A phase II randomized study of neoadjuvant pembrolizumab (P) alone or in combination with vidutolimod (V) in high-risk resectable melanoma: ECOG-ACRIN EA6194.

Abstract

LBA9505 Background: Advances in the neoadjuvant (neo) setting of locoregionally advanced melanoma have recently transformed practice. However, there continues to be a need to enhance efficacy while minimizing systemic toxicity. Preliminary data support an important role for vidutolimod (V), a CpG-A TLR9 agonist packaged within a virus-like particle given intratumorally (IT) in combination with IV anti-PD1. Methods: A U.S. intergroup randomized phase II trial of pembrolizumab (P) vs P + V in patients (pts) with resectable clinical AJCC8 stages IIIB-D. It planned to randomize ~60 pts (for 54 evaluable) 1:1 to Arm A (neo P 200 mg IV Q3W x3) or Arm B (neo P 200 mg IV Q3W x3 + V 5 mg SC x1 then 10 mg IT QW x6) followed by definitive surgery then adjuvant P 400 mg IV Q6W x8, stratified by stage (IIIB/C vs IIID). Primary endpoint was pathologic (path) complete response (pCR) on each arm. Secondary endpoints included path responses, recurrence, overall survival, event-free survival [EFS: disease progression (PD), recurrence or death] and safety. Results: EA6194 enrolled 57 pts March 2021-March 2024, 19 female, 38 male, all cutaneous primary (1 acral on Arm B), median age 64 (26-88), 29 on Arm A [10 IIIB (8N1b, 1N1c, 1N2b), 19 IIIC (3N1b, 1N1c, 3N2b, 3N2c, 7N3b, 2N3c)] and 28 on Arm B [13 IIIB (11 N1b, 2 N2b), 13 IIIC (5 N1b, 2N2b, 2N2c, 3N3b, 1N3c), 2 IIID (N3b)]. The median numbers of neo P/adjuvant P doses were similar for both arms at 2/7. Median number/total dose of V were 7/60 mg. Among pts who initiated treatment, highest grade related AEs (Gr 3/4) were 25% in Arm A (N=28) and 29% in Arm B (N=28) including in Arm B diarrhea (1), injection site reaction (1), cytokine release (1), wound dehiscence (1), lymphocytopenia (1), pain (1), headache (1), hypertension (1), hypotension (1), all Gr 3 and one Gr 4 hyperglycemia. Median time to surgery from randomization 2.5 months. Median follow up time from enrollment 19 months. There were 3 deaths on Arm A and 1 on Arm B. On Arm A 25 pts had surgery, 6 path non-response (pNR), 2 partial (pPR), 3 near-pCR, 14 pCR (56%; 95% CI, 35 - 76). MPR (pCR + near-pCR) was 17/25 (68%; 95% CI, 46 - 85). Among these, 3 had recurrence after surgery (1 pNR, 1 near-pCR, 1 pCR). On Arm B 27 pts had surgery, 3 pNR, 2 pPR, 2 near-pCR, 20 pCR (74%, 95%, CI 54 - 89). MPR 22/27 (79%; 95% CI 62 - 94). Among these, 2 had recurrence after surgery (1 pNR, 1 pPR). Table 1 summarizes efficacy data including all enrolled pts. Conclusions: Neoadjuvant P + Vdemonstrated acceptable safety and encouraging clinical activity in pts with resectable clinical stages IIIB/IIIC/IIID melanoma when considering Arm A and historical controls, warranting further investigation. Clinical trial information: NCT04708418 . Arm A:P (N=29*) Arm B:P + V (N=28*) pCR (%; 95% CI) 14 (48; 29 - 67) 20 (71; 51 - 87) MPR (%; 95% CI) 17 (59; 39 - 76) 22 (79; 59 - 92) 1-year EFS (95% CI) 75% (59 – 91) 89% (78 - 100) *4 on Arm A and 1 on Arm B did not have surgery due to PD.