Neoadjuvant oncolytic virus orienx010 and toripalimab in resectable acral melanoma: a phase Ib trial

Abstract

Neoadjuvant PD-1 inhibitor is promising in cutaneous melanoma but remains unknown in acral melanoma (AM). This phase Ib trial study (Clinicaltrials.gov NCT04197882) assessed the efficacy and safety of the combination of neoadjuvant oncolytic virus orienX010 (ori) and anti-PD-1 toripalimab (tori) for resectable AM. Thirty patients of stage III/IV received neoadjuvant therapy of ori and tori for 12 weeks before surgery, followed by adjuvant treatment with tori for 1 year. Primary endpoints were radiographic and pathological response rates, with secondary endpoints of 1- and 2-year recurrence-free survival (RFS) rates, event-free survival (EFS) rates, and safety. Twenty-seven completed surgery and tori adjuvant treatment and median follow-up was 35.7 months. Radiographic and pathological response rates were 36.7% and 77.8%, with complete response rates of 3.3% and 14.8%, 1- and 2-year RFS rates of 85.2% and 81.5%, and 1- and 2-year EFS rates of 83% and 73%, respectively. Adverse events occurred in all patients, mainly grade 1-2. There was no correlation between PET/CT evaluation and pathological response or progression-free survival/overall survival. Patients with pathological response showed tumor beds with high tertiary lymphoid structures (TLSs) and tumor-infiltrating lymphocytes (TILs). Cytokines and chemokines analysis showed the combination therapy significantly increases the secretion of proinflammatory cytokines and chemokines in both responders and non-responders. Therefore, neoadjuvant ori and tori demonstrated promising antitumor activity with high response rates and high 2-year RFS/EFS for AM with acceptable tolerability.

Fig. 1

Study design and consort diagram with patient disposition

Fig. 2

Response data. a: Radiographic response; b: Pathologic response: Red circle indicates no tumor residue, pCR

Fig. 3

Recurrence-free survival curves. a Relapse-free survival (time from surgery to recurrence in patients that underwent surgery). b Probability of being relapse-free based on any pathologic response versus no pathologic response. c Event-free survival rates (time from treatment initiation to recurrence in all patients). d Case 11, pre-treatment histologic image: hematoxylin and eosin staining of tumor biopsy specimen prior to treatment reveals massive atypical melanoma cells within the tissue (magnification 200×). e Case 11, post-treatment histologic image: Hematoxylin and eosin staining of the surgical resection specimen demonstrates no evidence of tumor cells but a pronounced TIL infiltration post-neoadjuvant therapy (magnification 200×)

Fig. 4

Comprehensive study flow and outcome summary