For phase 2 clinical trials in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC), the selection of primary endpoints should focus on evaluating treatment efficacy, safety, and patient-centered outcomes. The following endpoints are commonly considered:

1. Objective Response Rate (ORR)

• ORR, which measures the proportion of patients achieving a significant reduction in tumor size (complete response [CR] or partial response [PR]), is a widely used primary endpoint in phase 2 trials.
• It is particularly relevant in R/M HNSCC due to the aggressive nature of the disease and the need to assess the tumor-shrinking potential of new therapies. For example, ORR was used as the primary endpoint in trials combining pembrolizumab with other agents ¹³¹⁷²⁵.
• ORR is typically assessed using standardized criteria such as RECIST 1.1 or iRECIST to ensure consistency and reliability ²⁵²⁷.

2. Progression-Free Survival (PFS)

• PFS measures the time from treatment initiation to disease progression or death. It is a meaningful endpoint for assessing the ability of a treatment to delay disease progression, especially in a population with limited treatment options.
• For instance, PFS was a primary endpoint in the KEYNOTE-048 trial, assessed using RECIST 1.1 criteria by central radiology review ¹⁷²⁷³¹.
• Median PFS in metastatic HNSCC is typically less than 6 months, highlighting the importance of this endpoint in evaluating new therapies ¹⁷.

3. Overall Survival (OS)

• OS, defined as the time from treatment initiation to death from any cause, is a critical endpoint in oncology trials. While more commonly used in phase 3 studies, it can also provide valuable preliminary survival data in phase 2 trials.
• OS was a primary endpoint in studies evaluating pembrolizumab and other immunotherapies, reflecting its importance in assessing long-term treatment benefits ^7172731.
• Median OS in R/M HNSCC is approximately 3-4 months after progression on first-line therapy, with a 1-year survival rate of only 5%, underscoring the need for therapies that improve survival outcomes ¹⁷.

4. Disease Control Rate (DCR)

• DCR, which includes CR, PR, and stable disease (SD), is another endpoint that provides a broader measure of treatment efficacy. It was used as a primary endpoint in trials evaluating combinations such as carboplatin and palbociclib ¹⁴.

5. Duration of Response (DOR)

• DOR measures how long a treatment response lasts and is particularly relevant in phase 2 trials to assess the durability of efficacy. For example, in the KN-052 study, 78% of participants maintained responses for six months or longer ⁷.

6. Safety and Tolerability

• Evaluating the safety and tolerability of treatments is a critical component of phase 2 trials, especially when testing novel agents or combinations.
• Safety endpoints often include the incidence of high-grade treatment-related adverse events (AEs), graded according to NCI CTCAE criteria. For instance, nivolumab monotherapy demonstrated a low frequency of high-grade AEs in platinum-refractory R/M HNSCC, making it a promising option ¹¹¹⁹³¹.

7. Patient-Reported Outcomes (PROs)

• PROs, such as quality of life (QoL), tumor-related symptom burden, and swallowing function, are increasingly recognized as important endpoints in R/M HNSCC trials.
• Validated tools like the EORTC QLQ-C30, H&N-35, and EAT-10 questionnaires are used to assess these outcomes, providing insights into the impact of treatment on patients' daily lives ³¹.

8. Biomarker-Based Endpoints

• Biomarker-driven endpoints, such as PD-L1 expression or immune profile-based signatures, are particularly relevant in trials involving immunotherapies.
• These endpoints help identify subgroups of patients more likely to benefit from specific treatments and refine patient selection. For example, PD-L1 positivity was an inclusion criterion in a pembrolizumab trial ¹⁸³¹.

9. Locoregional Tumor Control

• This endpoint evaluates the ability of a treatment to control the tumor within the local or regional area, addressing tumor-related symptom burden, which is a significant concern for patients with R/M HNSCC ³¹.

10. Exploratory Molecular and Immune Markers

• Exploratory endpoints, such as molecular and immune correlative studies, are often included to identify biomarkers that predict treatment response or resistance. These are particularly valuable in trials with small sample sizes ⁸.

Summary of Key Considerations

The choice of primary endpoints in phase 2 trials for R/M HNSCC depends on the trial's objectives, such as assessing efficacy, safety, or patient-centered outcomes. Commonly used endpoints include ORR, PFS, OS, and DOR, with additional considerations for safety, PROs, and biomarker-based measures. These endpoints provide early signals of efficacy and safety, guiding the design of subsequent phase 3 trials ^{78111314171819252731}.