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FDA Pipeline: Two Fast Track Designations for Cavrotolimod in Nonmelanoma Skin Cancers


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The U.S. Food and Drug Administration (FDA) has granted two Fast Track designations to cavrotolimod (AST-008). The designations include cavrotolimod in combination with anti–PD-1 therapy for the treatment of patients with locally advanced or metastatic Merkel cell carcinoma refractory to prior anti–PD-1 blockade, and cavrotolimod in combination with anti–PD-1/anti–PD-L1 therapy for the treatment of patients with locally advanced or metastatic cutaneous squamous cell carcinoma refractory to prior anti–PD1/PD-L1 blockade.

Cavrotolimod is a spherical nucleic acid toll-like receptor 9 (TLR9) agonist designed to activate the patient’s innate and adaptive immune systems in order to potentially induce anticancer immune responses.

A phase Ib dose-escalation stage of an open-label, multicenter trial was designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of intratumoral cavrotolimod injections alone and in combination with intravenous pembrolizumab in patients with advanced solid tumors. The patients from the phase Ib stage included those with advanced or metastatic Merkel cell carcinoma, head and neck squamous cell carcinoma, cutaneous squamous cell carcinoma, melanoma, and leiomyosarcoma.

A summary of the key highlights from the phase Ib stage of the trial include:

  • No serious treatment-related adverse events or dose-limiting toxicities were observed.
  • The confirmed overall response rate was 21% (4 of 19 evaluable patients) in the phase IB dose-escalation stage across all doses, reflecting one complete response and three partial responses.
  • The confirmed overall response rate was 33% (2 of 6 evaluated patients) in the highest dose cohort (32 mg), which was selected as the phase II recommended dose.
  • Overall responses occurred in two patients with advanced Merkel cell carcinoma and two patients with melanoma.
  • Three of four responders had disease progression on anti–PD-1 therapy at the time of enrollment in the trial.
  • Durable and ongoing responses yielded a progression-free survival exceeding 6 months in all four responders and 16 months in two responders.
  • In addition to the four overall responses, target tumor shrinkage occurred in one patient with cutaneous squamous cell carcinoma and two patients with melanoma.
  • Increases in leukocytes in injected tumors after treatment with cavrotolimod alone and in combination with pembrolizumab vs baseline. Uninjected tumors also showed increased immune cell levels after patients received cavrotolimod plus pembrolizumab.
  • The researchers observed dose-dependent activation of key immune cells, including cytotoxic T cells and natural killer cells, as well as increases in cytokine/chemokine levels in patients’ blood after cavrotolimod treatment alone and cavrotolimod/pembrolizumab treatment.
  • Systemic (abscopal) effects were observed, with regression in noninjected tumors distant from injected lesions.
  • The cavrotolimod pharmacodynamic profile corroborated the efficacy data, as increased serum cytokines/chemokines, activated immune cells, and tumor infiltration by immune cells were observed.

“I am encouraged by the phase Ib dose-escalation results and excited about the potential of cavrotolimod to address the significant unmet need facing these patients,” said Michael Wong, MD, PhD, Professor at The University of Texas MD Anderson Cancer Center and co-principal investigator in the phase Ib/II clinical trial.

“These Fast Track designations underscore the pressing need to develop new therapies to treat refractory nonmelanoma skin cancers as well as the promising preclinical and initial clinical results of cavrotolimod in patients with locally advanced or metastatic Merkel cell carcinoma and cutaneous squamous cell carcinoma,” said Shailender Bhatia, MD, Associate Professor at University of Washington and Fred Hutchinson Cancer Research Center and co-principal investigator in the phase Ib/II clinical trial.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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