RARE DISEASE
Squamous cell carcinoma of the oropharynx
Squamous cell carcinoma of the oropharynx
Squamous cell carcinoma of the oropharynx
Drug discovery
7
drugs
With orphan designations
Overview
Squamous cell carcinoma of the oropharynx (OPSCC) is a head and neck malignancy primarily linked to HPV infection (70-80% of cases) or tobacco/alcohol use. HPV-positive tumors, often affecting the tonsils/base of tongue, present with cervical lymphadenopathy and have superior prognosis compared to HPV-negative tumors, which typically involve older patients and advanced stages [1][5][9]. Diagnosis relies on biopsy and imaging, with treatment strategies emphasizing organ preservation through surgery, radiotherapy, chemotherapy, or combined modalities [5][15].
Burden
Annual U.S. incidence: ~11.5/100,000 persons, with rising HPV-driven cases in younger cohorts [2][14][18].
5-year survival: >80% for HPV-positive vs. <50% for HPV-negative tumors [9][14].
Economic and functional burdens from treatment toxicities (e.g., dysphagia) and rising healthcare costs [12][16].
Therapies
Early-stage: Transoral surgery (e.g., TORS) or definitive radiotherapy (RT) [3][15].
Locally advanced: Concurrent cisplatin-based chemoradiation (standard) or cetuximab for cisplatin-ineligible patients [11][15][19].
Adjuvant therapy: Postoperative RT ± cisplatin for high-risk features (e.g., extracapsular extension, positive margins) [7][15].
Categories: rare neoplastic diseases, rare otorhinolaryngological diseases
Research Papers
666 drug discovery papers related to Squamous cell carcinoma of the oropharynx, with 3 first-in-class and 4 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
666 drug discovery papers related to Squamous cell carcinoma of the oropharynx, with 3 first-in-class and 4 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-08 | Human Papillomavirus DNA and p16 Expression in Oral and Oropharyngeal Squamous Cell Carcinoma: A Cross-Sectional Clinicopathologic Study in Western India
Background: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is biologically and clinically distinct from conventional tobacco- and alcohol-related head and neck squamous cell carcinoma. Indian data remain heterogeneous because oral cavity and oropharyngeal tumors are often analyzed together despite their different etiologic patterns. This study evaluated p16INK4a (p16) expression and high-risk HPV DNA detection in oral cavity and oropharyngeal squamous cell carcinoma and assessed their association with clinicopathologic variables. Materials and methods: This cross-sectional observational study included 100 adult patients with biopsy-proven squamous cell carcinoma of the oral cavity or oropharynx treated at a tertiary care center in Surat, Gujarat, India. Demographic characteristics, tobacco-related habits, tumor site, clinical presentation, and histopathological findings were recorded. All cases underwent hematoxylin and eosin examination and p16 immunohistochemistry. Fresh tissue was available for high-risk HPV DNA testing in 89 cases and was analyzed for HPV genotypes 16, 18, and 45 using multiplex real-time polymerase chain reaction. Associations were tested using the chi-square test or Fisher's exact test, as appropriate, and effect size was estimated using Cramer's V. Results: p16 positivity was identified in six of 100 cases (6.0%), and HPV DNA was detected in five of 89 tested cases (5.6%). All p16-positive and HPV DNA-positive patients were male. p16 positivity was significantly more frequent in oropharyngeal tumors than in oral cavity tumors (5/24, 20.8% vs. 1/76, 1.3%; p=0.0028). The base of the tongue was the most common p16-positive subsite (4/6, 66.7%). p16 expression was significantly associated with HPV DNA detection, with five of six p16-positive tumors showing HPV DNA positivity and no HPV DNA detection among p16-negative tumors (Fisher's exact p < 0.001). Most p16-positive cases had no documented history of tobacco chewing, smoking, or alcohol consumption. Conclusion: p16 expression and HPV DNA detection were uncommon in this Western Indian cohort, likely reflecting the predominance of oral cavity tumors and traditional risk-factor-associated disease. Biomarker-positive cases were concentrated in male patients with oropharyngeal tumors, particularly tumors involving the base of the tongue. Because HPV DNA testing was performed in 89 cases and was limited to genotypes 16, 18, and 45, these findings should be interpreted as a site-aware assessment of common high-risk HPV types rather than a comprehensive estimate of all HPV-driven disease. Combining p16 expression with HPV DNA testing may provide a more balanced assessment of HPV involvement than either test alone, particularly in resource-limited settings.
