Breakthrough Clinical Results
Bicara Therapeutics announced that the FDA has granted Breakthrough Therapy Designation (BTD) to ficerafusp alfa in combination with pembrolizumab for the first-line treatment of patients with metastatic or unresectable, recurrent (R/M) head and neck squamous cell carcinoma (HNSCC) whose tumors express programmed death-ligand 1 (CPS ≥1), excluding HPV-positive oropharyngeal squamous cell carcinoma. The designation was supported by Phase 1/1b trial results demonstrating deep and durable clinical benefit. Bicara is advancing ficerafusp alfa in the pivotal Phase 2/3 FORTIFI-HN01 trial.
Key Highlights
- FDA granted Breakthrough Therapy Designation to ficerafusp alfa in combination with pembrolizumab.
- Designation is for first-line treatment of HPV-negative R/M HNSCC patients with PD-L1 CPS ≥1.
- BTD supported by Phase 1/1b data showing deep and durable clinical benefit.
- Ficerafusp alfa is being evaluated in the pivotal Phase 2/3 FORTIFI-HN01 trial.
Incidence and Prevalence
Latest Global Estimates of Head and Neck Cancer Incidence and Prevalence
Head and neck cancers collectively represent the sixth most common cancer worldwide according to the most recent data from 2023, with over 500,000 annually reported incident cases worldwide. These cancers are also the eighth most common cause of cancer death worldwide.
The incidence of global head and neck cancer has increased markedly in the last 10 years, posing a serious threat to public health. Together with brain cancers, head and neck cancers account for more than 873,000 cases annually worldwide, with an increasing incidence each year.
According to GLOBOCAN group data from 2020, head and neck squamous cell carcinoma (HNSCC) constituted the seventh most prevalent human malignancy and the most common human cancer in the world. Most head and neck cancers are squamous cell carcinomas (HNSCCs), which are highly aggressive tumors. Over 90% of oral cavity cancers originate from squamous cells.
Regional variations in incidence are significant: - The age standardized incidence rate in males exceeds 30/100,000 in regions of France, Hong Kong, the Indian sub-continent, Central and Eastern Europe, Spain, Italy, Brazil, and among US blacks. - High rates (>10/100,000) in females are found in the Indian sub-continent, Hong Kong and Philippines. - The highest incidence rate reported is 63.58 in males (France, Bas-Rhin) and 15.97 in females (India, Madras).
A 2023 study showed that oral cancer (OC) incidence increased from 4.19 to 27.19 per 100,000 population in men with an average annual percentage change (AAPC) of 5.1% between 1980-1984 and 2015-2019. For women, oral cancer incidence increased from 1.16 to 2.8 per 100,000 population with an AAPC of 3.1% during the same period.
While the overall incidence rates show a declining trend in both sexes in India, Hong Kong, Brazil and US whites, an increasing trend is observed in most other populations, particularly in Central and Eastern Europe, Scandinavia, Canada, Japan and Australia. Several countries in Europe showed a significant increase of oral cancer prevalence, such as Germany, especially in men.
In North America and the European Union, head and neck cancer accounts for 3% to 4% of all cancer diagnoses, while in Southeast Asia and Africa, it accounts for approximately 8% to 10% of all cancers.
The five-year relative survival varies from 20-90% depending upon the subsite of origin and the clinical extent of disease. The mortality rates remain at high levels, despite many important advances in therapy. The overall survival rate for HNSCC patients is low, not exceeding 40-60%.
The variation in incidence by subsite is mostly related to the distribution of major risk factors such as tobacco or betel quid chewing, cigarette or bidi smoking, and alcohol consumption. Mouth and tongue cancers are more common in the Indian sub-continent, nasopharyngeal cancer is more common in Hong Kong, and pharyngeal and/or laryngeal cancers are more common in other populations.
Key Unmet Needs and Target Populations in Head and Neck Cancer
Disease Challenges
Recurrent and/or metastatic (R/M) disease develops in >50% of patients despite aggressive multimodal treatment approaches, representing a significant unmet need. Tumor recurrence occurs in 40-60% of cases, leading to poor survival outcomes. Despite breakthroughs in treatment strategies, patients' survival has not increased substantially in the last few decades.
The lack of common genetic drivers for tailored therapies and scarcity of reliable biomarkers for treatment selection in HNSCC present major challenges. There is an urgent need for quick and reliable biomarkers and therapeutic targets.
Treatment Limitations
Limited response rates with checkpoint inhibitor monotherapy necessitate strategies to strengthen tumor-directed immune responses. Immune checkpoint inhibitors combined with radiotherapy show promise but have largely negative results in clinical trials, suggesting need for optimization.
