Updated Results From KEYNOTE-695 Do Not Meet ORR Primary Endpoint in Advanced Melanoma

Primary results from the phase 2 KEYNOTE-695 study (NCT03132675) did not meet the prespecified end point of overall response rate (ORR) for previously treated patients with unresectable or metastatic (Stage III/IV) melanoma to the combination of pembrolizumab (Keytruda) and a proprietary interleukin 12 (IL–12) intratumoral tavokinogene telseplasmid and electroporation (TAVO-EP).¹

The encoding plasmid in combination with the anti-PD-1 therapy is meant for patients who had a confirmed disease progression after at least 12 weeks of exposure to a prior anti-PD-1 therapy like pembrolizumab or nivolumab monotherapy.

In this trial, there was a total of 98 efficacy evaluable patients that had at least 1 post-baseline tumor assessment with a confirmed ORR per RECIST v1.1 by blinded independent central review (BICR) assessment of 10.2% (95% CI, 5%-17.97%).

This was short of what researchers set as the pre-specified clinically meaningful ORR of 17% or greater (95% CI, 10.2%-25.8%). Moreover, the BICR results for the patients were lower than the ORR per RECIST v1.1, with an investigator assessment ORR of 18.8%, of the 101 patients previously reported as part of the secondary end points of the KEYNOTE-695 trial.

According to BICR assessment, 4 patients had a complete response, 6 patients had a partial response, 25 patients had stable disease as their best response, and the disease control rate was 35.7%. Patients with a durable response rate of 24 weeks or more was just 8.2% but the median duration of response was 25.5 months (range, 6.83-not reached).

Previous reports showed that among the 105 patients enrolled after a median follow-up of 33.4 months there was a median overall survival of 22.7 months (95% CI, 14.4-35.5). Interim data of the first 56 patients enrolled in study 54 patients had an ORR of 30% with 3 partial responses and 13 patients with a partial response.2 Tumor reduction was also seen in 12 patients who had inaccessible lesions or accessible untreated lesions.

"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 blinded central readers did not confirm the previously reported results by investigator assessment of the KEYNOTE-695 phase 2 clinical trial in this patient population,” said Robert Arch, PhD, chief executive officer of OncoSec, in a press release. “However, we remain optimistic that the observed long duration of response and overall survival of 22.7 months in this heavily pre-treated patient population…provide rationale for further development of TAVO-EP in combination with anti-PD-1 therapy.”

The phase 2 study had a treatment period of up to 2 years with patients given TAVO-EP to the accessible lesions at days 1, 5, and 8 every 6 weeks along with 200 mg of pembrolizumab given intravenously.³ The ant-PD-1 therapy was given on day 1 of each 3-week cycle for up to 18 TAVO-EP cycles and 35 pembrolizumab cycles or until disease progression.

As many accessible lesions as deemed feasible by the treating physician were treated if the lesion was greater in size than 0.3 cm x 0.3 cm. All patients had to have pathologically documented unresectable melanoma with progressive locally advanced or metastatic disease and received treatment with an FDA-approved anti-PD-1 monoclonal antibody. Moreover, they needed to have a resolution or improvement of anti-PD-1 monoclonal antibody related adverse events (AEs) back down to at least Grade 0-1 with 10 or more mg/day of prednisone for immune related adverse events prior to the first dose of the study drug. They also had to have no history of common toxicity criteria AEs or grade 4 immune related AEs.

In the updated findings, grade 3 treatment-related AEs (TRAEs) were observed in 4.8% of all enrolled patients with no patients experiencing a grade 4 or 5 TRAE. This is consistent with previous reports but the rate of grade 3 TRAEs regardless of cause was 23.2% in the interim analysis. Overall, researchers saw these were well tolerated in patients in the updated analysis.

“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," said Arch, in the press release.

^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. OncoSec Medical Incorporated. April 3, 2023. Accessed: April 24, 2023. https://prn.to/43Wz7Cd}

^{2. Fernandez-Penas P, Carlino M, Tsai K, et al. 799 Durable responses and immune activation with intratumoral electroporation of pIL-12 plus pembrolizumab in actively progressing anti-PD-1 refractory advanced melanoma: KEYNOTE 695 interim dataJournal for ImmunoTherapy of Cancer 2020;8. doi: 10.1136/jitc-2020-SITC2020.0799}

^{3. Tavo and Pembrolizumab in Patients With Stage III/IV Melanoma Progressing on Either Pembrolizumab or Nivolumab Treatment (Keynote-695). ClinicalTrials.gov. April 28, 2017. Accessed: April 24, 2023. https://bit.ly/3mSzP2Y}