Head and neck cancers comprise approximately 4% of all new cancer diagnoses globally and represent approximately 110,000 new cancer diagnoses and 17,000 cancer deaths annually in the United States.

Head and neck cancers are a heterogenous group of malignancies where prognosis and treatment varies by histology, anatomic site, and molecular characteristics. Historically, these malignancies were commonly associated with tobacco, areca nut, and alcohol use. While these risk factors remain important in some populations, increases in human papillomavirus (HPV)-associated disease and improved molecular characterization of head and neck cancers continue to improve understanding of etiologies and treatment approaches.

Patients diagnosed with early-stage head and neck cancers—especially HPV-associated oropharyngeal, Epstein-Barr virus–associated nasopharyngeal, and thyroid malignancies—have high cure rates; however, management of long-term treatment complications is challenging, and treatment options for patients with recurrent and metastatic disease remain limited. This year’s Head and Neck Cancer Almanac from The ASCO Post focuses on advances in the treatment of nasopharyngeal cancers, optimizing treatment of locally advanced head and neck squamous cell carcinoma based on HPV status, increasing immunotherapy-based regimens in recurrent/metastatic head and neck squamous cell carcinoma, and novel agents based on HPV status.

GUEST EDITORS

Thomas J. Roberts, MD, MBA

Lori Wirth, MD

Dr. Roberts is Instructor in Medicine at Harvard Medical School and a medical oncologist in the Center for Head and Neck Cancers at Massachusetts General Hospital. His research focuses on the epidemiology of head and neck cancers and approaches to improve the quality of care for patients with cancer. Dr. Wirth is Associate Professor in Medicine at Harvard Medical School and Medical Director of the Center for Head and Neck Cancers at Massachusetts General Hospital. Her research focuses on combined-modality therapy for head and neck cancer and novel treatments for advanced thyroid cancers.

Optimizing Treatment of Nasopharyngeal Cancers

Results from several large, randomized trials presented recently continue to expand the evidence base guiding management of nasopharyngeal carcinomas. The current standard of care for locally advanced nasopharyngeal carcinoma of gemcitabine/cisplatin induction followed by concurrent chemoradiotherapy was established by Zhang et al in 2019.¹ At the 2023 ASCO Annual Meeting, Tang et al presented randomized data affirming the survival benefit associated with gemcitabine/cisplatin in locally advanced nasopharyngeal carcinoma.² Although this study compared adjuvant rather than induction chemotherapy regimens, it found that among 240 patients with N2 or N3 nasopharyngeal carcinoma, adjuvant gemcitabine/cisplatin was associated with superior 3-year survival compared to cisplatin/fluorouracil (83.9% vs 71.5%; hazard ratio [HR] = 0.54).

Two trials presented at ASCO 2023 contributed to the growing body of literature supporting the use of immunotherapy in nasopharyngeal carcinoma. The CONTINUUM trial randomly assigned 425 patients in China with stage III/IV nasophargyneal carcinoma to receive gemcitabine/cisplatin induction followed by concurrent chemoradiotherapy with or without sintilimab, a novel PD-1 antibody with a higher affinity for PD-1 than other immune checkpoint inhibitors.^3,4  The investigators found a 3-year event-free survival of 86.1% among patients who received sintilimab vs 76.0% among patients who received standard of care (HR = 0.59). Updated survival data from the JUPITER-02 trial showed that patients with recurrent/metastatic nasopharyngeal carcinoma who were randomly assigned to receive toripalimab, another novel PD-1 inhibitor, in addition to gemcitabine/cisplatin had a 3-year overall survival of 64.5% compared to 49.2% among patients receiving gemcitabine/cisplatin alone (HR = 0.63).⁵ Both trials reported benefits from the addition of PD-1 inhibitors regardless of PD-L1 expression, suggesting the addition of immunotherapy to chemotherapy may soon become standard of care for patients with nasopharyngeal carcinoma in both curative and recurrent/metastatic disease.

