Currently, more clinical studies are needed to determine the optimal first-line treatment regimen for patients with R/M HNSCC. Table 4 summarizes the data on the efficacy of first-line treatment regimens in the studies of R/M HNSCC mentioned in this discussion. This study describes the clinical and treatment characteristics of patients with R/M HNSCC who received first-line treatment with PD-1 inhibitors combined with taxanes regimens in Hunan, China, and its surrounding areas in a real-world setting. It provided the median PFS and OS, as well as the 12-month and 24-month PFS and OS rates for this cohort of patients. The prognostic factors associated with receiving PD-1 inhibitors combined with taxanes regimens were also identified. After a literature search, it was found that this study is currently the first in China to describe the efficacy and safety of first-line PD-1 inhibitor combined with taxanes chemotherapy for the treatment of R/M HNSCC in a real-world setting.

Regarding clinical characteristics, the median age, gender distribution, ECOG PS score, CPS score, and HPV positivity rate in our study population are similar to those observed in the KEYNOTE-048 trial’s immunotherapy combined with the chemotherapy group. However, there were notable differences in the primary tumor sites. The KEYNOTE-048 study reported the highest proportion of oropharyngeal cancers, whereas this study found a greater prevalence of oral cancers, which may be related to the higher incidence of oral cancers in the Hunan region due to betel quid chewing. Additionally, this study observed a lower proportion of patients with distant organ metastases compared to the KEYNOTE-048 study (32% vs. 73%).

In terms of efficacy, the ORR for the pembrolizumab combination chemotherapy group in the KEYNOTE-048 study was 36.3% [10]. Interim data from the KEYNOTE-B10 study reported an ORR of 49% [26]. A prospective phase II study presented by Chinese researchers at the same conference, which included 20 patients with recurrent/metastatic HNSCC treated with pembrolizumab combined with albumin-bound taxanes and cisplatin, achieved an ORR of up to 80% [24]. Conversely, a prospective phase I/II study in Austria involving 22 patients with recurrent/metastatic HNSCC treated with pembrolizumab and docetaxel reported an ORR of only 22.7% [28]. The present study observed an ORR of 51.9%. A prospective phase II study conducted by Japanese researchers, which included 35 patients with R/M HNSCC who had previously received PD-1 inhibitor and platinum-based therapy, reported an ORR of 69.6% for second-line treatment with paclitaxel and biweekly cetuximab [29]. These results indicate that similar regimens can yield significantly different ORRs across various regions and populations, highlighting the need for further clinical research to clarify efficacy variations between different regions and populations. A multicenter real-world study conducted in the United States, which involved first-line treatment of recurrent/metastatic HNSCC with pembrolizumab, platinum-based agents, and taxanes, reported a median real-world time to next treatment (rwTTNT) of 8.7 months (n = 83) [27], which is similar to the findings of this study. An Austrian study involving 22 patients with recurrent/metastatic HNSCC who received first-line treatment with pembrolizumab and docetaxel reported a median PFS of 5.8 months [28]. In a prospective phase II study conducted by Japanese researchers involving 35 patients with R/M HNSCC, the mPFS for second-line treatment with paclitaxel and biweekly cetuximab, following prior treatment with PD-1 inhibitor and platinum-based therapy, was reported to be 5.5 months [29]. Additionally, a prospective phase II study presented by Chinese researchers at the 2022 ESMO Annual Meeting, which included 20 patients treated first-line with pembrolizumab, albumin-bound taxanes, and cisplatin, showed a median PFS of 6.9 months [24]. In this study, the median PFS was 8.7 months, with a 12-month PFS rate of 43.6%, both of which are higher than the results reported in the KEYNOTE-048 study for the immunotherapy combination chemotherapy group (median PFS: 4.9 months, 12-month PFS rate: 17%). However, the median PFS of the above regimens did not exceed 10 months, indicating that R/M HNSCC remains highly susceptible to progression even after systemic therapy. This high propensity for progression is a major factor contributing to the poor prognosis of patients with R/M HNSCC. Therefore, there is a need for further exploration of medication use for patients entering the maintenance phase of treatment. The median OS in this study was 16.7 months, which was slightly higher than that of the KEYNOTE-048 study immune combination chemotherapy group (13.0 months), while the median OS of the KEYNOTE-B10 study published interim data was 13.1 months [26] A real-world study in the United States that included 83 patients reported a median rwOS of 14.9 months with first-line use of pembrolizumab combined with platinum and taxanes for patients with R/M HNSCC [27]. In an Austrian study that included 22 patients with R/M HNSCC, a median OS of up to 21.3 months was achieved with the first-line use of pembrolizumab and docetaxel [28]. In a prospective phase II study conducted by Japanese researchers involving 35 patients with R/M HNSCC, the mOS for those receiving second-line treatment with paclitaxel and biweekly cetuximab, after prior treatment with PD-1 inhibitor and platinum-based therapy, was reported to be 13.3 months [29]. In this study, the 12-month OS rate was 60.1% and the 24-month OS rate was 36.9%. In comparison, the KEYNOTE-048 study’s immune combination chemotherapy group had 12-month and 24-month OS rates of 53% and 29%, respectively [10], suggesting that substituting taxanes for 5-Fu might be a more effective treatment option.

