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NEXUS: a phase I dose escalation study of selinexor plus nivolumab and ipilimumab in Asian patients with
Joan R Choo1, Santhiay Nathan Jeraj1, Raghav Sundar1,2
1Department of Haematology-Oncology, National University Health System, National University Cancer Institute, Singapore, Singapore.
Background:
Selinexor (SEL) is an oral inhibitor of nuclear export protein Exportin 1 (XPO1) previously shown to upregulate programmed cell death protein 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression.
Objective:
To investigate the safety and antitumor activity of SEL, nivolumab (NIVO), and ipilimumab (IPI) in Asian patients with treatment-refractory solid organ cancers.
Design:
Phase I study of escalating doses of SEL in combination with NIVO + IPI. Patients were enrolled in a 3 + 3 design.
Methods:
NIVO and IPI were dosed at 240 mg Q2W and 1 mg/kg Q6W, respectively. SEL was dosed with a 2-week monotherapy run-in prior to triplet therapy, at dose levels (DL) 1 (40 mg once/week) and DL2 (60 mg once/week). Dose-limiting toxicity (DLT) was assessed over the first 6 weeks.
Results:
Twelve patients were enrolled; 11 were evaluable for response, and 6 were evaluable for DLT (1 had a non-treatment-related stroke and 5 had progressive disease (PD) prior to completion of the DLT period). The median age was 64.5 (range 39-78) years. The median line of prior therapy was 3 (range 2-5). Dose escalation proceeded through DL1 (n = 7, 3 evaluable for DLT) and DL2 (n = 5, 3 evaluable for DLT). No DLTs were observed among evaluable patients. No patients required dose reduction of SEL. Most frequent treatment-related AEs were fatigue (5/12; G ⩾ 3 = 1), nausea (5/12; G ⩾ 3 = 0), anorexia (4/12; G ⩾ 3 = 0), transaminitis (2/12; G ⩾ 3 = 0), and hypomagnesemia (2/12; G ⩾ 3 = 0). The recommended phase II dose was SEL 60 mg once/week combined with NIVO + IPI. One patient had a partial response (PR; progression-free survival (PFS) of 61 days), 3 had prolonged stable disease (SD; PFS of 141, 344, and 442 days, respectively), and 7 had PD. All patients with SD or PR had previously progressed on immunotherapy but experienced prolonged disease control on SEL in combination with NIVO + IPI.
Conclusion:
SEL in combination with NIVO + IPI was well tolerated without any new safety signals. The combination showed promising and durable antitumor activity in Asian patients with advanced malignancies who had failed prior immunotherapy and merits further investigation.
Trial Registration:
NCT04850755 (https://clinicaltrials.gov/study/NCT04850755).
Insights
Selinexor combined with nivolumab and ipilimumab showed promising antitumor activity in Asian patients with advanced cancers who previously failed immunotherapy. This combination therapy was well-tolerated, indicating potential for further investigation in treating refractory solid organ cancers.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Selinexor (SEL) is an oral inhibitor of Exportin 1 (XPO1) that upregulates PD-L1 and CTLA-4 expression.
- Investigating novel therapeutic combinations is crucial for overcoming resistance in advanced cancers.
Purpose of the Study:
- To evaluate the safety and antitumor activity of Selinexor (SEL) in combination with nivolumab (NIVO) and ipilimumab (IPI).
- To determine the recommended Phase II dose of this triplet therapy in Asian patients with treatment-refractory solid organ cancers.
Main Methods:
- A Phase I, 3+3 dose escalation study was conducted.
- Patients received escalating doses of SEL with standard doses of NIVO and IPI, with SEL having a 2-week monotherapy run-in.
- Dose-limiting toxicity (DLT) was assessed over the first 6 weeks.
Main Results:
- Twelve patients were enrolled; 11 were evaluable for response.
- No dose-limiting toxicities were observed. The most frequent treatment-related adverse events included fatigue and nausea.
- The recommended Phase II dose was determined to be SEL 60 mg once/week combined with NIVO + IPI.
- One partial response and three cases of prolonged stable disease were observed, with all responders having previously progressed on immunotherapy.
Conclusions:
- The combination of SEL, NIVO, and IPI was well-tolerated in Asian patients with advanced malignancies.
- This triplet therapy demonstrated promising and durable antitumor activity in patients refractory to prior immunotherapy.
- Further investigation of this combination is warranted for patients with advanced solid organ cancers.
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