De-escalation in HPV-Associated Head and Neck Cancers

Management of acute and long-term treatment complications in patients with HPV-associated oropharyngeal carcinomas remains challenging, and optimal strategies and patient selection criteria for de-intensification studies need to be defined. Strategies being investigated include reductions in radiation dose, response-tailored dose reduction after induction chemotherapy, and use of novel biomarkers such as HPV circulating tumor DNA to guide treatment. Updated results from the Quarterback trial, presented at ASCO 2023, showed that response to induction chemotherapy may be a reasonable way to select patients for dose-reduced chemoradiotherapy, but further randomized studies are needed to evaluate this approach.⁶ The DARS study represents an alternative approach to reduce long-term complications from chemoradiotherapy. In this randomized phase III trial of patients with oropharyngeal carcinoma or hypopharyngeal squamous cell carcinoma, patients who received dysphagia-optimized intensity-modulated radiation therapy (IMRT) had significantly improved swallowing function 12 months following treatment compared to patients who received standard IMRT.⁷

Treatment Intensification for Locally Advanced HPV-Negative Disease

Outcomes among patients with unresectable, locally advanced HPV-negative head and neck squamous cell carcinoma remain poor. Two trials reported on efforts to intensify therapy for these patients. In KEYNOTE-412, a phase III trial of 804 patients with locally advanced HPV-negative head and neck squamous cell carcinoma presented at ESMO Congress 2022, patients were randomly assigned to chemoradiotherapy with or without pembrolizumab. Results showed a trend towards improved event-free survival (HR = 0.83, 95% confidence interval [CI] = 0.68–1.03), but this difference was not statistically significant.⁸ Five-year survival updates were reported from a randomized phase II trial of chemoradiotherapy with or without xevinapant, the results of which were originally presented at ESMO 2020.⁹ This study enrolled patients with locally advanced head and neck squamous cell carcinoma and at least a 10-year pack history of smoking, and results showed an improved 5-year overall survival among patients who received xevinapant vs placebo (28% vs 53%; HR = 0.47, 95% CI = 0.27–0.84).

Immunotherapy-Based Regimens for Recurrent/Metastatic Disease

Since the publication of KEYNOTE-048 in 2019, pembrolizumab with or without chemotherapy has been standard of care for first-line recurrent/metastatic head and neck squamous cell carcinoma.¹⁰ However, the KEYNOTE-048 regimen, pembrolizumab plus platinum and fluorouracil, is associated with significant toxicity, with 85% of patients experiencing an adverse event of grade 3 or greater. Two recent trials provide alternatives for patients who are ineligible for fluorouracil or cisplatin. KEYNOTE-B10 evaluated pembrolizumab plus platinum and paclitaxel in recurrent/metastatic head and neck squamous cell carcinoma. Among 92 patients, the overall response rate was 43%, and the median overall survival was 12.1 months with a manageable toxicity profile.¹¹ The FRAIL-IMMUNE trial (GORTEC 2018-03) evaluated durvalumab with weekly carboplatin and paclitaxel among 64 cisplatin-ineligible patients with recurrent/metastatic head and neck squamous cell carcinoma. Investigators reported a 1-year survival rate of 76% and median overall survival of 18 months.¹² Results from the head and neck cohort of the COSMIC-021 study showed activity with cabozantinib and atezolizumab in a pretreated population, suggesting this combination could become another chemotherapy-free regimen for patients with recurrent/metastatic HSNCC.¹³

HPV Status–Based Novel Agents in the Recurrent/Metastatic Setting

Improved understanding of head and neck squamous cell carcinoma and mechanisms of resistance to therapy have led to the development of several novel agents now under investigation. In a phase II trial of ficlatuzumab, an antihepatocyte growth factor monoclonal antibody, with or without cetuximab, subgroup analyses by HPV status showed overall response rates with the combination of 0% (0 of 16) in HPV-positive and 38% (6 of 16) in HPV-negative head and neck squamous cell carcinoma.¹⁴ Similarly, a phase I dose expansion trial of BCA101, a bispecific EGFR/TGFbeta antibody, in combination with pembrolizumab showed overall response rates of 65% (13 of 20) in HPV-negative and 22% (2 of 11) in HPV-positive head and neck squamous cell carcinoma.¹⁵

