Cetuximab Outperforms Durvalumab for Head and Neck Cancer When Cisplatin Isn’t an Option

December 19, 2024, by Edward Winstead

The chemotherapy drug cisplatin, combined with radiation therapy, is a standard treatment for people newly diagnosed with locally advanced head and neck cancer. But about one-third of people with such cancers have other health conditions, such as hearing loss or kidney disease, that make them unable to receive the drug.

It’s been unclear what the optimal treatment should be for these patients. And it’s an important question, because most people diagnosed with head and neck cancer have locally advanced disease—meaning their tumors are relatively large but haven’t spread to other parts of the body.

New results from a clinical trial could help answer that question, according to the researchers who led the study. The NCI-supported trial compared two potential alternatives to cisplatin in nearly 200 people with locally advanced head and neck cancer.

In the study, participants given the targeted drug cetuximab (Erbitux) along with radiation therapy had better outcomes than those given the immunotherapy drug durvalumab (Imfinzi) along with radiation therapy.

At a median follow-up of 2.3 years, 64% of those in the cetuximab group were alive and free of disease progression, a measure known as progression-free survival, compared with 51% of those in the durvalumab group. The findings were published in the Lancet Oncology on November 14.

The researchers ended the trial early after a planned analysis of interim results showed that the participants randomly assigned to receive durvalumab would likely do worse than those assigned to receive cetuximab. After the trial ended, the investigators continued to follow the patients.

“Our results support the idea that radiation with cetuximab is a very good alternative for patients who cannot get standard cisplatin,” said study leader Loren Mell, M.D., a radiation oncologist at the University of California San Diego School of Medicine.

“We had high hopes for durvalumab, but cetuximab seems to be a better drug for this group of patients,” Dr. Mell continued.

These new results could inform the direction of future trials, said Charalampos Floudas, M.D., of NCI’s Center for Cancer Research, who treats head and neck cancers but was not involved in the trial.  

The findings, Dr. Floudas noted, are consistent with those of a recent randomized clinical trial comparing the immunotherapy drug pembrolizumab (Keytruda) and cetuximab in people with locally advanced head and neck cancer who could not take cisplatin. In that trial, combining pembrolizumab with radiation therapy did not slow the growth of tumors or improve patient survival compared with cetuximab and radiation therapy.

“For whatever reason, immunotherapy with radiation is not an effective treatment approach for many of our head and neck patients,” Dr. Mell said. “This has led us to pursue different strategies for those who cannot take cisplatin.”

Comparing different types of cancer drugs in an understudied population

People with locally advanced head and neck cancer who are unable to receive cisplatin tend to be older and often have underlying health conditions that make them ineligible to participate in clinical trials.

“This group is understudied,” Dr. Mell said. “The dearth of clinical trials devoted to these patients has led to the high degree of uncertainty about the optimal treatment.”

Previous studies have yielded conflicting data for and against several alternatives to cisplatin in combination with radiation. These alternatives have included other chemotherapy drugs like docetaxel or the combination of carboplatin and paclitaxel, the researchers noted.

“One of the prevailing questions in the field right now is whether giving patients combination chemotherapy is better than giving a targeted therapy like cetuximab,” Dr. Mell said.

When he and his colleagues in NRG Oncology, part of NCI’s National Clinical Trials Network, developed their trial, cetuximab was considered a primary alternative to cisplatin.

The investigators decided to compare cetuximab with durvalumab, a type of immunotherapy drug called an immune checkpoint inhibitor, in part because other immune checkpoint inhibitors are already used to treat people with head and neck cancers that have come back or spread (metastasized) to other parts of the body.

Durvalumab had also shown promise in a previous nonrandomized trial involving people with head and neck cancer who could not receive cisplatin. And other studies have suggested that radiation may make immunotherapy drugs more effective for some people with head and neck cancer.

Similar side effects between the treatment groups in the trial

In the trial, more than half of the participants were aged 70 years or older and the majority were male and White. The most common reasons participants were not eligible for cisplatin included kidney problems, hearing loss, and nerve pain known as peripheral neuropathy.   

Of the study participants, 123 were randomly assigned to the durvalumab group and 63 to the cetuximab group. NCI and AstraZeneca, the maker of durvalumab, funded the clinical trial.

The progression-free survival rate of 64% among the cetuximab group appears to be the highest reported to date from a multicenter randomized trial involving this population of patients, the researchers noted.

When the researchers analyzed treatment responses among subgroups of patients, such as those whose tumors had certain characteristics, cetuximab was superior across the board. But the subgroup analyses should be interpreted with caution because of the trial’s early closure and the small sizes of the subgroups, the researchers wrote.

The incidence of side effects was similar in the two groups, the researchers found. The most common severe side effects (grade 3 or 4) were difficulty swallowing (22% in the durvalumab group versus 30% in the cetuximab group), low numbers of lymphocytes in the blood (28% versus 33%), and sores in the mouth (11% versus 18%).

Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related side effects, the researchers reported.

Designing trials based on solid evidence from previous studies

Although more research is needed to define the optimal treatment for patients with locally advanced head and neck cancer who cannot get cisplatin, the study has answered important questions, Dr. Mell said.

“Prior to this study, we didn’t know if it was even feasible to conduct a study in patients who were medically frail,” Dr. Mell said. “We established that we could run trials in this group, which will allow us to answer questions.”

It is still possible, he added, that durvalumab and radiation therapy might benefit certain patients whose tumors are responsive to immunotherapy.

In an accompanying editorial, Naomi Kiyota, M.D., Ph.D., who specializes in treating head and neck cancers at Kobe University Hospital in Japan, agreed. Clinical trials now underway could reveal clues about how best to use these drugs, Dr. Kiyota noted.

For instance, participants in two clinical trials are receiving an immunotherapy drug (either volrustomig or dostarlimab [Jemperli]) after they completed chemotherapy and radiation therapy. A similar sequence of treatments—giving immunotherapy after chemotherapy and radiation—helped some patients with lung cancer live longer in a clinical trial, Dr. Kiyota wrote.

As researchers develop new trials for people with locally advanced head and neck cancer, Dr. Mell suggested, cetuximab can be used as a comparison treatment.

“An important finding of our study was that cetuximab seemed to be a better drug than we were anticipating,” Dr. Mell said. “That result, along with those from the earlier studies, should help allay concerns about whether the drug is effective for this group of patients.”