RARE DISEASE
Squamous cell carcinoma of the oral cavity
Squamous cell carcinoma of the oral cavity
Squamous cell carcinoma of the oral cavity
Drug discovery
7
drugs
With orphan designations
Overview
Oral squamous cell carcinoma (OSCC) is a malignant tumor originating from the mucosal squamous epithelium, primarily affecting the tongue, floor of the mouth, and mandibular alveolus. Major risk factors include tobacco use, alcohol consumption, HPV infection, and poor oral hygiene. OSCC often presents as nonhealing ulcers or erythroplakia/leukoplakia and is diagnosed via biopsy. Treatment involves surgery, radiotherapy, and chemotherapy, with prognosis influenced by staging and risk factors [1][2][5][13].
Burden
Global 5-year survival: ~63% (early-stage) vs. <50% (advanced), with high recurrence (3–7% annually) [5][9][18].
Accounts for 377,713 annual cases worldwide, disproportionately impacting low-resource regions [8][14].
Significant morbidity due to speech/swallowing impairments and treatment-related toxicity [5][15].
Therapies
Early-stage (I/II): Surgery or radiation, with surgery preferred for functional preservation [3][7][11].
Advanced-stage (III/IV): Multimodal therapy (surgery + adjuvant chemoradiation), with cisplatin or cetuximab commonly used [3][4][15].
Emerging approaches include immunotherapy (pembrolizumab/nivolumab) and targeted therapies [4][15].
Categories: rare neoplastic diseases, rare otorhinolaryngological diseases
Research Papers
1,339 drug discovery papers about Squamous cell carcinoma of the oral cavity, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,339 drug discovery papers about Squamous cell carcinoma of the oral cavity, with 4 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-18 | Ferroptosis Biomarkers in HPV-Negative Head and Neck Squamous Cell Carcinoma
Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer of the oral cavity, pharynx, larynx and upper airway. HNSCC is subdivided into distinct clinical entities based on the presence or absence of high-risk human papillomavirus (HPV) infection. While HPV-positive HNSCC patients respond better to conventional and targeted therapies than HPV-negative cases, recurrence is more frequent in HPV-negative cases with limited treatment options. Ferroptosis is a form of iron-based programmed cell death caused by excessive lipid peroxide accumulation. Biomarkers of ferroptosis have proven useful for identifying and triggering ferroptosis in models of treatment-resistant cancers. Identifying and understanding ferroptosis biomarker function in HPV-negative HNSCC allows the possibility for more effective treatment strategies. Methods: Literature searches combined with the public online ferroptosis database FerrDB V3 were utilized for the objective identification and classification of established and non-established ferroptosis biomarkers in HPV-negative HNSCC. Additional novel biomarkers were identified based on known roles in HNSCC oncogenesis. Results: A total of 30 ferroptosis biomarkers were identified associated with HPV-negative disease. Biomarkers were grouped according to shared biological functions, with each marker summarized for prognostic and mechanistic roles in HNSCC ferroptosis. Conclusions: The described biomarkers present a means for stratifying tumors for ferroptotic induction, with several offering potential novel methods for overcoming refractory HPV-negative disease. These biomarkers may warrant further investigation into devising future patient-tolerant strategies that selectively activate ferroptosis in HPV-negative HNSCC.
2026-06-03 | Ultra-low-dose immunotherapy plus oral metronomic chemotherapy versus paclitaxel-carboplatin in platinum-sensitive recurrent or metastatic head and neck squamous cell carcinoma: A randomized phase III trial.
