1093P - Neoadjuvant (NeoAd) intratumoral (IT) TAVO-EP (plasmid IL-12 electro gene transfer) in combination with nivolumab (NIVO) for patients (pts) with operable locoregionally advanced melanoma

Background

IT TAVO-EP (tavokinogene telseplasmid delivered by electroporation) results in localized expression of IL-12 in the tumor microenvironment. This phase II study (NCT04526730) was designed to evaluate NeoAd TAVO-EP in combination with NIVO in subjects with operable, locoregionally advanced melanoma. Pts provided an IRB-approved (Advarra IRB Pro00041794) written informed consent.

Methods

The NeoAd phase comprised up to 3 x4-week cycles of TAVO-EP on days 1, 8 and 15 (optional) concurrently with 480 mg NIVO iv on day 8 of each cycle. Surgery followed and later adjuvant NIVO was initiated. Primary endpoint was pathologic complete response (pCR), secondary endpoints included near pCR (≤10% viable tumor), pathologic major response (pMR; pCR + near pCR) and nonresponse (pNR), among others. Biomaterials were collected at screening, C1D8, C2D1, pre-surgery and during adjuvant phase.

Results

16 pts (7 female, 9 male, cutaneous primary, age 30 – 88) were treated; 9 Stage IIIB, 5 IIIC, 2 IV (M1a) as clinically assessed. Highest-grade (Gr3) treatment-related adverse events included 1 hyponatremia, 2 diarrhea/colitis, 1 pancreatitis, 1 hypertension. One pt currently in NeoAd phase. Among the 15 pts who completed NeoAd phase, median number of NeoAd NIVO was 3 (range 1 - 3) and TAVO-EP 7 (3 - 9). Preoperative response rate (RECIST, unconfirmed) was 9/15 (60%; 95% CI: 55.7- 68.3%); 2 PD, 4 SD, 6 PR, 3 CR. One pt with PR declined surgery and 1 with early distant PD did not have surgery. Among 13 pts who had surgery: 2 pNR, 3 near pCR, 8 pCR; pMR rate was 11/14 (78.6%; 95%CI: 73.7–81.9%). Among those with pMR, there was no melanoma relapse to date with a median follow up of 11.4 months (range 0.9 – 24.6) from surgery. At baseline, many pts had low levels of CD8+ TIL, PD-L1, and IFN-gamma signature scores. Combination therapy induced local and systemic proinflammation changes, including increases in immune-related gene expression profiles, CD8+ TIL and peritumoral T cells.

Conclusions

NeoAd IT TAVO-EP and iv NIVO exhibited promising clinical activity and a favorable safety profile. Enhanced immune activation in responding patients supports the proposed immune mechanisms.

Clinical trial identification

NCT04526730.

Editorial acknowledgement

We are grateful to our patients and family members who volunteered to participate in this clinical trial. We are also grateful to the investigators, reserach coordinators and data managers who contributed to this study.

Legal entity responsible for the study

Moffitt Cancer Center.

Funding

OncoSec.

Disclosure

A. Tarhini: Financial Interests, Institutional, Funding, Contracted Research: OncoSec, Genentech-Roche, Regeneron; Financial Interests, Institutional, Advisory Board, Contracted Research: Bristol Myers Squib, Sanofi-Genzyme, Clinigen, Nektar, Merck, Acrotech, Pfizer, Scholar Rock, Checkmate; Financial Interests, Personal, Advisory Board: OncoSec, Bristol Myers Squibb, Merck, Eisai, Instil Bio, Regeneron, Sanofi-Genzyme, Novartis, Partner Therapeutics, Genentech/Roche, BioNTech, Concert AI, AstraZeneca, Pfizer. E. Browning, D. Canton: Financial Interests, Personal, Financially compensated role, Employee: OncoSec. V.K. Sondak: Financial Interests, Personal, Advisory Board: Merck, Bristol Myers Squibb, Iovance, OncoSec, Regeneron, Ultimovacs; Financial Interests, Personal, Other, Independent Data Safety Monitoring Committee: Alkermes, Novartis; Financial Interests, Personal, Other, Independent medical monitor for clinical trial: Genesis Drug Discovery & Development; Financial Interests, Institutional, Research Grant, Research grant to institution: Turnstone Biologics; Financial Interests, Institutional, Coordinating PI, Per patient funding to institution to support clinical trial: Skyline DX; Financial Interests, Institutional, Local PI, Research grant to institution: Neogene Therapeutics. All other authors have declared no conflicts of interest.