Abstract
This open-label, multicenter, phase 1b/2 trial assessed the safety and efficacy of toripalimab plus cetuximab in patients with platinum-refractory (Cohort A) or previously untreated programmed cell death-ligand 1 (PD-L1)-positive (Cohort B) recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Patients received toripalimab 240 mg intravenously (IV) every 3 weeks and cetuximab (400 mg/m² loading, then 250 mg/m² weekly maintenance). Primary endpoints were safety in phase 1b and objective response rate (ORR) as assessed by the Independent Review Committee (Cohort A) and investigator (Cohort B) in phase 2. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). By October 25, 2024, 88 patients were enrolled (Cohort A: 45; cohort B: 43). In Cohort A, confirmed ORR was 60.0% (95% confidence interval [CI]: 44.3%, 74.3%), median PFS was 9.9 months (95% CI: 4.2, 19.4), and median OS was 14.1 months (95% CI: 8.5, 17.7). PD-L1-positive (combined positive score [CPS] ≥1) patients appeared to benefit more than PD-L1-negative (CPS < 1) patients (ORR: 64.5% vs. 40.0%, median PFS: 10.4 vs. 4.0 months, median OS: 15.4 vs. 13.3 months). In Cohort B, confirmed ORR was 44.2% (95% CI: 29.1%, 60.1%), median PFS was 8.2 months (95% CI: 4.2, 17.1), and median OS was 18.1 months (95% CI: 10.6, inestimable). Grade ≥3 treatment-emergent adverse events occurred in 53.3% (Cohort A) and 51.2% (Cohort B) of the patients in phase 2. No novel safety signals were identified. Toripalimab combined with cetuximab demonstrated manageable safety and promising efficacy for R/M HNSCC, warranting further investigation. Clinical trial number: NCT04856631.
Subject terms: Head and neck cancer, Cancer therapy
Introduction
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of malignancies that arise from the mucosal surfaces of the oral cavity, pharynx, larynx, and sinonasal tract. The major risk factors are tobacco use, alcohol consumption, and human papillomavirus (HPV) infection1,2. In 2022, China reported an estimated 94,600 new cases and 52,100 deaths, excluding nasopharyngeal carcinoma.3 Globally, the disease burden accounted for 771,000 new cases and 385,000 deaths.4 While early-stage HNSCC is often curable with surgery and/or radiation, a proportion of patients (10–50%) experience locoregional recurrence or distant metastasis.5 Recurrent or metastatic (R/M) HNSCC carries a poor prognosis, with a median overall survival (OS) of only 10.1 months for patients treated with the EXTREME regimen (cetuximab combined with chemotherapy) as a first-line therapy and less than 6 months for patients treated with cetuximab monotherapy as a later-line therapy.6,7
The advent of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape for R/M HNSCC. Programmed death-1 (PD-1) inhibitors as monotherapy or in combination with chemotherapy have been established as standard first- or second-line options for the treatment of R/M HNSCC in multiple clinical guidelines.8–10 Monotherapy with nivolumab and pembrolizumab has demonstrated median OS improvements of 8.4 months and 7.5 months compared to standard therapy, respectively, in patients with platinum-resistant or platinum-refractory R/M HNSCC, and both agents were approved by the U.S. Food and Drug Administration (FDA) in 2016.11,12 For previously untreated R/M HNSCC, pembrolizumab monotherapy prolonged OS in PD-L1-positive patients (combined positive score [CPS] ≥1, median OS: 12.3 months), while pembrolizumab combined with chemotherapy benefited the entire population (regardless of PD-L1 CPS expression, median OS: 13.0 months).13,14 On the basis of these findings, pembrolizumab received initial FDA approval in 2019. Subsequently, these approvals were extended to the Chinese market. In 2019, the National Medical Products Administration (NMPA) approved nivolumab monotherapy for patients with PD-L1-positive R/M HNSCC who failed platinum-based therapy. Pembrolizumab monotherapy was initially approved for the treatment of untreated R/M HNSCC patients with PD-L1 CPS ≥ 20 in 2020 and was later expanded to patients with PD-L1 CPS ≥ 1 in 2025. Despite these advancements, the objective response rate (ORR) to PD-1 inhibitors remains modest (20% in first-line treatment; 13–18% in second-line treatment), highlighting the limited short-term antitumor activity of these regimens.12–15 Although the combination of PD-1 inhibitors and platinum-based chemotherapy demonstrates an improved ORR (36.3%) in previously untreated R/M HNSCC, this regimen is associated with poor tolerability with significant hematologic, renal, and gastrointestinal toxicities.13,14 Moreover, the 5-year survival rate of 15.4–23.9% indicates the need for further advancements in long-term outcomes.13,14 These limitations illustrate critical unmet needs in both first- and second-line therapies for R/M HNSCC. Therefore, exploration of novel therapeutic strategies and combinations is warranted.
Emerging evidence suggests synergistic antitumor activity through combinatorial approaches targeting immune checkpoints and oncogenic signaling pathways. Preclinical immune-reconstituted human tumor xenograft models have indicated that epidermal growth factor receptor (EGFR) blockade with cetuximab might enhance immunogenicity by modulating the tumor microenvironment, promoting antigen presentation, and augmenting T-cell cytotoxicity.16,17 Clinically, this synergy has been evaluated in several prospective trials in Western populations. Nivolumab combined with cetuximab demonstrated a median OS of 11.4 months and 20.2 months in pretreated and untreated R/M HNSCC cohorts, respectively.18 Similarly, pembrolizumab combined with cetuximab achieved a 45% ORR at 6 months in patients with R/M HNSCC (88% of whom were previously untreated for R/M disease).19 These findings support the rationale for dual blockade of EGFR and PD-1/PD-L1 as a strategy to enhance therapeutic efficacy.