LBA6007 Background: Standard first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) includes platinum-based chemotherapy (PBC) combined with pembrolizumab or cetuximab; however, these regimens remain inaccessible for many patients globally, particularly in resource-limited settings. Triple oral metronomic chemotherapy combined with ultra-low-dose immunotherapy (TMC-I) has demonstrated promising activity and tolerability in earlier studies. We conducted a randomized phase III trial comparing TMC-I with PBC (paclitaxel and carboplatin) in patients with R/M-HNSCC receiving first-line palliative therapy. Methods: In this open-label, multicenter, phase III trial conducted at two centers, 422 patients with R/M-HNSCC were randomized (1:1) to receive paclitaxel 175 mg/m² plus carboplatin AUC 6 every 3 weeks (Arm-A) or TMC-I (oral methotrexate 9 mg/m² weekly, celecoxib 200 mg twice daily, erlotinib 150 mg daily, and nivolumab 20 mg IV every 3 weeks) (Arm-B). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and quality of life (QoL). The planned sample size of 422 patients (211 per arm) provided 80% power with a two-sided α of 0.05. The trial was registered with the Clinical Trials Registry–India (CTRI/2024/01/061661). Results: The median age was 49.5 years (IQR 42–58), 85.5% were male, 78.9% had oral tobacco use, 76.3% had oral cavity primaries, 25.6% had metastatic disease, and 30.6% had ECOG performance status 2. After a median follow-up of 10.8 months (95% CI 8.1–13.6) in Arm-A and 11.9 months (95% CI 10.3–13.4) in Arm-B, the primary endpoint of OS was significantly improved with TMC-I compared with PBC. Twelve-month OS was 46% versus 23%, and six-month OS was 69% versus 52% (p < 0.001). Median OS was 10.3 versus 6.2 months (HR 0.565, 95% CI 0.439–0.728; p < 0.001). Median PFS was 5.5 versus 2.7 months (HR 0.465, 95% CI 0.371–0.582; p < 0.001). ORR was higher with TMC-I than with PBC (53.4% vs 24.1%; p < 0.001), with fewer grade ≥3 adverse events (34.1% vs 46.4%; p = 0.010). No treatment-related deaths were observed, and patient-reported QoL was preserved with TMC-I. Conclusion: TMC-I significantly improved survival outcomes and response rates while reducing severe toxicity and preserving QoL compared with PBC. At approximately USD 230 per month, TMC-I represents a promising and cost-effective first-line treatment option for patients with R/M-HNSCC. Clinical trial information: CTRI/2024/01/061661.
2026-05-27 | Metronomic adjuvant chemotherapy (MACE) in locally advanced oral cavity squamous cell carcinoma post-surgery and adjuvant treatment (MACE postop): A phase III randomized controlled trial.
6002 Background: The role of maintenance systemic therapy following definitive surgery and adjuvant treatment in locally advanced oral cavity squamous cell carcinoma (OCSCC) remains undefined. This phase III trial evaluated whether oral metronomic adjuvant chemotherapy (MACE) improves survival compared with observation. Methods: This multicenter, open-label, phase III superiority trial conducted in India enrolled patients with stage II–IV OCSCC (AJCC 7th edition) who were clinico-radiologically disease-free 1–2 months after completion of definitive surgery with adjuvant treatment. Patients were randomly assigned (1:1) to observation (OBS) or oral MACE for up to 18 cycles. MACE comprised methotrexate 15 mg/m² once weekly (four doses per 28-day cycle) plus celecoxib 200 mg twice daily. Adherence to MACE was monitored at 3-monthly follow-up visits using patient-reported medication logs, supplemented by objective verification through review of returned empty drug containers. The primary endpoint was 2-year overall survival (OS). The planned sample size was 712; accrual was stopped early following emerging external evidence, with ethics committee approval. Results: Between February 2017 and April 2025, 410 patients were enrolled (OBS, n=208; MACE, n=202); approximately three-quarters had stage IV disease in both arms. The median number of MACE cycles delivered was 15; 92 patients discontinued treatment, most commonly because of noncompliance (n=55) or disease progression (n=27). At a median follow-up of 42.5 months, 129 deaths were observed (70 in OBS and 59 in MACE). Two-year OS was 70.2% (95% CI, 63.0–76.2) in the OBS arm and 79.2% (95% CI, 72.5–84.4) in the MACE arm (hazard ratio [HR], 0.76; p=0.13). Two-year progression-free survival was 68.0% (95% CI, 61.0–74.1) with OBS and 77.0% (95% CI, 70.2–82.4) with MACE (HR, 0.72; p=0.044). Distant recurrences occurred in 30 patients (14.4%) in the OBS arm and 17 patients (8.4%) in the MACE arm, while second primary malignancies were observed in 8 (3.8%) and 3 (1.5%) patients, respectively. Grade 3–4 toxicity with MACE was observed in 6.9%. Exploratory subgroup analyses suggested greater benefit in patients with extranodal extension and stage IV disease. The average cost of MACE per cycle, including toxicity management, was approximately USD 10. Conclusions: MACE following definitive local therapy did not significantly improve overall survival in locally advanced OCSCC. However, a statistically significant improvement in progression-free survival was observed, driven by a reduction in distant metastases and second primary malignancies. These findings suggest that selected high-risk subgroups—particularly patients with extranodal extension and advanced-stage disease—may derive benefit from this low-cost and well-tolerated strategy. Clinical trial information: CTRI/2017/02/007777.
