Efficacy of two programmed cell death 1 combination regimens in recurrent and/or metastatic head and neck carcinoma: A real-world retrospective study

Abstract

BACKGROUND

The combination of programmed cell death 1 (PD-1) inhibitors with molecularly targeted agents, including anti-epidermal growth factor receptor monoclonal antibody (cetuximab) and multi-targeted tyrosine kinase inhibitor (such as anlotinib), has emerged as promising therapeutic strategies in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, comparisons of efficacy between the dual-agent regimens remain unexplored.

AIM

To evaluate the comparative survival benefits and treatment responses of PD-1 inhibitor plus cetuximab vs PD-1 inhibitor plus anlotinib in R/M HNSCC.

METHODS

In this real-world study, 24 patients who received PD-1 inhibitors combined with targeted agents at Peking University Cancer Hospital between November 2018 and May 2024 were retrospectively assessed. Patients were stratified into two groups: Anti-PD-1 plus cetuximab (n = 13) and anti-PD-1 plus anlotinib (n = 11). Clinical characteristics and follow-up outcomes were collected, and the overall response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) of the two strategies were analyzed.

RESULTS

The anti-PD-1 plus cetuximab group achieved an ORR of 27.3% and a DCR of 90.9%, while the anti-PD-1 plus anlotinib group showed an ORR of 40.0% and a DCR of 100%. The anti-PD-1 plus cetuximab group demonstrated significantly prolonged OS compared to the anti-PD-1 plus anlotinib group (19.2 months vs 5.8 months; hazard ratios = 0.37; P = 0.036). Survival benefits were consistently observed in subgroups, including patients with programmed death-ligand 1 combined positive score (CPS) ≥ 20 (29.7 months vs 4.1 months; P = 0.013), CPS ≥ 1 (29.7 months vs 4.1 months; P = 0.034), and those receiving first-line treatment (29.7 months vs 4.4 months; P = 0.024). PFS differences were not statistically significant (6.5 months vs 4.4 months, P = 0.448).

CONCLUSION

Both combination strategies showed antitumor activity in R/M HNSCC. In this retrospective real-world cohort, PD-1 inhibitor plus cetuximab was associated with prolonged OS, whereas PD-1 inhibitor plus anlotinib showed favorable disease control. Larger prospective studies are warranted to confirm these findings.

Key Words: Head and neck squamous cell carcinoma; Programmed cell death 1 inhibitor; Cetuximab; Anlotinib; Immuno-targeted therapy

Core Tip: Programmed cell death 1 (PD-1) inhibitors combined with cetuximab or anlotinib exhibit distinct therapeutic profiles in recurrent and/or metastatic head and neck squamous cell carcinoma. In this real-world cohort study, PD-1 inhibitor plus cetuximab was associated with significantly prolonged overall survival, whereas PD-1 inhibitor plus anlotinib showed favorable tumor response and disease control. These distinct efficacy profiles may help inform individualized treatment selection for PD-1-based immunotherapy-targeted therapy combinations.

INTRODUCTION

Head and neck squamous cell carcinoma (HNSCC) comprises a group of highly aggressive malignancies arising from the epithelium of the oral cavity, pharynx, and larynx. HNSCC represents a major global oncological burden, accounting for approximately 890000 new cases and 450000 deaths annually, with its incidence increasing by nearly 30% in recent decades[1]. Tobacco use, alcohol consumption, and areca nut exposure constitute the primary risk factors for HNSCC in developing regions, whereas human papillomavirus-associated disease accounts for a substantial proportion of cases in developed countries[2,3]. Despite multimodal treatment, including surgery, radiation therapy, and systemic therapy, approximately half of patients eventually develop recurrent and/or metastatic (R/M) disease[4].

