Can Keytruda finally break into early head and neck cancer?

The FDA has started a priority review of MSD's Keytruda as neoadjuvant and adjuvant treatment of locally advanced head and neck squamous cell carcinoma (HNSCC), with a decision due by 23rd June.

If approved, Keytruda (pembrolizumab) would finally provide an immunotherapy option for patients with early-stage HNSCC, who are generally treated at the moment with surgery – if feasible – and chemoradiotherapy.

MSD's filing is based on the results of the phase 3 KEYNOTE-689 study in patients receiving surgery for locally advanced stage 3 or 4a HNSCC. When added to the standard of care (adjuvant radiotherapy with or without cisplatin) both before and after surgery, Keytruda achieved a statistically significant improvement in event-free survival (EFS).

The study also revealed a significant improvement in major pathological response (mPR), a secondary endpoint, for patients taking Keytruda, said MSD, which is known as Merck & Co in the US and Canada. The company said it intends to present the data at a future medical congress.

The marketing application comes more than two years after the PD-1 inhibitor missed the mark in the phase 3 KEYNOTE-412 trial in newly diagnosed patients with locally advanced HNSCC who were not eligible for treatment with surgery.

Keytruda has been approved since 2016 as a second-line option after chemotherapy for patients with more advanced HNSCC that has spread to other parts of the body and moved into the first-line setting in 2019 as monotherapy or in combination with chemo for patients whose tumours express elevated levels of the PD-L1 biomarker.

"The standard of care for patients with resectable locally advanced [HNSCC] has remained the same for over two decades, representing a significant unmet need for new treatment options," remarked Dr Marjorie Green, head of oncology clinical development at Merck Research Laboratories.

"Based on the compelling results of the KEYNOTE-689 trial, we hope to reduce the risk of recurrence and disease progression in earlier stages of disease," she added.

One issue that could hypothetically affect the outcome of the review is the stance taken by the FDA's oncologic drug experts on 'perioperative' data that emerged during an assessment of AstraZeneca's Imfinzi (durvalumab) as neoadjuvant/adjuvant therapy for resectable non-small cell lung cancer (NSCLC) last year.

The advisors told the FDA that any studies on perioperative regimens for resectable NSCLC include an assessment of the contribution of each treatment phase individually, to answer questions such as whether the post-surgery use added to the toxicity of treatment without any additional clinical benefit.

The only other immunotherapy approved to treat HNSCC is Bristol-Myers Squibb's Opdivo (nivolumab), which can be used as a second-line option after chemotherapy for advanced disease, but failed to move into the first-line setting after failing a trial as a combination with companion immunotherapy Yervoy (ipilimumab). Merck KGaA/Pfizer's Bavencio (avelumab) also missed the mark in a phase 3 study in locally advanced HNSCC reported in 2020.

Head and neck cancer is the sixth most common cancer in the world, with almost two-thirds of patients diagnosed when they have locally advanced disease.