Intratumoral BO-112 Plus Pembrolizumab Shows Promise in Anti–PD-1–Resistant Melanoma

For patients with advanced melanoma who have developed resistance to anti–PD-1 therapies, a challenging clinical scenario with no established standard of care, a recent phase 2 clinical trial (NCT04570332) offers encouraging results. The SPOTLIGHT-203 study investigated the efficacy and safety of combining intratumorally administered BO-112, a synthetic double-stranded RNA nanoplexed with polyethylenimine, with intravenous pembrolizumab (Keytruda). The findings indicate that this combination may be a viable strategy to overcome anti–PD-1 resistance in this difficult-to-treat population.

The trial met its primary end point, demonstrating an objective response rate (ORR) of 25% in the modified intention-to-treat (ITT) population of 40 evaluable patients. This ORR included a 10% complete response rate and a 15% partial response rate, alongside 40% of patients achieving stable disease. These responses were confirmed by independent central radiology review, underscoring the clinical activity of the combination. The median duration of response was not reached (NR), with responses proving durable in a significant proportion of patients.

Median progression-free survival (PFS) for the 42 patients in the ITT population was 3.7 months (95% CI, 2.2-9.2). While this PFS is in line with other reported strategies for anti–PD-1–resistant melanoma, the overall survival (OS) data appear particularly promising. The median OS was not reached (95% CI, 9.9-NR), with 54% of patients alive at 24 months.

The combination of BO-112 and pembrolizumab exhibited a favorable safety profile, consistent with previous findings from the phase 1 trial. Treatment-emergent adverse events (TEAEs) of any cause occurred in all patients, but only 16 patients (38.1%) experienced grade 3 to 5 AEs. Crucially, only 4 (9.5%) of these were considered drug-related, and no treatment-related deaths occurred. The most common AEs were asthenia, pyrexia, diarrhea, chills, and nausea, which are generally consistent with immune activation and manageable.

About BO-112

BO-112 is a synthetic double-stranded RNA that mimics viral infections, designed to activate the innate immune system. Administered intratumorally, it acts as a toll-like receptor 3 agonist. This mechanism is believed to "remodel" the tumor microenvironment from an immunologically "cold" state (where the tumor is largely invisible to the immune system) to a "hot" one, facilitating recognition and attack by adaptive immunity.

Preclinical data and earlier clinical data study suggested that intratumoral BO-112 could overcome anti–PD-1 resistance by enhancing T-cell infiltration and activation within the tumor.

The current phase 2 trial was specifically designed to evaluate this combination's clinical activity in patients with confirmed anti–PD-1–resistant melanoma.

Study Design and Patient Characteristics

The multicenter, open-label phase 2 study enrolled 42 patients with advanced and/or metastatic unresectable stage III or IV melanoma who had confirmed progressive disease on prior anti–PD-1–containing treatment. Patients were required to have at least 1 measurable lesion amenable to intratumoral injection. Key exclusion criteria included uveal melanoma, previous severe immune-related AEs requiring prolonged systemic steroids, and prior intratumoral treatments.

Patients received intratumoral BO-112 once weekly for 7 weeks, then once every 3 weeks, in combination with 200 mg intravenous pembrolizumab every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, death, or up to 2 years. Efficacy assessments were performed by independent central radiology review, and safety was continuously monitored.

“The response rate observed in our study is in line with other phase 2 clinical trials in anti–PD-1 resistance. Response rate varies from 21.4% for pembrolizumab and lenvatinib [Lenvima] in the LEAP004 [NCT03776136] to 36.4% for [tumor-infiltrating lymphocytes] in the lifileucel [Amtagvi] (LN-144 [NCT02360579]) studies. Importantly, these 2 studies allowed more than 1 previous line of treatment in contrast to ours, which allowed only 1,” study authors wrote.

Subgroup Analysis and Future Directions

While the overall results are encouraging, a post hoc analysis revealed some notable differences in response based on baseline characteristics. Patients with acral melanoma and/or very high lactate dehydrogenase levels (≥3× upper limit of normal) showed less benefit in terms of response. When these patients were excluded from the analysis, the median PFS improved to 6.5 months (95% CI, 3.7-17.6). Conversely, 2 of 3 patients with mucosal melanoma, a subtype often associated with poor prognosis, achieved partial responses, warranting further investigation.

Molecular analyses from baseline and on-treatment biopsies suggested a potential correlation between NRAS or BRAF mutations and clinical benefit, particularly in patients without MYC amplifications. However, baseline PD-L1 expression and posttreatment CD8 expression did not correlate with benefit. These exploratory biomarker findings require validation in larger, prospective studies.

The study authors conclude that the observed ORR, coupled with the promising OS data and favorable toxicity profile, warrants further investigation of intratumoral BO-112 with pembrolizumab in randomized clinical trials for anti–PD-1–resistant melanoma. The ease of administration compared to oncolytic viruses, which have similar ORRs in this setting, but inherent biosafety management issues, further strengthens the argument for continued exploration of this strategy.

REFERENCE:

Márquez-Rodas I, Dutriaux C, Saiag P, et al. BO-112 plus pembrolizumab for patients with anti–PD-1–resistant advanced melanoma: phase II clinical trial SPOTLIGHT-203. J Clin Oncol. 0, JCO-24-02595. doi:10.1200/JCO-24-02595