For more than a decade after 2008, the EXTREME regimen (platinum-based chemotherapy plus cetuximab) served as the standard first-line treatment for R/M HNSCC. Nevertheless, the prognosis remained unfavorable, with a median overall survival (OS) of less than 12 months. The emergence of immune checkpoint inhibitors has transformed the treatment landscape for advanced malignancies, including HNSCC. Pembrolizumab, an immune checkpoint inhibitor targeting programmed cell death 1 (PD-1), demonstrated promising antitumor activity and a manageable safety profile in patients with platinum-refractory R/M HNSCC in the KEYNOTE-012[5], KEYNOTE-055[6], and KEYNOTE-040[7] trials. Subsequently, the landmark KEYNOTE-048 trial[8] established pembrolizumab-based regimens as standard first-line treatments for R/M HNSCC from 2019 onward: Pembrolizumab monotherapy for patients with a programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 and pembrolizumab combined with platinum-based chemotherapy for patients regardless of PD-L1 CPS. These regimens achieved median OS ranging from 12.3 months to 14.9 months and overall response rates (ORRs) ranging from 19% to 45%, depending on PD-L1 expression. Real-world data from Vietnam further indicated that pembrolizumab monotherapy provided clinically meaningful efficacy and favorable safety in patients with R/M HNSCC receiving later-line treatment, with greater benefit observed in those with a PD-L1 CPS ≥ 20, supporting its use in resource-limited settings[9].

However, pembrolizumab combined with chemotherapy is associated with greater toxicity than pembrolizumab monotherapy, with grade 3-5 treatment-related adverse events occurring in 71% of patients receiving immunochemotherapy compared with 17% of those receiving monotherapy. Accordingly, novel PD-1 inhibitor-based combinations have been investigated to achieve a more favorable balance between efficacy and safety. Current investigational strategies primarily include dual-immunotherapy regimens[10,11], and combinations of immunotherapy with targeted agents[12-15]. While some trials have failed to meet their primary endpoints[11,16], others have demonstrated encouraging results[12-14].

Epidermal growth factor receptor (EGFR) is expressed in more than 90% of HNSCCs, and its overexpression is associated with poor prognosis[17-19]. Cetuximab, an anti-EGFR antibody, is the only targeted agent approved by the United States Food and Drug Administration for HNSCC and can be administered as monotherapy, concurrently with radiation therapy, or in combination with platinum-based chemotherapy. The combination of pembrolizumab and cetuximab has demonstrated promising clinical activity in R/M HNSCC, with an ORR of 45% and a median OS of 18.4 months in a phase II study[20]. This combination was also relatively well tolerated. Similarly, a study evaluating nivolumab, another PD-1 inhibitor, in combination with cetuximab demonstrated clinical activity in a comparable patient population, with a 6-month ORR of 37%, a median progression-free survival (PFS) of 7.8 months, and a median OS of 14.5 months[21].

Another combination strategy involves multitargeted tyrosine kinase inhibitors (TKIs), such as cabozantinib[13], lenvatinib[15], and anlotinib[22]. Anlotinib[23] exerts antiangiogenic and antiproliferative effects by targeting vascular endothelial growth factor receptors 1/2/3, fibroblast growth factor receptors 1/2/3/4, platelet-derived growth factor receptors α/β, stem cell factor receptor (c-Kit), and RET proto-oncogene. Clinical evidence suggests that combining anlotinib with PD-1 inhibitors may produce synergistic antitumor activity in solid malignancies, including R/M HNSCC[24-26]. Our previous study of anlotinib combined with sintilimab, a PD-1 inhibitor, in patients with R/M HNSCC reported an ORR of 50% and a disease control rate (DCR) of 100%, although the median OS was limited to 4.29 months[27].

Although PD-1 inhibitors combined with either cetuximab or anlotinib have shown promising activity in HNSCC, the comparative efficacy of these two therapeutic strategies in R/M HNSCC remains unclear. To address this knowledge gap, we conducted a real-world retrospective study comparing the survival outcomes and treatment responses associated with PD-1 inhibitor plus cetuximab vs PD-1 inhibitor plus anlotinib in patients with R/M HNSCC.

MATERIALS AND METHODS

Patient cohort

This study was designed as a retrospective observational study and patients with R/M HNSCC who received PD-1 inhibitors in combination with targeted agents from November 2018 to May 2024 at Peking University Cancer Hospital were screened. PD-1 inhibitors included pembrolizumab, sintilimab, toripalimab, and tislelizumab. Targeted agents included anti-EGFR antibody (cetuximab), and multi-targeting TKIs (anlotinib and lenvatinib). Patients were excluded if they had previously received immunotherapy, had no measurable lesion defined by the Response Evaluation Criteria in Solid Tumors version 1.1, had resectable recurrent disease, or were lost to follow-up.

The study profile of this work is illustrated in Figure 1. The protocol of this study was approved by the Ethics Committee of Peking University Cancer Hospital (No. 2019YJZ12). Written informed consent was obtained from all participants in accordance with the Declaration of Helsinki.