2026-04-15 | Nutritional prehabilitation in head and neck cancer patients (PreHead) - A randomized controlled trial study protocol.
Up to 60% of patients with head and neck cancer are malnourished upon first presentation. Malnutrition has been associated with a higher risk of adverse events and decreased quality of life and survival. Patients with a high risk of malnutrition often receive pretreatment dietary treatment before surgery or (chemo)radiotherapy, i.e., nutritional prehabilitation. However, previous research suggests that patients with a low or medium risk of malnutrition may also benefit from nutritional prehabilitation. To investigate the effect of nutritional prehabilitation on adverse events, nutritional status, patient-reported quality of life, tumor recurrence, and (disease-specific and overall) survival. To evaluate the cost-effectiveness of nutritional prehabilitation compared with standard care. A single-center, non-blinded, randomized controlled trial. Patients with locoregionally advanced stage (III or IV) primary mucosal squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx treated with curative intent and with a low or medium risk of malnutrition according to the Malnutrition Universal Screening tool. Based on a power analysis, a total of 128 patients will be included. The intervention arm will receive nutritional prehabilitation and the control arm will receive standard care (no nutritional prehabilitation). Adverse events (i.e., surgical complications and (chemo)radiotherapy toxicity). Complications will be measured within 30 days after surgery using the Clavien-Dindo classification. Toxicity will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), 6 and 12 weeks after the start of (chemo)radiotherapy. It is hypothesized that nutritional prehabilitation, compared with no nutritional prehabilitation, will result in fewer (severe) adverse events, improvement of nutritional status, higher quality of life, equal risk of recurrence and better survival. It is hypothesized that the intervention will be cost-effective. The trial is registered in the Dutch Trial Register under registration number NL87676.042.24.
2026-04-14 | Salivary adjuncts for the early detection of potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) in the oral cavity and on the lip in adults: a living systematic review protocol
abstract not found
2026-07-18 | Ferroptosis Biomarkers in HPV-Negative Head and Neck Squamous Cell Carcinoma
Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer of the oral cavity, pharynx, larynx and upper airway. HNSCC is subdivided into distinct clinical entities based on the presence or absence of high-risk human papillomavirus (HPV) infection. While HPV-positive HNSCC patients respond better to conventional and targeted therapies than HPV-negative cases, recurrence is more frequent in HPV-negative cases with limited treatment options. Ferroptosis is a form of iron-based programmed cell death caused by excessive lipid peroxide accumulation. Biomarkers of ferroptosis have proven useful for identifying and triggering ferroptosis in models of treatment-resistant cancers. Identifying and understanding ferroptosis biomarker function in HPV-negative HNSCC allows the possibility for more effective treatment strategies. Methods: Literature searches combined with the public online ferroptosis database FerrDB V3 were utilized for the objective identification and classification of established and non-established ferroptosis biomarkers in HPV-negative HNSCC. Additional novel biomarkers were identified based on known roles in HNSCC oncogenesis. Results: A total of 30 ferroptosis biomarkers were identified associated with HPV-negative disease. Biomarkers were grouped according to shared biological functions, with each marker summarized for prognostic and mechanistic roles in HNSCC ferroptosis. Conclusions: The described biomarkers present a means for stratifying tumors for ferroptotic induction, with several offering potential novel methods for overcoming refractory HPV-negative disease. These biomarkers may warrant further investigation into devising future patient-tolerant strategies that selectively activate ferroptosis in HPV-negative HNSCC.
2026-06-03 | Ultra-low-dose immunotherapy plus oral metronomic chemotherapy versus paclitaxel-carboplatin in platinum-sensitive recurrent or metastatic head and neck squamous cell carcinoma: A randomized phase III trial.
