Disease Analysis: Head and Neck Cancer

Overview

Head and neck cancers (HNCs) are defined as any cancer that begins in cells of the oral cavity, pharynx, nose, sinuses, or salivary glands. These cancers are grouped together due to historical similarities in etiology, disease presentation, and manifestation. The vast majority of these cases (>90%), collectively referred to as head and neck squamous cell carcinomas (HNSCCs), appear in squamous epithelial cells lining the mucous membranes of these regions.

Latest key takeaways

• Datamonitor Healthcare estimates that in 2021, there were 910,700 incident cases of head and neck cancer (HNC) worldwide, and expects that number to increase to 967,000 incident cases by 2027.
• The majority of HNC diagnoses (75.2%) worldwide are in men, ranging from 64.9% to 76.3% across regions.
• Though a heterogenous group of diseases, the overwhelming majority (>90%) of HNCs are comprised of head and neck squamous cell carcinomas (HNSCCs). Nasopharyngeal cancer, a type of HNSCC, is widespread in East Asia but comparatively rare in Western nations.
• Most HNSCC patients are treated with surgery, radiotherapy (RT), and/or platinum-based chemotherapy.
• Erbitux, once among the dominant branded systemic therapies for HNSCC, is being eclipsed by checkpoint inhibitors. Erbitux is approved for use in combination with RT to treat patients with locally or regionally advanced HNSCC, in combination with chemotherapy for first-line recurrent/metastatic HNSCC, and as monotherapy for second-line recurrent/metastatic HNSCC.
• ASP-1929 is a cetuximab antibody conjugated to an infrared dye and is used in combination with light delivered through a fiber-optic catheter. The antibody-drug conjugate has received approval in Japan (where it is marketed as Akalux) based on Phase II results. A Phase III trial, LUZERA-301, is enrolling third-line or later, unresectable, locoregional HNSCC patients, and has an estimated primary completion date (PCD) of September 2024.
• HNSCC tumors are highly immunogenic and have elevated expression of immune checkpoint modulators. As such, there has been much interest in the development of immunotherapies to allow for targeted treatment programs.
• The first immunotherapies approved for recurrent/metastatic HNSCCs are anti-PD-1/PD-L1 immune checkpoint inhibitors (ICIs) Keytruda (for first and second line) and Opdivo (second line only). In this setting, Datamonitor Healthcare expects that ICIs will be used primarily for first-line patients, which should allow Keytruda, which is approved both as monotherapy and in combination with chemotherapy, to dominate over Opdivo.
• The tyrosine kinase inhibitor Lenvima is being evaluated in combination with Keytruda for first-line recurrent/metastatic HNSCC in the LEAP-010 Phase III trial. The combined approach of checkpoint blockade and anti-angiogenic intervention has proven efficacy in other solid tumor indications, particularly renal cell carcinoma, but it remains to be seen how such a regimen will fare in HNC.
• Numerous setbacks involving pipeline therapies for advanced HNSCCs such as Imfinzi, Gilotrif, Bavencio, retifanlimab, and enoblituzumab have allowed Keytruda to consolidate its leading position in this setting. More generally, these failures reflect the unusually challenging R&D sphere in HNSCC, where the average probability a drug candidate advances from Phase III is 22.7%, significantly lower than the average of 46.4% in oncology as a whole.
• With high rates of recurrence and no approved targeted therapies, locally advanced HNSCCs remain an area of high unmet need, as well as a potentially lucrative setting. The immunocytokine cocktail Multikine has shown some benefit as a neoadjuvant therapy among low-risk localized tumors, but the agent’s irregular development history and its trial’s mixed efficacy profile may prove barriers to approval.
• Keytruda is also in Phase III trials in the locally advanced HNSCC setting. In July 2022, Merck reported that the KEYNOTE-412 study had failed to meet its primary endpoint of event-free survival. KEYNOTE-412 enrolled early-stage, non-resectable patients and evaluated Keytruda combined with chemoradiation followed by Keytruda maintenance. Another trial, KEYNOTE-689, is evaluating Keytruda as single-agent neoadjuvant therapy and in combination with radiotherapy (and cisplatin for high-risk patients) as adjuvant therapy for resectable HNSCC, and has an estimated PCD of July 2025.
• The other PD-1/PD-L1 antibody in Phase III development for newly diagnosed, locally advanced HNSCC is Tecentriq. The IMvoke010 trial is evaluating Tecentriq as a single-agent adjuvant therapy for high-risk, locally advanced HNSCC. This may offer an attractive alternative by using checkpoint inhibition as a monotherapy in locally advanced HNSCC, thereby avoiding the toxicity of platinum-based chemotherapy.
• Xevinapant, which promotes apoptosis, is being evaluated in two Phase III trials enrolling previously untreated locally advanced patients. One study is evaluating xevinapant + radiochemotherapy in unresectable patients, while the other study is evaluating xevinapant in combination with adjuvant, post-operative radiotherapy in resected, high-risk, chemotherapy-ineligible patients. Another drug being developed for locally advanced HNSCC is NBTXR3, a radioenhancer that is injected intratumorally and amplifies the radiation dose during RT. A Phase III trial, NANORAY-312, is comparing NBTXR3 + RT ± Erbitux versus RT ± Erbitux. The trial is enrolling high-risk, chemotherapy-ineligible elderly patients.
• Three new regimens are being developed for second-line recurrent/metastatic HNSCC: buparlisib, a PI3 kinase inhibitor, combined with weekly paclitaxel; ISA101, a therapeutic anti-HPV16 vaccine, combined with Regeneron’s PD-1 inhibitor Libtayo in patients with HPV16-positive oropharyngeal cancer; and tipifarnib, an inhibitor of the posttranslational attachment of farnesyl groups to signaling proteins such as HRAS, in patients with HRAS-mutated HNSCC (HRAS is mutated in only 6% of HNSCCs at initial diagnosis).
• Toripalimab, tislelizumab, and penpulimab are three Chinese-developed PD-1 inhibitors close to approval for nasopharyngeal cancer, which accounts for approximately 3.3% of all HNCs in the US. Following the success of the JUPITER-02 trial and the failure of Keytruda’s KEYNOTE-122 study, Shanghai Junshi’s toripalimab stands to become one of the first targeted agents launched in this indication, and the company’s first approved drug in a Western market. Toripalimab combined with chemotherapy improved PFS and OS in first-line recurrent/metastatic patients compared to chemotherapy alone. Although inspection of a Chinese manufacturing has been delayed by COVID-19 restrictions, an FDA approval is now expected by December 2022. BeiGene’s tislelizumab was combined with chemotherapy in the RATIONALE 309 Phase III trial. RATIONALE 309 met its primary endpoint of PFS, and a regulatory submission to the FDA for first-line treatment is expected during Q4 2022. Akeso’s penpulimab is currently under FDA regulatory review for third-line or later nasopharyngeal cancer. While approval was expected in H1 2022, there have been no updates following its BLA submission in May 2021.