The JAVELIN Head and Neck 100 trial randomly assigned 697 patients who had already undergone chemoradiotherapy for locally advanced, untreated disease to receive either avelumab or placebo.
This was the first phase 3 trial in which an immune checkpoint inhibitor was given concurrently with radiotherapy in addition to chemotherapy for any indication, noted the researchers. Checkpoint inhibitors have proved effective for recurrent or metastatic disease after standard options have failed. The current trial was one of the few trials to combine a checkpoint inhibitor with standard-of-care treatment in the first-line setting.
Not only did avelumab fail to improve outcomes, but there was also a trend for better progression-free survival (PFS) in the placebo arm, suggesting that avelumab may have had an “antagonistic effect,” the team reports.
Although not statistically significant, survival curves separated in favor of placebo. There was no obvious explanation for what happened, said lead investigator Nancy Lee, MD, of Memorial Sloan Kettering Cancer Center, New York.
“Be very careful when you are thinking about immunotherapy with fractionated radiotherapy,” Dr. Lee said in an interview.
The trial was terminated early for futility. The results were published online in The Lancet Oncology.
Possible detrimental effect?
The trial was conducted in patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity. Overall, 66% of patients had human papillomavirus (HPV)–negative disease, which is associated with poorer prognosis. The rest had HPV-positive disease.
Participants received either avelumab at 10 mg/kg intravenously or placebo along with cisplatin every 3 weeks and 70 Gy of intensity-modulated radiotherapy delivered in 35 fractions during the 9-week concurrent chemoradiotherapy phase of the trial. This was followed by avelumab or placebo maintenance for up to 12 months.
At a median follow-up of almost 15 months, the median PFS was not reached in the avelumab arm (118 events; 95% confidence interval, 16.9 months – not estimable) or in the placebo arm (106 events; 95% CI, 23 months – not estimable).
There was a hint of PFS benefit in a subgroup of 36 patients with tumors showing high PD-LI expression who were taking avelumab.
However, the overall results show that PFS (hazard ratio [HR], 1.21; 95% CI, .93-1.57; P = .920) and overall survival (HR, 1.31; 95% CI, 0.93–1.85; P = .937) trended in favor of placebo.
The findings cannot be explained by increased toxicity in the avelumab arm because there were no substantial safety differences in comparison with placebo, the researchers said.
Concurrent chemotherapy was probably not a problem either. There are robust data on the use of avelumab and other checkpoint inhibitors in combination with chemotherapy for numerous oncology indications. Two such drugs – pembrolizumab and nivolumab – are approved for recurrent or metastatic squamous cell head and neck cancer in combination with chemotherapy.
Dr. Lee suspects the findings could be due to a previously unrecognized negative interaction between avelumab and the high-volume fractionated radiotherapy used for locally advanced head and neck cancer.
“With chemoradiotherapy, we are killing T cells, but we are curing patients. What’s weird is why, when we combine it with immunotherapy, it looks like there’s a detrimental effect. That’s the mystery. We are looking [at tissue samples] to find out mechanistically or biologically why we saw what we saw,” she said.