Researchers are developing innovative clinical trial designs for head and neck cancer after analyzing disappointing results from major phase 3 studies. The KEYNOTE-412 and JAVELIN Head and Neck 100 trials, which evaluated adding immunotherapy to standard chemoradiotherapy, failed to demonstrate significant survival benefits in locally advanced head and neck squamous cell carcinoma (HNSCC). However, these setbacks have spurred new approaches that are showing early promise.
"There were a lot of questions about those studies and why they might have failed. Some [surmise] that it may have been just the timing," explains Dr. Trisha Wise-Draper, professor of medicine in the Division of Hematology/Oncology and section head of medical oncology at UC Health, Ohio. "There have been subsequent studies, at least in the adjuvant setting, that sequence the pembrolizumab or PD-1 inhibitor after the radiation, instead of concurrently. This may be a better sequential way of doing it to enhance the immune response, rather than doing concurrent treatment."
Rethinking Treatment Sequencing
The timing and sequence of immunotherapy administration have emerged as critical factors potentially determining efficacy. A phase 2 trial (NCT02777385) in the adjuvant setting found that patients who received pembrolizumab sequentially after chemoradiation had numerically superior 1-year and 2-year progression-free survival compared to those receiving concurrent treatment.
This sequential approach appears to better enhance immune responses against tumor cells, possibly by allowing radiation to first create an immunogenic environment before introducing checkpoint inhibition.
Promising Neoadjuvant Approaches
In the neoadjuvant setting, two landmark phase 2 trials have shown encouraging results. Dr. Ravindra Uppaluri and colleagues conducted a study (NCT02296684) evaluating pembrolizumab before surgery in patients with resectable locally advanced, HPV-unrelated head and neck cancer. The trial demonstrated that neoadjuvant pembrolizumab was safe, with 44% of patients showing pathologic tumor response, though no pathologic complete responses were observed.
Similarly, Dr. Wise-Draper's phase 2 trial (NCT02641093) evaluated pembrolizumab in both neoadjuvant and adjuvant settings. Patients with resectable, clinical stage T3 to T4 HNSCC received pembrolizumab prior to surgery, followed by risk-stratified adjuvant therapy. The results were striking: intermediate-risk patients achieved a 97% one-year disease-free survival rate, substantially higher than the historical 65-68%.
"Findings from those studies suggest that one dose alone could induce a pathological response in these patients, but two doses had a better response," notes Dr. Wise-Draper. "In addition, my study showed that if you had a pathological response that led to better survival outcomes, it was a better predictor than the usual risk factors we used for high-risk disease."
KEYNOTE-689: A Potential Game-Changer
These promising phase 2 results led to the development of the phase 3 KEYNOTE-689 trial (NCT03765918), which recently reported topline findings. For patients with resectable locally advanced HNSCC, perioperative pembrolizumab led to statistically significant and clinically meaningful improvement in event-free survival compared with adjuvant radiotherapy (with or without cisplatin) alone.
The trial also showed significant improvement in major pathological response, a key secondary endpoint. These results have already formed the basis for a supplemental biologics license application for pembrolizumab in this setting, potentially establishing a new standard of care.
The study enrolled approximately 704 patients who were randomized to receive either pembrolizumab before surgery followed by adjuvant therapy with pembrolizumab plus standard radiotherapy (with or without cisplatin based on risk status), or standard treatment without immunotherapy.
GORTEC: Focusing on Adjuvant Therapy
While KEYNOTE-689 evaluated both neoadjuvant and adjuvant immunotherapy, the GORTEC phase 3 trial (NCT03576417) focused solely on adjuvant treatment with nivolumab. This study demonstrated a statistically significant improvement in disease-free survival when nivolumab was added to standard post-surgical radiotherapy and cisplatin.
"The GORTEC study looked at the same patient population, but the investigators did not give neoadjuvant therapy; they only gave adjuvant nivolumab. In that study, they also reported increased disease-free survival," explains Dr. Wise-Draper.
This raises important questions about which phase of treatment—neoadjuvant, adjuvant, or both—is driving the improved outcomes. "We need to determine the benefit of the neoadjuvant vs adjuvant approach. I think the FDA is going to require clarification before approvals are granted," Dr. Wise-Draper notes.
Exploring Chemoimmunotherapy Combinations
Other innovative approaches include combining immunotherapy with chemotherapy in the neoadjuvant setting. A phase 2 trial evaluating camrelizumab (a PD-1 inhibitor) plus paclitaxel and cisplatin in patients with resectable locally advanced HNSCC showed an impressive objective response rate of 96.7%, with a pathologic complete response rate of 37.0%.
However, Dr. Wise-Draper cautions against overinterpreting these results: "The investigators showed an 89% response rate, which sounds fantastic. But if you review historical data for induction studies, where only chemotherapy was used, it becomes apparent that the findings did not impact overall survival. We know that chemotherapy works; we know it causes a response. The question now is, is this response different because we're giving it before surgery?"
The Role of Pathological Response
A key question emerging from these studies is whether pathological response is a critical factor in improving survival. If so, researchers may need to focus on enhancing this response through combination approaches.
Dr. Wise-Draper highlighted ongoing studies investigating stereotactic body radiation therapy combined with immunotherapy before surgery, an approach inspired by similar strategies in rectal cancer. This technique aims to induce a stronger immune response by targeting the tumor more precisely.
Implications for Clinical Practice
Despite the promising data, Dr. Wise-Draper advises caution for community oncologists. "Outside of the recurrent and metastatic setting, where we have clear indications about when to give immunotherapy, I think it's still too early to give it in the definitive setting," she says. "I'd wait until we have a little bit more information, especially with giving immunotherapy before surgery, until we have the results from the clinical trial."
Head and neck cancer treatment is at a pivotal moment, with immunotherapy poised to revolutionize standard care. While questions remain about optimal timing and combinations, recent progress offers hope for improved survival and quality of life for patients with this challenging disease.
The upcoming data from KEYNOTE-689, GORTEC, and other trials will provide critical insights into how best to integrate immunotherapy into treatment protocols, potentially establishing new standards of care for head and neck cancer patients.