For platinum-refractory patients, options are limited as the benefit of platinum rechallenge would be minimal. Patients with PD-L1 CPS <1 have few options beyond the EXTREME regimen. External beam reirradiation remains controversial with a narrow therapeutic ratio.
Vulnerable Populations
Frail patients with R/M HNSCC who cannot tolerate chemotherapy may only be suitable for pembrolizumab monotherapy, but long-term disease stabilizations remain the exception.
Older patients with head and neck squamous cell carcinoma are underrepresented in randomized clinical trials, and evidence-based guidelines are lacking for this population.
Ethnic disparities exist in survival and mortality rates, with Māori individuals in New Zealand experiencing worse outcomes: - Diagnosed 5-7 years younger (mean age 58.0 vs 64.3 years) - Die 7-10 years earlier (mean age 63.5 vs 72.3 years) - Present with more advanced disease (only 14.5% with localized disease vs 24.0%) - Show increased regional lymph node involvement (39.1% vs 30.5%)
Emerging Approaches
Patient-derived organoids (PDOs) show promise for drug- and radiosensitivity screens, with successful establishment in 77% of cases with tumor cell content of ≥30%. However, advanced patient age, prior radiotherapy, and delays in tissue processing are negative predictors for PDO engraftment.
Carbon ion reirradiation (CIR) is emerging as "a feasible, effective treatment with acceptable toxicity and good local control" and "a valuable alternative to surgical salvage and palliative chemotherapy in selected patients."
Supportive Care Gaps
Advance care planning is overall poor in patients undergoing surgery for oral cancer, with only 10.3% of patients having documented planning.
Cancer survivorship clinics are not widely available, and longitudinal supportive care has not advanced at a pace commensurate with improvements in cancer control. Studies show 43.36% of survivor discussions pertain to chronic emotion disturbance with significant implications for other domains of life.
Recent Studies
Recent Head and Neck Cancer Studies: Interventions and Outcomes
OraRad Study (2023)
The Clinical Registry of Dental Outcomes in patients with head and neck cancer surveyed participants approximately 4 years post-radiation therapy. While not an intervention study, it revealed important outcomes including dry mouth (75%), problems swallowing (38%), dental caries (22%), and difficulty keeping mouth open during dental procedures (17%). Notably, 92% of respondents understood the effects of cancer treatment on oral health, and 80% received adequate information from their dentists.
Hypoxia-Related Genes Study (2021)
This study identified four hypoxia-related genes (ALDOA, P4HA1, PGK1, and VEGFA) as biomarkers for predicting overall survival in oral squamous cell carcinoma (OSCC) patients. A nomogram was established to reliably predict long-term survival. Results suggested that poor prognosis in high-risk patients might be related to immunosuppressive microenvironments.
Steroids for Osteoradionecrosis Prevention (2019)
This systematic review evaluated peritreatment steroids for preventing osteoradionecrosis in head and neck cancer patients undergoing radiation therapy. Analysis of 25,328 participants showed steroids were associated with a significantly lower risk of osteoradionecrosis (hazard ratio: 0.74, relative risk: 0.04). However, the studies had limited quality with high risk for bias.
Modified DCF Chemotherapy Study (2020)
This study evaluated modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) as first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma. Among 80 patients, efficacy outcomes included complete response (2.5%), partial response (43.8%), and stable response (25%), with a disease control rate of 71.3%. Median progression-free survival was 7 months and overall survival was 11.5 months.
Immune Checkpoint Inhibitor Studies (2022)
Nivolumab was evaluated in real-world settings in India, showing median progression-free survival of 2 months and median overall survival of 5 months, with 15% partial response and 10% stable disease. Pembrolizumab was recommended as first-line treatment either as monotherapy or combined with chemotherapy. A 2020 meta-analysis reported the most common adverse event was fatigue (14.7%), with increased aspartate aminotransferase (1.6%) being the most common grade ≥3 event.
Apatinib Mesylate Study (2022)
This study compared different doses of apatinib mesylate with chemotherapy, finding that the lower dose (250 mg) combined with chemotherapy achieved optimal efficacy with highest safety and least adverse effects compared to the 500 mg dose.
Palliative Radiotherapy Comparison (2022)
This randomized trial compared one-week versus two-week palliative radiotherapy regimens. Both showed comparable clinical outcomes and quality of life scores, but the one-week regimen (20 Gy in 5 fractions) significantly reduced treatment time and financial toxicity compared to the two-week regimen.