What to do about melanoma immunotherapy resistance? New drug BO-112 shows preliminary clinical benefits.
Immunotherapy has emerged as a new direction in melanoma treatment in recent years, but subsequent treatment options are very limited once tumors develop resistance to this therapy. Preliminary analysis data from the Phase 2 SPOTLIGHT-203 trial, presented at the 2021 SITC Annual Meeting, showed that the addition of BO-112 to Keytruda (pembrolizumab) provided clinical benefit to patients with unresectable malignant melanoma whose disease had progressed after receiving PD-1 immunotherapy.
BO-112 is a double-stranded synthetic RNA formulated with polyethylene imine, which can imitate the structure of a double-stranded RNA molecule into tumor cells, and this double-stranded RNA molecule has been found to be the genetic material of certain viruses. When directly injected into the tumor, it can activate dendritic cells, infiltrate CD8 T cells, induce interferon and apoptosis, and cause apoptosis of immunogenic cells, increasing the inhibition of immune checkpoints.
BO-112 can activate the innate immune system through TLR3, RIG-1, MDA-5, and PKR, which leads to increased expression of type I and TYPE II IFN, which is independent of MHC-1 expression. When the congenital immune system and the adaptive immune system are connected, it will lead to effective antigen presentation and an increase in CD8-positive lymphocytes, which will lead to apoptosis of cancer cells.
BO-112 international test data
THE SPOTLIGHT-203 TRIAL (NCT04570332) RECRUITED NON-RESECTABLE PATIENTS WITH STAGE III OR IV MELANOMA WHO CONFIRMED THEIR DISEASE PROGRESS IN TWO CONSECUTIVE IMAGING EVALUATIONS DURING ANTI-PD-1-BASED TREATMENT. In order to be eligible for selection, patients also need to have an ECOG performance status of 0 or 1. Study participants received BO112 treatment every week for 7 weeks, and then received BO112 treatment every 3 weeks in combination with 200 mg of Keytruda every 3 weeks.
The main endpoint of the trial is the ORR based on the RECIST v1.1 standard; if less than 8 patients respond to treatment, the study will not meet the statistical criteria. Important secondary endpoints include safety, DCR, response duration, ORR, progression-free survival (PFS), total survival (OS), and pharmacokinetics.
By August 24, 2021, recruitment for the trial was complete, with 42 patients enrolled. All patients had confirmed disease progression prior to enrollment; all but one patient had stage AJCC 8 disease. The median age was 68.0 years (range 27.0–88.0 years), and 59% were male. 74% of patients (n = 31) had cutaneous melanoma, 19% (n = 8) had apicoblastic melanoma, and 7% (n = 3) had mucosal melanoma.
86% of patients (n = 36) had BRAF wild-type disease, and 14% (n = 6) had BRAF mutant disease. 43% of patients (n = 18) had previously received Keytruda monotherapy, 36% (n = 15) had previously received Opdivo (nivolumab) monotherapy, 14% (n = 6) had received Yervoy (ipilimumab) plus Opdivo, and 7% (n = 3) had previously received other anti-PD-1 combinations. 79% of patients (n = 33) had previously received treatment for advanced disease, and 21% (n = 9) had previously received adjuvant therapy.
In addition, 59% (n= 25) of patients had normal lactate dehydrogenase levels (LDH) and 41% (n= 17) had higher LDH. The LDH of the four patients was 3 times the upper limit of normal (ULN) at baseline, and all patients developed progressive diseases no later than week 8. As of October 14, 2021, the median period of treatment was 12 weeks, and 30 patients were still receiving treatment.
Among the 37 patients with evaluable responses, the combination caused an objective response rate (ORR) of 27%; 2 patients obtained a pathological complete response (CRs) at week 8. In addition, 37.8% of patients (n= 14) were stable at week 8, which means that the disease control rate (DCR) was 64.9%. All responders experienced higher tumor size reduction. Other data showed that after using this combination in 3 patients with mucosal melanoma, the ORR was 75% and the DCR was 100%. At the time of the speech, the PFS and OS data were still immature.
Regarding safety, 88.1% of patients experienced at least one adverse event (AE), with 19% experiencing grade 3 to 5 AEs. Additionally, 31 patients experienced at least one BO-112-related AE; this included one grade 4 infusion reaction. The most common BO-112-related AEs included wheezing (50%), fever (38%), diarrhea (33%), vomiting (24%), chills (21%), nausea (21%), decreased appetite (14%), headache (14%), and injection site pain/discomfort/hematoma/allergy (14%). Other common AEs included arthralgia (12%), pruritus (12%), flu-like illness (10%), back pain (10%), fatigue (7%), hypertension (7%), peripheral edema (7%), temperature regulation disorder (5%), musculoskeletal pain (2%), neutropenia (2%), and tumor hemorrhage (2%). No patients discontinued treatment due to AEs. Further trials evaluating this therapy are ongoing.
Reminder: For melanoma patients who are resistant to PD-1 immunotherapy, the new drug BO-112 has obvious clinical benefit trends. It is hoped that the therapy will obtain better trial results, be approved as soon as possible and be used clinically for the benefit of more cancer patients.