Toripalimab (JS001), a humanized IgG4κ anti-PD-1 monoclonal antibody, has been approved in China for a range of malignancies, including melanoma, nasopharyngeal carcinoma, urothelial carcinoma, esophageal squamous cell carcinoma, and non-small cell lung cancer.20–24 Additionally, it has been approved by the United States FDA for the treatment of nasopharyngeal carcinoma.24,25 Building on the evidence of preclinical synergy and promising early-phase data for the combinations of PD-(L)1 inhibitors and EGFR inhibitors, an open-label, single-arm, multicenter, phase 1b/2 study was conducted to evaluate the safety and efficacy of toripalimab in combination with cetuximab in Chinese patients with R/M HNSCC.
Results
Patients
Adult R/M HNSCC patients who had progressed upon first-line platinum-containing treatment were enrolled in phase 1b and phase 2 Cohort A; treat-naive patients with positive PD-L1 expression were enrolled in phase 2 Cohort B. In phase 1b, 6 patients were first enrolled to receive toripalimab 240 mg Q3W plus cetuximab weekly. Among them, 1 patient died (tumor hemorrhage and asphyxia and was determined not to be related to the study treatment by SMC) before receiving C1D15 administration, and another patient was enrolled according to the protocol. Fewer than 2 DLTs were observed; thus, 6 additional patients were enrolled. In phase 2, patients received toripalimab 240 mg Q3W in combination with cetuximab at a loading dose of 400 mg/m² IV on day 1, followed by a maintenance dose of 250 mg/m² weekly.
Between April 6, 2021, and October 25, 2024, 130 patients signed informed consent forms and were screened. Finally, 45 patients were enrolled in phase 2 Cohort A (all 13 patients from phase 1b were incorporated into Cohort A), and 43 patients were enrolled in phase 2 Cohort B (Fig. 1). The median duration of follow-up was 14.0 (range: 0–36) months in Cohort A and 17.0 (range: 0–28) months in Cohort B. All patients were included in the full analysis set (FAS) and safety analysis set (SS).
Fig. 1.
Participants enrollment and disposition. The initial dose administered was toripalimab 240 mg in combination with cetuximab 400 mg/m² (C1D1) and 250 mg/m² (subsequent cycles). This regimen was confirmed as RP2D. All 13 patients from Phase 1b were incorporated into Cohort A. DLT dose-limiting toxicity, PKCS pharmacokinetic parameter set, FAS full analysis set, SS safety set, RP2D recommended phase 2 dose
The baseline demographics and disease characteristics of each cohort are outlined in Table 1. The median age of the patients was 59.0 years (range: 32–74) in Cohort A and 60.0 years (range: 41–73) in Cohort B. The majority of patients were male (77.8% in Cohort A and 90.7% in Cohort B). The oral cavity was the most prevalent primary site in both cohorts (42.2% in Cohort A and 48.8% in Cohort B). As prespecified in the protocol, HPV test results were collected from 12 patients with oropharyngeal cancer, including 7 patients in Cohort A (6 patients with oropharyngeal cancer and 1 patient with oropharyngeal and oral cancer) and 5 patients in Cohort B (all with oropharyngeal cancer). All 12 patients tested negative for HPV p16. In Cohort A, 20 patients (44.4%) experienced relapse on or within 6 months after platinum-based neoadjuvant/adjuvant therapy, 20 patients (44.4%) failed first-line systemic therapy, 5 patients (11.1%) failed second-line systemic therapy, and 18 (40.0%) had distant metastases. PD-L1 status was available in 41 of 45 patients (91.1%), with 31 patients (68.9%) having PD-L1 CPS ≥ 1 and 22 patients (48.9%) having PD-L1 CPS ≥ 20. In Cohort B, 23 patients (53.5%) had local recurrence, 14 patients (32.6%) had recurrent disease with distant metastasis, 6 patients (14%) had locally advanced disease (unresectable disease, had no surgery or radiotherapy options), and 18 patients (41.9%) had a PD-L1 CPS ≥ 20.
Table 1.
Demographic and Baseline Characteristics (Full Analysis Set)
| Phase 1b N=13 | Phase 2 Cohort A N=45 | Phase 2 Cohort B N=43 | |
|---|---|---|---|
| Median age, year (range) | 58.0 (36-74) | 59.0 (32-74) | 60.0 (41-73) |
| Sex, n (%) | |||
| Male | 11 (84.6) | 35 (77.8) | 39 (90.7) |
| Female | 2 (15.4) | 10 (22.2) | 4 (9.3) |
| ECOG performance status, n (%) | |||
| 0 | 1 (7.7) | 8 (17.8) | 7 (16.3) |
| 1 | 12 (92.3) | 37 (82.2) | 36 (83.7) |
| Smoking history, n (%) | 7 (53.8) | 24 (53.3) | 33 (76.7) |
| Alcohol history, n (%) | 7 (53.8) | 22 (48.9) | 30 (69.8) |
| Primary tumor site, n (%) | |||
| Oral cavity | 4 (30.8) | 19 (42.2) | 21 (48.8) |
| Larynx | 2 (15.4) | 10 (22.2) | 11 (25.6) |
| Hypopharynx | 3 (23.1) | 8 (17.8) | 6 (14.0) |
| Oropharynx | 2 (15.4) | 6 (13.3) | 5 (11.6) |
| Paranasal sinuses | 1 (7.7) | 1 (2.2) | 0 |
| Oral cavity and oropharynxa | 1 (7.7) | 1 (2.2) | 0 |
| HPV p16 status, n (%)b | |||
| n | 3 | 7 | 5 |
| Positive | 0 | 0 | 0 |
| Negative | 3 (100) | 7 (100) | 5 (100) |
| PD-L1 combined positive score, n (%) | |||
| <1 | 4 (30.8) | 10 (22.2) | 0 |
| 1–19 | 4 (30.8) | 9 (20.0) | 25 (58.1) |
| ≥20 | 5 (38.5) | 22 (48.9) | 18 (41.9) |
| Not available | 0 | 4 (8.9) | 0 |
| Distant metastases, n (%) | 7 (53.8) | 18 (40) | 14 (32.6) |
