Intratumoral BO-112 With Pembrolizumab Shows Clinical Benefit in Advanced Melanoma

Intratumoral administration of BO-112 in combination with pembrolizumab (Keytruda) demonstrated a satisfactory objective response rate in patients with advanced melanoma whose disease has progressed following anti-PD-1-based therapy, meeting the primary end point of the phase 2 SPOTLIGHT-203/KEYNOTE-B77 trial (NCT04570332).¹

BO-112 is a double stranded synthetic RNA formulated polyethyleneimine. According to background information presented in a poster during the Society for Immunotherapy of Cancer (SITC) Annual Meeting, BO-112 can mimic a viral infection and induce an immune response. Pembrolizumab has been FDA approved for the treatment of patients with advanced or unresectable melanoma following progression on prior therapies since 2014, based on findings from the melanoma cohort in the KEYNOTE-001 (NCT01295827) trial.²

Per the eligibility protocol, all patients had unresectable stage III or IV melanoma, confirmed progression while being treated with an anti-PD-1/PD-L1, and an ECOG performance status of 1 or lower. Patients were treated with intratumoral BO-112 once per week for 7 weeks followed by every 3 weeks (Q3W) thereafter, plus treated with intravenous pembrolizumab 200 mg Q3W.¹

The primary end point of ORR (ORR) was assessed by independent review per RECIST v1.1 criteria. Secondary end points in the study include safety, disease control rate (DCR), duration of response, progression-free survival, overall survival, and pharmacokinetics.

A total of 42 patients were enrolled in the study. According to characteristics recorded at baseline, the population was 59% male and the median age was 68 years (range, 27-88). In terms of melanoma type, the most common in the study population was cutaneous melanoma (74%), followed by acral (19%), and mucosal (7%). Fourteen percent of the patients had a BRAF mutation and 86% had BRAF wild type.

Prior treatment was pembrolizumab monotherapy for most patients enrolled (43%), but 36% received prior nivolumab (Opdivo), 14% were previously treated with the immunotherapy combination of nivolumab plus ipilimumab (Yervoy), and 7% received other anti-PD-1 therapies in earlier settings. The majority of patients (79%) were previously treated in the advanced disease setting, but 21% received prior anti-PD-1/PD-L1 therapy in the adjuvant setting.

Laboratory tests given at baseline showed that 41% of the population had higher than the upper limit of normal lactate dehydrogenase, and the remaining 59% had normal values.

The first response to BO-122 with pembrolizumab observed in the study was a shrinkage in skin target lesions on the head in 1 patient after just 3 cycles, which was considered a partial response (PR). In another patient who received 3 cycles of BO-122 and pembrolizumab, skin target lesion on the legs showed some shrinkage, but the biggest response in this patient was in non-target lesions.

CT scans by central review conducted in 3 patients who had progressive disease (PD) after prior anti-PD-1 therapy showed a complete response(CR) at week 28, and 2 partial responses at week 8 of treatment with BO-112 in combination with pembrolizumab.

Overall, 37 of the 42 patients were evaluable for response as of the data cutoff date of October 14, 2021. The ORR in the overall population was 27%, which included 2 CRs at week 8 and 14 cases of stable disease for a DCR of 64.9%.

Patients who responded to BO-112/pembrolizumab were subsequently evaluated for tumor size reduction, and the analysis showed that all 4 patients had higher tumor size reduction.

Patients were on treatment for a median duration of 12 weeks, with 30 patients still on treatment. However, survival data were still immature at data cutoff.

In terms of safety, adverse events (AEs) were observed in 88.1% of patients, including grade 3 to 5 AEs in 19%. Further, BO-112 related AEs were observed in 31 patients, with 4 cases of BO-112-related infusion reaction being grade 3 to 5 in severity. The most common grade 1/2 AEs observed during the study were asthenia (50%), pyrexia (38%), diarrhea (33%), and vomiting (24%).

No patients discontinued treatment due to AEs. Overall, the safety profile of the combination was manageable.

Investigators concluded from this research that there is a clear clinical benefit of administering BO-112 and pembrolizumab in patients with advanced melanoma that have progressive disease on anti-PD-1-based therapy. Moreover, findings from 3 patients with mucosal melanoma who have an ORR of 75% and DCR of 100% suggest that some subgroups benefit more than others. Contrarily, findings from the population of patients with very high LDH suggest that some patients can have poorer outcomes.

To further investigate this treatment strategy, investigators have launched a pivotal trial.

_References:

_{1. Rodas M, Saiag P, Merina L, 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 2021; November 10-14 2021; Washington, DC. Abstract 961.}

_{2. Raedler LA. Keytruda (Pembrolizumab): First pd-1 inhibitor approved for previously treated unresectable or metastatic melanoma. Am Health Drug Benefits. 2015;8(Spec Feature):96-100. PMC4665064.}