Regarding factors affecting efficacy, this study did not find a correlation between HPV infection status and treatment outcomes. In contrast, most previous real-world studies on R/M HNSCC have shown a better prognosis for HPV-positive patients. This discrepancy may be related to the low rate of HPV detection in this study. In this study, patients in the population with a CPS < 1 had poorer OS, but the small sample size prevented finding statistically significant differences. There were also no significant differences in efficacy between patients with CPS scores of 1–19 and those with CPS scores ≥ 20. This may be due to the low CPS detection rate in the study population and the variability in the platforms of the reagents used for CPS testing across different hospitals, which could affect the results analysis. In addition, we found that patients who had the opportunity to undergo radiotherapy after treatment with this regimen had better PFS and OS than those who failed to gain access to radiotherapy, further demonstrating the importance of radiotherapy in HNSCC. This study also revealed that hypopharyngeal carcinoma had a poorer OS compared to other types of HNSCC (HR = 2.13, P = 0.088). However, due to the small sample size for hypopharyngeal carcinoma (N = 14), the result was not statistically significant. Previous research has similarly indicated that hypopharyngeal carcinoma generally has a worse prognosis than other head and neck squamous cell carcinomas [30]. Additionally, this study compared the efficacy based on the selection of platinum-based drugs, the type of taxanes used, and the origin of the PD-1 inhibitors (imported vs. domestic). No significant differences in efficacy were observed among these factors. Meanwhile, a recent head-to-head comparison between sindilizumab and pembrolizumab in patients with advanced non-small cell lung cancer conducted by Professor Wu Yilong’s team did not reveal any statistically significant differences in efficacy between the two treatments [31]. This indicates that imported and domestic PD-1 inhibitors have comparable efficacy. These clinical characteristics mentioned have not been addressed in previous studies on R/M HNSCC, providing valuable reference points for drug selection tailored to patients with different economic conditions.

In terms of safety, the TPExtreme and KEYNOTE-B10 studies have confirmed both the efficacy and safety of taxanes. Other studies have also demonstrated the good tolerability of docetaxel [32, 33]. In our study, no fatal adverse reactions were recorded, and only one patient discontinued treatment due to adverse reactions.

This study represents the first real-world investigation in China to describe the efficacy and safety of a PD-1 inhibitor combined with a taxane-based chemotherapy regimen as a first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Currently, first-line treatment decisions for R/M HNSCC continue to rely on findings from the KEYNOTE-048 study. The publication of our findings provides clinicians with valuable real-world evidence to support the use of a PD-1 inhibitor in combination with taxane-based chemotherapy for this patient population. When contextualized alongside recently released data from other countries on similar treatment regimens, our results suggest that PD-1 inhibitors combined with taxane-based chemotherapy are poised to replace the treatment paradigm established by the KEYNOTE-048 study. This regimen has the potential to become the most prevalent first-line treatment approach for R/M HNSCC in the near future. In addition to analyzing conventional outcomes such as objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), our study also compared the efficacy across different platinum agents, taxane agents, and sources of PD-1 inhibitors (imported versus domestically manufactured). Notably, no significant differences in efficacy were observed based on these clinical characteristics. These findings address a gap in prior R/M HNSCC clinical studies and provide valuable guidance for drug selection, especially for patients with varying economic circumstances.

This study shares several limitations commonly observed in real-world studies. For instance, the inability to control for confounding biases through study design, missing data, and potential issues with data accuracy. A notable example involves performance status (PS) scores: among the recorded data, 152 patients were categorized as having a PS score of 1, while only 2 patients were categorized as having a PS score of 2. Such a distribution is unlikely in clinical practice. After consulting clinical staff from participating institutions, it was determined that this discrepancy arose because, in some cases, healthcare providers did not conduct detailed PS assessments for patients with better physical conditions to save time, and inaccurately recorded patients with a true PS score of 0 as having a PS score of 1. Although this does not affect the prognostic outcome data of this study, it may impact the reliability of the multivariate analysis of prognostic factors.Additionally, the patient population in this study was primarily from Hunan Province and surrounding regions, limiting its generalizability to a national level. The relatively small sample size and short follow-up period further constrain the study’s findings. Post-progression treatment strategies, which are critical to patient outcomes, were not explored in this study. Furthermore, comorbidities, which could influence both treatment efficacy and prognosis, were also not analyzed. Another limitation is the exclusion of patients who discontinued treatment after the first cycle, which may restrict the reliability of the conclusions when compared with other clinical studies. There were 42 patients whose PD-L1 combined positive score (CPS) was unknown, and variations in CPS detection platforms across hospitals might have introduced bias into the results. CPS has been established as a prognostic factor for recurrent and metastatic HNSCC patients, and its absence for a subset of patients could limit the study’s findings. Similarly, HPV infection status was unknown for 69 patients in the study. The lack of this data may have impacted the conclusions regarding the correlation between HPV infection status and prognosis. We look forward to further clinical research to address these gaps.