| Phase1b and Cohort A prior treatment line, n (%) | |||
| Neo-adjuvant or adjuvant | 5 (38.5) | 20 (44.4) | NA |
| First-line | 7 (53.8) | 20 (44.4) | NA |
| Second-line | 1 (7.7) | 5 (11.1) | NA |
| Cohort B disease status, n (%) | |||
| Locally recurrence | NA | NA | 23 (53.5) |
| Recurrence and metastasis | NA | NA | 14 (32.6) |
| Locally advancedc | NA | NA | 6 (14.0) |
ECOG Eastern Cooperative Oncology Group, HPV human papillomavirus, PD-L1 programmed death ligand-1, NA not applicable
aA patient whose primary tumor site was located at the oral cavity and oropharynx junction, partially located in the oral cavity and partially in the oropharynx
bAs prespecified in the protocol, HPV status was assessed exclusively for patients with oropharyngeal cancers, including 11 patients with oropharyngeal cancer and 1 patient with oropharyngeal and oral cancer. The percentage of p16-positive/negative patients was calculated based on patients who were tested for HPV status
cLocally advanced disease included patients with newly diagnosed nonmetastatic and unresectable disease (had no surgery or radiotherapy options)
Determination of RP2D
In phase 1b, one of the primary endpoints was the incidence and severity of DLT events. PK profiles were also evaluated to further support RP2D determination. The RP2D was determined by the Safety Monitoring Committee (SMC) based on an integrated analysis of safety and PK data from the 13 patients receiving the initial dose regimen and completed the protocol-specified 21-day dose-limiting toxicity (DLT) evaluation. During this time, no DLTs were observed. Pharmacokinetic (PK) parameters of toripalimab in combination with cetuximab after multiple doses showed that toripalimab had a mean maximum concentration (Cmax) of 113 μg/mL, a mean area under the curve from time zero to infinity (AUC 0-inf) of 28,517 h*μg/mL and a mean clearance (CL) of 9.35 mL/h, while cetuximab had corresponding values of 202 μg/mL, 16,619 h*μg/mL and 25.6 mL/h. Detailed PK parameters of toripalimab and cetuximab following single and multiple dosing are presented in Supplementary Table 1. These parameters in this study were found to be comparable with those observed in monotherapy studies of toripalimab and cetuximab.(https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125084s279lbl.pdf), (https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761240Orig1s002lbl.pdf). Importantly, PK analysis revealed no evidence of a drug‒drug interaction when toripalimab was administered in combination with cetuximab. Based on these findings, the recommended phase 2 dose (RP2D) was determined to be toripalimab 240 mg every 3 weeks (Q3W), in combination with cetuximab at a loading dose of 400 mg/m² IV on day 1 of the first cycle, followed by a maintenance dose of 250 mg/m² weekly.
Efficacy
The primary endpoint in phase 2 was ORR per RECIST version 1.1. Simon’s two-stage design was used to further evaluate the efficacy for each cohort. In Cohort A, the Independent Review Committee (IRC) assessment demonstrated that 1 patient (2.2%) achieved a complete response, 26 patients (57.8%) achieved a partial response, and 9 patients (20.0%) achieved stable disease, yielding a confirmed ORR of 60.0% (95% confidence interval [CI]: 44.3%, 74.3%) and a disease control rate (DCR) of 80.0% (95% CI: 65.4%, 90.4%) (Table 2). The median duration of response (DoR) for patients who achieved a partial or complete response was 17.9 months (95% CI: 7.8, 17.9) (Supplementary Fig. 1a). Tumor burden reduction was observed in 33 of 43 evaluable patients (76.7%), with 28 patients showing a reduction of at least 30% in the sum of target lesion diameters from baseline (Supplementary Fig. 1b, c). The median progression-free survival (PFS) was 9.9 months (95% CI: 4.2, 19.4), and the 1-year PFS rate was 40.8% (95% CI: 23.9%, 57.0%) (Fig. 2a). The investigator-assessed outcomes showed a tumor response benefit consistent with the IRC assessment (Table 2). The median OS was 14.1 months (95% CI: 8.5, 17.7), and the 1-year OS rate was 57.8% (95% CI: 42.1%, 70.6%) (Fig. 2b).
Table 2.
Tumor Response in Phase 2 (Full Analysis Set)
| Cohort Aa N=45 | Cohort Ba N=43 | ||
|---|---|---|---|
| Independent assessment | Investigators assessment | Investigators assessment | |
| Confirmed best overall response, n (%)b | 43 | 43 | 39 |
| Complete response | 1 (2.2) | 6 (13.3) | 3 (7.0) |
| Partial response | 26 (57.8) | 15 (33.3) | 16 (37.2) |
| Stable disease | 9 (20.0) | 14 (31.1) | 15 (34.9) |
| Progressive disease | 3 (6.7) | 7 (15.6) | 3 (7.0) |
| Inestimable | 4 (8.9) | 1 (2.2) | 2 (4.7) |
| Confirmed objective response rate, n (%) | 27 (60.0) | 21 (46.7) | 19 (44.2) |
| 95% CI | 44.3, 74.3 | 31.7, 62.1 | 29.1, 60.1 |
| Confirmed disease control rate, n (%) | 36 (80.0) | 35 (77.8) | 34 (79.1) |
| 95% CI | 65.4, 90.4 | 62.9, 88.8 | 64.0, 90.0 |
aThe primary endpoints in phase 2 were ORR per RECIST version 1.1, assessed by IRC for Cohort A and by investigators for Cohort B
bTwo patients in Cohort A and 4 patients in Cohort B died before tumor assessment, and no data were obtained
Fig. 2.