Figure 1 Flow chart demonstrating the study cohort. R/M HNSCC: Recurrent and/or metastatic head and neck squamous cell carcinoma.

Therapeutic regimens

All the patients received at least one dose of PD-1 inhibitor combined with cetuximab or anlotinib. One of the following PD-1 inhibitors was intravenously administered according to investigator’s choice: Pembrolizumab (200 mg once every 3 weeks), sintilimab (200 mg once every 3 weeks), toripalimab (240 mg once every 3 weeks), or tislelizumab (200 mg once every 3 weeks). Cetuximab was administered with an initial loading dose of 400 mg/m² intravenously followed by 250 mg/m² intravenously once weekly. Anlotinib (12 mg) was taken orally daily for the first 14 days in a 3-week cycle. The combination regimens might be discontinued when disease progression or intolerable adverse reactions occurred. Additionally, dosage adjustments of anlotinib to either 10 mg or 8 mg once daily were permitted based on the tolerability during the treatment.

Assessments

Baseline demographic characteristics and disease progression status of each patient were collected through the electronic medical record system during hospitalization. Tumor PD-L1 expression was analyzed by using PD-L1 IHC 22C3 assay (Dako, Carpinteria, CA). Efficacy assessments were performed according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Patients without post-treatment image in our institution were censored in efficacy analysis. Follow-up of the patients was mainly conducted through mobile phone with the communication with the relatives. OS was defined as the interval from the initiation of the treatment to the date of death due to any cause or last follow-up. PFS was defined as the interval from the date of the treatment to the date of disease progression or death due to any cause, whichever occurred first. Time to response (TTR) for patients with partial response (PR) or complete response (CR) was the time from treatment to the first response. Duration of response (DOR) was defined as the time from the first response to disease progression or death. Time to progression (TTP) for patients with stable disease (SD) was defined as the time from treatment to disease progression or death.

Statistical analysis

The statistical data presented in this study were analyzed by using SPSS software. For variables such as demographic data, continuous variables are presented as median and interquartile range, and categorical variables are expressed as percentages. OS, PFS, TTR, DOR and TTP were estimated using the Kaplan-Meier survival method, and hazard ratio (HR) and 95% confidence interval (CI) were estimated using the Cox proportional hazards model. Because this retrospective observational study was conducted in a real-world setting, no prespecified sample size calculation was performed to ensure adequate statistical power for formal comparative hypothesis testing. Therefore, all P values derived from between-group comparisons should be interpreted as exploratory rather than confirmatory.

RESULTS

Patient characteristics

A total of 24 patients were suitable to be included in our study. Immunotherapy regimens included sintilimab (n = 17), pembrolizumab (n = 7), toripalimab (n = 1), and tislelizumab (n = 1). We divided the patients into two treatment groups: The anti-PD-1 plus cetuximab group (n = 13), and anti-PD-1 plus anlotinib group (n = 11). The baseline characteristics are summarized in detail (Table 1). There were no significant differences in age, gender, smoking history, drinking history, primary tumor site, P16 status, prior radiotherapy history, treatment lines or PD-L1 CPS between the two treatment groups (all P > 0.05). However, all 13 patients (100%) were locoregional recurrence in the anti-PD-1 plus cetuximab group, whereas 4 patients (36.4%) had both locoregional recurrence and distant metastasis in the anti-PD-1 plus anlotinib group (P = 0.031).

Table 1 Demographics and clinical characteristics of the study cohort, n (%).

