MSK radiation oncologist Dr. Nancy Lee helped design the clinical trial showing that immunotherapy given around surgery could reduce recurrence of some head and neck cancers.
People with locally advanced head and neck squamous cell carcinoma (HNSCC) now have a new treatment option that could extend their lives with fewer side effects. The U.S. Food and Drug Administration (FDA) has approved the immunotherapy drug pembrolizumab (Keytruda®) to be given before and after surgery for HNSCC in combination with standard therapy.
A phase 3 clinical trial showed that adding pembrolizumab to standard treatments such as radiation therapy and chemotherapy significantly reduced the risk of disease progression, recurrence, or death. The results also suggested that giving pembrolizumab could allow some patients to avoid chemotherapy after surgery.
Nancy Lee, MD, a radiation oncologist at Memorial Sloan Kettering Cancer Center (MSK), helped design the study and was a co-chair of the trial. “This is the first FDA approval in nearly two decades of a treatment for this patient group,” she says. “It will be practice-changing and benefit many people.”
Results from the multicenter trial were published June 19 in the New England Journal of Medicine.
Locally advanced (generally stage 3) head and neck squamous cell carcinoma is cancer that has grown outside its original location but has not yet spread to distant sites. It can be challenging to treat. About one-third of patients experience relapse within 12 months and less than half survive five years.
The phase 3 KEYNOTE-689 trial’s main goal — known as an endpoint — was “event-free survival,” meaning the cancer has not come back. After 36 months, event-free survival was 27% higher for patients receiving pembrolizumab plus standard treatment compared with the control group, which received only standard treatment.
“It’s very exciting to see not just a significant improvement in event-free survival but also less toxic follow-up treatments after surgery,” says Dr. Lee, a leading international expert in head and neck cancer radiation oncology. “Now some patients should be able to avoid chemotherapy, because pembrolizumab shrinks the tumor before removal and keeps the cancer from returning.”
Trial Results Show Pembrolizumab’s Effectiveness
Pembrolizumab is an immunotherapy drug called a checkpoint inhibitor that blocks the interaction between two proteins, PD-1 and PD-L1. It is already approved for head and neck cancer that has spread to distant sites or returned after prior treatment. The new trial was investigating whether pembrolizumab could jump-start the cancer-fighting process before surgery — when the tumor presents a conspicuous target — and then help mop up straggling cancer cells after it has been removed.
The FDA approval is for patients whose tumors express PD-L1 at a sufficient level. This suggests pembrolizumab will be effective.
The study included 714 patients with locally advanced, previously untreated stage 3 or 4 HNSCC whose tumors expressed PD-L1. The patients were split into two groups:
- One group received pembrolizumab plus standard treatment, which is surgery followed by radiation therapy, or radiation plus chemotherapy.
- Another group received this standard treatment without pembrolizumab.
After 36 months the pembrolizumab group had a higher event-free survival (60%) than the group receiving standard of care (46%).
Adding pembrolizumab was both more effective at shrinking the tumor before surgery and reducing the risk of cancer coming back, compared with standard-of-care therapy alone. The addition of pembrolizumab did not increase toxicity or interfere with patients’ ability to tolerate surgery.
“It is important that adding pembrolizumab doesn’t cause problems with the surgery to remove the tumor, which is usually the first step for successful treatment,” Dr. Lee says. “In fact, we are seeing that pembrolizumab has an effect of reducing the tumor so there is less disease remaining. This lets us de-escalate treatment afterwards from chemo plus radiation to simply giving radiation.”
Adding pembrolizumab had the greatest benefit in people whose tumors expressed the highest levels of PD-L1. Researchers quantify this expression by assigning a combined positive score (CPS) to tumor samples.
- In patients with a CPS of 10 or more who received pembrolizumab, risk of the cancer returning decreased by 34%. In addition, the tumor shrank dramatically in 13% of these patients — 90% of the tumor had been destroyed at the time of surgery.
- In a broader group of patients (CPS of 1 of more) recurrence risk declined by 30%.
- In the overall patient group, recurrence risk decreased by 27%.
Survival With Less Treatment
Dr. Lee has led multiple studies showing that some head and neck cancers can be successfully treated with reduced radiation doses. This technique has already changed treatment for many head and neck cancers. The new study shows that immunotherapy could help further reduce the burden of treatment in addition to improving survival.
“We designed this trial very carefully to get a definitive answer, and it took about 10 years to complete, but we are seeing the results with this FDA approval,” Dr. Lee says. “As a field, we’re very, very excited about what this means for our patients.”