PFS and OS in Cohort A and Cohort B. a Kaplan–Meier curves of progression-free survival (PFS) as assessed by IRC per RECIST v1.1 in Cohort A. b Kaplan–Meier curves of overall survival (OS) in Cohort A. c Kaplan–Meier curves of PFS as assessed by investigator per RECIST v1.1 in Cohort B. d Kaplan–Meier curves of OS in Cohort B. IRC = Independent Review Committee, INV = investigator, NE = inestimable
In Cohort B (n = 43), investigator assessment demonstrated that 3 patients (7.0%) achieved a complete response, 16 patients (37.2%) achieved a partial response, and 15 patients (34.9%) achieved stable disease, yielding a confirmed ORR of 44.2% (95% CI: 29.1%, 60.1%) and a DCR of 79.1% (95% CI: 64.0%, 90.0%) (Table 2). The median DoR for patients who achieved a partial or complete response was not reached (NR) (Supplementary Fig. 1d). Tumor burden reduction was observed in 34 of 39 evaluable patients (87.2%), with 24 patients showing a reduction of at least 30% in the sum of target lesion diameters from baseline (Supplementary Fig. 1e, f). The median PFS was 8.2 months (95% CI: 4.2, 17.1), and the 1-year PFS rate was 44.0% (95% CI: 28.3%, 58.7%) (Fig. 2c). The median OS was 18.1 months (95% CI: 10.6, inestimable), and the 1-year OS rate was 62.0% (95% CI: 45.6%, 74.8%) (Fig. 2d).
Safety
In Cohort A, the median duration of treatment with toripalimab and cetuximab was 24.1 weeks (range: 1.1–151.0). All patients experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs (incidence ≥25%) included rash (37.8%), anemia (35.6%), and hypothyroidism (26.7%) (Table 3). Grade ≥3 TEAEs were observed in 24 patients (53.3%) (detailed data are presented in Supplementary Table 2), with 14 (31.1%) considered to be related to the study treatment (Supplementary Table 3). Immune-related AEs (irAEs) occurred in 12 patients (26.7%), and all of these were grade 1–2. Infusion-related reactions (IRRs) occurred in 7 patients (15.6%), toripalimab-related IRRs occurred in 2 patients (4.4%), and cetuximab-related IRRs occurred in 5 patients (11.1%). Of these, one Grade ≥3 infusion-related reaction was reported and considered related to cetuximab. TEAEs leading to discontinuation occurred in 8 patients (Supplementary Table 4). Serious adverse events (SAEs) were reported in 21 patients (46.7%). Fatal TEAEs were reported in 7 patients, including tumor hemorrhage in 2 patients and shock hemorrhagic, pulmonary embolism, myocardial infarction, head and neck cancer, and septic shock in 1 patient each, all of which were judged by the investigators as unrelated to the study treatment.
Table 3.
Treatment-Emergent Adverse Events with Incidence ≥ 10% in Phase 2 (Safety Set)
| Cohort A (N=45) | Cohort B (N=43) | Total (N=88) | ||||
|---|---|---|---|---|---|---|
| Any grade | Grade≥3 | Any grade | Grade≥3 | Any grade | Grade≥3 | |
| Any TEAEsa,b, n (%) | 45 (100) | 24 (53.3) | 42 (97.7) | 22 (51.2) | 87 (98.9) | 46 (52.3) |
| Rash | 17 (37.8) | 1 (2.2) | 17 (39.5) | 2 (4.7) | 34 (38.6) | 3 (3.4) |
| Anemia | 16 (35.6) | 2 (4.4) | 16 (37.2) | 1 (2.3) | 32 (36.4) | 3 (3.4) |
| Hypothyroidism | 12 (26.7) | 0 | 6 (14.0) | 0 | 18 (20.5) | 0 |
| Hematuria | 10 (22.2) | 0 | 8 (18.6) | 0 | 18 (20.5) | 0 |
| Hypomagnesaemia | 11 (24.4) | 5 (11.1) | 10 (23.3) | 2 (4.7) | 21 (23.9) | 7 (8.0) |
| Acneiform dermatitis | 7 (15.6) | 0 | 13 (30.2) | 2 (4.7) | 20 (22.7) | 2 (2.3) |
| Hypokalemia | 10 (22.2) | 3 (6.7) | 9 (20.9) | 1 (2.3) | 19 (21.6) | 4 (4.5) |
| COVID-19 | 10 (22.2) | 1 (2.2) | 6 (14.0) | 0 | 16 (18.2) | 1 (1.1) |
| Pyrexia | 9 (20.0) | 0 | 8 (18.6) | 0 | 17 (19.3) | 0 |
| Weight decreased | 9 (20.0) | 0 | 6 (14.0) | 1 (2.3) | 15 (17.0) | 1 (1.1) |
| Aspartate aminotransferase increased | 8 (17.8) | 0 | 7 (16.3) | 1 (2.3) | 15 (17.0) | 1 (1.1) |
| Alanine aminotransferase increased | 8 (17.8) | 0 | 6 (14.0) | 1 (2.3) | 14 (15.9) | 1 (1.1) |
| Weight increased | 5 (11.1) | 0 | 9 (20.9) | 0 | 14 (15.9) | 0 |
| Proteinuria | 9 (20.0) | 0 | 4 (9.3) | 0 | 13 (14.8) | 0 |
| Paronychia | 8 (17.8) | 0 | 4 (9.3) | 0 | 12 (13.6) | 0 |
| Constipation | 7 (15.6) | 0 | 3 (7.0) | 0 | 10 (11.4) | 0 |
| Diarrhea | 8 (17.8) | 0 | 1 (2.3) | 0 | 9 (10.2) | 0 |
| Infectious pneumonia | 7 (15.6) | 1 (2.2) | 2 (4.7) | 2 (4.7) | 9 (10.2) | 3 (3.4) |
| Insomnia | 5 (11.1) | 0 | 4 (9.3) | 0 | 9 (10.2) | 0 |
| Hypoalbuminemia | 4 (8.9) | 0 | 5 (11.6) | 0 | 9 (10.2) | 0 |
| Oral mucositis | 6 (13.3) | 3 (6.7) | 2 (4.7) | 0 | 8 (9.1) | 3 (3.4) |
| Gamma-glutamyl transferase increased | 7 (15.6) | 0 | 1 (2.3) | 0 | 8 (9.1) | 0 |
| Fibrinogen increased | 5 (11.1) | 0 | 3 (7.0) | 0 | 8 (9.1) | 0 |
| Leukopenia | 5 (11.1) | 2 (4.4) | 3 (7.0) | 1 (2.3) | 8 (9.1) | 3 (3.4) |
| Vomiting | 5 (11.1) | 0 | 2 (4.7) | 0 | 7 (8.0) | 0 |
| Cough | 5 (11.1) | 0 | 2 (4.7) | 0 | 7 (8.0) | 0 |
| Asthenia | 5 (11.1) | 0 | 2 (4.7) | 0 | 7 (8.0) | 0 |
| Anorexia | 5 (11.1) | 0 | 1 (2.3) | 0 | 6 (6.8) | 0 |
| Hyperuricemia | 5 (11.1) | 0 | 0 | 0 | 5 (5.7) | 0 |
TEAE treatment-emergent adverse event