2026-06-30 | Determination of budding grades in squamous cell carcinomas of the oropharynx
The World Health Organization report on the prevalence of oropharyngeal cancer (OC) places it in sixth place among men and tenth among women worldwide. A pressing problem is the increase in OC cases in recent decades among young patients, which researchers associate infection with high-risk human papillomavirus (HPV). Among all OC, many histological forms are squamous cell carcinomas (SCC). It should be noted that HPV-associated carcinomas have a better prognosis, namely up to 20% of patients do not show recurrence after treatment, which is significantly different from the course observed in patients with HPV-unassociated OC. In the context of cancer prognosis, another important prognostic indicator is interesting - tumor budding (TB), which actively develops on the side of the invasive front of the tumor and is often described in literature as an independent factor of poor prognosis, early vascular invasion and metastasis. There are very few studies comparing the intensity of TB and HPV association for the prognosis of SCC and they mostly concern tumors of other areas of the head and neck, which determines the relevance of this work.The aim of the work is to investigate the distribution of tumor budding gradations according to clinical and morphological characteristics of oropharyngeal squamous cell carcinomas important for prognosis, in particular, to assess the relationship of budding with HPV association (p16 status) and proliferation index (Ki-67 expression).For the study, biopsy and surgical material samples of SCC of the oropharynx of 69 patients (21 women and 48 men) who were in the oncology department of the Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov, Dnipro from 2019 to 2022 and received appropriate treatment were selected. The age of the patients ranged from 45 to 86 years; the average age was 64.09±8.95 years. IHC was performed according to the TermoScientific (TS) protocols with primary antibodies p16 (sp1, RTU, LabVision, USA) and Ki-67 (sp6, RTU, LabVision, USA), and the Lab Vision Quanto (TS, USA) imaging system.The distribution of TB grades according to the three-level system (from 0 to 4 cells - 1 (low), from 5 to 9 clusters – 2 (moderate), from 10 and more – 3 (high) according to clinical and morphological indicators showed a statistically significant difference only by the sex of the patients, namely the gradation of high budding levels among men was significantly higher than among women (10 out of 11 (90.91%) compared to 1 out of 11 (9.09%), (p<0.05), this is probably due to the prevalence of such bad habits among men as smoking and alcohol abuse, which are frequent etiological causes of head and neck cancer development, as an alternative path to the development of OC without HPV infection.Distribution of TB grades in HPV-positive samples (p16 – positive) and HPV-negative (p16-negative) OC demonstrated the largest number of HPV-negative carcinomas in the subgroup with 3 budding grades, namely with grade 1 HPV-negative (p16-negative) were 59.38% of samples (19 out of 32), with grade 2 – 57.69% of samples (15 out of 26), and with grade 3 – already 90.91% of samples (10 out of 11), (p<0.05), which confirms the more unfavorable prognosis of HPV-unassociated OC.The proliferation index by Ki-67 did not show a statistically significant relationship with the distribution of TB grades, which makes the latter an independent factor in the prognosis in SCC of the oropharynx.
2026-05-28 | ERBIOTAX (TTCC-2022-02): A phase II, multicenter, randomized study of cetuximab with or without weekly paclitaxel after progression on first-line pembrolizumab plus platinum/5-FU in recurrent or metastatic head and neck squamous cell carcinoma.
