Tavokinogene/Pembrolizumab Yields Responses but Misses End Point in Melanoma

Although tavokinogene telseplasmid (TAVO-EP) plus pembrolizumab (Keytruda) induced some responses, it did not reach the primary end point of overall response rate (ORR) in patients with advanced melanoma refractory to a prior anti–PD-1 agent, according to a press release from OncoSec Medical Incorporated on data from the phase 2 KEYNOTE-695 trial (NCT03132675).

"We remain optimistic that the observed long [DOR] and [OS]…in this heavily pre-treated patient population, together with previously reported preliminary results from [the investigator-sponsored trial] in the neoadjuvant melanoma setting, provide rationale for further development of [tavokinogene telseplasmid] in combination with anti–PD-1 therapy," according to the manufacturers of tavokinogene telseplasmid.

Among 98 evaluable patients, the confirmed ORR by blinded independent central review and RECIST v1.1 criteria was 10.2% (95% CI, 5.00%-17.97%), which did not meet the trial’s pre-specified threshold of at least 17% (95% CI, 10.2%-25.8%). Additionally, 4 patients experienced a complete response (CR), 6 had a partial response (PR), and 25 patients had stabled disease as a best response. Moreover, the disease control rate was 35.7%. The durable response rate of at 24 weeks or more was 8.2%, and the median duration of response (DOR) was 25.5 months (range, 6.83-not reached).

With a median follow-up of 33.4 months in a previous read out, the median overall survival (OS) for in 105 patients was 22.7 months (95% CI, 14.4%-35.5%). Moreover, the regimen was also well tolerated among patients, with 4.8% of patients having grade 3 treatment-related adverse effects (TRAEs). Additionally, investigators reported that there were no grade 4 or 5 TRAEs.

Plans to advance tavokinogene telseplasmid as treatment for neoadjuvant melanoma were supported by an investigator-sponsored phase 2 trial (NCT04526730) in which investigators assessed the interleukin-12 (IL-12) encoding plasmid in combination with nivolumab (Opdivo).

Based on interim data presented at the 37th Annual Meeting of the Society of Immunotherapy of Cancer, tavokinogene plus nivolumab yielded an ORR of 70.0% and a major pathological response rate of 88.9%, which included a complete pathological response rate of 66.7%.² Investigators observed responses even among those predicted to be non-responders to immune checkpoint blockade by biomarker analysis, supporting the mechanism of action of IL-12.

Investigators plan to meet with the FDA in May 2023 to discuss a phase 2 randomized trial design as well as future development plans for tavokinogene telseplasmid in the neoadjuvant setting.

“It is disappointing that review by blinded central readers did not confirm the previously reported results by investigator assessment of the phase 2 KEYNOTE-695 clinical trial in this patient population,” Robert Arch, PhD, chief executive officer of OncoSec, said in the press release.

“However, we remain optimistic that the observed long [DOR] and [OS]…in this heavily pre-treated patient population, together with previously reported preliminary results from [the investigator-sponsored trial] in the neoadjuvant melanoma setting, provide rationale for further development of [tavokinogene telseplasmid] in combination with anti–PD-1 therapy.”

Tavokinogene telseplasmid enables the intratumoral delivery of IL-12, a naturally occurring protein with immune-stimulating functions. Investigators believe that this approach, which employs electroporation, may produce a localized expression of IL-12 in the tumor microenvironment, effectively stimulating the immune system to target and attack tumors.

In the phase 2 KEYNOTE-695 trial, patients received intratumoral tavokinogene telseplasmid delivered by electroporation on days 1, 5, and 8 every 6 weeks plus 200 mg of intravenous pembrolizumab on day 1 of each 3-week cycle. Patients received tavokinogene telseplasmid for up to 18 cycles and pembrolizumab for up to 35 cycles or until disease progression.

Secondary end points of the trial included DOR, progression-free survival, and OS.

Patients 18 years or older with pathologically confirmed unresectable stage III or IV melanoma with progressive locally advanced or metastatic disease were eligible to enroll on the trial. Additional inclusion criteria included having an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, and adequate organ function.

Reference

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 6, 2023. bit.ly/3ZOpItp
2. Tarhini AA, Eroglu Z, Sarnaik AA, et al. Neoadjuvant intratumoral TAVO-EP (plasmid IL-12 electro gene transfer) in combination with nivolumab; preliminary clinical and biomarker data in patients with operable locoregionally advanced melanoma. Presented at the 37th Annual Meeting of the Society of Immunotherapy of Cancer; November 8-12; Boston, MA. Abstract 617.