LBA6007 Background: Standard first-line therapy for recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) includes platinum-based chemotherapy (PBC) combined with pembrolizumab or cetuximab; however, these regimens remain inaccessible for many patients globally, particularly in resource-limited settings. Triple oral metronomic chemotherapy combined with ultra-low-dose immunotherapy (TMC-I) has demonstrated promising activity and tolerability in earlier studies. We conducted a randomized phase III trial comparing TMC-I with PBC (paclitaxel and carboplatin) in patients with R/M-HNSCC receiving first-line palliative therapy. Methods: In this open-label, multicenter, phase III trial conducted at two centers, 422 patients with R/M-HNSCC were randomized (1:1) to receive paclitaxel 175 mg/m² plus carboplatin AUC 6 every 3 weeks (Arm-A) or TMC-I (oral methotrexate 9 mg/m² weekly, celecoxib 200 mg twice daily, erlotinib 150 mg daily, and nivolumab 20 mg IV every 3 weeks) (Arm-B). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), safety, and quality of life (QoL). The planned sample size of 422 patients (211 per arm) provided 80% power with a two-sided α of 0.05. The trial was registered with the Clinical Trials Registry–India (CTRI/2024/01/061661). Results: The median age was 49.5 years (IQR 42–58), 85.5% were male, 78.9% had oral tobacco use, 76.3% had oral cavity primaries, 25.6% had metastatic disease, and 30.6% had ECOG performance status 2. After a median follow-up of 10.8 months (95% CI 8.1–13.6) in Arm-A and 11.9 months (95% CI 10.3–13.4) in Arm-B, the primary endpoint of OS was significantly improved with TMC-I compared with PBC. Twelve-month OS was 46% versus 23%, and six-month OS was 69% versus 52% (p < 0.001). Median OS was 10.3 versus 6.2 months (HR 0.565, 95% CI 0.439–0.728; p < 0.001). Median PFS was 5.5 versus 2.7 months (HR 0.465, 95% CI 0.371–0.582; p < 0.001). ORR was higher with TMC-I than with PBC (53.4% vs 24.1%; p < 0.001), with fewer grade ≥3 adverse events (34.1% vs 46.4%; p = 0.010). No treatment-related deaths were observed, and patient-reported QoL was preserved with TMC-I. Conclusion: TMC-I significantly improved survival outcomes and response rates while reducing severe toxicity and preserving QoL compared with PBC. At approximately USD 230 per month, TMC-I represents a promising and cost-effective first-line treatment option for patients with R/M-HNSCC. Clinical trial information: CTRI/2024/01/061661.
2026-05-27 | Metronomic adjuvant chemotherapy (MACE) in locally advanced oral cavity squamous cell carcinoma post-surgery and adjuvant treatment (MACE postop): A phase III randomized controlled trial.
6002 Background: The role of maintenance systemic therapy following definitive surgery and adjuvant treatment in locally advanced oral cavity squamous cell carcinoma (OCSCC) remains undefined. This phase III trial evaluated whether oral metronomic adjuvant chemotherapy (MACE) improves survival compared with observation. Methods: This multicenter, open-label, phase III superiority trial conducted in India enrolled patients with stage II–IV OCSCC (AJCC 7th edition) who were clinico-radiologically disease-free 1–2 months after completion of definitive surgery with adjuvant treatment. Patients were randomly assigned (1:1) to observation (OBS) or oral MACE for up to 18 cycles. MACE comprised methotrexate 15 mg/m² once weekly (four doses per 28-day cycle) plus celecoxib 200 mg twice daily. Adherence to MACE was monitored at 3-monthly follow-up visits using patient-reported medication logs, supplemented by objective verification through review of returned empty drug containers. The primary endpoint was 2-year overall survival (OS). The planned sample size was 712; accrual was stopped early following emerging external evidence, with ethics committee approval. Results: Between February 2017 and April 2025, 410 patients were enrolled (OBS, n=208; MACE, n=202); approximately three-quarters had stage IV disease in both arms. The median number of MACE cycles delivered was 15; 92 patients discontinued treatment, most commonly because of noncompliance (n=55) or disease progression (n=27). At a median follow-up of 42.5 months, 129 deaths were observed (70 in OBS and 59 in MACE). Two-year OS was 70.2% (95% CI, 63.0–76.2) in the OBS arm and 79.2% (95% CI, 72.5–84.4) in the MACE arm (hazard ratio [HR], 0.76; p=0.13). Two-year progression-free survival was 68.0% (95% CI, 61.0–74.1) with OBS and 77.0% (95% CI, 70.2–82.4) with MACE (HR, 0.72; p=0.044). Distant recurrences occurred in 30 patients (14.4%) in the OBS arm and 17 patients (8.4%) in the MACE arm, while second primary malignancies were observed in 8 (3.8%) and 3 (1.5%) patients, respectively. Grade 3–4 toxicity with MACE was observed in 6.9%. Exploratory subgroup analyses suggested greater benefit in patients with extranodal extension and stage IV disease. The average cost of MACE per cycle, including toxicity management, was approximately USD 10. Conclusions: MACE following definitive local therapy did not significantly improve overall survival in locally advanced OCSCC. However, a statistically significant improvement in progression-free survival was observed, driven by a reduction in distant metastases and second primary malignancies. These findings suggest that selected high-risk subgroups—particularly patients with extranodal extension and advanced-stage disease—may derive benefit from this low-cost and well-tolerated strategy. Clinical trial information: CTRI/2017/02/007777.