TPS6131 Background: Pembrolizumab, with or without platinum–5FU (PF), is the current first-line (1L) standard of care for PD-L1–positive recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). However, no established standard of care exists after progression on immune checkpoint inhibitors (ICI). Emerging evidence suggests that cetuximab administered post-ICI achieves higher objective response rates (ORR) and longer progression-free (PFS) and overall survival (OS) compared with historical second-line (2L) cetuximab outcomes from the pre-ICI era. We hypothesize that 2L treatment with cetuximab +/- paclitaxel may be more effective after ICI failure than previously observed in the pre-ICI era. Methods: This is a multicenter, open-label, randomized, non-comparative, two-arm, investigator-initiated phase 2 trial. Patients will be randomized (2:1) to cetuximab plus paclitaxel (Arm A: ERBITAX) or cetuximab monotherapy (Arm B), administered on Days 1, 8 and 15 of 21-day cycles for 4 cycles, followed in both arms by biweekly cetuximab monotherapy until disease progression, death, unacceptable toxicity, or withdrawal of consent. A total of 65 evaluable patients will be enrolled: 41 in Arm A (H0: ORR 25%, H1: 45%, 80% power, two-sided alpha 0.05) and 24 in Arm B (H0: ORR 10%, H1: 30%, 80% power, two-sided alpha 0.05). The primary endpoint is ORR in each arm. Secondary endpoints include disease control rate (DCR), PFS, OS, health-related quality of life (EORTC QLQ-C30, EORTC QLQ-H&N35 and EuroQol EQ-5D) and safety. Baseline tumor tissue (all patients) and on-treatment samples (between cycles 2-5 in 50% of patients; optionally at progression), as well as serial plasma samples will be collected for translational exploratory studies. Patients must have histologically confirmed SCCHN of oral cavity, oropharynx (HPV-positive or HPV-negative), hypopharynx, or larynx, with confirmed progression per RECIST 1.1. on or after 1L pembro + PF. The study started enrollment in June 2025, with 7 patients enrolled by December 23, 2025. The total accrual period is 18 months. Clinical trial identifiers: NCT06856213; EUDRACT 2024-514953-31-00. Trial supported by Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany, providing study medication and financial support. Clinical trial information: NCT06856213 .
2026-07-08 | Human Papillomavirus DNA and p16 Expression in Oral and Oropharyngeal Squamous Cell Carcinoma: A Cross-Sectional Clinicopathologic Study in Western India
Background: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is biologically and clinically distinct from conventional tobacco- and alcohol-related head and neck squamous cell carcinoma. Indian data remain heterogeneous because oral cavity and oropharyngeal tumors are often analyzed together despite their different etiologic patterns. This study evaluated p16INK4a (p16) expression and high-risk HPV DNA detection in oral cavity and oropharyngeal squamous cell carcinoma and assessed their association with clinicopathologic variables. Materials and methods: This cross-sectional observational study included 100 adult patients with biopsy-proven squamous cell carcinoma of the oral cavity or oropharynx treated at a tertiary care center in Surat, Gujarat, India. Demographic characteristics, tobacco-related habits, tumor site, clinical presentation, and histopathological findings were recorded. All cases underwent hematoxylin and eosin examination and p16 immunohistochemistry. Fresh tissue was available for high-risk HPV DNA testing in 89 cases and was analyzed for HPV genotypes 16, 18, and 45 using multiplex real-time polymerase chain reaction. Associations were tested using the chi-square test or Fisher's exact test, as appropriate, and effect size was estimated using Cramer's V. Results: p16 positivity was identified in six of 100 cases (6.0%), and HPV DNA was detected in five of 89 tested cases (5.6%). All p16-positive and HPV DNA-positive patients were male. p16 positivity was significantly more frequent in oropharyngeal tumors than in oral cavity tumors (5/24, 20.8% vs. 1/76, 1.3%; p=0.0028). The base of the tongue was the most common p16-positive subsite (4/6, 66.7%). p16 expression was significantly associated with HPV DNA detection, with five of six p16-positive tumors showing HPV DNA positivity and no HPV DNA detection among p16-negative tumors (Fisher's exact p < 0.001). Most p16-positive cases had no documented history of tobacco chewing, smoking, or alcohol consumption. Conclusion: p16 expression and HPV DNA detection were uncommon in this Western Indian cohort, likely reflecting the predominance of oral cavity tumors and traditional risk-factor-associated disease. Biomarker-positive cases were concentrated in male patients with oropharyngeal tumors, particularly tumors involving the base of the tongue. Because HPV DNA testing was performed in 89 cases and was limited to genotypes 16, 18, and 45, these findings should be interpreted as a site-aware assessment of common high-risk HPV types rather than a comprehensive estimate of all HPV-driven disease. Combining p16 expression with HPV DNA testing may provide a more balanced assessment of HPV involvement than either test alone, particularly in resource-limited settings.