Characteristics	Total (n = 24)	Anti-PD-1 plus cetuximab (n = 13)	Anti-PD-1 plus anlotinib (n = 11)	P value
Median age, years (IQR)	55.5 (50-68)	51 (46-70)	61 (54.5-67)	0.324
Sex
Male	15 (62.5)	8 (61.5)	7 (63.6)	1.000
Female	9 (37.5)	5 (38.5)	4 (36.4)
Smoking history
Former or current	13 (54.2)	7 (53.8)	6 (54.5)	1.000
Never	11 (45.8)	6 (46.2)	5 (45.5)
Alcohol abuse				1.000
Former or current	8 (33.3)	4 (30.8)	4 (36.4)
Never	16 (66.7)	9 (69.2)	7 (63.6)
Primary tumor site				1.0001
Oral cavity	12 (50.0)	6 (46.2)	6 (54.5)
Oropharynx	2 (8.3)	2 (15.4)	0 (0)
Hypopharynx	4 (16.7)	3 (23.1)	1 (9.1)
Larynx	5 (20.8)	2 (15.4)	3 (27.3)
Nasal cavity	1 (4.2)	0 (0)	1 (9.1)
Recurrence pattern				0.031a
Local or regional recurrence only	20 (83.3)	13 (100.0)	7 (63.6)
With distant metastasis	4 (16.7)	0 (0)	4 (36.4)
P16 immunohistochemistry				0.942
Positive	2 (8.3)	1 (7.7)	1 (9.1)
Negative	14 (58.3)	8 (61.5)	6 (54.5)
Unknown status	8 (33.3)	4 (30.8)	4 (36.4)
Previous radiotherapy				0.482
Yes	22 (91.7)	11 (84.6)	11 (100)
No	2 (8.3)	2 (15.4)	0 (0)
Treatment line				1.000
First	18 (75.0)	10 (76.9)	8 (72.7)
Second	6 (25.0)	3 (23.1)	3 (27.3)
PD-L1 CPS				0.6222
< 1	4 (16.7)	1 (7.7)	3 (27.3)
1-20	2 (8.3)	2 (15.4)	0 (0)
≥ 20	9 (37.5)	6 (46.2)	3 (27.3)
Inadequate tissue sample	9 (37.5)	4 (30.8)	5 (45.5)

¹Oropharynx, hypopharynx, larynx, and nasal cavity” were grouped together as one group for statistical analysis.

²Combined positive score (CPS) of < 1 and CPS of 1-20” were grouped together as one group for statistical analysis.

^aP < 0.05.

PD-1: Programmed cell death 1; CPS: Combined positive score; PD-L1: Programmed death-ligand 1; IQR: Interquartile range.

Clinical efficacy

At the data cutoff on December 5, 2024, 1 (9.1%) patient in the anti-PD-1 plus cetuximab group achieved CR, 2 (18.2%) patients showed PR, and 7 (63.6%) patients had a SD. Therefore, the ORR was 27.3%, and the DCR was 90.9% (Table 2). In contrast, the anti-PD-1 plus anlotinib group had 4 (40.0%) patients with PR and 6 (60.0%) with SD, resulting in an ORR of 40.0% and a DCR of 100%. The best percentage change in target lesions from baseline is shown in Figure 2. Radiological results of the computed tomography scans for the patient with CR are illustrated in Figure 3.

Figure 2 Waterfall plot of best overall response based on target lesions only. 21 (87.5%) of 24 patients are included. 3 participants are excluded in the efficacy analysis due to the lack of post-treatment image for Response Evaluation Criteria in Solid Tumors. PD-1: Programmed cell death 1.

Figure 3 Radiological changes of target lesions at the primary site in a female patient with control rate. A: Baseline imaging at recurrence; B: After the administration of pembrolizumab plus cetuximab.

Table 2 Best overall response, n (%).

	Anti-PD-1 plus cetuximab (n = 11)	Anti-PD-1 plus anlotinib (n = 10)
Best overall response
Complete response	1 (9.1)	0 (0)
Partial response	2 (18.2)	4 (40.0)
Stable disease	7 (63.6)	6 (60.0)
Progressive disease	1 (9.1)	0 (0)
ORR, %	27.3	40.0
DCR, %	90.9	100

PD-1: Programmed cell death 1; ORR: Overall response rate; DCR: Disease control rate.

The median follow-up time was 26.9 months (95%CI: 13.3-40.6) in the anti-PD-1 plus cetuximab group and 7.1 months (95%CI: 4.5-15.4) in the anti-PD-1 plus anlotinib group. Median TTR for patients achieving PR or CR in the anti-PD-1 plus cetuximab group was 1.4 months (range 1.4-1.5), compared to 2.4 months (range 1.3-4.2) in the anti-PD-1 plus anlotinib group (P = 0.148). For these patients, the median DOR was 26.4 months (range 2.9-26.4) and 2.8 months (range 0-3.0), respectively (P = 0.221). For patients with SD, median TTP was 3.6 months (95%CI: 1.4-5.9) and 3.0 months (95%CI: 0.48-5.5) in the anti-PD-1 plus cetuximab group and anti-PD-1 plus anlotinib group, respectively (P = 0.540).

