Phase 2 KEYNOTE-695 Trial for Melanoma Treatment Did Not Reach Primary Endpoint

The phase 2 KEYNOTE-695 trial (NCT03132675), conducted by OncoSec Medical Incorporated, observed the efficacy of the combination of interleukin 12 (IL-12) encoding plasmid tavokinogene telseplasmid (TAVO-EP) plus IV pembrolizumab (Keytruda, Merck & Dohme LLC). Study participants had to be diagnosed with unresectable or metastatic melanoma, stage III/IV, who were progressing on either pembrolizumab or nivolumab (Opdivo). Patients in the trial had confirmed disease progression after at least 12 weeks exposure to immediate prior anti-PD-1 antibody therapy.¹

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Researchers observed patients during a treatment period of up to 2 years. Eligible patients were treated with tavo-EP to lesions every 6 weeks on days 1, 5, and 8. Then, they were treated with IV pembrolizumab (200 mg) on day 1 of each 30week cycle. Patients underwent 18 TAVO-EP cycles and 35 pembrolizumab cycles from baseline in a span of 2 years or until disease progression. The trial’s last patient started treatment in December 2020 and the clinical database lock happened in October 2022. Overall response rate (ORR) per blinded independent central review (BICR) served as the trial’s primary end point. Secondary end points included investigator-assessed ORR, DOR, progression-free survival (PFS), immune PFS, immune ORR, and overall survival (OS).²

“Among 98 efficacy evaluable patients with at least one post-baseline tumor assessment, the confirmedORR per response evaluation criteria in solid tumors (RECIST) v1.1 by BICR assessment is 10.2% (95% confidence interval: 5.00, 17.97), which did not achieve the pre-specified clinically meaningful ORR of ≥17% (95% CI: 10.2, 25.8),” study researchers noted. “The BICR review results for 98 efficacy evaluable patients are lower than the ORR per RECIST v1.1 by investigator assessment of 18.8% for the 101 patients previously reported as the key secondary endpoint of the KEYNOTE-695 trial."

Per BICR, 4 patients achieved a complete response, 6 had a partial response, and 25 had stable disease, translating to a disease control rate of 35.7%. Additionally, 8.2% of patients had a durable response of at least 24 weeks, and the median duration of response (DOR) was 25.5 months (range, 6.83-not reached).

Regarding safety, TAVO-EP plus pembrolizumab was well tolerated, and 4.8% of patients experienced grade 3 treatment-related adverse effects (TRAEs). No grade 4 or 5 TRAEs have been reported in KEYNOTE-695 or any other clinical trials evaluating TAVO-EP plus pembrolizumab.

“Treatment of patients with anti–PD-1 refractory melanoma remains difficult with limited success for immune checkpoint inhibitor combinations and exploratory therapeutic approaches. It is disappointing that review by [BICR] did not confirm the previously reported results by investigator assessment of the KEYNOTE-695 phase 2 clinical trial in this patient population,” Robert Arch, PhD, chief executive officer of OncoSec Medical Incorporated, stated in a news release. “However, we remain optimistic that the observed long duration of response and OS of 22.7 months in this heavily pretreated patient population, together with previously reported preliminary results from [an investigator-sponsored trial from Ahmad Tarhini, MD, PhD, of Moffitt Cancer Center] in the neoadjuvant melanoma setting, provide rationale for further development of TAVO-EP in combination with anti–PD-1 therapy.”

TAVO-EP plus nivolumab is being investigated in an investigator-sponsored phase 2 trial (NCT04526730) as neoadjuvant treatment in patients with operable locally/regionally advanced melanoma. Interim data from the study presented at the 2023 SITC Annual Meeting showed that the combination elicited an ORR of 70% per RECIST v1.1 criteria. Additionally, 88.9% of patients experienced a major pathological response, including 66.7% of patients who had a complete pathologic response.

A meeting with the FDA to discuss a phase 2 randomized trial design and future development plans in the neoadjuvant setting for melanoma is scheduled for May 2023.

References

1. OncoSec announces clinical data of the KEYNOTE-695 trial assessing TAVO™-EP in combination with Keytruda® (pembrolizumab) in patients with advanced melanoma refractory to anti-PD-1 treatment. News release. OncoSec Medical Incorporated. April 3, 2023. Accessed April 4, 2023. https://ir.oncosec.com/press-releases/

2. Tavo and pembrolizumab in patients with stage III/IV melanoma progressing on either pembrolizumab or nivolumab treatment (Keynote-695). ClinicalTrials.gov. Updated March 27, 2023. Accessed April 4, 2023. https://clinicaltrials.gov/ct2/show/NCT03132675