2026-06-30 | Determination of budding grades in squamous cell carcinomas of the oropharynx
The World Health Organization report on the prevalence of oropharyngeal cancer (OC) places it in sixth place among men and tenth among women worldwide. A pressing problem is the increase in OC cases in recent decades among young patients, which researchers associate infection with high-risk human papillomavirus (HPV). Among all OC, many histological forms are squamous cell carcinomas (SCC). It should be noted that HPV-associated carcinomas have a better prognosis, namely up to 20% of patients do not show recurrence after treatment, which is significantly different from the course observed in patients with HPV-unassociated OC. In the context of cancer prognosis, another important prognostic indicator is interesting - tumor budding (TB), which actively develops on the side of the invasive front of the tumor and is often described in literature as an independent factor of poor prognosis, early vascular invasion and metastasis. There are very few studies comparing the intensity of TB and HPV association for the prognosis of SCC and they mostly concern tumors of other areas of the head and neck, which determines the relevance of this work.The aim of the work is to investigate the distribution of tumor budding gradations according to clinical and morphological characteristics of oropharyngeal squamous cell carcinomas important for prognosis, in particular, to assess the relationship of budding with HPV association (p16 status) and proliferation index (Ki-67 expression).For the study, biopsy and surgical material samples of SCC of the oropharynx of 69 patients (21 women and 48 men) who were in the oncology department of the Dnipropetrovsk Regional Clinical Hospital named after I.I. Mechnikov, Dnipro from 2019 to 2022 and received appropriate treatment were selected. The age of the patients ranged from 45 to 86 years; the average age was 64.09±8.95 years. IHC was performed according to the TermoScientific (TS) protocols with primary antibodies p16 (sp1, RTU, LabVision, USA) and Ki-67 (sp6, RTU, LabVision, USA), and the Lab Vision Quanto (TS, USA) imaging system.The distribution of TB grades according to the three-level system (from 0 to 4 cells - 1 (low), from 5 to 9 clusters – 2 (moderate), from 10 and more – 3 (high) according to clinical and morphological indicators showed a statistically significant difference only by the sex of the patients, namely the gradation of high budding levels among men was significantly higher than among women (10 out of 11 (90.91%) compared to 1 out of 11 (9.09%), (p<0.05), this is probably due to the prevalence of such bad habits among men as smoking and alcohol abuse, which are frequent etiological causes of head and neck cancer development, as an alternative path to the development of OC without HPV infection.Distribution of TB grades in HPV-positive samples (p16 – positive) and HPV-negative (p16-negative) OC demonstrated the largest number of HPV-negative carcinomas in the subgroup with 3 budding grades, namely with grade 1 HPV-negative (p16-negative) were 59.38% of samples (19 out of 32), with grade 2 – 57.69% of samples (15 out of 26), and with grade 3 – already 90.91% of samples (10 out of 11), (p<0.05), which confirms the more unfavorable prognosis of HPV-unassociated OC.The proliferation index by Ki-67 did not show a statistically significant relationship with the distribution of TB grades, which makes the latter an independent factor in the prognosis in SCC of the oropharynx.
2026-05-28 | ERBIOTAX (TTCC-2022-02): A phase II, multicenter, randomized study of cetuximab with or without weekly paclitaxel after progression on first-line pembrolizumab plus platinum/5-FU in recurrent or metastatic head and neck squamous cell carcinoma.
