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

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. 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. 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. 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.