aAll adverse events were documented within 60 days after the last dose of study treatments or before starting a new antitumor therapy, whichever occurred first
bThe severity of adverse events was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0
In Cohort B, the median duration of treatment with toripalimab and cetuximab was 29.1 weeks (range: 0.1–117.3). A total of 42 patients (97.7%) experienced at least one TEAE. The most common TEAEs (incidence ≥25%) included rash (39.5%), anemia (37.2%), and acneiform dermatitis (30.2%) (Table 3). Grade ≥3 TEAEs were observed in 22 patients (51.2%) (detailed data are presented in Supplementary Table 2), with 14 (32.6%) considered related to the study treatment (Supplementary Table 3). IrAEs were reported in 3 patients (7.0%), with one case of grade 3 immune-mediated myocarditis. Infusion-related reactions occurred in 5 patients (11.6%), with toripalimab-related IRRs occurring in 2 (4.7%) and cetuximab-related IRRs occurring in 5 (11.6%). Of these, one grade 3 hypertension related to toripalimab and cetuximab, as well as one grade 3 event related to cetuximab, were reported. TEAEs leading to discontinuation occurred in 1 patient (Grade 3, Rash) (Supplementary Table 4). SAEs occurred in 15 patients (34.9%). Fatal TEAEs were reported in 2 patients: 1 respiratory failure considered related to study treatment and 1 unexplained death judged unrelated to study treatment.
Immunogenicity
Exploratory analyses of the immunogenicity profiles of the combination were conducted. Anti-drug antibody (ADA) was assessed in a total of 82 patients who had pre- and posttreatment serum samples. The overall incidence of treatment-emergent ADA of toripalimab and cetuximab were 3.7% (N = 3) and 8.5% (N = 7), respectively. Although the potential for misleading inferences when comparing the incidence of ADA in this study with that observed in other studies, the results of this study were comparable to those reported in previous research.
Biomarker
The relationships between clinical outcomes and tumor PD-L1 expression levels and HPV status were analyzed to explore potential biomarkers. In Cohort A, among the 41 patients with available PD-L1 status, 10 patients (24.4%) had a PD-L1 CPS < 1, and 31 patients (75.6%) had a PD-L1 CPS ≥ 1. Patients with positive PD-L1 expression (CPS ≥ 1) showed a trend toward better clinical outcomes than PD-L1 negativity, as evidenced by a higher ORR (64.5% vs. 40.0%) and longer median PFS (10.4 months vs. 4.0 months) as assessed by IRC, as well as improved survival (median OS: 15.4 months vs. 13.3 months; 12-month OS rate: 61.3% vs. 50.0%) (Table 4). When stratified by a CPS cutoff of 20, no numerical differences in clinical outcomes were observed between the CPS < 20 and CPS ≥ 20 subgroups.
Table 4.
Efficacy Outcomes by PD-L1 Stratification in Cohort A and Cohort B
| Cohort A (N=41)a | Cohort B (N=43) | |||||
|---|---|---|---|---|---|---|
| PD-L1 Stratification | CPS <1 n=10 | CPS≥1 n=31 | CPS <20 n=19 | CPS≥20 n=22 | CPS <20 n=25 | CPS≥20 n=18 |
| ORR, n (%), [95% CI]b | 4 (40.0) [12.2, 73.8] | 20 (64.5) [45.4, 80.8] | 12 (63.2) [38.4, 83.7] | 12 (54.5) [32.2, 75.6] | 10 (40.0) [21.1, 61.3] | 9 (50.0) [26.0, 74.0] |
| DCR, n (%), [95% CI]b | 7 (70.0) [34.8, 93.3] | 26 (83.9) [66.3, 94.5] | 16 (84.2) [60.4, 96.6] | 17 (77.3) [54.6, 92.2] | 19 (76.0) [54.9, 90.6] | 15 (83.3) [58.6, 96.4] |
| Median PFS, month (95% CI)b | 4.0 (1.4, NE) | 10.4 (4.2, 19.4) | 10.0 (3.0, 19.4) | 10.4 (2.9, NE) | 8.2 (3.3, NE) | 8.2 (3.9, NE) |
| 6-month PFS rate, % (95% CI)b | 43.8 (10.1, 74.2) | 59.7 (39.9, 74.9) | 63.0 (35.4, 81.4) | 52.3 (29.3, 71.0) | 51.2 (29.3, 69.5) | 58.8 (32.5, 77.8) |
| 12-month PFS rate, % (95% CI)b | 43.8 (10.1, 74.2) | 45.6 (25.8, 63.5) | 40.5 (12.8, 67.2) | 45.8 (23.2, 65.9) | 41.9 (21.6, 61.0) | 47.1 (23.0, 68.0) |
| Median OS, month, (95% CI) | 13.3 (5.2, 16.7) | 15.4 (8.5, 27.3) | 14.9 (7.2, 17.7) | 14.7 (4.7, 31.2) | 14.3 (8.7, 26.8) | NE (9.3, NE) |
| 6-month OS rate, % (95% CI) | 80.0 (40.9, 94.6) | 74.2 (55.0, 86.2) | 84.2 (58.7, 94.6) | 68.2 (44.6, 83.4) | 84.0 (62.8, 93.7) | 83.3 (56.8, 94.3) |
| 12-month OS rate, % (95% CI) | 50.0 (18.4, 75.3) | 61.3 (42.0, 75.8) | 57.9 (33.2, 76.3) | 59.1 (36.1, 76.2) | 54.0 (32.3, 71.5) | 72.2 (45.6, 87.4) |
PD-L1 programmed cell death-ligand 1, CPS combined positive score, ORR objective response rate, CI confidence interval, DCR disease control rate, PFS progression-free survival, OS overall survival, NE inestimable
aCorrelation analysis between PD-L1 expression and efficacy was performed in patients with available PD-L1 status
bTumor assessments were performed by an Independent Review Committee for Cohort A and by the investigators for Cohort B
In Cohort B, among the 43 available PD-L1-positive patients, 25 patients had a PD-L1 CPS < 20, and 18 patients (41.9%) had a PD-L1 CPS ≥ 20. A numerically higher 12-month OS rate (72.2% vs. 54.0%) and ORR (50.0% vs. 40.0%) were observed in the PD-L1 CPS ≥ 20 subgroup than in the CPS < 20 subgroup.
