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Published on: April 22, 2019
Mitomycin-C for HPV-Positive and HPV-Negative Platinum-Refractory, Recurrent or Metastatic Head and Neck Squamous
Peter Oppelt1,2, Jessica Ley2, Christine Auberle1,2
1Alvin J. Siteman Cancer Center, St. Louis, MO 63110, USA.
Background/Objectives:
Functional p53 is critical for anti-tumor activity of mitomycin-C. In wild-type TP53 human papillomavirus (HPV)-positive squamous cell carcinoma (SCC) cell lines, mitomycin-C repressed E6 oncoprotein expression and induced p53, p21, and Bax, resulting in apoptosis. In mutant TP53 HPV-negative SCC cell lines, mitomycin-C was inactive. The primary aim of this trial was to determine the objective response rate (ORR) with mitomycin-C among patients with HPV-positive (cohort A) and HPV-negative (cohort B) platinum-refractory, recurrent or metastatic head and neck SCC (RM-HNSCC).
Methods:
Patients with platinum-refractory RM-HNSCC received mitomycin-C (10 mg/m2 on day one every five weeks) until discontinuation criteria were met. Tumor response was assessed by RECIST1.1. We hypothesized an ORR of ≥30% (H1) with mitomycin-C (vs. H0 ORR of ≤10%). Using a two-stage Simon phase 2 design for each cohort, 2 or more responses among 12 evaluable patients were required to enroll 23 additional patients. H1 was accepted if 6 or more responses occurred among 35 evaluable patients (power 0.90; one-sided α = 0.10).
Results:
Forty-seven patients were treated with mitomycin-C: 34 in cohort A and 13 in cohort B. Tumor response occurred in 3 of 33 evaluable patients in cohort A (ORR 9.1%, 95%CI: 0-19.4) and in 0 of 12 evaluable patients in cohort B. The duration of tumor responses in cohort A was 2.3, 2.5, and 4.5 months. The most common treatment-related AEs of any grade were anemia (96%), fatigue (62%), and thrombocytopenia (40%). No treatment-related deaths occurred.
Conclusions:
Mitomycin-C had limited activity in HPV-positive, and no activity in HPV-negative, platinum-refractory RM-HNSCC.
Insights
Mitomycin-C showed limited effectiveness in treating platinum-refractory head and neck squamous cell carcinoma (HNSCC) in patients with HPV-positive tumors. The drug demonstrated no activity in HPV-negative HNSCC patients.
Area of Science:
- Oncology
- Cancer Therapeutics
- Head and Neck Cancer Research
Background:
- Functional p53 is crucial for mitomycin-C's anti-tumor effects.
- Mitomycin-C activates apoptosis in HPV-positive SCC cell lines by inducing p53 and related proteins.
- Mitomycin-C is ineffective in HPV-negative SCC cell lines with mutant TP53.
Purpose of the Study:
- To evaluate the objective response rate (ORR) of mitomycin-C in patients with platinum-refractory, recurrent or metastatic head and neck SCC (RM-HNSCC).
- To assess mitomycin-C efficacy separately in HPV-positive (cohort A) and HPV-negative (cohort B) RM-HNSCC populations.
Main Methods:
- A two-stage Simon phase 2 trial design was employed for each cohort.
- Patients received mitomycin-C (10 mg/m² every five weeks) until treatment discontinuation.
- Tumor response was evaluated using RECIST 1.1 criteria.
Main Results:
- The ORR for mitomycin-C in HPV-positive RM-HNSCC was 9.1% (3/33 evaluable patients).
- No objective responses were observed in HPV-negative RM-HNSCC patients (0/12 evaluable).
- Common adverse events included anemia (96%), fatigue (62%), and thrombocytopenia (40%).
Conclusions:
- Mitomycin-C demonstrated limited clinical activity in platinum-refractory HPV-positive RM-HNSCC.
- Mitomycin-C showed no activity in platinum-refractory HPV-negative RM-HNSCC.
- The study suggests limited utility of mitomycin-C for these patient populations.