The anti-PD-1 plus cetuximab group had a longer OS compared to the anti-PD-1 plus anlotinib group (19.2 months vs 5.8 months; P = 0.036; Figure 4A). Subgroup analysis of OS by PD-L1 expression also showed the difference. In patients with CPS ≥ 20, median OS was 29.7 months (95%CI: 0-64.5) in the anti-PD-1 plus cetuximab group and 4.1 months (95%CI: 0.4-7.8) in the anti-PD-1 plus anlotinib group (P = 0.013; Figure 4B). In the patients with CPS ≥ 1, the anti-PD-1 plus cetuximab group had a median OS of 29.7 months (95%CI: 0-64.7) compared to 4.1 months (95%CI: 0.4-7.8) in the anti-PD-1 plus anlotinib group (P = 0.034; Figure 4C). The anti-PD-1 plus cetuximab group demonstrated numerically longer, though not statistically significant, PFS compared to the anti-PD-1 plus anlotinib group in both the overall population (6.5 months vs 4.4 months; P = 0.448; Figure 4D) or PD-L1 subgroups (CPS ≥ 20: 27.8 months vs 4.1 months, P = 0.107; CPS ≥ 1: 4.7 months vs 4.1 months, P = 0.054; Supplementary Figure 1).

Figure 4 Kaplan-Meier curves of overall survival and progression-free survival for enrolled patients. A: Overall survival (OS) of all patients; B: OS of patients with combined positive score (CPS) ≥ 20; C: OS of patients with CPS ≥ 1; D: Progression-free survival of all patients. OS: Overall survival; CI: Confidence interval; HR: Hazard ratio; CPS: Combined positive score; PD-1: Programmed cell death 1.

Further analysis did not reveal any significant difference in OS between patients receiving pembrolizumab or sintilimab in the anti-PD-1 plus cetuximab group (P = 0.685; Figure 5). Notably, for patients who received PD-1 inhibitor plus targeted therapy as their first-line treatment, anti-PD-1 plus cetuximab group had a longer OS compared to the anti-PD-1 plus anlotinib group (29.7 months vs 4.4 months; P = 0.024; Figure 6).

Figure 5 Kaplan-Meier curves representing overall survival of patients treated with anti-programmed cell death 1 plus anti-epidermal growth factor receptor stratified by programmed cell death 1 antibody. OS: Overall survival.

Figure 6 Kaplan-Meier curves representing overall survival of patients in the first-line treatment for recurrent or metastatic disease. OS: Overall survival; CI: Confidence interval; HR: Hazard ratio; PD-1: Programmed cell death 1.

Treatment-related grade 1-2 adverse events were not systematically captured because of the retrospective nature of the medical record review. All documented grade ≥ 3 adverse events in the two groups are summarized in Table 3.

Table 3 Summary of grade ≥ 3 adverse events.

Event, n	Anti-PD-1 plus cetuximab (n = 11)	Anti-PD-1 plus anlotinib (n = 10)
Tumor pain	1	5
Decreased appetite	2	3
Tumor hemorrhage	1	2
Hypertension	0	3
Hypokalemia	0	1
Rash	1	1
Pneumonia	0	1
Diarrhea	0	1
Ascites	1	0

PD-1: Programmed cell death 1.

DISCUSSION

In this real-world study comparing PD-1 inhibitor plus cetuximab with PD-1 inhibitor plus anlotinib in patients with R/M HNSCC, both regimens demonstrated promising antitumor activity but exhibited distinct efficacy patterns. The anti-PD-1 plus anlotinib group showed higher ORR (40.0% vs 27.3%) and DCR (100% vs 90.9%). However, the anti-PD-1 plus cetuximab combination was associated with significantly longer OS (19.2 months vs 5.8 months; HR = 0.37), with consistent survival benefits observed in patients with CPS ≥ 20 (29.7 months vs 4.1 months; HR = 0.09) and CPS ≥ 1 (29.7 months vs 4.1 months; HR = 0.20). Furthermore, among patients who received a PD-1 inhibitor plus a targeted agent as first-line treatment, the anti-PD-1 plus cetuximab group had longer OS than the anti-PD-1 plus anlotinib group (29.7 months vs 4.4 months).

The efficacy outcomes observed in the anti-PD-1 plus cetuximab group were consistent with those reported in previous studies of R/M HNSCC. In the study by Sacco et al[20], pembrolizumab combined with cetuximab yielded a median PFS of 6.5 months and a median OS of 18.4 months. Similarly, in the study by Chung et al[21], nivolumab combined with cetuximab achieved a median PFS of 7.8 months and a median OS of 14.5 months. However, the ORR observed in our study was more modest at 27.3%, compared with the ORRs of 45% and 37% at 6 months reported in the two aforementioned studies, respectively. This discrepancy may be attributable to differences in patient selection, particularly the lower proportion of patients with oropharyngeal carcinoma in our cohort (15.4%) than in the two previous studies (39% and 47%, respectively).

