Durvalumab Does Not Surpass Cetuximab in Head and Neck Cancer

Christina Henson, MD, discusses recent phase 3 trial results comparing durvalumab to cetuximab in head and neck cancer, and why the trial was stopped early.

Cisplatin’s significant toxicity profile limits its applicability as a treatment option in many patients with locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC). When looking for less toxic alternatives, cetuximab (Erbitux) has emerged as a commonly used substitute, however, it comes with its own set of adverse effects (AEs).

The recently published phase 3 NRG-HN004 trial (NCT03258554) explored the use of durvalumab (Imfinzi) or cetuximab in this patient population. Christina Henson, MD, Residency Program Director for Radiation Oncology at Oklahoma University, spoke with CancerNetwork® about the trial's design, rationale, and its premature closure due to efficacy concerns. She discusses the surprising results that revealed a significantly lower cure rate in the durvalumab arm compared with cetuximab.

Despite the trial's negative outcome, Henson underscores its significance in shaping future research directions in HNSCC. She emphasizes the value of early data analysis in identifying ineffective treatments and preventing unnecessary patient exposure to potentially harmful therapies.

CancerNetwork: What was the basis behind designing this trial?

Henson: The standard treatment for head and neck cancers, for most of them, and for most stages, is a combination of radiation and a chemotherapy agent called cisplatin. The issue with that is that cisplatin has a lot of toxicities that we would like to try to avoid, or that make some patients ineligible to receive it, because they have preexisting conditions that make them not a good candidate. They might already have hearing loss, kidney damage, have neuropathy, or just patients over a certain age, who have other medical comorbidities [and may not be] candidates for cisplatin. There’s this constant search to find something for those patients. The current best thing that we have is a drug called cetuximab, that’s been the most studied in this patient population, but it too, has adverse effects. This study was looking to compare an immunotherapy agent called durvalumab to cetuximab, in hopes that it would be equivalent or better.

What were the results of the trial?

The trial was intended to go a lot longer than it did, and the goal was to recruit a lot more patients than it ended up recruiting. The reason that it did not is because it closed early, because the planned analysis of the data at that point showed that the experimental arm was not performing as well as the control arm, the cetuximab arm. What we saw after following the patients for 2 years after they received treatment, was that the cure rates were about 13% lower in the experimental arm, which is a pretty big difference.

What AEs were observed with this trial?

Since durvalumab is an immunotherapy agent. It does have some different AEs from what we see with cetuximab and cisplatin. It can cause autoimmune types of AEs. Those are rare, but they do happen. Cetuximab is known to enhance the AEs of the radiation. The patients tend to get a reaction inside of their throat that can cause throat pain, trouble swallowing, or dry mouth. Cetuximab can also cause a brisk, thin rash in some patients that is itchy. Those are some of the [AEs] that we see.

The trial did close early, but why are these results important for head and neck cancer research?

It checked 1 [treatment option] off the list of possible things that we keep in mind that might be a good fit for this patient population. Unfortunately, we had promising preclinical data that did not pan out in the actual clinical trial. That’s why it’s important that we have early analysis of these studies, like we did, so that we can stop early if it seems like something’s not working, and it just helps us better design future trials. This is a drug, or maybe a category of drugs, that we are not going to keep testing. This patient population will look for something new and different

What do you hope your colleagues take away from this conversation?

It’s always disappointing when we have a trial that comes out to be negative and we did not find something that benefits our patients, but it also can show us the importance of good trial design and help us to better design future trials. It also just keeps us motivated to keep trying to find [treatment options] for these patients. It’s not easy, but it’s important to get results like these, even when they do not go the way that we expect them to. That’s part of science. It’s not always going to work out the way that we expect it to.

As a radiation oncologist, what is on the horizon that you are excited to see come to fruition over the next couple of years?

There are some trials that are looking at how to make radiation more effective, or how to make radiation less toxic. I’m interested in the drugs, but I’m very passionate about the radiation side of things. There’s also a trial that we have open at my institution, and open at other institutions, that is looking at a nanoparticle that can be injected into head and neck cancers that makes the radiation work better. It’s an inert molecule, but once the radiation hits it, it activates to target the tumor cells directly. I think [studies] like that are very exciting, too.

Is there anything else you would like to highlight about your field?

One thing I always try to bring up whenever I can, in settings like this and with patients, is the importance of the human papillomavirus (HPV) vaccine. About 80% of these cancers nowadays are due to the HPV virus. Fewer people are smoking, but more people are contracting the HPV virus and developing these types of cancers. A lot of my patients have no idea that there is a vaccine for that. [I am] just trying to spread awareness about that from a cancer prevention standpoint.

Reference

Mell LK, Torres-Saavedra PA, Wong SJ, et al. Radiotherapy with cetuximab or durvalumab for locoregionally advanced head and neck cancer in patients with a contraindication to cisplatin (NRG-HN004): an open-label, multicentre, parallel-group, randomised, phase 2/3 trial. Lancet Oncol. 2024;25(12):1576-1588. doi:10.1016/S1470-2045(24)00507-2