The early halt of a phase 3 trial of avelumab (Bavencio) plus chemoradiotherapy for the treatment of squamous cell head and neck cancer raises a question: does combining a checkpoint inhibitor with radiotherapy hurt patients?
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 (an anti-PD-L1 antibody) 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, note the reserachers. Checkpoint inhibitors have proven 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. “It was really surprising” and “a little bit [alarming].” There was no obvious explanation for what happened, commented lead investigator Nancy Lee, MD, vice chair of the Department of Radiation Oncology at Memorial Sloan Kettering Cancer Center, New York City.
“Be very careful when you are thinking about immunotherapy with fractionated radiotherapy,” Lee commented to Medscape Medical News.
The trial was terminated early for futility. The results were published online April 1 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 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/placebo maintenance for up to 12 months.
After a median follow-up of almost 15 months, median PFS was not reached in the avelumab group (118 events; 95% CI, 16.9 months – not estimable) or in the placebo arm (106 events; 95% CI, 23 months – not estimable).
There was a hint of benefit in PFS 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 comment.
Concurrent chemotherapy was also probably not a problem. 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.
Lee suspects that 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.
Results From Similar Study Eagerly Awaited
A nearly identical phase 3 trial is underway: the Keynote 412 trial is investigating the addition of the anti-PD-1 antibody pembrolizumab to chemoradiotherapy in the first-line treatment of locally advanced squamous cell head and neck cancer.
If this study also suggests worse survival with the immune checkpoint inhibitor, then it’s unlikely there was something specific about avelumab that accounts for the JAVELIN findings, and “we can say we shouldn’t consider using immunotherapy with radiation at all,” Lee said.
“It could be that there is a detrimental effect of the combination of checkpoint inhibitors with definitive radiotherapy,” commented Sjouke Oosting, MD, PhD, medical oncologist at the University Medical Center Groningen, Groningen, the Netherlands. She was commenting after the JAVELIN results with avelumab were presented at a conference last year and said she now “eagerly awaits” the results with pembrolizumab.
For the time being, Lee said, “We have to be cautious.” Checkpoint inhibitors might still prove useful in some relationship to first-line chemoradiotherapy.
Studies are underway; one trial is investigating the adjuvant use of immunotherapy after upfront chemoradiotherapy for head and neck cancer.
The JAVELIN trial with avelumab was funded by Pfizer and Merck. The KEYNOTE trial with pembrolizumab is funded by Merck. Lee is an advisor for and has received research funding from both companies. Oosting has received research grants from Celldex and Novartis.
Lancet Oncol. Published online April 1, 2021. Abstract
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a Newhouse journalism degree from Syracuse University. He is an award-winning medical journalist who worked for McClatchy and Bloomberg before joining Medscape, and also an MIT Knight Science Journalism fellow. Email: [email protected]