KEY TAKEAWAYS
- The phase I trial aimed to evaluate the safety and efficacy of combined Cabo-CTX therapy in R/M HNSCC pts.
- The primary endpoint was MTD. Secondary endpoints include ORR, PFS, and OS.
- The study found that the Cabo-CTX combination showed tolerable side effects, with liver toxicity being the most common.
Cetuximab (CTX) is a standard therapy for head and neck squamous cell carcinoma (HNSCC), but resistance can develop due to AXL activation. Cabozantinib (Cabo), a tyrosine kinase inhibitor (TKI) of AXL/c-MET/VEGFR, showed antitumor activity in HNSCC preclinical models. Researchers aimed to evaluate the safety and efficacy of combined Cabo-CTX therapy in recurrent/metastatic (R/M) HNSCC pts.
The study eligibility criteria were RECIST v1.1 measurable disease and incurable ll R/M HNSCC. Prior cetuximab (CTX) treatment was acceptable. Pts initially received a 400 mg/m2 CTX loading dose, followed by 250 mg/m2 weekly doses. Later, the CTX maintenance dose was adjusted to 500 mg/m2 every two weeks. Cabo was administered concurrently on days 1-28 of each 28-day cycle. The primary endpoint was to determine the maximally tolerated dose (MTD) of cabo, utilizing a 3+3 dose-escalation design. Tumor responses were evaluated every two cycles. Secondary objectives included assessing the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Of 22 pts enrolled, 2 did not initiate treatment. Among the treated pts, the median age was 59 (range 33-71), and the majority were male (90%, n = 18). The primary tumor sites included oropharynx (n = 13), oral cavity (n = 3), larynx (n = 2), hypopharynx (n = 1), and unknown primary (n = 1). HPV testing was positive for p16 antigen in 11 oropharyngeal cancers (85%). Most pts had prior treatments with immune checkpoint inhibitors (n = 19), chemotherapy (n = 19), cetuximab (n = 16), or other TKI (n = 2), 12 pts received biweekly cetuximab dosing at 500 mg/m2. The initial cabozantinib dose was 40 mg for the first 11 pts and 60 mg thereafter, representing the MTD.
There were no dose-limiting toxicities (DLT) observed. Common adverse events (AEs) included fatigue (80%), acneiform rash (75%), increased aspartate aminotransferase (AST) (70%), anemia (70%), and hypothyroidism (70%). Grade ≥3 AEs occurred in 65% of pts (n = 13), with increased AST (45%), increased alkaline phosphatase (15%), increased bilirubin (10%), and erythrodysesthesia (10%). AEs led to dose reductions in 20% (n = 4) and treatment discontinuation in 15% (n = 3). Regarding efficacy, 4 pts had partial responses (PRs), resulting in an ORR of 20%. The disease control rate (DCR) was 75% for the entire study population and 75% for those who had previously received CTX treatment. The median PFS was 3.4 months, and the median OS was 8.1 months.PFS varied based on HPV status, with a median PFS of 7.1 months for HPV-positive patients compared to 3.1 months for HPV-negative patients (P= 0.03).
The study found that the Cabo-CTX combination showed tolerable side effects, with liver toxicity being the most common. The regimen also showed promising efficacy in HNSCC pts, including those previously resistant to CTX.
Source: https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.6025
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT03667482
Antoine Desilets, David G. Pfister, Winston Wong, Eric Jeffrey Sherman, James Vincent Fetten, Kin Wai (Tony) Hung, Lara Dunn, Alan Loh Ho, and Loren S. Michel. DOI: 10.1200/JCO.2023.41.16_suppl.6025 Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) 6025-6025.
