ENB-003 Plus Pembrolizumab Elicits Safety, Activity in Ovarian Cancer and Other Advanced, Refractory Solid Tumors

Treatment with the combination of the ETBR inhibitor ENB-003 and pembrolizumab (Keytruda) was well tolerated and produced preliminary signs of clinical activity in patients with platinum-refractory or -resistant, microsatellite stable (MSS) ovarian cancer, and those with other advanced refractory solid tumors, according to topline data from the phase 1/2 ENBolden-101 trial (NCT04205227).¹

Findings showed that evaluable patients treated across all cohorts (n = 30), irrespective of ETBR status, experienced a disease control rate (DCR) of 33%, including 1 patient with platinum-refractory, PD-L1–negative, MSS ovarian cancer who achieved a 95% partial response (PR) with a 12-month duration. Additionally, 9 patients experienced stable disease (SD), and 20 patients had progressive disease (PD).

Among all patients with platinum-refractory/MSS ovarian cancer (n = 5), the DCR was 80%.

In patients with ETBR-high disease, the DCR was 33% in cohorts 1 to 5, including 1 patient with a PR, 4 with SD, and 10 with PD. Those who were ETBR-high in cohort 6 achieved a DCR of 83%, including 5 patients with SD and 1 with PD. In ETBR-low patients in cohort 6, all 9 patients experienced PD. Notably, ETBR-low patients were not included in cohorts 1 to 5.

No dose-limiting toxicities were observed in any of the 6 cohorts. The most common any-grade treatment-emergent adverse effects (AEs) included fatigue (28.2%), constipation (26.1%), abdominal pain (26.1%), nausea (23.9%), anemia (17.4%), and diarrhea (17.4%). Serious AEs of grade 3 or higher considered possibly related to study treatment included fatigue (n = 4), diarrhea (n = 3), dyspnea (n = 3), constipation (n = 2), and rash (n = 2).

“The completion of enrollment of the phase 1 ENBOLDEN-101 first-in-[human] study is a significant milestone for our company. We are extremely encouraged by the results in heavily treated [patients with] cancer refractory to standard-of-care treatment,” Sumayah Jamal, MD, PhD, president, chief scientific officer, and co-founder of ENB Therapeutics, stated in a news release. “Our data suggest potential efficacy in patients that do not historically respond to immunotherapy and support further clinical development. We are grateful to our patients and their families for their participation in our study. “

Preclinical models investigated the use of ENB-003 as a single agent and in combination with anti–PD-1 agents, and antitumor activity was observed in anti–PD-1–resistant models of melanoma, ovarian cancer, pancreatic cancer, bladder cancer, breast cancer, and squamous cell carcinoma. Furthermore, ENB-003 plus anti–PD-1 therapy was superior to standard-of-care FOLFIRINOX in a syngeneic pancreatic cancer model.²

ENBolden-101 is a multicenter, open-label, phase 1/2 study investigating the combination of ENB-003 and pembrolizumab in adult patients with advanced refractory solid tumors. All patients are required to have a life expectancy of more than 3 months and an ECOG performance status of 0 or 1.3 Fresh biopsies for ETBR and a biomarker analysis are preferred for all patients, particularly in those with superficial primary or metastatic lesions. Those without a fresh biopsy must have archival tumor tissue obtained within 24 months of screening.

Patients were excluded if they experienced a grade 3 or higher immune-related AE that led to discontinuation of prior treatment with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent, or an agent directed to another stimulatory or co-inhibitory T-cell receptor. Other exclusion criteria include prior radiotherapy within 2 weeks of the start of study treatment or a history of radiation pneumonitis; treatment with an investigational agent or device within 4 weeks of first study treatment; and known active central nervous system metastases and/or carcinomatous meningitis.

Part 1 of the study featured a 3+3 dose-escalation design, where patients with EBTR-positive tumors received 1 of 6 escalating doses of ENB-003, ranging from 150 µg to 2000 µg, in combination with 200 mg of pembrolizumab once every 3 weeks. Patients were given a 1-week run-in with ENB-003 prior to receiving the combination.²

Cohorts 1 to 5 featured 15 patients with evaluable disease who were treated with ENB-003 at doses ranging from 150 ug to 1000 ug. In cohort 6, 15 patients with evaluable disease received ENB-003 at 2000 ug with a dosing frequency that doubled to 6 doses every 3 weeks after patients in cohorts 1 to 5 received 6 doses every 6 weeks.¹

Safety/tolerability is the primary end point of part 1. Secondary end points include antitumor effects. Biomarkers and pharmacodynamics are exploratory end points.²

Previously reported findings presented at the 2022 Summit for Cancer Immunotherapy showed that the addition of ENB-003 to pembrolizumab did not produce any additional toxicity beyond the known toxicity profile of pembrolizumab.

Regarding efficacy, patients treated with the combination (n = 16) experienced a DCR of 50%. A total of 7 patients achieved SD, and 8 patients had PD. One patient with anti–PD-1 refractory head and neck squamous cell carcinoma experienced SD for 7 months.

References

1. ENB Therapeutics presents top-line results from phase 1b ENBOLDEN-101 study in solid tumors refractory to standard of care at the Immuno-oncology Summit 2023. News release. ENB Therapeutics. July 18, 2023. Accessed July 20, 2023. https://www.businesswire.com/news/home/20230717370427/en/ENB-Therapeutics-Presents-Top-line-Results-from-Phase-1b-ENBOLDEN-101-Study-in-Solid-Tumors-Refractory-to-Standard-of-Care-at-the-Immuno-oncology-Summit-2023
2. Jamal S, Nagrial A, Carlino M, et al. ENB-003, an ETBR inhibitor, in combination with pembrolizumab for advanced refractory solid tumors. Presented at: 2022 Summit for Cancer Immunotherapy; November 19-21, 2022; Montreal, Quebec, Canada. Poster 143.
3. ENB003 plus pembrolizumab phase 1b/​2a in solid tumors. ClinicalTrials.gov. Updated June 15, 2023. Accessed July 20, 2023. https://clinicaltrials.gov/study/NCT04205227