Background Neoadjuvant PD-1 blockade produces major pathological responses (MPR) in ~30% of patients (pts) with high-risk resectable MEL with durable relapse-free benefit, and increased circulating activated CD8+ T cells.^1,2 Vidutolimod (vidu) comprises a CpG-A oligodeoxynucleotide packaged within a virus-like particle (VLP) and is designed to activate tumor-associated plasmacytoid dendritic cells (pDC) via TLR9, inducing an IFN-rich tumor microenvironment and anti-tumor CD8+ T cell responses. Vidu/anti-PD-1 resulted in durable tumor responses in PD-1 refractory MEL.³ This phase II study evaluated the pathological, clinical and immunological activities of neoadjuvant vidu/nivo in high-risk stage III B/C/D resectable MEL.

Methods Vidu/nivo was administered over 7 weeks (vidu 10mg IT Q1W x7, nivo 240mg Q2W x3) pre-surgery. Post-surgery, vidu/nivo (vidu SC 5mg, nivo 480mg Q4W) was continued for 48 weeks. Primary endpoints included MPR rate, and incidence of DLT. Secondary endpoints were radiographic response, relapse-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS). Pathological response assessment was performed to evaluate % residual volume of tumor (RVT) per consensus criteria^4-6 by 3 blinded dermatopathologists: 0% (pCR); 0%50% (pNR). Radiographic response assessed using RECIST v1.1. Serial blood, tumor and stool were collected for correlative analyses.

Results 31 pts were enrolled, of whom 30 evaluable for per-protocol (PP) analyses as 1 pt progressed pre-surgery. No DLTs were observed. 8 Gr3 TRAE, including hypertension (7/8) and colitis (1/8) were observed; no delays in surgery occurred. ORR by BICR was 45% (all) and 47% (PP). In PP population, MPR was observed in 57% (17/30) including 47% pCR (14/30) and 10% pMR (3/30). With median follow-up of 26.5 months, median RFS was not reached (table 1). Post-treatment, MPR was associated with increased CD8+ tumor infiltrating lymphocytes (p<0.0001), and peripheral immune activation and pDC activation by multiparameter flow cytometry (p < 0.001). Spatial investigation of immune cell infiltrates by mIHC revealed significantly immune cell infiltrates (p<0.05) and higher pDC (p=0.053) within tumor (but not stroma) of MPRs post-treatment (figure 1a,b). Deconvoluted RNAseq confirmed these findings compared to a control cohort of PD-1 treated MEL.

Conclusions Neoadjuvant vidu/nivo has minimal tox and demonstrated promising activity with 47% pCR rate and 57% MPR rate. MPR was associated with improved 1-/2- year RFS (94%/88%), and 1-/2- year DMFS (94%/94%) and 2-year OS (100%). MPR is associated with pDC and immune infiltrate (figure 1c). Further evaluation of this combination is ongoing in an ongoing randomized phase II trial (EA6194, NCT04708418).

Acknowledgements We thank and Checkmate Pharmaceuticals for funding and vidutolimod.

This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483.

This research was supported by the Melanoma Research Foundation Breakthrough Consortium (MRFBC) Award (Davar, Stein); NIH R01 CA257265 (Zarour, Davar); and NIH P50 CA254865 (Zarour).

Trial Registration Clinical trial information: NCT03618641.

References

1. Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med. 2018 Nov;24(11):1649–1654.

2. Huang AC, Orlowski RJ, Xu X, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med. 2019 Mar;25(3):454–461. doi: 10.1038/s41591-019-0357-y.

3. Ribas A, Medina T, Kirkwood JM, et al. Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma. Cancer Discov. 2021 Dec 1;11(12):2998–3007. doi: 10.1158/2159-8290.CD-21-0425.

4. Tetzlaff MT, Messina JL, Stein JE, et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann Oncol. 2018 Aug 1;29(8):1861–1868.

5. Cottrell TR, Thompson ED, Forde PM, et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann Oncol. 2018 Aug 1;29(8):1853–1860. doi: 10.1093/annonc/mdy218.

6. Stein JE, Soni A, Danilova L, et al. Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response. Ann Oncol. 2019 Apr 1;30(4):589–596. doi: 10.1093/annonc/mdz019.

Ethics Approval The study was approved by University of Pittsburgh's Institutional Review Board, approval number MOD19040237-002.

Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

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Abstract 605 Figure 1

Multiplex IHC (mIHC) Analysis of Post-treatment Samples by GeoMx Spatial Analysis