Sacituzumab Tirumotecan and Toripalimab in the First-line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Patients With trop2 and CPS Positive: A Prospective, Single Arm, Phase II Trial
Trial Snapshot
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- Enrollment
- 39
- Locations
- 1
- Primary Endpoint
- objective response rate
Study Overview
Brief Summary
This study is a single center, non controlled, prospective phase II clinical trial to evaluate the efficacy and safety of Sacituzumab Tirumotecan and Toripalimab in the first-line treatment of recurrent/metastatic head and neck squamous cell carcinoma patients with trop2 and CPS positive. The participants would receive Sacituzumab Tirumotecan and Toripalimab until termination criteria are met.
Detailed Description
Despite advances in diagnosis and treatment, more than 65% of patients with head and neck squamous cell carcinoma still experience recurrence, metastasis, or both. Patients with locally recurrent head and neck cancer who are ineligible for salvage surgery, radiotherapy, or their combination have a very poor prognosis, similar to that of patients with distant metastatic head and neck cancer (survival of 6-9 months without treatment). Due to the limitations of previous radiotherapy (especially dose and irradiation fields) and the constraints of normal tissue tolerance, which restrict the feasibility and success of re-irradiation, systemic therapy with active drugs (platinum agents, taxanes, antifolates, and cetuximab) has become the cornerstone of palliative therapy. The choice between single-agent therapy or combination therapy (two or three drugs) depends on the toxicity of these drugs, the patient's performance status, comorbidities, frailty, age, symptoms, and characteristics related to previous treatment (disease stage, specific drugs, combination regimens, response, and time to progression). The phase III EXTREME (Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer) trial demonstrated that adding cetuximab to fluorouracil plus platinum (cisplatin or carboplatin) chemotherapy significantly improved overall survival (10.1 months vs. 7.4 months; hazard ratio for death, 0.80; 95% CI, 0.64-0.99; P=0.04), progression-free survival (5.6 months vs. 3.3 months), and overall response rate (36% vs. 20%) compared with chemotherapy alone, thus supporting chemotherapy plus cetuximab as the first-line standard treatment. Unfortunately, cetuximab requires weekly administration, which can cause infusion reactions and skin reactions, resulting in poor quality of life for patients.
The discovery that regulating the immune system can induce regression of solid tumors has transformed our understanding and treatment of cancer. In particular, the successful development of programmed death receptor 1 (PD-1) immune checkpoint inhibitors has significantly influenced the treatment of head and neck squamous cell carcinoma. In patients with recurrent or metastatic head and neck cancer who have received platinum-based therapy, the anti-PD-1 antibodies pembrolizumab and nivolumab have achieved durable responses and improved survival. Therefore, the U.S. Food and Drug Administration (FDA) approved these two drugs for second-line treatment of advanced head and neck squamous cell carcinoma in 2016 and pembrolizumab for first-line treatment of advanced head and neck squamous cell carcinoma in 2019.
The use of pembrolizumab in first-line treatment of advanced head and neck squamous cell carcinoma is mainly based on the success of the phase 3 KEYNOTE-048 study. In the KEYNOTE-048 study, 882 previously untreated patients with recurrent or metastatic head and neck squamous cell carcinoma were randomly assigned to receive pembrolizumab monotherapy, pembrolizumab plus chemotherapy (fluorouracil and platinum agents), or the standard treatment regimen of fluorouracil plus platinum agents plus cetuximab (the regimen in the EXTREME trial). In patients with tumors expressing PD-L1 (using a combined positive score cutoff of ≥20% or ≥1%), both pembrolizumab monotherapy and pembrolizumab plus chemotherapy improved the primary endpoint of overall survival compared with the EXTREME regimen (see Supplementary Appendix for details). Compared with the EXTREME regimen, pembrolizumab had a lower response rate but more durable responses and fewer associated toxic effects. In the overall population not selected based on PD-L1, pembrolizumab monotherapy did not improve survival compared with the EXTREME regimen, while pembrolizumab plus chemotherapy improved survival (13.0 months vs. 10.7 months; hazard ratio for death, 0.77; 95% CI, 0.63-0.93; P=0.003).
