EDP1503 With or Without Pembrolizumab Has Clinical Activity Across Solid Tumors

EDP1503, an investigational monoclonal microbial product, was safe and well-tolerated when administered in combination with pembrolizumab (Keytruda), and mechanistically drove some responses seen in a phase 1/2 study of patients with a number of solid tumors, according to preliminary data presented at the 2020 ESMO World Congress on Gastrointestinal Cancer Virtual Meeting.¹

Findings from the open-label investigation (NCT03775850) of EDP1503 alone and in combination with pembrolizumab showed that at the data cutoff date of May 29, 2020, treatment with single-agent EDP1503 2 weeks prior to combination dosing with pembrolizumab led to partial responses (PRs) in 2 patients with triple-negative breast cancer (TNBC) and 2 with non–small cell lung cancer (NSCLC). These partial responses (PRs) translated to an overall response rate of 14% (4 of 29) across 29 patients with malignancies across tumor types. Both patients with TNBC have ongoing PRs. Moreover, 5 patients had stable disease, including 1 patient with TNBC; 2 patients with NSCLC; 1 patient with renal cell carcinoma (RCC); and 1 patient with bladder cancer.¹

MSS CRC

The poster presentation also encompassed new data from 2 tumor specific cohorts, microsatellite stable colorectal cancer (MSS CRC) and TNBC. Of the 33 patients who received EDP1503 monotherapy prior to pembrolizumab co-administration, 7 had best response of stable disease (SD) and 3 had prolonged SD that lasted longer than 9 months. The disease control rate was 21% (7 of 33).^1,2

Biomarker analyses of patients with MSS CRC performed before and after a 2 week regimen of EDP1503 monotherapy indicated that increased tumor infiltrating CD8:Treg ratios induced by the experimental agent correlated with treatment duration. Results from these analyses also provided evidence that EDP1503 was catalyzing some of the clinical responses seen in this cohort, investigators said.¹

These data were assessed at the cutoff of May 29, 2020. The median on-treatment time was 58 days, and each patient received EDP1503 at the low dose of 2 enteric capsules twice daily. All patients with MSS CRC are currently off study.¹

TNBC

In the TNBC cohort, 8 patients received high-dose EDP1503 and 3, low-dose EDP1503. In the patients treated with the higher dose, the overall response rate (ORR) was 25% (2 of 8), and the disease control rate was 37.5% (3 of 8). Among response-evaluable patients on the high dose, the ORR was 33% (2 of 6), with 2 patients awaiting first response assessment.^1,2

These ORR data are promising, because existing evidence from studies of anti–PD-1 single agents in heavily pretreated TNBC have only yielded an ORR of 5% to 10%. Consequently, this study continues to enroll patients with TNBC, with additional results from this cohort expected in the fourth quarter of 2020. Newly accrued patients will receive high-dose EDP1503.^1,2

General Efficacy and Methods

Overall, evidence of the clinical translation of preclinical data suggesting a potential anticancer effect with EDP1503 was observed in patients with TNBC and NSCLC, validating the investigational therapy’s viability across histologies. Although detailed findings from investigators’ evaluation of EDP1503 in combination with pembrolizumab were not included in the poster presentation, Loise Francisco-Anderson, PhD, the study’s lead author, said the doublet regimen was safe and well-tolerated with no treatment-related grade 4 or 5 adverse events (AEs) or serious AEs. Francisco-Anderson is the vice president of Discovery, Innovation, and Oncology at Evelo Biosciences, Inc., EDP1503’s developer.¹

The phase 1/2 study was designed to enroll approximately 120 patients with advanced metastatic colorectal carcinoma, TNBC, and checkpoint inhibitor relapsed tumors. Patients with NSCLC, bladder cancer, RCC, gastroesophageal cancer, and microsatellite instability–high disease were also permitted.³ The data presented at the ESMO World Congress on Gastrointestinal Cancer included 33 patients with MSS CRC, 11 with TNBC, and 18 patients with malignancies in other tumor types who relapsed on prior PD-1/PD-L1 therapy.¹

Primary end points included the safety and tolerability of EDP1503 in combination with pembrolizumab and the number of patients with EDP1503-related AEs assessed via Common Terminology Criteria for Adverse Events version 5.0; the safety and tolerability of EDP1503 alone and in combination with pembrolizumab assessed via clinical laboratory evaluations; and the evidence of antitumor activity of EDP1503 based on ORR.¹

Patients received a 14-day run-in of EDP1503 monotherapy, followed by EDP1503 in combination with pembrolizumab. EDP1503 was administered via 2 to 4 capsules; pembrolizumab, at 200 mg via intravenous infusion every 3 weeks.¹

EDP1503

EDP1503 is an orally delivered strain of Bifidobacterium animalis lactis that has demonstrated effective preclinical antitumor responses due to activation of innate and adaptive immune mechanisms. Enrichment of specific intestinal microbes has been shown to enhance antitumor responses to PD-1 blockade in murine models and patients with cancer, supporting the rationale for combining EDP1503 with the anti–PD-1 agent, pembrolizumab.^1,4

Mechanistically, EDP1503 induces systemic antitumor immunity. Systemic immunity is regulated by interactions of commensal bacteria with immune cells in the gut, and single strains of microbes can alter systemic immunology without systemic exposure. Preclinically, EDP1503 had pleiotropic effects on the systemic immune system and notably induced a proinflammatory gene signature in CXCL10, IL12p70, interferon-γ, interleukin (IL)-1β, TNFα, and IL-6; activated effector lymphocyte populations, including NK, NKT, and CD4- and CD8-positive; and induced a proinflammatory chemotactic signature within the tumor microenvironment. EDP1503’s pleiotropic effects are driven through interactions with multiple pattern recognition receptors.^1,4

The small intestine is EDP1503’s primary site of action, and colonization is not required for pharmacological activity, investigators concluded.¹

References

1. Francisco-Anderson L, Shariffudin S, Gardner H, et al. EDP1503 induces antitumor responses via gut-mediated activation of both innate and adaptive immunity. Presented at: ESMO World Congress on Gastrointestinal Cancer 2020. July 1-4, 2020; Virtual. Abstract P-325.
2. Evelo Biosciences to present clinical data from phase 1/2 trial of EDP1503 at ESMO World Congress on Gastrointestinal Cancer Virtual Meeting [news release]. Published July 1, 2020. https://bit.ly/2BwnV73. Accessed July 2, 2020.
3. A study of EDP1503 in patients with colorectal cancer, breast cancer, and checkpoint inhibitor relapsed tumors. ClinicalTrials.gov identifier: NCT03775850. https://clinicaltrials.gov/ct2/show/NCT03775850. Updated May 27, 2020. Accessed July 2, 2020.
4. Gardner HA, Kashyap S, Ponichtera H, et al. Monoclonal microbial EDP1503 to induce antitumor responses via gut-mediated activation of both innate and adaptive immunity. J Clin Oncol. 2019;37(suppl 15):e14241. doi:10.1200/JCO.2019.37.15