Discussion
This study indicated that the combination of toripalimab and cetuximab exhibited promising clinical activity and a manageable safety profile in Chinese patients with R/M HNSCC. This is, to the best of our knowledge, the first study to evaluate this combination regimen in a Chinese R/M HNSCC population, providing valuable insights into a combination strategy of EGFR targeting and ICIs.
In Cohort A, which enrolled patients with platinum-resistant or platinum-refractory R/M HNSCC, toripalimab combined with cetuximab yielded a confirmed ORR of 60.0%, a DCR of 80.0%, a median PFS of 9.9 months, and a median OS of 14.1 months in the total population (regardless of PD-L1 CPS expression). The results of this study indicated promising efficacy outcomes in the context of historical data and existing therapeutic approaches. Historical data for PD-1 monotherapy in R/M HNSCC have reported an ORR of less than 20%, a DCR of approximately 35%, a median PFS of approximately 2 months, and a median OS of approximately 8 months.11,12,15,26 Moreover, cetuximab monotherapy has shown an ORR of less than 15%.7 In a study evaluating nivolumab plus cetuximab, 45 patients with R/M HNSCC who had failed prior systemic therapy were enrolled, including 22 patients (48.9%) with HPV p16-positive oropharyngeal cancer or unknown primary cancer. The study showed that the median OS was 11.5 months, the median PFS was 3.4 months, the ORR was 22.2%, and the DCR was 66.7%.18 Similarly, in another study evaluating durvalumab plus cetuximab, 35 patients with R/M HNSCC were enrolled, of whom 18 patients (54%) had received previous systemic therapy, and 4 patients (11%) had HPV-related oropharyngeal cancer. The study showed that the median OS was 9.6 months, the PFS was 5.8 months, the ORR was 39%, and the DCR was 60.6%.27 The relatively low response observed in these two studies may be attributed to the inclusion of a higher proportion of patients who had prior exposure to either ICIs or cetuximab (69% in the first study and 30% in the second study), while our study excluded such patients, which may lead to the observed differences in treatment response. The encouraging efficacy observed with dual PD-1/EGFR blockade supports its potential as a more effective therapeutic option for patients with platinum resistance. A phase 3, randomized controlled trial of pembrolizumab plus cetuximab for patients with platinum-refractory R/M HNSCC is ongoing (NCT06589804). Additionally, from the perspective of the mechanism of action, a hypothesis supported by preclinical evidence revealed that EGFR inhibitors can modulate the tumor microenvironment to enhance the activity of immune checkpoint inhibitors.28
In Cohort B, which enrolled patients with untreated PD-L1-positive R/M HNSCC, toripalimab combined with cetuximab showed an ORR of 44.2%, a DCR of 79.1%, a median PFS of 8.2 months, a median OS of 18.1 months, and a 12-month OS rate of 62.0%. The current NCCN clinical guideline-recommended standards of care (SOC), such as pembrolizumab plus chemotherapy, showed an ORR of 37.2%, a DCR of 67.4%, a median PFS of 5.1 months, and a median OS of 13.6 months for PD-L1-positive patients, as well as pembrolizumab monotherapy with an ORR of 19.1%, a DCR of 51.4%, a median PFS of 3.2 months, and a median OS of 12.3 months.13 Based on the efficacy data of these SOCs, our study results suggest that the combination of cetuximab and toripalimab may provide synergistic benefits and mitigate the risk of early disease progression. Furthermore, the findings in this study align with prior clinical evidence supporting combination strategies of cetuximab and PD-(L)1 inhibitors. For instance, in a study evaluating nivolumab plus cetuximab, 43 patients with untreated R/M HNSCC were enrolled, of whom 14 patients (33%) had HPV p16-positive oropharyngeal cancer, and the majority (77%) were PD-L1 positive (CPS ≥ 1). The regimen yielded an ORR of 37% and a DCR of 69.8%, with a median PFS of 6.2 months and a 12-month OS rate of 61.0%.18 In another study evaluating pembrolizumab plus cetuximab (n = 33), which primarily enrolled untreated R/M HNSCC patients (88%), 33% of the patients had HPV-related oropharyngeal cancer, and 33% of patients were PD-L1 positive (CPS ≥ 1). This regimen showed a 6-month ORR of 45%, a DCR of 60.6%, and a median OS of 18.4 months.19
Exploratory biomarker analyses revealed a correlation between PD-L1 expression and treatment efficacy. In patients with platinum-refractory R/M HNSCC (Cohort A), those with PD-L1 CPS ≥ 1 demonstrated numerically improved outcomes compared to those with CPS < 1. This finding aligns with previous studies linking PD-L1 expression to significantly improved OS with ICIs.13,29–32 Consequently, Cohort B prospectively enrolled patients with CPS ≥ 1 to further evaluate the benefits of the combination regimen in the PD-L1-positive subgroup. The results showed promising clinical efficacy in patients with PD-L1 CPS ≥ 1, and a trend toward an improved 12-month OS rate was also observed in the PD-L1 CPS ≥ 20 subgroup compared to the PD-L1 CPS < 20 subgroup. However, it is imperative to interpret these findings with caution due to the limited sample size in each subgroup, which lacked sufficient power for robust assessments. Additionally, previous studies have demonstrated that patients with HPV-positive status exhibited a favorable prognosis compared to those with HPV-negative status.32–34 In our study, all 12 patients with oropharyngeal cancer were confirmed as HPV-negative, yet the combination of toripalimab and cetuximab still demonstrated robust efficacy in the entire enrolled population.
