Combo of BO-112 and Pembrolizumab Elicits Response in Advanced Melanoma

In patients with advanced melanoma who were resistant to anti–PD-1 therapies, adding BO-112 to pembrolizumab (Keytruda) demonstrated efficacy and safety, according to final results from the phase 2 SPOTLIGHT203 trial (NCT04570332).¹

At a median follow-up of 4.1 months (95% CI, 3.9-6.3), findings showed that among patients evaluable for response (n = 40), the combination of BO-112 and pembrolizumab achieved an overall response rate (ORR) of 25%, including a complete response rate of 10% and a partial response rate of 15%. Additionally, 40% had stable disease, and the disease control rate (DCR) was 65%.

“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,” lead study author Iván Márquez-Rodas, MD, PhD, of Hospital General Universitario Gregorio Marañón in Madrid, Spain, said in the presentation.

In patients with advanced melanoma, up to 70% of those who receive anti–PD-1 therapies will experience disease progression, and there is no current standard-of-care therapy in the second line for these patients.²

BO-112 is a synthetic nanoplexed dsRNA designed to activate TLR3, RIG-1, and MDA5. The agent improves antigen presentation through the interferon-independent increase in MHC-I expression, enhances T-cell infiltration, and elicits immunogenic cell death to overcome resistance to anti–PD-1 therapies.

A first-in-human phase 1 trial (NCT02828098) explored BO-112 alone and in combination with a PD-1 inhibitor in adult patients with aggressive solid tumors, including melanoma, where the agent displayed safety and the ability to revert resistance to anti–PD-1 therapies.3 Initial data from SPOTLIGHT203 read out during the 2021 SITC Annual Meeting, which also showed BO-112 and pembrolizumab produced clinical benefit.

SPOTLIGHT203 enrolled 42 patients who were at least 18 years of age with unresectable stage III or IV cutaneous, acral, or mucosal melanoma and confirmed progressive disease following anti–PD-1 therapy per SITC criteria. Patients were also required to have known BRAF-mutated or BRAF wild-type disease; measurable and injectable disease; only 1 prior line of systemic therapy; and an ECOG performance status of 0 or 1.

Patients were administered BO-112 injections at a dose of up to 2 mg and in up to 8 lesions per cycle once per week for the first 7 weeks, followed by once every 3 weeks, for up to 2 years. Additionally, 200 mg of intravenous pembrolizumab was administered every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, death, withdrawal of consent, or study termination. Notably, BO-112 was also stopped if lesions were no longer injectable.

The study’s primary end point was ORR by RECIST v1.1 per independent radiologist central review. Secondary end points included DCR; duration of response (DOR); progression-free survival (PFS) and overall survival (OS); safety; biomarkers; and radiomics.

The median age of enrolled patients was 65 years (range, 27-88) and 57% were male. Most patients presented with cutaneous melanoma (71%) compared with acral (21%) or mucosal melanoma (7%). Most patients had BRAF wild-type disease (83%) vs BRAF-mutated disease (17%). At baseline, 48% of patients enrolled with M1a-b stage disease (48%), M1c-d stage disease (45%), or unresectable stage III disease (7%). Notably, 41% of patients had high (above the upper limit of normal [ULN]) LDH.

Prior treatment included ipilimumab plus nivolumab (14%); nivolumab alone (33%); pembrolizumab alone (43%); or other anti–PD-1 combinations (10%). The median duration of previous treatment was 30 weeks (range, 6-128), and the prior treatment indication was either adjuvant (24%) or advanced disease (76%). Notably, 62% of patients had primary prior resistance and 38% had secondary prior resistance.

Additional data showed patients with cutaneous melanoma and mucosal melanoma achieved ORRs of 28% and 67%, respectively. Notably, no patients with acral melanoma or an LDH 3 times above the ULN (n = 4) had a response. Additionally, the ORRs were 43% and 21% for patients with BRAF-mutated and BRAF wild-type disease, respectively. Patients with secondary resistance to prior therapy had a 38% ORR compared with 17% for patients with primary prior resistance. Patients with prior treatment in the adjuvant setting (n = 8) or in the advanced setting (n = 32) had ORRs of 13% and 28%, respectively.

Among injected lesions (n = 38), 26% demonstrated a greater than 30% reduction and 53% achieved any reduction. In non-injected lesions (n = 28), 11% had a greater than 30% reduction and 25% experienced any reduction.

The median DOR was not reached (NR; 95% CI, 2 months–NR), and the percentage of patients in response after 6 months was 66.7% (95% CI, 16%-91.4%).

The median PFS in the intention-to-treat population (n = 42) was 3.8 months (95% CI, 3.6-NR). However, in patients with non-acral disease and LDH greater than 3 times the ULN (n = 29), the median PFS was NR (95% CI, 3.8-NR) compared with 2.2 months (95% CI, 0.8-3.6) in patients with acral disease and/or LDH 3 times above the ULN (n = 13).

The median exposure to BO-112 was 3.93 months (95% CI, 3.5-5.8) compared with 3.85 months (95% CI, 3.9-6.3) for pembrolizumab. Notably, treatment was ongoing in 31% of patients at the time of data cutoff.

All 42 patients experienced at least 1 adverse effect (AE) of any grade and 36% encountered a grade 3 or higher AE. Notably, 83% of patients had at least 1 treatment-related AE (TRAE) of any grade; however, 5% experienced a grade 3 or 4 TRAE. Serious AEs occurred in 29% of patients, including serious TRAEs in 7%. Furthermore, 19% of patients discontinued treatment due to AEs, although no patients discontinued treatment due to TRAEs.

The most common grade 1 or 2 TRAEs were asthenia (50%); pyrexia (38%); diarrhea (33%); vomiting (24%); chills (21%); nausea (21%); decreased appetite (14%); headache (14%); injection site pain, discomfort, hematoma, or hypersensitivity (14%); arthralgia (12%); pruritus (12%); influenza-like illness (10%); and back pain (10%).

Based on the findings of SPOTLIGHT203, Márquez-Rodas recommended further research with BO-112 in randomized clinical trials.

_References

_{1. Márquez-Rodas I, Dutriaux C, Saiag P, et al. Efficacy of intratumoral BO-112 with systemic pembrolizumab in patients with advanced melanoma refractory to anti-PD-1-based therapy: final results of SPOTLIGHT-203 phase 2 study. Presented at. 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT014.}

_{2. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol. 2022;40(2):127-137. doi:10.1200/JCO.21.02229}

_{3. Márquez-Rodas I, Longo F, Rodriguez-Ruiz ME, et al. Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti-PD-1 for patients with anti-PD-1-refractory tumors. Sci Transl Med. 2020;12(565):eabb0391. doi:10.1126/scitranslmed.abb0391}