanced HNSCC who were recruited regardless of their PD-L1 or HPV status. Importantly, said Seiwert, patients in this cohort received a fixed dose of Keytruda (200 mg every three weeks), representing “a very convenient dosing schedule.”

Eligible patients had measureable disease based on RECIST 1.1 response evaluation criteria and an ECOG performance status of 0 or 1. The majority of enrollees were male (83 percent), and 56.8 percent had received two or more lines of therapy for disease recurrence. Radiographic imaging was used to assess tumor response every eight weeks. Patients were treated as long as they didn’t show progression of disease or as long as they demonstrated clinical improvement, Seiwert explained.

Of 117 evaluable patients, 29 (24.8 percent; [95 percent confidence interval (CI), 17.3—33.6]) responded to treatment with Keytruda. For patients with HPV-positive HNSCC, the ORR was 20.6 percent, and in the HPV-negative cohort, ORR was 27.2 percent.

“In addition to the 25 percent response rate,” said Seiwert, “about 25 percent also had stable disease, so when we take these together, we have a disease control rate of about 50 percent, which is remarkable in this disease, especially in a heavily pretreated population.”

Moreover, he said, about two-thirds of patients had received two or more prior lines of therapy, which generally is an indicator of a very poor prognosis.

For the 56 percent of patients whose tumors decreased in size, Seiwert said the responses often occurred early at eight or 16 weeks, although there were a few outliers with late responses.

“Importantly, those patients who did respond oftentimes continued to have responses — 86 percent of patients had durable responses in this cohort,” he continued, adding that not only are responders remaining on the therapy, but so are many patients who have stable disease, with a total of 40 patients staying on the drug.

“Overall, and in keeping with what we already know about pembrolizumab, this was a very well-tolerated agent,” said Seiwert, “certainly better tolerated than what we usually see in head and neck cancer with aggressive chemotherapy and radiotherapy.”

Serious side effects were reported in fewer than 10 percent of patients. The most common side effects were fatigue (15.2 percent of patients), hypothyroidism (9.1 percent), and decreased appetite and rash, each occurring in 7.6 percent of patients. Four patients discontinued treatment due to immune-related side effects: two due to grade 2 interstitial lung disease and grade 3 colitis, respectively, and two patients for grade 3 pneumonitis.

Analysis of the findings based on biomarker status is ongoing, and Seiwert is hopeful that with the emergence of new potential biomarkers, researchers will be able to pinpoint which patients with HNSCC are most likely to benefit from the immunotherapy.

For example, another related study that Seiwert and colleagues are reporting at ASCO (abstract 6017) has shown that the expression of the gene signature interferon-gamma in head and neck tumors had a very strong negative predictive value of response to Keytruda. “In the future, these results may help us, if validated, to determine which patients should or should not [be given] pembrolizumab,” Seiwert said.

Pembrolizumab versus standard treatment for HNSCC also is being evaluated in two phase 3 trials that are currently recruiting participants (NCT02252042 and NCT02358031

Seiwert TY, Haddad RI, Gupta S, et al. Antitumor activity of the anti-PD-1 antibody pembrolizumab in biomarker-unselected patients with R/M head and neck cancer: preliminary results from the KEYNOTE-012 expansion cohort. J Clin Oncol. 2015;(suppl; abstr LBA6008).