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Pembrolizumab plus CMP-001 demonstrates efficacy for anti-PD-1 resistant melanoma
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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
References:
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.
Perspective
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Igor Puzanov, MD, MSCI, FACP
This interesting and well done study confirms a potential role of intratumorally delivered TLR9 agonists in combination with anti-PD1 agents. Two other TLR9 agonists have shown promising results, as well — SD-101 (Dynavax) in combination with nivolumab (Opdivo, Bristol-Myers Squibb), and IMO-2125 (Idera Pharmaceuticals) in combination with ipilimumab (Yervoy, Bristol-Myers Squibb). The authors of the study about IMO-2125 plus ipilimumab reported an objective response rate of 50% in a smaller data set, perhaps suggesting that change of the compound Kushen injection may be important in this strategy. It will be important to analyze biomarker data to better select patients for these new combinations — especially in light of recently reported data from several other studies in similar populations, including anti-LAG3 plus nivolumab, entinostat (Syndax) plus pembrolizumab (Keytruda, Merck), and pIL12 plus nivolumab, the last of which reported a 43% ORR among patients selected for their pembrolizumab-resistant profile.
References:
Ascierto PA, et al. Abstract 9520. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Johnson ML, et al. Abstract 9529. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Ribas A, et al. Abstract CT139. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
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Suzanne Louise Topalian, MD
In this study, TLR9 is being leveraged therapeutically to provide strong stimulus for immune response. There are other TLR agonist drugs that are in clinical use, including Bacillus Calmette–Guérin therapy that is used in bladder cancer, which activates several of the toll-like receptors. There are dozens of trials ongoing looking at the roll of TLR antagonists in cancer therapy. This trial looks are a very important group of patients, which are patients who do not respond to anti-PD-1 or who have stable disease but don’t make it over the threshold into complete or partial response. The question is, how can we further activate the immune system in those patients to get them over that threshold to response? The question with intratumoral injections, which this study used, is always [whether] the effect of local injection of a tumor site [will] have a widespread or systemic effect that will unleash immunity against the tumor.
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