TAVO-EP Plus Pembrolizumab Fails to Meet ORR End Point in Anti–PD-1–Refractory Advanced Melanoma

The combination of the interleukin-12 (IL-12) encoding plasmid TAVO™-EP (tavokinogene telseplasmid) plus pembrolizumab (Keytruda) did not meet the prespecified primary end point for overall response rate (ORR) in patients with advanced melanoma that was refractory to anti–PD-1 therapy, according to data from the phase 2 KEYNOTE-695 trial (NCT03132675).¹

Findings showed that in treated patients who underwent at least 1 post-baseline tumor assessment (n = 98), the ORR by blinded independent central review (BICR) was 10.2% (95% CI, 5.00%-17.97%) per RECIST v1.1 criteria. This failed to meet the clinically meaningful ORR threshold of at least 17% (95% CI, 10.2%-25.8%). The BICR-assessed ORR was lower than the 18.8% investigator-assessed ORR among 101 patients previously reported as a key secondary end point of the study.

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).

“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 overall survival [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 enables the intratumoral delivery of DNA-based IL-12, which is a naturally occurring protein with immune-stimulating functions. TAVO-EP employs electroporation and is designed to produce a localized expression of IL-12 in the tumor microenvironment to stimulate the immune system to target and attack tumors.

KEYNOTE-695 enrolled patients with histological or cytological confirmed stage III or IV unresectable melanoma with progressive locally advanced or metastatic disease who were refractory to either pembrolizumab or nivolumab (Opdivo) either as monotherapy or in combination with other checkpoint inhibitors or targeted therapies.²

Enrolled patients were given intratumoral TAVO-EP on days 1, 5, and 8 of every 6-week cycle plus 200 mg of intravenous pembrolizumab once every 3 weeks. Treatment continued for up to 18 cycles of TAVO-EP and 35 cycles of pembrolizumab, or until disease progression.

ORR per 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 OS.

Previously reported data from KEYNOTE-695 trial showed that at a median follow-up of 33.4 months, the median OS was 22.7 months (95% CI, 14.4-35.5) among all 105 enrolled patients.¹

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.

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.

“We plan to discuss these data and a draft protocol for TAVO-EP in combination with pembrolizumab for a randomized phase 2 trial in the neoadjuvant setting at the upcoming meeting with the FDA to potentially initiate the trial in the second half of 2023,” Arch added. “I want to thank all patients who participated in the KEYNOTE-695 trial, the clinical teams who conducted this trial, and everybody at OncoSec who remain focused on developing TAVO-EP as a novel intratumoral treatment approach for cancer patients with unmet medical needs."

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