Currently, numerous ongoing clinical trials are combining targeted therapy and immunotherapy. The rationale for these combination therapies is that the two therapies integrate different immunological and tumor biological mechanisms to enhance anti-tumor activity; in addition, some evidence suggests that targeted therapy can enhance certain links in the "cancer-immune cycle" (such as tumor antigenicity, T cell priming/transport/infiltration, etc.) and synergistically enhance immunotherapy. TROP2 (trophoblast cell surface antigen 2), a transmembrane glycoprotein, plays an important role in tumor occurrence and development by regulating calcium signaling pathways, cyclin expression, and cell adhesion functions. Studies have shown that TROP2 is highly expressed in head and neck squamous cell carcinoma (HNSCC), and its abnormal elevation is significantly associated with the invasive phenotype of tumor cells, lymph node metastasis, and poor prognosis of patients. Compared with normal tissues, the expression level of TROP2 in head and neck cancer tissues can be several to dozens of times higher, making it a promising target for targeted therapy. The expression level of Trop2 in head and neck squamous cell carcinoma (HNSCC) is high, with a positive rate of up to 86%, and it is associated with poor prognosis in patients.
The TROPiCS-03 basket study is an ongoing, open-label, multi-cohort, phase 2 study evaluating the anti-tumor activity and safety of the TROP2 ADC drug Sacituzumab Govitecan (SG) in patients with advanced solid tumors, including head and neck squamous cell carcinoma (HNSCC). A total of 43 adult patients with histologically confirmed locally recurrent or metastatic HNSCC who had disease progression after platinum-based chemotherapy and anti-PD-(L)1 inhibitor therapy (combined or sequential) were enrolled. The median duration of SG treatment for all patients was 2.5 months (0.3-12.3 months), and the median number of treatment cycles was 4 (1-17 cycles). The investigator-assessed ORR was 16%, all of which were partial responses (PR); the median DoR was 4.2 months, and the 6-month DoR rate was 43%. In terms of other secondary endpoints, the median PFS was 4.1 months, with 6-month and 12-month PFS rates of 32% and 12%, respectively; the median OS was 9.0 months, with 6-month and 12-month OS rates of 75% and 28%, respectively. In terms of safety, all patients experienced treatment-emergent adverse events (TEAEs) of any grade, the most common being diarrhea, nausea, and neutropenia, each occurring in 20 patients (47%). Grade 3 or higher TEAEs occurred in 25 patients (58%), the most common being neutropenia (33%), anemia (9%), and leukopenia (9%), indicating potential efficacy and safety in advanced head and neck cancer.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Aged 18-75 years, regardless of gender; Histologically or cytologically confirmed newly diagnosed locally advanced, recurrent or metastatic head and neck squamous cell carcinoma (primary tumor sites include oropharynx, oral cavity, hypopharynx, and larynx) that cannot be cured by local treatment. No anti-tumor systemic treatment has been received in the recurrent or metastatic stage (systemic treatment as part of local advanced tumor treatment is allowed, provided that more than 6 months have passed from the end of treatment to the signing of informed consent); ECOG performance status of 0 or 1; Expected survival period ≥ 12 weeks; At least one measurable lesion according to RECIST 1.1 criteria. Lesions that have received previous radiotherapy can be used as measurable lesions if disease progression occurs; Availability of tumor tissue for PD-L1 detection (paraffin-embedded specimens within 2 years or fresh tumor tissue); PD-L1 CPS ≥ 1 and positive trop2 expression, detected by immunohistochemistry; For oropharyngeal cancer patients, P16 detection status, detected by IHC;
- •Normal function of major organs within 2 weeks before treatment, meeting the following criteria:
- •Bone marrow function: Hemoglobin ≥ 100g/L, white blood cell count ≥ 4.0×10^9/L or neutrophil count ≥ 2.0×10^9/L, platelet count ≥ 100×10^9/L without blood transfusion or colony-stimulating factor support; Liver function: Serum total bilirubin level ≤ 1.5 times the upper limit of normal, aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 times the upper limit of normal; Renal function: Serum creatinine level < 1.5 times the upper limit of normal or creatinine clearance rate ≥ 60ml/min, blood urea nitrogen ≤ 200mg/L; Urinary protein < +; if urinary protein is +, the 24-hour total protein must be < 500mg; Blood glucose: Within the normal range and/or for diabetic patients, blood glucose is controlled in a stable state during treatment; Cardiac function: No myocardial infarction within 1 year; no unstable angina; no symptomatic severe arrhythmia; no cardiac insufficiency; For women of childbearing age, serum pregnancy test results must be negative within 7 days before the first administration of the trial drug; males with reproductive capacity or females with the possibility of pregnancy must use highly effective contraceptive methods (such as oral contraceptives, intrauterine devices, abstinence, or barrier contraception combined with spermicides) throughout the trial, and continue contraception for 12 months after the end of treatment; Subjects voluntarily participate in this study, sign the informed consent form, have good compliance, and cooperate with follow-up; Patients whom doctors believe can benefit from the treatment.
