The combination of BO-112 and pembrolizumab demonstrated meaningful clinical activity in patients with advanced melanoma who had developed resistance to anti-PD-1 therapies, according to final results from the phase 2 SPOTLIGHT203 trial presented at the 2022 AACR Annual Meeting. The study addresses a critical unmet need, as up to 70% of patients with advanced melanoma experience disease progression on anti-PD-1 therapies, with no current standard-of-care therapy available in the second line.
Clinical Efficacy Results
At a median follow-up of 4.1 months (95% CI, 3.9-6.3), the combination achieved an overall response rate (ORR) of 25% among 40 evaluable patients, including a complete response rate of 10% and partial response rate of 15%. The disease control rate reached 65%, with 40% of patients achieving stable disease.
"The responses happened in patients including [those with] BRAF-mutated and wild-type melanoma, mucosal histology, and secondary anti-PD-1 resistance. However, patients with acral melanoma or very high lactate dehydrogenase [LDH] have no clinical benefit," reported lead study author Iván Márquez-Rodas, MD, PhD, of Hospital General Universitario Gregorio Marañón in Madrid, Spain.
Subgroup Analysis
Response rates varied significantly across patient subgroups. Patients with cutaneous melanoma achieved an ORR of 28%, while those with mucosal melanoma demonstrated a notably higher response rate of 67%. In contrast, no patients with acral melanoma or LDH levels 3 times above the upper limit of normal responded to treatment.
BRAF mutation status also influenced outcomes, with BRAF-mutated patients achieving a 43% ORR compared to 21% in BRAF wild-type disease. Patients with secondary resistance to prior therapy showed superior responses (38% ORR) compared to those with primary resistance (17% ORR).
Treatment Protocol and Patient Population
SPOTLIGHT203 enrolled 42 patients aged 18 years or older with unresectable stage III or IV cutaneous, acral, or mucosal melanoma who had confirmed progressive disease following anti-PD-1 therapy. Patients received BO-112 injections at doses up to 2 mg in up to 8 lesions per cycle once weekly for the first 7 weeks, followed by once every 3 weeks for up to 2 years. Pembrolizumab was administered intravenously at 200 mg every 3 weeks.
The median patient age was 65 years (range, 27-88), with 57% being male. Most patients presented with cutaneous melanoma (71%), followed by acral (21%) and mucosal melanoma (7%). BRAF wild-type disease was predominant (83%) versus BRAF-mutated disease (17%).
Survival Outcomes
The median duration of response was not reached (95% CI, 2 months–NR), with 66.7% of responding patients maintaining their response at 6 months (95% CI, 16%-91.4%). The median progression-free survival in the intention-to-treat population was 3.8 months (95% CI, 3.6-NR).
Notably, patients with non-acral disease and LDH not exceeding 3 times the upper limit of normal (n = 29) had a median PFS that was not reached (95% CI, 3.8-NR), compared to 2.2 months (95% CI, 0.8-3.6) in patients with acral disease and/or very high LDH levels (n = 13).
Safety Profile
The combination demonstrated a manageable safety profile. All 42 patients experienced at least one adverse event of any grade, with 36% encountering grade 3 or higher events. Treatment-related adverse events occurred in 83% of patients, but only 5% experienced grade 3 or 4 treatment-related events.
The most common grade 1 or 2 treatment-related adverse events included asthenia (50%), pyrexia (38%), diarrhea (33%), vomiting (24%), chills (21%), and nausea (21%). Serious adverse events occurred in 29% of patients, with serious treatment-related events in 7%. While 19% of patients discontinued treatment due to adverse events, no patients discontinued specifically due to treatment-related adverse events.
Mechanism of Action
BO-112 is a synthetic nanoplexed dsRNA designed to activate TLR3, RIG-1, and MDA5 pathways. The agent improves antigen presentation through interferon-independent increases in MHC-I expression, enhances T-cell infiltration, and elicits immunogenic cell death to overcome resistance to anti-PD-1 therapies.
Previous research in a first-in-human phase 1 trial explored BO-112 alone and in combination with PD-1 inhibitors in adult patients with aggressive solid tumors, where the agent demonstrated safety and the ability to revert resistance to anti-PD-1 therapies.
Based on these findings, Márquez-Rodas recommended further research with BO-112 in randomized clinical trials to validate these promising results in a larger patient population.
