FDA Grants Orphan Drug Designation to Cavrotolimod for Merkel Cell Carcinoma

The FDA has granted an orphan drug designation to cavrotolimod for the treatment of patients with Merkel cell carcinoma.

The FDA has granted an orphan drug designation to cavrotolimod (AST-008) for the treatment of patients with Merkel cell carcinoma (MCC), according to an announcement from Exicure, Inc.1

The spherical acid toll-line receptor 9 agonist was designed to activate the innate and adaptive immune systems to induce strong antitumor responses.

“We are excited to have been granted orphan drug designation by the FDA for cavrotolimod for MCC,” Douglas E. Feltner, MD, chief medical officer of Exicure, stated in a press release. “This designation marks significant progress toward our goal of fulfilling the unmet medical need and finding a treatment for [patients with] MCC.”

Previously, in January 2021, cavrotolimod was also granted fast track designations for use in combination with an anti–PD-1 agent in those with locally advanced or metastatic MCC who proved to be refractory to prior PD-1 blockade, as well as for use in combination with an anti–PD-1/PD-1 drug in those with advanced or metastatic cutaneous squamous cell carcinoma who are refractory to prior PD-1/PD-L1 blockade.

The agent is under evaluation in a phase 1b trial, where it is being combined with pembrolizumab (Keytruda) or cemiplimab-rwlc (Libtayo) in patients with cancer, including those with MCC. For the dose-escalation portion of the trial, investigators examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of the agent as a monotherapy and in combination. A primary objective of the research was to identify the recommended phase 2 dose (RP2D) for the agent.

A total of 20 patients were enrolled to the trial; half of the patients had melanoma, 5 had MCC, 2 had CSCC, 2 had head and neck squamous cell carcinoma, and 1 had leiomyosarcoma. Eighty-five percent of patients had experienced progressive disease while receiving a PD-1 agent at the time of study enrollment.

Cavrotolimod induced an overall response rate (ORR) of 21% (n = 4/19). In patients who received the agent at the highest dose evaluated, 32 mg, the ORR was 33% (n = 2/6). Due to the benefit observed with the higher dose, 32 mg was determined to be the RP2D of the agent.2

Responses were reported in 2 patients with advanced MCC and 2 with melanoma. Of the 4 responders, 3 had been progressing on an anti–PD-1 therapy at the time of study enrollment. Notably, 40% of patients with MCC experienced a response with cavrotolimod; this included 1 patient achieved a complete response (CR). The median duration of response had not yet been reached in these responders. At a median follow-up of 11 months, no responders experienced progressive disease.

Additionally, 1 patient with CSCC and 2 patients with melanoma were found to have a reduction in target tumor lesions with the agent, while translated to 37% of evaluable patients experiencing tumor shrinkage with treatment.

An increase in serum cytokines/chemokines, activation of immune cells, and immune cell infiltration in the tumor was observed in pharmacodynamic analyses.

Cavrotolimod was found to be well tolerated. The majority of patients, or 98%, reported treatment-emergent adverse effects, but they were low grade. Notably, at the time of data cutoff, no serious toxicities associated with the agent were observed. The most commonly experienced effects included flu-like symptoms and reactions at the injection site.

The phase 2 trial (NCT033684785) of the agent is ongoing. Here, the agent will continue to be explored in combination with either pembrolizumab or cemiplimab specifically in patients with metastatic MCC or CSCC, respectively. All participants have experienced disease progression, despite having received an FDA-approved PD-1 or PD-L1 agent.3

In the first half of the research, 20 patients were dosed twice with cavrotolimod monotherapy and then went on to receive pembrolizumab at the beginning of the second treatment cycle. Once the maximum-tolerated dose or highest escalation dose level was reached, or significant efficacy was reported at any examined dose level and the RP2D was identified, the 2-stage expansion cohort would be assessed.

Early data from the first half of the trial showed that treatment with the agent, either as a monotherapy or in combination with pembrolizumab, elicited cytokine and chemokine expression and activated immune cells in patients with MCC. Of 4 patients with MCC, 1 achieved disease stability, as well as a reduction in their tumor lesion for more than 12 weeks. Another patient achieved a CR in their target lesion with the agent, along with a confirmed overall partial response that lasted for more than 24 weeks. 

In the second half of the research, investigators are further examining the RP2D of the agent in 2 cohorts: those with MCC and those with CSCC. Those in the MCC cohort were given intravenous (IV) cavrotolimod plus a fixed, standard dose of pembrolizumab. Those in the CSCC cohort received IV cavrotolimod paired with a fixed, standard dose of cemiplimab.


  1. Exicure granted orphan drug designation by the US Food and Drug Administration for cavrotolimod. News release. March 3, 2021. Accessed March 5, 2021. http://bit.ly/38fEukL
  2. Pipeline: Cavrotolimod (AST-008). Exicure, Inc. website. Accessed March 5, 2021. http://bit.ly/3oNKCqV.
  3. Intratumoral cavrotolimod combined with pembrolizumab or cemiplimab in patients with advanced solid tumors. ClinicalTrials.gov. Updated October 23, 2020. Accessed March 5, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03684785.