Exclusion Criteria
- •Disease progression occurring within 6 months after systemic treatment for locally advanced head and neck squamous cell carcinoma; A history of primary nasopharyngeal carcinoma; Central nervous system metastasis and/or carcinomatous meningitis; Patients with hearing loss ≥ grade 2 or neuropathy ≥ grade 2 who are currently receiving anti-tumor treatment; Patients who have participated in or are participating in other drug/therapy clinical trials within 4 weeks before the first administration of the study drug; Patients who have received hematopoietic stimulating factors (such as granulocyte colony-stimulating factor (G-CSF), erythropoietin, etc.) within 1 week before the first administration of the study drug; Positive results for HIV antibody or Treponema pallidum antibody tests;
- •Patients with active hepatitis B or hepatitis C:
- •For those with positive HBsAg or HBcAb, additional HBV DNA testing is required (if the result is higher than the upper limit of the normal range); For those with positive HCV antibody test results, additional HCV RNA testing is required (if the result is higher than the upper limit of the normal range); Active lung diseases (interstitial pneumonia, pneumonia, obstructive pulmonary disease, asthma) or a history of active pulmonary tuberculosis; Patients with any active autoimmune disease or a history of autoimmune disease (including but not limited to: autoimmune hepatitis, interstitial pneumonia, uveitis, enteritis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism; vitiligo that does not require systemic treatment can be included; asthma that has been completely relieved in childhood and requires no intervention in adulthood can be included; asthma in patients requiring medical intervention with bronchodilators cannot be included); Patients who are using immunosuppressants or systemic hormone therapy for the purpose of immunosuppression (dose > 10mg/day prednisone or other hormones with equivalent efficacy) and continue to use them within 2 weeks before enrollment;
- •Having any uncontrollable clinical problems, including but not limited to:
- •Persistent or active (severe) infections; Poorly controlled diabetes; Cardiac diseases (New York Heart Association class III/IV congestive heart failure or heart block); The following conditions occurring within 6 months before the first dose: deep vein thrombosis or pulmonary embolism; myocardial infarction; severe or unstable arrhythmia or angina pectoris; percutaneous coronary intervention, acute coronary syndrome, coronary artery bypass grafting; cerebrovascular accident, transient ischemic attack, cerebral embolism.
- •Large amounts of pleural effusion or ascites with clinical symptoms requiring symptomatic treatment; Patients who received cytochrome P450 3A4 (CYP3A4) inhibitors within one week before screening; A history of stem cell transplantation or organ transplantation; Patients with a history of psychoactive substance abuse who are unable to abstain or a history of mental disorders; Other severe, acute or chronic medical diseases or laboratory test abnormalities that the researcher judges may increase the risks related to study participation or may interfere with the interpretation of study results; Patients judged by the researcher to have poor compliance, or other conditions that make them unsuitable for participating in this trial; A history of other malignant tumors within 5 years, except for cured basal cell carcinoma of the skin, squamous cell carcinoma of the skin, early-stage prostate cancer, and carcinoma in situ of the cervix.
Arms & Interventions
Sacituzumab Tirumotecan and Toripalimab
Intervention: Sacituzumab Tirumotecan and Toripalimab (Drug)
Outcomes
Primary Outcomes
objective response rate
Time Frame: 12 months
ORR was defined as the percentage of participants in the analysis population who have a Complete Response (CR: disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1.
Secondary Outcomes
- Progression Free Survival(12 months)
- Number of Participants Experiencing an Adverse Event (AE)(12 months)
- overall survival(12 months)
Investigators
ren guoxin
Principal Investigator
Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University