The combination of pembrolizumab and CMP-001, an intratumoral toll-like receptor 9 agonist, demonstrated antitumor activity among patients with metastatic melanoma resistant to PD-1 checkpoint inhibition, according to study results presented at American Association for Cancer Research Annual Meeting.
“Checkpoint inhibition is quickly becoming a key tool for oncologists to treat cancer,”
Mohammed Milhem, MBBS, clinical professor of internal medicine at University of Iowa, said in a press release. “However, there are many patients that either initially respond to checkpoint inhibition and then progress, or never respond to this therapy to begin with. Finding safe and effective therapies for these patients is critical.”
Prior research showed tumors with increased interferon gene expression are more responsive to PD-1 inhibition. The toll-like receptor (TLR) 9 pathway is a known inducer of interferon production.
Milhem and colleagues conducted a phase 1b trial of 85 patients with advanced melanoma who did not respond to or progressed during anti-PD-1 therapy. Researchers enrolled patients in a dose escalation phase (n = 44) or dose expansion phase (n = 41).
In the dose escalation phase, researchers administered CMP-001 (Checkmate Pharmaceuticals) via intratumoral injection at doses of 1 mg to 10 mg, plus the anti-PD-1 therapy pembrolizumab (Keytruda, Merck). Injections occurred either once per week for 7 weeks followed by every 3 weeks until discontinuation (n = 40), or once per week for 2 weeks followed by every three weeks until discontinuation (n = 13).
“The majority of patients who got their lesions injected [had] lesions that were found on the skin, lymph nodes or soft tissue, so [they] were accessible via ultrasound or could actually be seen,” Milhem said during a press conference. “One patient had a visceral lesion injected, and that was in the liver, without any untoward effects.”
Overall, 15 patients responded, equating to an objective response rate of 22%. Two patients achieved complete responses and 13 achieved partial responses. ORR was 22.5% (95% CI, 11-39) among those who received CMP-001 weekly and 15% among those who received CMP-001 every 3 weeks.
Researchers reported an ORR of 33.3% (95% CI, 13-59) among patients who received weekly doses of 3 mg or 5 mg.
Among the patients who responded, 11 remain on study at the time of analysis, and three of them had maintained their response for more than 1 year.
Researchers observed one dose-limiting toxicity. No maximum tolerated dose was identified.
Milhem and colleagues also observed a reduction in noninjected tumors in cutaneous, nodal, hepatic and splenic metastases.
Safety data were available from 63 patients. The most common manageable toxicities included fever, nausea/vomiting, headache, hypotension and rigors. The most common grade 3 or grade 4 adverse events included hypotension (n = 7), anemia (n = 2), chills (n = 2), hypertension (n = 2) and fever (n = 2).
“The combination of CMP-001 and pembrolizumab appears well tolerated and produced deep and durable systemic clinical responses,” Milhem said. “Enrollment into the expansion phase of this study continues. Clinical investigation in other tumor types is underway.” – by Cassie Homer
Milhem M, et al. Abstract CT144. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
Disclosures: Checkmate Pharmaceuticals sponsored and managed this study. Milhem reports no relevant financial disclosures.