This study evaluated the safety and clinical benefit of
ecromeximab (
KW2871) combined with high-dose interferon-α2b (HDI) in patients with metastatic
melanoma. We also carried out pharmacokinetic and immune monitoring studies of this combination. This was an open-label, phase 1/2 study of
ecromeximab plus HDI in patients with measurable metastatic
melanoma. Eligible patients received
ecromeximab-HDI combination
therapy:
ecromeximab administered intravenously once every 2 weeks and HDI at a dose of 20 million units (MU)/m administered intravenously for 5 consecutive days per week for the first 4 weeks (induction phase) and then at 10 MU/m subcutaneously thrice weekly through week 14 (maintenance phase). Patients were treated with combination
therapy until
disease progression or limiting toxicity. Three dose-escalation cohorts (5, 10, and 20 mg/m) of
ecromeximab were planned. Thirty-six evaluable patients were enrolled including six in each of cohorts 1 and 2, and 24 in cohort 3. Median progression-free survival was 2.53 months [95% confidence interval (CI):1.93-3.83] and it was 1.93 months (95% CI: 1.00-3.80) in cohort 3. The median overall survival was 10.28 months (95% CI: 6.93-16.77) and 7.78 months (95% CI: 6.03-13.97) in cohort 3. There was no significant difference in progression-free survival or overall survival by BRAF mutation status. The response rate was 5.6% (95% CI: 0.68-18.7), with two patients showing an objective response (one complete response and one partial response), and the clinical benefit rate was 78% (95% CI: 61-90). Stable disease as best response was observed in 26 (72%) patients including five in each of cohorts 1 and 2, and 16 in cohort 3. Treatment-emergent adverse events considered related to
ecromeximab treatment occurred in four (66.7%) patients in cohort 1, five (83.3%) patients in cohort 2, and seven (29.2%) patients in cohort 3. Among TEAEs with a maximum severity of grade 3 or 4, those that occurred only in cohort 3 were related to
pain,
electrolyte imbalance, blood cell decreases, and
allergic reaction. Safety and efficacies considered related to
ecromeximab occurred in cohort 3 and included grade 3
hypersensitivity [one (4.2%)] and grade 2
hypotension [one (4.2%)]. Regimen-limiting toxicities occurred in two (8.3%) patients in cohort 3:
hypersensitivity (with
hypertension,
supraventricular tachycardia,
bronchospasm,
chills, and
dyspnea) and
hypotension. One patient out of 31 examined showed a low-level transient positivity for human antichimeric
antibodies against
ecromeximab. Pharmacokinetic measurements by
enzyme-linked
immunosorbent assay determined that administration of HDI does not influence serum levels of
ecromeximab at 5, 10, and 20 mg/m dose levels.
Ecromeximab in combination with HDI was generally well tolerated in patients with metastatic
melanoma and has shown low immunogenicity. However, the clinical activity was limited, suggesting that future development of this combination should be deprioritized and that other combinations, such as with
immune checkpoint inhibitors, should be considered.