The safety profile of the combination of toripalimab with cetuximab was consistent with the known toxicities of each agent, as well as with previously reported data for other PD-(L)1 inhibitors in combination with cetuximab,18,19,27 with no unexpected safety signal. In Cohort A, 93.3% of patients experienced treatment-related adverse events (TRAEs), with 31.1% experiencing grade ≥3 TRAEs. In Cohort B, 93.0% of patients experienced TRAEs, with 32.6% experiencing grade ≥3 TRAEs. Although cross-trial comparisons must be made cautiously, the incidence of grade ≥3 TRAEs in this study was numerically much lower than that observed in previous studies of PD-1 inhibitors combined with chemotherapy (71.7%) or the EXTREME regimen (69.3%) for R/M HNSCC.9 Notably, Grade ≥3 irAEs were rare (1 patient, 1.1%), suggesting that the combination of toripalimab and cetuximab did not appear to increase either the incidence or severity of irAEs compared to historical data of PD-(L)1 monotherapy. Furthermore, 3 patients (3.4%) experienced grade 3 IRRs, all of which were resolved well with standard management, suggesting that the addition of toripalimab did not increase the frequency or risk of cetuximab-related infusion reactions. Collectively, the combination of toripalimab and cetuximab maintained a favorable and manageable safety profile in patients with R/M HNSCC, with no additional toxicity or safety concerns observed.
While this study provides valuable insights, some limitations should be acknowledged. First, the single-arm design and comparatively small sample size constrain the ability to derive definitive conclusions on treatment efficacy. Second, due to limitations in research funding, Cohort B did not undergo IRC evaluation, which might provide more objective assessment results. Third, the patients with oropharyngeal cancers enrolled in our study were all HPV-negative, precluding definitive conclusions on the potential benefits of this treatment regimen for HPV-positive patients. Given the increasing prevalence of HPV-positive oropharyngeal cancers in China and globally, further exploration into the effects of HPV status on treatment benefits is of considerable clinical significance. Finally, this study exclusively enrolled a Chinese population. Although epidemiological characteristics (tumor subsites and HPV prevalence) may differ between Asian and non-Asian populations, the results from previous studies suggest similar treatment benefit trends across subpopulations.13,14 The results of this study are also comparable with those of non-Asian patients treated with other PD-(L)1 inhibitors combined with cetuximab, implying the potential generalizability of this combination regimen.18,19,27 Nevertheless, global randomized trials with larger sample sizes, especially for HPV-positive patients, remain necessary to further validate these findings.
In conclusion, toripalimab combined with cetuximab offers encouraging clinical efficacy in both platinum-refractory and untreated PD-L1-positive R/M HNSCC. Its favorable safety profile further supports its potential as a viable treatment option.
Methods
Study design and patients
This phase 1b/2 trial was conducted across 22 centers in China and consisted of two phases: a dose-finding (phase 1b) and an expansion (phase 2, Cohort A and Cohort B) phase. Patients with histologically or cytologically confirmed advanced R/M HNSCC originating from the oral cavity, oropharynx, hypopharynx, larynx, or paranasal sinuses who were ineligible for curative surgery or radiotherapy were enrolled in this study. In phase 1b and phase 2 Cohort A, patients who had progressed upon first-line platinum-containing treatment or developed R/M disease on or within 6 months of platinum-containing therapy in the neoadjuvant/adjuvant or primary (i.e., with radiation) setting for locally advanced disease were enrolled. In phase 2 Cohort B, patients with positive PD-L1 expression (CPS ≥ 1) and no prior exposure to systemic therapies for R/M disease or who progressed at least 6 months after systemic therapy with curative intent for local-regional disease were enrolled. Additional key eligibility criteria included the following: aged 18–75 years old, provision of tumor tissue for PD-L1 expression analysis, HPV status assessment (for oropharyngeal cancers only), presence of at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1, and adequate organ function. Patients with a history of prior immunotherapy (e.g., PD-(L)1 inhibitors, CTLA-4 inhibitors) or EGFR inhibitors were excluded from the study. The full eligibility criteria are detailed in Supplement 2.
The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and prevailing legislation and regulations. The study protocol and all subsequent amendments were reviewed and approved by the independent ethics committee at each study site (Supplementary Table 5). Written informed consent was obtained from all patients prior to their enrollment in the study.
Procedures
In phase 1b, the first 6 patients were enrolled to receive toripalimab 240 mg intravenously (IV) Q3W in combination with cetuximab at a loading dose of 400 mg/m² IV on day 1 of the first cycle, followed by a maintenance dose of 250 mg/m² weekly. DLTs were evaluated during the first cycle (21 days) to assess the tolerability of this dose level. If fewer than 2 DLTs ( < 2/6) were observed, 6 additional patients were enrolled at the same dose level for further evaluation. Conversely, if 2 or more DLTs ( ≥ 2/6) were observed, the maintenance dose for cetuximab would be reduced to 200 mg/m² for subsequent enrolled patients, and the tolerability of this adjusted combination dose level would be re-evaluated. The detailed DLT criteria are provided in Supplementary Text 1. The RP2D was determined by the Safety Monitoring Committee (SMC) based on an integrated analysis of safety and PK data from the 13 patients receiving the selected regimen. In phase 2, patients received toripalimab in combination with cetuximab at the RP2D established during phase 1b, and Simon’s two-stage design was used to further evaluate the efficacy of the combination regimen for each cohort. Patients received study treatment for a maximum of 2 years or until the occurrence of disease progression or death, intolerable toxicity, or withdrawal of consent by patients.