2026-04-15 | Nutritional prehabilitation in head and neck cancer patients (PreHead) - A randomized controlled trial study protocol.
Up to 60% of patients with head and neck cancer are malnourished upon first presentation. Malnutrition has been associated with a higher risk of adverse events and decreased quality of life and survival. Patients with a high risk of malnutrition often receive pretreatment dietary treatment before surgery or (chemo)radiotherapy, i.e., nutritional prehabilitation. However, previous research suggests that patients with a low or medium risk of malnutrition may also benefit from nutritional prehabilitation. To investigate the effect of nutritional prehabilitation on adverse events, nutritional status, patient-reported quality of life, tumor recurrence, and (disease-specific and overall) survival. To evaluate the cost-effectiveness of nutritional prehabilitation compared with standard care. A single-center, non-blinded, randomized controlled trial. Patients with locoregionally advanced stage (III or IV) primary mucosal squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx treated with curative intent and with a low or medium risk of malnutrition according to the Malnutrition Universal Screening tool. Based on a power analysis, a total of 128 patients will be included. The intervention arm will receive nutritional prehabilitation and the control arm will receive standard care (no nutritional prehabilitation). Adverse events (i.e., surgical complications and (chemo)radiotherapy toxicity). Complications will be measured within 30 days after surgery using the Clavien-Dindo classification. Toxicity will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), 6 and 12 weeks after the start of (chemo)radiotherapy. It is hypothesized that nutritional prehabilitation, compared with no nutritional prehabilitation, will result in fewer (severe) adverse events, improvement of nutritional status, higher quality of life, equal risk of recurrence and better survival. It is hypothesized that the intervention will be cost-effective. The trial is registered in the Dutch Trial Register under registration number NL87676.042.24.
2026-04-14 | Salivary adjuncts for the early detection of potentially malignant disorders (OPMDs) and oral squamous cell carcinoma (OSCC) in the oral cavity and on the lip in adults: a living systematic review protocol
abstract not found
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Drug Discovery Landscape
7 orphan drug designations for Squamous cell carcinoma of the oral cavity.
7 orphan drug designations for Squamous cell carcinoma of the oral cavity.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Cisplatin transmucosal system | small molecules | FDA | 2022-07-13 | — | Privo Technologies |
zinflavonoids | small molecules | FDA | 2021-01-07 | — | Aveta Biomics, Inc. |
cisplatin | small molecules | FDA | 2015-11-03 | — | Privo Technologies |
adenoviral vector expressing the E.coli purine nucleoside phosphorylase gene and fludarabine | gene therapies | FDA | 2015-06-08 | — | GeoVax, Inc. |
Copper meso-5,15-bis[3-[(1,2-dicarba-closododecaboranyl)methoxy]phenyl]-meso-12,20-dinitroporphyrin | small molecules | EMA | 2013-06-27 | — | Turnkey Pharmaconsulting Ireland Limited |
Nimorazole maleate | small molecules | EMA | 2012-02-09 | — | [INACTIVE] Conventia Medical LLP |
Cisplatin/epinephrine | small molecules | FDA | 2000-04-03 | — | Matrix Pharmaceutical, Inc. |
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