Distinct patterns of grade ≥ 3 adverse events were observed between the two groups. Hypertension and tumor hemorrhage were more common among patients receiving anti-PD-1 plus anlotinib, consistent with the established toxicity profile of antiangiogenic agents. Grade ≥ 3 rash occurred in both groups but differed in its clinical characteristics. In the cetuximab combination group, rash was consistent with typical cetuximab-associated skin toxicity, whereas in the anlotinib group, rash was immune-related and was controlled with corticosteroids. In addition, tumor pain and decreased appetite were reported in both groups and were largely attributable to tumor progression. Because of the retrospective design, only grade ≥ 3 adverse events were analyzed, and mild grade 1-2 toxicities could not be comprehensively captured. Future prospective studies are warranted to more fully characterize the safety profiles of these two combination strategies.

The higher ORR observed in the anti-PD-1 plus anlotinib group may be attributable to the antiangiogenic effects of anlotinib, which can promote tumor vascular normalization[28] and modulate the tumor microenvironment[29], thereby potentially enhancing the activity of PD-1 inhibitors. However, as previously reported, rapid tumor shrinkage may be accompanied by an increased risk of hemorrhage in patients with R/M HNSCC, highlighting the need for close clinical monitoring. Notably, despite the lower ORR, the anti-PD-1 plus cetuximab group demonstrated significantly longer OS than the anti-PD-1 plus anlotinib group (19.2 months vs 5.8 months), suggesting that initial tumor response may not reliably predict sustained survival benefit. This observation is also consistent with findings from the LEAP-010 trial (NCT04199104), in which the addition of lenvatinib to pembrolizumab failed to improve OS in R/M HNSCC despite producing a higher ORR. Although an imbalance in baseline recurrence patterns was observed, with all 13 patients (100%) in the cetuximab group presenting with locoregional recurrence alone, whereas four patients (36.4%) in the anti-PD-1 plus anlotinib group had concomitant distant metastases (P = 0.031), contemporary evidence suggests that distant metastasis may not necessarily confer inferior survival in R/M HNSCC[30,31]. One possible explanation is that locoregional recurrent disease is more likely than distant metastasis to cause life-threatening complications, including hemorrhage, infection, and airway obstruction. This interpretation is consistent with our clinical observations, as no deaths in the present study were directly attributable to distant metastatic disease. Notably, among patients who received a PD-1 inhibitor combined with targeted therapy as first-line treatment, the anti-PD-1 plus cetuximab group achieved longer OS than the anti-PD-1 plus anlotinib group (29.7 months vs 4.4 months). The median OS of 29.7 months represents a particularly favorable survival signal compared with outcomes reported in previously published studies of R/M HNSCC. Although this finding was derived from a limited sample, it provides a rationale for further evaluation of PD-1 inhibition combined with cetuximab in randomized controlled trials.

Our study has several limitations. First, the relatively small sample size and retrospective design may have introduced selection bias and limited the statistical power to detect differences in survival outcomes. Second, four different PD-1 inhibitors were used in this cohort. Although subgroup analysis showed no significant difference in OS between pembrolizumab and sintilimab, the potential influence of heterogeneity among the PD-1 inhibitors cannot be excluded and may represent a source of confounding. Third, because of the retrospective nature of the study, adverse events were not consistently documented, which may have resulted in underestimation of treatment-related toxicity.

CONCLUSION

Our preliminary findings suggest that PD-1 inhibitors combined with targeted agents represent potentially effective treatment strategies for R/M HNSCC. In this retrospective cohort, PD-1 inhibitor plus cetuximab was associated with prolonged OS, while PD-1 inhibitor plus anlotinib showed a trend toward favorable tumor response and disease control. Given the small sample size, retrospective design, and baseline imbalances between the treatment groups, these results should be interpreted as exploratory. Larger prospective studies are warranted to confirm these findings and further define the optimal selection of PD-1-based immunotherapy-targeted therapy combinations.

ACKNOWLEDGEMENTS

We thank all the patients who participated in this study. We are also grateful to all investigators and staff involved in this study for their hard work.