TPS6131 Background: Pembrolizumab, with or without platinum–5FU (PF), is the current first-line (1L) standard of care for PD-L1–positive recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). However, no established standard of care exists after progression on immune checkpoint inhibitors (ICI). Emerging evidence suggests that cetuximab administered post-ICI achieves higher objective response rates (ORR) and longer progression-free (PFS) and overall survival (OS) compared with historical second-line (2L) cetuximab outcomes from the pre-ICI era. We hypothesize that 2L treatment with cetuximab +/- paclitaxel may be more effective after ICI failure than previously observed in the pre-ICI era. Methods: This is a multicenter, open-label, randomized, non-comparative, two-arm, investigator-initiated phase 2 trial. Patients will be randomized (2:1) to cetuximab plus paclitaxel (Arm A: ERBITAX) or cetuximab monotherapy (Arm B), administered on Days 1, 8 and 15 of 21-day cycles for 4 cycles, followed in both arms by biweekly cetuximab monotherapy until disease progression, death, unacceptable toxicity, or withdrawal of consent. A total of 65 evaluable patients will be enrolled: 41 in Arm A (H0: ORR 25%, H1: 45%, 80% power, two-sided alpha 0.05) and 24 in Arm B (H0: ORR 10%, H1: 30%, 80% power, two-sided alpha 0.05). The primary endpoint is ORR in each arm. Secondary endpoints include disease control rate (DCR), PFS, OS, health-related quality of life (EORTC QLQ-C30, EORTC QLQ-H&N35 and EuroQol EQ-5D) and safety. Baseline tumor tissue (all patients) and on-treatment samples (between cycles 2-5 in 50% of patients; optionally at progression), as well as serial plasma samples will be collected for translational exploratory studies. Patients must have histologically confirmed SCCHN of oral cavity, oropharynx (HPV-positive or HPV-negative), hypopharynx, or larynx, with confirmed progression per RECIST 1.1. on or after 1L pembro + PF. The study started enrollment in June 2025, with 7 patients enrolled by December 23, 2025. The total accrual period is 18 months. Clinical trial identifiers: NCT06856213; EUDRACT 2024-514953-31-00. Trial supported by Merck, S.L.U., Madrid, Spain, an affiliate of Merck KGaA, Darmstadt, Germany, providing study medication and financial support. Clinical trial information: NCT06856213 .
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Drug Discovery Landscape
7 orphan drug designations for Squamous cell carcinoma of the oropharynx, including 1 approved therapy.
7 orphan drug designations for Squamous cell carcinoma of the oropharynx, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adenovirus serotype-5 (Ad5) vector that contains a modified non-oncogenic fused early 6 (E6) and early 7 (E7) gene of the human papillomavirus (HPV); (Ad5 [E1-, E2b-]-E6/E7) | gene therapies | FDA | 2014-09-04 | — | Etubics Corporation |
live attenuated bioengineered Listeria monocytogenes immunotherapy | vaccines | FDA | 2013-11-04 | — | Ayala Pharmaceuticals, Inc. |
HPV-16 cancer therapeutic trojan peptide vaccine | vaccines | FDA | 2009-01-12 | — | Gliknik, Inc. |
MAGE-A3 cancer therapeutic Trojan peptide vaccine | vaccines | FDA | 2008-11-24 | — | Gliknik, Inc. |
Humanised antibody fragment (Ep-CAM)-truncated Pseudomonas exotoxin A fusion protein | antibodies | EMA | 2005-06-20 | — | Viventia Biotech (EU) Limited |
recombinant fusion protein with a truncated form of the cytotoxic protein Pseudomonas exotoxin | proteins | FDA | 2005-01-28 | — | Sesen Bio, Inc. (Sesen Bio) |
cetuximab [Erbitux] | antibodies | FDA | 2000-07-03 | 2006-03-01 | ImClone Systems Incorporated |
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