Vidutolimod/Nivolumab Under Evaluation in PD-1–Refractory Advanced Melanoma

The safety and efficacy of the combination of vidutolimod (CMP-001) and nivolumab (Opdivo) is currently under investigation in patients with PD-1–refractory advanced melanoma, as part of the ongoing phase 2 CMP-001-010 trial (NCT04698187).¹

In May 2021, patient dosing with the combination was initiated for the trial. Previously, dosing with vidutolimod/nivolumab was also initiated in another phase 2/3 trial (NCT04695977)² that is examining the safety and efficacy of the frontline regimen compared with single-agent nivolumab in patients with metastatic or unresectable melanoma. Findings from both of the trials are expected to support a biologics license application for the doublet as a potential option for patients with PD-1–refractory advanced disease.

"Initiation of dosing in this pivotal trial is an important milestone as we move toward potential registration of vidutolimod in melanoma," Barry Labinger, president and chief executive officer of Checkmate Pharmaceuticals, stated in a press release. "Melanoma is estimated to be the fifth most diagnosed cancer in the United States, with more than 100,000 new cases and 7,000 deaths per year. There is a significant unmet medical need for patients who have progressed following treatment with anti–PD-1 therapy since there is no well-established standard of care."

Vidutolimod, an advanced generation toll-like receptor 9 agonist, is delivered as a biologic virus-like particle and utilizes CpG-A oligodeoxynucleotide as a key component. The mechanism of action of the agent provides it with the potential to produce tumor-targeted T cells that are able to eliminate a tumor locally and systemically when paired with checkpoint inhibitors.³ This combination has been hypothesized to improve outcomes for patients whose tumors are not responsive to immunotherapy agents.

The multicenter, open-label study plans to enroll an estimated 100 patients. To be eligible for enrollment, patients needed to be at least 18 years of age and have histopathologically-confirmed diagnosis of malignant melanoma that is metastatic or unresectable at the time of screening.⁴ Patients also needed to be refractory to PD-1 blockade either as monotherapy or in combination with other options. Additionally, patients had to have measurable disease, an ECOG performance status of 0 or 1, and acceptable organ function.

Those who have been diagnosed with uveal, acral, or mucosal melanoma; who have received radiation therapy; or have been treated with complementary therapy 2 weeks prior to the first study dose were not able to enroll to the trial. Additional exclusion criteria include those who require corticosteroids equal to 10 mg of prednisone per day, have a history of grade 4 immune-related adverse effects (AE) from an anti–PD-1 antibody, those who have not fully recovered from previous AEs, or those who have a history of, or active, pneumonitis or interstitial lung disease.

Patients enrolled to the trial will receive 10 mg of intravenous vidutolimod weekly for 7 doses followed by administration every 3 weeks. Additionally, patients will be given 360 mg of nivolumab intravenously every 3 weeks.

The primary outcome measure for the study is objective response rate (ORR). Key secondary outcomes include safety and tolerability, duration of response (DOR), treatment response in non-injected target lesions, progression-free survival, and overall survival, among others.

Vidutolimod was previously examined in combination with pembrolizumab (Keytruda) and was found to overcome PD-1 blockade resistance in patients with advanced melanoma.⁵ The results of the phase 1 CMP-001-001 trial (NCT02680184), which were presented during the 2020 SITC Annual Meeting, demonstrated that the combination elicited a best ORR per RECIST v1.1 criteria of 23.5% (95% CI, 15.5%-33.1%) Moreover, post-progression responders achieved a best ORR of 27.6% (95% CI, 19.0%-37.6%). Those who had previously progressed on PD-1 blockade experienced a DOR of 19.9 months.

Vidutolimod is alo under examination in combination with pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinoma as part of a phase 2 study (NCT04633278).⁵ The trial will specifically be focused on patients who have not previously received a PD-1–blocking antibody.

References

1. Checkmate Pharmaceuticals announces initiation of patient dosing in potential registration trial of vidutolimod (CMP-001) in patients with anti-PD-1 refractory advanced melanoma. News release. Checkmate Pharmaceuticals, Inc. May 4, 2021. Accessed May 20, 2021. https://bit.ly/2RUtC6R 
2. CMP-001 in combination with nivolumab compared to nivolumab monotherapy in subjects with advanced melanoma. ClinicalTrials.gov. Updated March 18, 2021. Accessed May 20, 2021. https://www.clinicaltrials.gov/ct2/show/NCT04695977
3. Mechanism of action: dedicated to harnessing the power of the immune system to combat cancer. Checkmate Pharmaceuticals. Accessed May 20, 2021. https://bit.ly/2SAyH4a
4. CMP-001 in combination with nivolumab in subjects with advanced melanoma. ClinicalTrials.gov. Updated May 14, 2021. Accessed May 20, 2021. https://clinicaltrials.gov/ct2/show/NCT04698187
5. M, Zakharia Y, Davar D, et al. Intratumoral injection of CMP-001, a toll-like (TLR9) receptor agonist, in combination with pembrolizumab reversed programmed death receptor 1 (PD-1) blockade resistance in advanced melanoma. Journal for ImmunoTherapy of Cancer. 2020;8. doi:10.1136/jitc-2020-SITC2020.0304
6. CMP-001 in combination with pembrolizumab in subjects with recurrent or metastatic head and neck squamous cell carcinoma. ClinicalTrials.gov. Updated May 17, 2021. Accessed May 20, 2021. https://clinicaltrials.gov/ct2/show/NCT04633278