Nature Communications | Phase II Clinical Study of CDK4/6 Inhibitor Dalpiciclib in Combination with Cetuximab for Anti-PD-1-Resistant Head and Neck Squamous Cell Carcinoma

This study is the first to report that the combination of CDK4/6 inhibitor dalpiciclib and cetuximab achieved an objective response rate of 67.9% in patients with anti-PD-1-resistant, HPV-negative recurrent or metastatic head and neck squamous cell carcinoma, significantly outperforming current second-line treatment options, with manageable safety.

 

Literature Overview

The article titled “Dalpiciclib combined with cetuximab in patients with HPV-negative, anti-PD-1-resistant recurrent or metastatic head and neck squamous cell carcinoma: A phase II trial,” published in Nature Communications, reviews and summarizes the efficacy and safety of combining the CDK4/6 inhibitor dalpiciclib with cetuximab in patients with HPV-negative, anti-PD-1-resistant recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The single-arm, prospective phase II trial enrolled 28 patients and demonstrated that this combination regimen achieved an objective response rate of 67.9%, a median progression-free survival of 7.0 months, and a median overall survival of 17.0 months, with manageable toxicity. These results provide a new treatment option for HNSCC patients who have failed anti-PD-1 therapy, offering significant clinical translational value.

Background Knowledge

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy worldwide, with the human papillomavirus (HPV)-negative subtype accounting for the majority of cases and associated with poor prognosis, particularly in the recurrent or metastatic (R/M) setting. In recent years, anti-PD-1 immunotherapy has become the standard first-line treatment; however, a large proportion of patients exhibit primary or acquired resistance, leading to treatment failure. After anti-PD-1 resistance, current second-line therapy primarily involves cetuximab (an anti-EGFR monoclonal antibody), but monotherapy yields an objective response rate (ORR) of only 13%–24% and a median overall survival (OS) of less than six months, indicating limited efficacy. HPV-negative HNSCC is frequently characterized by hyperactivation of the CDK4/6 pathway, including CCND1 amplification and CDKN2A deletion, suggesting potential therapeutic benefit from CDK4/6 inhibitors. Additionally, EGFR is highly expressed in over 90% of HNSCC cases and can drive cell cycle progression, supporting a synergistic antitumor mechanism when combining CDK4/6 and EGFR inhibitors. Previous studies have shown that palbociclib combined with cetuximab has some activity in patients resistant to platinum or cetuximab, but this combination has not yet been evaluated in the anti-PD-1-resistant population. This study addresses this unmet clinical need by investigating the efficacy and safety of dalpiciclib (a domestically developed selective CDK4/6 inhibitor) in combination with cetuximab in patients with anti-PD-1-resistant, HPV-negative R/M HNSCC, thereby filling a critical research gap in this field.

 

 

Research Methods and Experiments

This was a single-center, single-arm, phase II clinical trial (NCT05721443) that enrolled 28 patients with histologically confirmed HPV-negative, anti-PD-1-refractory recurrent or metastatic HNSCC who had not previously received cetuximab. Patients received oral dalpiciclib (150 mg daily, days 1–21) in combination with intravenous cetuximab (400 mg/m² in the first cycle, followed by 250 mg/m² weekly) in 28-day cycles until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR), and secondary endpoints included PFS, OS, DOR, and safety. Biomarker analyses included PD-L1 CPS assessment, NGS sequencing, and multiplex immunofluorescence analysis. All patients underwent efficacy and safety evaluations, with tumor responses assessed using RECIST 1.1 criteria and survival endpoints estimated using the Kaplan-Meier method.

Key Conclusions and Perspectives

• Among the 28 evaluable patients, the objective response rate (ORR) reached 67.9% (19/28), with a 95% CI of 49.0%–82.0%, significantly higher than the historical control range of 13%–24% for cetuximab monotherapy
• The median progression-free survival (PFS) was 7.0 months (95% CI: 4.13–NR), with a 6-month PFS rate of 53.6%; the median overall survival (OS) was 17.0 months (95% CI: 10.75–23.25), and the 12-month OS rate was 67.9%
• Treatment-related adverse events (TRAEs) occurred in all patients, mostly grade 1–2, with the most common being neutropenia (89.3%) and leukopenia (89.3%); the incidence of grade 3 TRAEs was 35.7%, primarily neutropenia and leukopenia (each 32.1%), with no grade 4–5 TRAEs reported
• Biomarker analyses showed that patients with PD-L1 CPS ≥ 1 or ≥ 20 still benefited from the combination therapy; those with CDK4 pathway-related gene alterations (CDKN2A deletion or CCND1 amplification) exhibited longer PFS, suggesting potential predictive value
• Four patients received anti-PD-1 rechallenge after disease progression, and among them, two who had previously responded to the combination therapy achieved partial remission again, suggesting that CDK4/6 inhibition may restore tumor sensitivity to immunotherapy

Research Significance and Prospects

This study is the first to demonstrate significant clinical activity of combining a CDK4/6 inhibitor with an EGFR inhibitor in patients with anti-PD-1-resistant, HPV-negative R/M HNSCC, achieving an ORR of 67.9%—far exceeding current second-line treatments—with manageable safety. These findings provide a novel, effective, and tolerable treatment strategy for patients who have failed immunotherapy, holding substantial clinical translational value.

Biomarker analyses suggest that genetic alterations in the CDK4 pathway may be associated with longer PFS, offering potential directions for future patient selection. Furthermore, the preliminary data on anti-PD-1 rechallenge indicate that CDK4/6 inhibition may remodel the tumor immune microenvironment and restore sensitivity to immunotherapy, providing a rationale for subsequent combination immunotherapies. However, this study employed a single-arm design with a small sample size and relatively short median follow-up, necessitating larger randomized controlled trials to confirm these findings. Future studies could explore optimizing this combination as a second-line or later therapy, as well as the potential for triplet regimens incorporating immunotherapy.

 

 

Conclusion

This study systematically evaluated the efficacy and safety of dalpiciclib in combination with cetuximab in patients with anti-PD-1-resistant, HPV-negative recurrent or metastatic head and neck squamous cell carcinoma. The results show that this combination regimen exhibits significant antitumor activity, with an objective response rate of 67.9%, a median progression-free survival of 7.0 months, and a median overall survival of 17.0 months, all markedly superior to current second-line standards of care. In terms of safety, although hematologic toxicities were common, most were grade 1–2, and grade 3 neutropenia and leukopenia were manageable, with no grade 4–5 treatment-related adverse events, indicating good tolerability. Biomarker analyses further revealed that genetic alterations in the CDK4 pathway may be associated with improved survival outcomes, and preliminary data from anti-PD-1 rechallenge suggest that this combination may restore immunosensitivity. Overall, this study provides a compelling new treatment option for patients with anti-PD-1-resistant HNSCC, with significant clinical implications, warranting further validation in larger populations.

 

Houyu Ju, Yunteng Wu, Chaoji Shi, Guoxin Ren, and Jingzhou Hu. Dalpicilib combined with cetuximab in patients with HPV-negative, anti-PD-1-resistant recurrent or metastatic head and neck squamous cell carcinoma: A phase II trial. Nature Communications.