Neoadjuvant Tavokinogene Telseplasmid Plus Nivolumab Under Evaluation in Advanced Melanoma

Pipeline Report | <b>Pipeline Report: January 2021</b>

The first patient with operable, locally or regionally advanced melanoma has been dosed with the intratumoral DNA plasmid-based interleukin-12 therapy tavokinogene telseplasmid in combination with nivolumab as a neoadjuvant treatment before surgery in the investigator-initiated, phase 2 OMS-104 trial.

The first patient with operable, locally or regionally advanced melanoma has been dosed with the intratumoral DNA plasmid-based interleukin-12 therapy tavokinogene telseplasmid (Tavo) in combination with nivolumab (Opdivo) as a neoadjuvant treatment before surgery in the investigator-initiated, phase 2 OMS-104 trial (NCT04526730).1

“While studies have shown relapse and overall survival [OS] advantages when checkpoint inhibitors are given alone following surgery, there is a need to investigate novel immunotherapeutic agents such as TAVO that can be given preoperatively in order to further enhance the clinical efficacy of immunotherapy in patients with advanced melanoma," Ahmad A. Tarhini, MD, PhD, director of Cutaneous Clinical and Translational Research at H. Lee Moffitt Cancer Center and Research Institute, stated in a press release.

PD-1 checkpoint inhibitors, when given in the neoadjuvant setting, have demonstrated promising results in clinical trials within this patient population, although rapid recurrence remains a challenge. To address this, investigators have hypothesized that tavokinogene telseplasmid, used in combination with nivolumab, may improve long-term clinical outcomes for a large proportion of patients by eliciting deep antitumor immune responses and completely eliminating tumors before surgery.

OMS-104, a phase 2, open-label, single-arm study, is examining the use of neoadjuvant tavokinogene telseplasmid delivered through gene electrotransfer plus nivolumab in patients with operable, locally or regionally advanced disease. The trial aims to enroll a total of 33 patients.

To be eligible for enrollment, patients have to be 18 years of age or older, a histologic diagnosis of melanoma, and must have disease considered to be surgically operable.2 Patients also had to have measurable disease per RECIST v1.1 criteria with at least 1 anatomically distinct lesion. Those with a known additional malignancy that is progressing or requires active treatment, who have human immunodeficiency virus, hepatitis B, or a diagnosis of immunodeficiency were excluded. Moreover, patients with a history of pneumonitis and interstitial lung disease were not included.

Patients will receive neoadjuvant tavokinogene telseplasmid during the first portion of the trial, which will be administered intratumorally for 3 cycles on days 1 and 8 every 4 weeks, with nivolumab being given intravenously (IV) after tavokinogene telseplasmid on the eighth day of every treatment cycle. Surgery is set to take place 2 to 4 weeks following the final dose of nivolumab, as well as radiologic and clinical assessment. Additionally, patients will receive up to nine 4-week cycles of adjuvant, single-agent nivolumab 2 to 4 weeks after surgery.

The primary end point of the study is pathological complete response, which will be estimated based on the proportion of patients who are found to not have a viable tumor on histologic evaluation at definitive surgery following the 12-week neoadjuvant period.

"The neoadjuvant approach utilizing TAVO in combination with checkpoint inhibitors as [is] being tested in this study may improve operability, pathologic tumor response and long-term disease control, which is highly desirable for these patients, who continue to have a high risk of recurrence and progression despite the use of standard therapy after surgery.”

IL-12 was recently examined in combination with pembrolizumab (Keytruda) in patients with PD-1–refractory advanced melanoma as part of the phase 2 KEYNOTE-695 study (NCT03132675).3

The phase 2 trial enrolled patients with unresectable or metastatic melanoma who had received anti–PD-1 therapy, either as a single agent or in combination, for 12 weeks prior to entry. To be eligible to participate, patients must have had confirmed progressive disease per RECIST v1.1 criteria with no intervening treatment prior to entry. They also needed to have measurable disease and at least 1 anatomically distinct lesion that was accessible for electroporation. The planned trial enrollment was 100 patients.

In the trial, patients were given IV pembrolizumab at 200 mg every 3 weeks in combination with tavokinogene telseplasmid, which was administered to at least 1 accessible lesion on days 1, 5, and 8 every 6 weeks until all lesions were treated.

The primary objective of the research was ORR per blinded independent review. Key secondary objectives included investigator-assessed ORR, duration of response, progression-free survival (PFS), intracranial PFS, iORR, and OS.

Results indicated that patients who were given the combination experienced an objective response rate (ORR) of 30% (95% CI, 18.0%-43.6%; n = 16/54) per investigator assessment in accordance with RECIST v1.1 criteria. The complete response rate with the approach was 6% and the partial response rate was 24%. Additionally, 19% of patients achieved stable disease and 52% experienced disease progression.

Tavokinogene telseplasmid is also under investigation in the phase 2 KEYNOTE-890 trial (NCT03567720) where it is being examined in combination with electroporation and pembrolizumab in patients with inoperable, locally advanced or metastatic triple-negative breast cancer (TNBC).4

To be eligible for participation, patients had to have a historically confirmed diagnosis of inoperable locally advanced or metastatic disease. Patients in cohort 1 had to have received at least 1 previous line of systemic chemotherapy or immunotherapy, while those in cohort 2had to have received neoadjuvant and adjuvant treatment in the nonmetastatic or operable disease setting and must not have progressed within 6 months of their last dose of neo(adjuvant) treatment. Patients had to be aged at least 18 years, an ECOG performance status of 0 to 1, a life expectancy of at least 6 months, measurable disease, and acceptable organ function.

Patients received intratumoral tavokinogene telseplasmid to the accessible lesions on day 1, 5, and 8 every 6 weeks plus IV pembrolizumab at 200 mg on day 1 of each 3-week cycle for up to 17 cycles of tavokinogene telseplasmid and 33 cycles of pembrolizumab from baseline. Those in cohort 2 received an approved standard-of-care chemotherapy, limited to nab-paclitaxel (Abraxane).

The primary end point of the trial was ORR in cohorts 1 and 2, while key secondary end points comprised ORR in cohort 2 per investigator review based on RECIST v1.1 criteria, DOR in cohort 1, PFS in cohort 1, iPFS in cohort 1, iORR in cohort 1, disease control rate in cohort 1, and OS in cohorts 1 and 2.

"TAVO delivers DNA plasmid-based IL-12 directly into the tumor using gene electrotransfer, which demonstrably enhances the immunogenicity of the treated tumors to yield productive 'in situ' vaccines,” Daniel J. O'Connor, president and chief executive officer of OncoSec, added in the release. “This principle has yielded striking results in post–PD-1 patients and is likely relevant in this earlier clinical setting. We look forward to exploring the utility of TAVO as a potential neoadjuvant therapy in a variety of solid tumor settings for patients in need of more effective treatment options."


  1. OncoSec announces first patient dosed in phase 2 trial of TAVO Plus OPDIVO as neoadjuvant therapy for melanoma. News release. OncoSec Immunotherapies. January 8, 2021. Accessed February 16, 2021.
  2. Neoadjuvant immunotherapy with Tavo + electroporation in combination with nivo. in melanoma patients. Updated February 4, 2021. Accessed February 16, 2021.
  3. Fernandez-Penas P, Carlino M, Tsai K, et al. 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 data. Journal for ImmunoTherapy of Cancer.Published online December 10, 2020. doi:10.1136/jitc-2020-SITC2020.0799
  4. Tavo and pembrolizumab with or without chemotherapy in patients with inoperable locally advanced or metastatic TNBC. Updated February 4, 2021. Accessed February 16, 2021.