TAK-981 Shown Safe With Efficacy Signal in Solid Tumors and Lymphomas

Subasumstat (TAK-981), a first-in-class, investigational, SUMO-activating enzyme inhibitor for the treatment of advanced or metastatic solid tumors or relapsed/refractory lymphoma, was found to have a manageable safety profile, according to phase 1 study results presented at the Society for Immunotherapy of Cancer 2021 Annual Meeting. 

Subasumstat is the first small-molecule inhibitor of SUMOylation to enter clinical trials. Blocking SUMOylation is meant to promote type 1 IFN-dependent innate immune response, therefore enhancing anti-itumor adaptive immunity.

During the phase 1/2 open-label, dose-escalation and dose-expansion study (NCT03648372), patients were randomly assigned to receive subasumstat either once per week or biweekly. Treatment was continued for 1 year or until disease progression or unacceptable toxicity. The primary end points of the study were dose-limiting toxicities and the frequency, severity, and duration of treatment-emergent adverse events (TEAEs). Secondary end points include pharmacokinetics and overall response rate.

In order to participate in the study, patients must be 18 years of age or older, have an ECOG performance status of 0 or 1, and have a diagnosis of advanced or metastatic solid tumors with no standard therapeutic option with a proven clinical benefit or relapsed or refractory lymphomas not amendable to therapies with proven clinical benefit, or with failure of 2 or more prior systemic therapies.

In total, 76 patients enrolled across 10 dose levels (3-40 mg biweekly and 60-120 mg once weekly). At the time of data cutoff, 17.1% of patients were still receiving the study drug. Disease progression amounted for 57.9% of reasons for treatment discontinuation, 10.5% discontinued for AEs, 7.9% for symptomatic deterioration, and 6.6% for withdrawal by the patient.

The median age of patients was 61 years of age (range, 38-79) and 55.3% were female. Tumor types included colorectal (26.3%), pancreatic (9.2%), kidney (6.6%), breast (5.3%), head and neck (5.3%), melanoma (5.3%), prostate (5.3%), adrenal (3.9%), non-small cell lung cancer (3.9%), endometrial (2.6%), appendix (2.6%), and other (23.7%). The median number of prior lines of therapy are 4 (range, 1-10).

In the 62 evaluable patients, 4 dose limiting toxicities were observed. Additionally, the maximum tolerated dose was found to be 120 mg biweekly. As of the April 2021 data cutoff, the median treatment duration was 2 cycles (range, 1-12).

In terms of safety, common TEAEs included fatigue (42.1%), nausea (39.5%), headache (31.6%), diarrhea (28.9%), pyrexia (27.6%), vomiting (23.7%), and decreased appetite (22.4%). Grade 3 or higher TEAEs included hypokalemia (9.2%), anemia (7.9%), lymphocyte count decrease (6.6%), dyspnea (5.3%), and abdominal pain (5.3%).

Cytokine release syndrome was seen in 11.8% of patients. All cases of grade 2 cytokine release syndrome resolved within 12 hours of onset with oral antipyretics, supportive oxygen, and/or intravenous fluids. 

One partial response was seen in a patient with human epidermal growth factor receptor 2- negative, hormone-receptor positive breast cancer who had received 8 prior lines of therapy. The patient was receiving 40 mg of subasumstat biweekly. The response was seen after 3 cycles. The response deepened after the patient’s dose was increase from 40 mg to 60 mg. Additionally, 17.1% of patients had stable disease. Anti-tumor activity is being investigated further in the ongoing dose-expansion phase of the trial. 

Dose-dependent activity was seen across a range of pharmacodynamic measures. This indicates that subasumstat is active across doses above ≥60 mg, as seen with biomarkers in the type 1 IFN pathway and NK cell activation. Pharmacodynamics and safety data suggest that the recommended phase 2 dose should be 90 mg biweekly.

_REFERENCE:

_{Dudek A, Juric D, Dowlati A, et al. First-in-human phase 1/2 study of the first-in-class SUMO-activating enzyme inhibitor TAK-981 in patients with advanced or metastatic solid tumors or relapsed/refractory lymphoma: phase 1 results. Presented at the SITC 2021 Annual Meeting. November 10-14; Washington DC.}