Among novel agents targeting HPV-associated oropharyngeal carcinoma, a phase I trial of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, showed a response rate of 42% (5 of 12) among HPV-positive patients with a CPS ≥ 1% who received CUE-101 in combination with pembrolizumab.¹⁶ In the VERSATILE-002 trial evaluating PDS0101, a novel HPV-targeted immunotherapy, in combination with pembrolizumab, the overall response rate among immune checkpoint inhibitor–naive HPV-positive patients was 26.5% (9 of 34), and the median progression-free survival was 10.4 months.¹⁷

These novel therapies require additional investigation, including randomized studies with larger sample sizes comparing them to standard therapies, but early data suggest improving understanding of the different biology of HPV-positive and HPV-negative head and neck squamous cell carcinoma may be leading to personalized therapeutic approaches based on HPV status.

Thyroid Cancer Advances

Early detection of thyroid cancers remains a key component of ensuring good prognoses for patients. Pichardo et al demonstrated the feasibility and potential benefits of population-based screening for medullary thyroid carcinoma. Using a population-based genomic screening cohort, they identified 75 patients with germline RET variants. Twenty of these patients underwent elective thyroidectomy, and 60% of these (12 of 20) were found to have pathologically-confirmed medullary thyroid carcinoma.¹⁸ To improve risk stratification of thyroid nodules, Xing et al developed a gene-imprinted in situ hybridization assay that can distinguish benign and malignant nodules with high accuracy.¹⁹ Advances in the treatment of advanced thyroid cancer were limited, and entities such as anaplastic thyroid cancer remain difficult to treat, as evidenced by the negative results from NRG/RTOG 1912, which added pazopanib to chemoradiotherapy.²⁰

These advances in the detection and treatment of head and neck cancers over the past year will continue to increase treatment personalization to improve disease control and management of treatment toxicities. 

DISCLOSURE: Dr. Roberts is employed by and has a leadership position in Biocon Biologics Ltd; owns stock in Syngene International Ltd; and has an immediate family member who is employed by, has a leadership role with, and owns stock in Bicara Therapeutics. Dr. Wirth has served as a consultant or advisor for Bayer, Coherus, Curie Therapeutics, Eisai, Exelexis, Lilly, Merck, METIS Precision Medicine, Morphic Therapeutic, and Tome Biosciences; has received research funding from Checkmate Pharmaceuticals, Eisai, Lilly, and Novartis; has provided expert testimony for Eisai; and has disclosed a relationship with PDS Biotechnology.

References

1. Zhang Y, Chen L, Hu GQ, et al. Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma. N Engl J Med 381:1124-1135, 2019.

2. Tang LQ, Liu LT, Liu H, et al: Concurrent chemoradiotherapy followed by adjuvant cisplatin-gemcitabine versus cisplatin-5-fluorouracil chemotherapy for N2-3 nasopharyngeal carcinoma: A multicentre, open-label, randomised, controlled phase 3 trial. 2023 ASCO Annual Meeting. Abstract 6000. Presented June 5, 2023.

3. Ma J, Sun Y, Liu X, et al: PD-1 blockade with sintilimab plus induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT) versus IC-CCRT in locoregionally advanced nasopharyngeal carcinoma. 2023 ASCO Annual Meeting. Abstract LBA6002. Presented June 5, 2023

4. Zhang L, Mai W, Jiang W, et al: Sintilimab: A promising anti-Tumor PD-1 antibody. Front Oncol 10:594558, 2020.

5. Mai HQ, Chen QY, Chen DP, et al: Final overall survival analysis of JUPITER-02. 2023 ASCO Annual Meeting. Abstract 6009. Presented June 5, 2023

6. Posner MR, Botzler J, Takahashi M, et al: The Quarterback trials: Phase 2 series of sequential studies of induction chemotherapy followed by reduced dose chemoradiation for human papillomavirus positive oropharynx cancer. 2023 ASCO Annual Meeting. Abstract 6020. Presented June 5, 2023.

