Accelerated HNSCC Approval on 42% ORR Masks Single-Arm Confirmatory Risk

FDA Grants Accelerated Approval to Rybrevant Faspro for HNSCC

The U.S. Food and Drug Administration (FDA) has granted accelerated approval to Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) for adults with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) whose disease has progressed after platinum-based chemotherapy and immunotherapy. This approval, the first in 10 years for this patient population, addresses a significant unmet medical need. The decision was based on an open-label clinical trial involving 102 patients, which demonstrated an overall response rate (ORR) of 42%. Among responders, 56% maintained their response for six months or longer, representing more than double the response rate observed with currently approved therapies. Confirmatory studies are required to verify long-term clinical benefit.

• Addressing a High Unmet Need in HNSCC: Rybrevant Faspro's accelerated approval by the FDA provides a crucial new treatment option for adults with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) who have progressed on prior platinum-based chemotherapy and immunotherapy. This approval is particularly significant as it is the first in a decade for this specific patient population, highlighting the severe limitations and poor outcomes associated with existing therapies for this aggressive and life-threatening disease.
• Demonstrated Efficacy in Clinical Trial: The approval was supported by data from an open-label, multicenter clinical trial involving 102 patients. Results showed a compelling overall response rate (ORR) of 42%, indicating a substantial proportion of patients experienced tumor shrinkage or disappearance. Furthermore, among those who responded, 56% maintained their response for at least six months, demonstrating a meaningful duration of benefit compared to the approximately 20% ORR seen with current standard treatments.
• Accelerated Approval Pathway and Confirmatory Studies: Rybrevant Faspro received accelerated approval based on surrogate endpoints, specifically overall response rate and duration of response, reflecting its potential to address a serious condition with unmet medical need. While this pathway allows for earlier access to promising therapies, the FDA has mandated confirmatory studies to definitively establish and describe the long-term clinical benefit, as it is not yet confirmed whether these surrogate endpoints translate into clinically meaningful improvements in long-term outcomes.

Addressing the Unmet Need in Recurrent/Metastatic HNSCC

Despite advances with immunotherapy, the prognosis of recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) remains poor, with most patients presenting with primary or acquired resistance to immune checkpoint inhibitors (ICIs). The optimal therapeutic strategy for patients with R/M HNSCC remains unclear, and there is an unmet need for effective and well tolerated treatments for patients who develop immunotherapy-resistant disease.

• Widespread immunotherapy resistance with poorly understood mechanisms: a proportion of patients will become immunotherapy resistant, indicating innate, adapted, or quickly acquired resistance, while the mechanisms of immunotherapy resistance are not yet fully understood and subsequent treatment options are limited.

• Low and non-durable response to current standards: Approximately 15% of advanced head and neck squamous cell carcinomas (HNSCC) respond to anti-PD-(L)1 monotherapies, and the response rate of immunotherapy is low; cetuximab provides restricted clinical benefits, and its response duration is limited by drug resistance, with cetuximab monotherapy historically having a low response rate of 13%.

• Limited, toxic salvage options after progression: upon progression on ICIs, the only standard of care treatment options are chemotherapy ± cetuximab combinations with high toxicity rates and limited efficacy, and treatment options remain poorly defined for those with low PD-L1 expression or those refractory to the EXTREME regimen (platinum-based chemotherapy plus cetuximab), which is generally not curative and many patients will experience recurrent disease and/or metastasis.

• Lack of reliable predictive biomarkers compounded by heterogeneity: PD-L1 expression assessed by Combined Positive Score (CPS) remains the only validated clinical biomarker, although its dynamic and heterogeneous nature limits accuracy, with temporal heterogeneity of PD-L1 status and substantial spatial heterogeneity that may lead to up- or down-categorization of CPS and incorrect stratification of patients to immunotherapy.

Reshaping the HNSCC Treatment Landscape with New Approvals

In recurrent or metastatic head and neck squamous cell carcinoma, the phase III KEYNOTE-048 trial established pembrolizumab, alone or in combination with chemotherapy, as a new first-line standard in PD-L1 positive cases. Pembrolizumab, as monotherapy in first-line recurrent or metastatic head and neck squamous cell carcinoma with a combined positive score ≥1 and in combination with platinum and 5-fluorouracil in the overall recurrent or metastatic head and neck squamous cell carcinoma population, received US FDA approval based on the KEYNOTE-048 trial. In 2019, the USA Food and Drug Administration approved pembrolizumab as the first-line treatment for patients with unresectable, recurrent, and metastatic HNSCC. Pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in overall survival of 2.3 mo (hazard ratio = 0.77, P = 0.0034) in the overall population and a net gain in overall survival of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime), while in patients with PD-L1 positive recurrent or metastatic HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME.

In the second-line setting, the CheckMate 141 and KEYNOTE-040 trials confirmed the survival benefit and favorable safety profile of PD-1 inhibitors. In 2016, nivolumab and pembrolizumab were approved as the second-line treatment for advanced metastatic HNSCC by the USA Food and Drug Administration. Anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care (standard single-agent systemic therapy), with net gain in overall survival with nivolumab of 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01] and with pembrolizumab of 1.5 mo (HR = 0.80 nominal P = 0.0161). By contrast, the anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T-lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes, and in locally advanced head and neck squamous cell carcinoma, immunotherapy using avelumab along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.

Refinement of this landscape has focused on biomarkers and chemotherapy-free and post-immunotherapy combinations. In the KEYNOTE-012 study in recurrent/metastatic head and neck squamous cell carcinoma (n=192), tumor mutational burden, clonality-weighted tumor mutational burden, and 18-gene T-cell-inflamed gene expression profile were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between neoantigen load and PD-L1 combined positive score and clinical response (p=0.0550 and p=0.0682, respectively). Pembrolizumab 200 mg intravenously every 3 weeks, combined with an initial loading dose of cetuximab 400 mg/m intravenously followed by 250 mg/m intravenously weekly, showed promising clinical activity in platinum-resistant or platinum-ineligible recurrent or metastatic HNSCC, with overall response rate of 45% (95% CI 28-62) by 6 months in 33 participants. After progression following immune checkpoint inhibitor therapy, weekly cetuximab and paclitaxel maintained high efficacy with objective response rate, disease control rate, median progression-free survival, and median overall survival of 44.4%, 72.2%, 3.8 months, and 9.6 months, respectively.