Pembrolizumab Plus Interleukin-12 Shows Activity in Metastatic Melanoma

Immune checkpoint inhibition with pembrolizumab (Keytruda) in combination with interleukin-12 (IL-12, Tavo) induced responses in patients with metastatic melanoma identified as anti-PD1 checkpoint resistant, according results from a phase II study, which was recently published in Clinical Cancer Research, OncoSec Medicalm Inc. announced in a press release.¹

An overall response rate (ORR) of 41% was observed with the combination along with a complete response (CR) rate of 36%.

"Combining pembrolizumab with TAVO electroporation improved responses for these patients who were predicted to have very poor responses to single-agent immune checkpoint inhibition," said Adil Daud, MD, clinical professor at the University of California San Francisco (UCSF) and director of melanoma clinical research at the UCSF Helen Diller Family Comprehensive Cancer Center. "By using electroporation to deliver TAVO locally, we were able to avoid many of the toxicities associated with systemic IL-12 administration, while still attaining clinical responses and inducing immune-cell infiltration in treated and untreated melanoma lesions."

Twenty-two patients were evaluable for efficacy in the study. The median progression-free survival was 5.6 months and the median overall survival was not yet reached after a median follow-up of 19.6 months. Clinical responses occurred regardless by baseline tumor-infiltrating lymphocyte (TIL) level or PD-L1 protein level by immunohistochemistry.^1,2

Few grade 3 or higher adverse events were observed with pembrolizumab plus IL-12, with the most common being pain, chills, sweat and cellulitis.¹

In a correlative analysis, investigator observed increased density of CD8-positive TIL ( P =.027) after treatment with pembrolizumab plus IL-12 compared with the level seen before treatment. In addition, there was a significant rise in the number of unique intratumoral T cell clones after treatment versus before treatment (P = .041). In intratumoral PD-L1 expression by IHC also showed a significant increase( P =.016).²

The ability of IL-12 to enhance the efficacy of anti-PD-1 therapy was an important hypothesis of the study, which was confirmed in the gene expression analysis. Treatment with pembrolizumab plus IL-12 led to increased intratumoral transcription of an immune-based gene set.

Patients in the open-label, multicenter study were adults aged 18 years or older with metastatic or unresectable melanoma with accessible lesions. To be eligible for enrollment patients withwere required to have a life expectancy of at least 6 months, and ECOG performance status of 0 to 1, and adequate organ function.

Pembrolizumab was administered to participant at a intravenous dose of 200 mg on day 1 of each cycle and IL-12 was administered at 0.5 mg/mL on days 1, 6, and 8 of each odd cycle. Treatment lasted for up to 2 years for patients who derived benefit from the combination as defined by stable disease or better.

The primary end point of the study of the ongoing study is ORR. Secondary end points are also being explored, including, the number of participants with AEs, duration of response, PFS, and OS.

Following treatment with pembrolizumab and IL-12, patients were followed for 30 days to monitor adverse events.

"These findings provided the clinical rational for our ongoing pivotal KEYNOTE-695 study of Tavo and Keytruda combination therapy in patients with anti-PD-1 checkpoint resistant metastatic melanoma. Because KEYNOTE-695 is treating patients with late-stage metastatic melanoma who have no FDA approved treatment options, nearly all study sites remain open and are actively recruiting patients during the current COVID-19 pandemic. We are targeting complete enrollment this year and look forward to providing an interim data update from this pivotal study at an appropriate scientific meeting or otherwise appropriate time this year.1"

A clinical updated on the pivotal, global, open-label KEYNOTE-695 study (NCT03132675) was announced in 2019. The combination of pembrolizumab and IL-12 achieved am approximate 24% ORR, meeting the primary end point of the study. Responses were also durable, lasting 10 months.³

_References:

_{1. OncoSec's Tavo™ in combination with KEYTRUDA® demonstrated 41% overall response rate and 36% complete response in a late-stage metastatic melanoma study featured in 'Clinical Cancer Research' [news release]. San Diego, California and Pennington, NJ: Oncosec Medical Incorporated; May 6, 2020. https://bit.ly/2WGvAGf. Accessed May 8, 2020.}

_{2. Algazi AP, Twitty CG, Tsai KK, et al. Phase II trial of il-12 plasmid transfection and pd-1 blockade in immunologically quiescent melanoma, Clin Cancer Res. [Published Online First May 2020]. https://bit.ly/3bmKo2t. Accessed May 8, 2020}

_{3. OncoSec provides KEYNOTE-695 clinical update and outlines 2019 milestones [news release]. San Diego, California and Pennington, NJ: Oncosec Medical Incorporated; February 1, 2019. https://bit.ly/3dvtCzg. Accessed May 8, 2020.}