7. Nutting C, Finneran L, Roe J, et al: Dysphagia-optimised intensity-modulated radiotherapy versus standard intensity-modulated radiotherapy in patients with head and neck cancer (DARS): A phase 3, multicentre, randomised, controlled trial. Lancet Oncol 24:868-880, 2023.

8. Machiels JP, Tao Y, Burtness B, et al: Primary results of the phase 3 KEYNOTE-412 study: Pembrolizumab plus chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced head and neck squamous cell carcinoma. ESMO Congress 2022. Abstract LBA5. Presented September 11, 2022.

9. Bourhis J, Le Tourneau C, Calderon B, et al: 5-year overall survival in patients with locally advanced squamous cell carcinoma of the head and neck treated with xevinapant + chemoradiotherapy (CRT) vs placebo + CRT in a randomized, phase II study. ESMO Congress 2022. Abstract LBA33. Presented September 10, 2022.

10. Burtness B, Harrington KJ, Greil R, et al: Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study. Lancet 394:1915-1928, 2019.

11. Dzienis MR, Cundom JE, Fuentes CS, et al: Pembrolizumab + carboplatin + paclitaxel as first-line therapy in recurrent/metastatic head and neck squamous cell carcinoma: Phase VI KEYNOTE-B10 study. ESMO Congress 2022. Abstract 651O. Presented September 12, 2022.

12. Fayette J, Cropet C, Gautier J, et al: Results of the multicenter phase II FRAIL-IMMUNE trial evaluating the efficacy and safety of durvalumab combined with weekly paclitaxel carboplatin in first line in patients with recurrent/metastatic squamous cell carcinoma of the head and neck not eligible for cisplatin-based therapies. 2023 ASCO Annual Meeting. Abstract 6003. Presented June 5, 2023.

13. Rottey S, Santoro A, Arnold S, et al: Cabozantinib plus atezolizumab in advanced head and neck cancer previously treated with platinum-containing chemotherapy. 2022 SITC Annual Meeting. Abstract 570. Presented November 10, 2022.

14. Bauman JE, Saba NF, Roe D, et al: Randomized phase II trial of ficlatuzumab with or without cetuximab in pan-refractory, recurrent/metastatic head and neck cancer. J Clin Oncol 41:3851-3862, 2023.

15. Hanna GJ, Kaczmar JM, Zandberg DP, et al: Dose expansion results of the bifunctional EGFR/TGFβ inhibitor BCA101 with pembrolizumab in patients with recurrent, metastatic head and neck squamous cell carcinoma. 2023 ASCO Annual Meeting. Abstract 6005. Presented June 5, 2023.

16. Chung CH, Dimitrios A, Colevas D, et al: A phase 1 dose-escalation and expansion study of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, given as monotherapy and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer. 2023 ASCO Annual Meeting. Abstract 6013. Presented June 5, 2023.

17.  Price KAR, Kaczmar JM, Worden FP, et al: Safety and efficacy of immune checkpoint inhibitor (ICI) naïve cohort from study of PDS0101 and pembrolizumab in HPV16-positive head and neck squamous cell carcinoma (HNSCC). 2023 ASCO Annual Meeting. Abstract 6012. Presented June 5, 2023.

18. Pichardo PFA, Hellums RN, Hao J, et al: Thyroidectomy outcomes in patients identified with RET pathogenic variants through a population genomic screening program. JAMA Otolaryngol Head Neck Surg 149:195-202, 2023.

19. Xu H, Zhang Y, Wu H, et al: High diagnostic accuracy of epigenetic imprinting biomarkers in thyroid nodules. J Clin Oncol 41:1296-1306, 2023.

20. Sherman EJ, Harris J, Bible KC, et al: Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): A randomised, double-blind, placebo-controlled, multicentre, phase 2 trial. Lancet Oncol 24:175-186, 2023.