Endpoints and assessments
In phase 1b, the primary endpoints included the incidence and severity of DLT events, adverse events (AEs), and SAEs. PK profiles were also evaluated to further support RP2D determination. In phase 2, the primary objective was to evaluate the efficacy of the combination regimen in platinum-refractory (Cohort A) and PD-L1-positive untreated (Cohort B) R/M HNSCC patients. The primary endpoint was ORR per RECIST version 1.1, assessed by IRC for Cohort A and by investigators for Cohort B. Secondary efficacy endpoints included ORR assessed by investigators, DoR, DCR, PFS assessed by IRC and investigators, and OS for Cohort A; DoR, DCR, PFS assessed by investigators and OS for Cohort B. Additionally, exploratory analyses of immunogenicity profiles were conducted. The potential correlations between clinical outcomes and tumor PD-L1 expression levels and HPV status were assessed.
All AEs were documented within 60 days after the last dose of study treatments. The AEs were graded for severity based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Imaging assessments were performed by computed tomography (CT) or magnetic resonance imaging (MRI) of the head, neck, chest, abdomen, and any sites with known or suspected tumor lesions at baseline. Efficacy assessment was performed at baseline and every 6 weeks ( ± 7 days) after the first dose of treatment for the first 12 months and every 9 weeks ( ± 7 days) thereafter. For patients who achieved a CR or PR, a re-evaluation was required a minimum of 4 weeks after the initial response assessment.
To assess PK parameters, the serum concentrations of toripalimab and cetuximab were measured using a validated Meso Scale Discovery (MSD) method. Samples were collected at the following time points: 0.5 h predose; 0 (post toripalimab/cetuximab); 2 h (±5 min), 6 h (±15 min) post cetuximab, and 24 h (±1 h), 48 h (±2 h), 96 h (±2 h), 168 h (±8 h), 336 h (±12 h), and 504 h post toripalimab on cycle 1 and cycle 3 day 1. Additionally, samples were collected at 0 (post toripalimab/cetuximab) on Cycle 2 and Day 1. ADAs against toripalimab and cetuximab in serum were detected using a rigorously validated MSD method. Blood samples were collected at baseline (pre-first dose), predose on Cycle 2 and Cycle 4 Day 1, every 12 weeks within the first year, and every 24 weeks thereafter.
Archival or fresh tumor biopsy samples were obtained from patients prior to treatment. PD-L1 expression was assessed using a validated immunohistochemistry (IHC) staining assay with the JS311 monoclonal antibody, performed at a central laboratory (MEDx, Suzhou, China).22 PD-L1 expression was determined by using CPS: the number of PD-L1-stained cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100.
Statistical analysis
For phase 1b, data were summarized by dose level. For phase 2, data were summarized by RP2D for each cohort separately, and the data from patients in phase 1b who received RP2D were pooled into Cohort A for analysis. Patients who received at least one dose of toripalimab were evaluated for safety and efficacy. The terms of AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 26.0. Two-sided 95% CIs of ORR and DCR were calculated using the Exact (Clopper-Pearson) method. The survival functions of PFS, DoR, and OS were estimated by the Kaplan‒Meier method. For the exploratory analyses, PD-L1 expression was categorized into groups based on the Combined Positive Score (CPS): CPS < 1; 1 ≤ CPS < 20; and CPS ≥ 20. Descriptive analysis of the relationship between PD-L1 expression and efficacy was performed in patients with available PD-L1 status. The PK parameters for individual patients were obtained using Phoenix WinNonlin software (version 8.3, Certara, Inc.) through a noncompartmental analysis model. Descriptive statistics were reported for the ADAs and PK parameters.
For Cohort A, a Simon’s minimax two-stage design (two-sided α = 0.05) was implemented to test the null hypothesis of an ORR of 20% (based on the historical data) against an alternative ORR of 40% for the combination of toripalimab and cetuximab, with 90% power.13,14,16 A total of 45 patients for Cohort A were enrolled in two stages: if >5 of 24 patients achieved CR or PR in stage 1, then an additional 21 patients would be enrolled in stage 2. Similarly, the same design was utilized for Cohort B to compare a null ORR of 25% versus an alternative ORR of 43% with 80% power.9 A total of 43 patients for Cohort B were enrolled in two stages: if > 6 of 23 patients achieved CR or PR in stage 1, then an additional 20 patients would be enrolled in stage 2. Further details of the statistical analyses are provided in Supplement 3.
Supplementary information
Acknowledgements
This work was supported by Shanghai Junshi Biosciences Co., Ltd. We extend our sincere appreciation to all patients, their families, and investigators involved in this study. This study was sponsored by Shanghai Junshi Biosciences Co., Ltd. This manuscript was developed with the assistance of a medical writer (Shan Zhang, Shanghai Junshi Biosciences Co., Ltd.) with the consent of all authors.
Author contributions
Conceptualization and design: Ye Guo, Xianming Luo, Mo Wang, Shijuan Kuang, Shuanghui Wei, Rong Deng designed the study. Provision of study materials or patients: All authors. Data analysis and interpretation: Ye Guo, Xianming Luo, Mo Wang, Shijuan Kuang, Shuanghui Wei, Rong Deng, and Shuanghui Wei. Manuscript writing and picture editing: Ye Guo, Xianming Luo, Mo Wang, Shijuan Kuang, Shuanghui Wei, Rong Deng. Final approval of manuscript: All authors have read and approved the article.
Data availability
All data and materials underlying this article are available within the submitted materials.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Ye Guo, Zhendong Li, Liqiong Xue.
Supplementary information
The online version contains supplementary material available at 10.1038/s41392-026-02707-3.
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Supplementary Materials
Data Availability Statement
All data and materials underlying this article are available within the submitted materials.