BO-112 Plus Pembrolizumab Improves ORR in Advanced Melanoma After Progression on Anti–PD-1 Therapy

The addition of BO-112 to pembrolizumab (Keytruda) produced clinical benefit in patients with unresectable malignant melanoma who have experienced disease progression on anti–PD-1 therapy, according to data from the preliminary analysis of the phase 2 SPOTLIGHT-203 trial (NCT04570332) presented during the 2021 SITC Annual Meeting.

Of 37 patients who were evaluable for response, the combination elicited an objective response rate (ORR) of 27%; 2 patients achieved a pathologic complete responses (CRs) by week 8. Moreover, 37.8% of patients (n = 14) had stable disease at week 8, which translated to a disease control rate (DCR) of 64.9%. All responders experienced a higher tumor size reduction.

“There is a clear trend for a clinical benefit in patients with confirmed anti–PD-L1–resistant melanoma,” Iván Márquez-Rodas MD, PhD, of Hospital General Universitario Gregorio Marañon, and colleagues, wrote in a poster presentation on the data with the combination.

BO-112 is a double-stranded synthetic RNA formulated with polyethyleneimine. The agent was designed to mimic a viral infection. When injected directly into a tumor, it activates dendritic cells, infiltrates CD8 T cells, induces interferons and apoptosis, and augments immunogenic cell death.

The agent can activate the innate immune system through TLR3, RIG-1, MDA-5, and PKR and this results in increased expression of type I and II IFN that is independent of MHC-1 expression. When the innate and adaptive immune system connects, it results in effective antigen presentation and increased CD8-positive lymphocytes that results in cancer cell death.

The study enrolled patients with unresectable stage III or IV melanoma who had confirmed progression on 2 consecutive imaging assessments while on an anti­–PD-1–based treatment. To be eligible for enrollment, patients also needed to have an ECOG performance status of 0 or 1.

Study participants received BO112 on a weekly basis for 7 weeks and then every 3 weeks thereafter in combination with pembrolizumab at 200 mg every 3 weeks.

The primary end point of the trial was ORR per RECIST v1.1 criteria; if less than 8 patients responded to treatment, the study would not meet the statistical bar. Important secondary end points included safety, DCR, duration of response, ORR, progression-free survival (PFS), overall survival (OS), and pharmacokinetics.

By August 24, 2021, recruitment for the trial was completed, and 42 patients were enrolled. All patients had confirmed disease progression prior to inclusion, and all but 1 had stage IV AJCC8 disease. The median age was 68.0 years (range, 27.0-88.0), and 59% were male. Seventy-four percent of patients (n = 31) had cutaneous melanoma, 19% (n = 8) had acral melanoma, and 7% (n = 3) had mucosal melanoma.

Eighty-six percent of patients (n = 36) had BRAF wild-type disease and 14% (n = 6) had BRAF-mutated disease. Forty-three percent of patients (n = 18) had undergone prior pembrolizumab monotherapy, 36% (n = 15) had prior nivolumab (Opdivo) monotherapy, 14% (n = 6) had ipilimumab (Yervoy) plus nivolumab, and 7% (n = 3) previously received other anti–PD-1 combinations. Seventy-nine percent of patients (n = 33) received prior therapy for advanced disease and 21% (n = 9) received prior adjuvant therapy.

Additionally, 59% (n = 25) of patients had normal lactate dehydrogenase level (LDH) levels and 41% (n = 17) had high LDH. Four patients had LDH that was 3 x upper limit of normal (ULN) at baseline, and all went on to develop progressive disease no later than week 8.

As of October 14, 2021, the median exposure to treatment was 12 weeks and 30 patients remained on treatment. Additional data showed that 3 patients with mucosal melanoma experienced an ORR of 75% with the combination, and a DCR of 100%. PFS and OS data were still immature at the time of the presentation.

Regarding safety, 88.1% of patients experienced at least 1 adverse effect (AE), with 19% of patients experiencing a grade 3 to 5 AE. Furthermore, 31 patients experienced at least 1 AE related to BO-112­; this included 1 grade 4 infusion reaction.

The most common BO-112–related AEs included asthenia (50%), pyrexia 38%), diarrhea (33%), vomiting (24%), chills (21%), nausea (21%), decreased appetite (14%), headache (14%), injection site pain/discomfort/hematoma/hypersensitivity (14%), arthralgia (12%), pruritus (12%), influenza-like illness (10%), back pain (10%), fatigue (7%), hypertension (7%), oedema peripheral (7%), temperature regulation disorder (5%), musculoskeletal pain (2%), neutropenia (2%), and tumor hemorrhage (2%). No patients discontinued treatment because of AEs.

A subsequent trial evaluating this approach is underway.

Reference

Rodas IM, Saiag P, Dutriaux C, et al. Preliminary results of a phase 2 study of intratumoral administration of BO-112 with pembrolizumab in patients with advanced melanoma that have progressive disease on anti–PD-1-based therapy. Presented at SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 961.