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Intratumoral injection of an investigational agent, BO-112, combined with pembrolizumab (Keytruda) demonstrated promising efficacy in certain patients with advanced melanoma refractory to anti-PD-1-based therapy, according to results from a single-arm phase II trial.

Ten of 40 evaluable patients responded to treatment -- six partial and four complete responses -- meeting the study's primary endpoint of at least a 20% overall response rate, reported Iván Márquez-Rodas, MD, PhD, of Hospital General Universitario Gregorio Marañón in Madrid, Spain.

BO-112 is a double stranded synthetic RNS formulated with polyethyleneimine that mimics a viral infection, Márquez-Rodas explained at the annual meeting of the American Association for Cancer Research. It produces immunogenic cell death through dendritic cell activation and an increase in CD8 T-cell infiltration and interferons induction.

All responses were among individuals with cutaneous melanoma (eight of 29 patients, 28%) and mucosal melanoma (two of three, 66.7%), while those with acral melanoma or very high elevated levels of lactate dehydrogenase (LDH; three times the upper limit of normal) achieved no clinical benefit at all.

And the response rate was higher for the injected lesions versus the non-injected lesions (26% vs 11%).

"The study design attempted to reverse drug resistance and this is always a big hurdle," commented discussant Stefania Scala, MD, PhD, of Istituto Nazionale Tumori IRCCS Fondazione Pascale in Italy. "On the positive side, we have a 25% overall response rate, with some of these durable. On the negative side, the overall response rate was driven by those lesions that were injected."

"If we look at the overall efficacy assessment, it really emulates injected lesions, suggesting lesions not injected contributed little or nothing to the overall efficacy," she added. "While intralesional injections can have a valuable role, this is usually only in a very limited number of patients. To have a successful treatment requires responses in untreated lesions."

Given the lower non-target response, session moderator Timothy Yap, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, asked Márquez-Rodas, "how are you going to prove that this is indeed a synergistic combination, not just with your target lesions that are being injected?"

"The only way to do that is to forbid injecting all the lesions you can," Márquez-Rodas said. "And we think that is an ethical issue. If you have a treatment that is amenable to be injected by a good radiologist, why not use that?"

Study Details

The included 42 patients with unresectable stage III/IV cutaneous, acral, or mucosal melanoma, and confirmed progressive disease while on anti-PD-1-based therapy. Patients were treated with 1-2 mg of BO-112 on a weekly basis for 7 weeks, and thereafter every 3 weeks in up to eight different lesions. Pembrolizumab 200 mg was administered every 3 weeks.

With a median follow-up of 4.1 months the median duration of response had not been reached, with half the responses still ongoing. In the intent-to-treat population, the median progression free survival was 3.8 months (95% CI 3.6-not reached).

"However, when excluding acral melanoma or very high LDH, the median PFS was not reached," Márquez-Rodas said, noting that this determination could guide the design of subsequent studies.

Responses per BRAF/NRAS status were 43% in BRAF-mutant disease, 31% in NRAS-mutant disease, and 17% in BRAF/NRAS wild-type tumors.

Márquez-Rodas said the combination was generally well tolerated, with just 5% of patients experiencing grade 3/4 adverse events (AEs) and none discontinuing treatment due to toxicity. Common AEs included asthenia, pyrexia, diarrhea, vomiting, and chills.

While the safety profile is "promising," Scala noted side effects such as fatigue or diarrhea are not tolerable in the long term. She suggested that while some of these side effects can be attributed to pembrolizumab, "it is likely patients with impactful toxicities to previous PD-1 agents probably wouldn't have enrolled in the trial."

"Are these toxicities driven by the addition of BO-112 to pembrolizumab?" she asked. "If this is ever proposed as an upfront strategy, this is important."

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