FDA Grants Fast Track Status to Cavrotolimod for Merkel Cell Carcinoma, CSCC

The FDA has granted fast track designations to cavrotolimod (AST-008) for use in combination with a PD-1 therapy in patients with locally advanced or metastatic Merkel cell carcinoma (MCC) that is refractory to previous PD-1 blockade and for use in combination with a PD-1/PD-L1 agent in those with advanced or metastatic cutaneous squamous cell carcinoma (CSCC) that is refractory to previous PD-1/PD-L1 blockade.

“There is an urgent need to investigate novel immunotherapeutic agents such as cavrotolimod that can be given to enhance the clinical efficacy of immunotherapy, particularly in patients with refractory solid tumors,” Adil Daud, MD, a clinical professor at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center and principal investigator in the phase 1b/2 trial of the agent, stated in a press release.

A spherical nucleic acid toll-like receptor 9 agonist, cavrotolimod was developed to activate the innate and adaptive immune systems to elicit strong antitumor responses in patients who receive it.

In the phase 1b dose-escalation portion of the trial, investigators set out to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cavrotolimod both as a single agent and in combination with pembrolizumab (Keytruda) or cemiplimab-rwlc (Libtayo); one of the key objectives was to determine the recommended phase 2 dose (RP2D) for the drug.

The trial enrolled a total of 20 patients; of these patients, 10 had melanoma, 5 had MCC, 2 had CSCC, 2 had head and neck squamous cell carcinoma, and 1 had leiomyosarcoma. At the time of enrollment, the majority of participants (85%) had experienced disease progression while receiving treatment with a PD-1 therapy.

Results from the trial showed that cavrotolimod elicited an overall response rate (ORR) of 21% (n = 4/19); the ORR was even higher, at 33%, in the group of patients who received the agent at the highest dose of 32 mg (n = 2/6); as such, this was identified as the recommended phase 2 dose of the drug.²

Additionally, overall responses were observed in 2 patients with advanced MCC and 2 patients with melanoma. Notably, 3 of the 4 patients who responded to treatment had been progressing on PD-1 therapy at the time of enrollment. Forty percent of patients with MCC responded to treatment with cavrotolimod; this included 1 complete response (CR).

Beyond the 4 confirmed responses observed with the agent, 1 patient with CSCC and 2 patients with melanoma experienced a reduction in target tumor lesions; this translated to 37% of evaluable patients having reported target tumor shrinkage. Notably, systemic effects were also reported, with noninjected tumors distant from injected lesions also showing regression.

The median duration of response to cavrotolimod had not yet been reached in the 4 patients who responded; at a median follow-up of 11 months, none of the responders had experienced disease progression.

Pharmacodynamic data revealed an increase in serum cytokines/chemokines, activation of immune cells, and immune cell infiltration in the tumor, thus supporting the efficacy information yielded.

Regarding safety, the agent was found to have favorable tolerability. Although 98% of patients experienced treatment-emergent toxicities, these effects were only grade 1 or 2 in severity. No serious adverse effects associated with treatment were reported at the time of data cutoff. The most frequently reported effects included flu-like symptoms and injection site reactions.

In the phase 2 portion of the trial (NCT03684785), which is ongoing, investigators are examining the agent in combination with pembrolizumab or cemiplimab in the treatment of patients with locally advanced or metastatic MCC or CSCC, respectively.³ All participants experienced progressive disease, despite treatment with an FDA-approved PD-1 or PD-L1 inhibitor.

In the phase 1b portion of the trial, investigators utilized a 3+3 dose-escalation design and set out to assess escalating or intermediate dose levels of the agent administered with a fixed dose of pembrolizumab in patients with solid tumors. Here, 5 ascending doses of the agent were evaluated in 5 cohorts, with at least 3 participants enrolled to each group. The objective was to determine the RP2D for the drug.

In this portion of the research, participants are dosed twice with single-agent cavrotolimod and then will go on to receive pembrolizumab at the start of the second treatment cycle. Once the maximum-tolerated dose or highest escalation cohort has been reached, or significant efficacy has been observed at a given dose level and the RP2D dose is identified, then a 2-stage expansion cohort will be evaluated.

Preliminary data presented in December 2019 from the phase 1b portion of the research, cavrotolimod monotherapy or in combination with pembrolizumab was found to induce cytokine and chemokine expression and activate immune cells in patients with MCC.

Of 4 total MCC patients, 1 who had previous disease progression on a PD-1 inhibitor, achieved stable disease with a reduction in their tumor lesion for longer than 12 weeks. Another patient with MCC experienced a CR in their target lesion and a confirmed overall partial response that persisted for longer than 24 weeks. Nine participants experienced disease progression, 2 had not yet been evaluated, and 1 patient was determined to be unevaluable.

Enrollment for the phase 1b portion of the trial has been completed with a total of 20 patients having received treatment with cavrotolimod.

In the phase 2 portion of the research, investigators will examine the RP2D of the agent in 2 cohorts: those with MCC and those with CSCC. In the cohort with MCC, patients received intravenous (IV) cavrotolimod in combination with a fixed, standard dose of pembrolizumab. In the cohort with CSCC, patients received IT cavrotolimod plus a fixed, standard dose of cemiplimab.

Moreover, this portion of the research will also include an exploratory expansion cohort, in which investigators will examine cavrotolimod plus pembrolizumab in participants with other advanced solid tumors, such as melanoma, who experienced disease progression on a PD-1 inhibitor.

“I am encouraged by the phase 1b dose-escalation results and excited about the potential of cavrotolimod to address the significant unmet need facing these patients,” Michael Wong, MD, PhD, professor at the University of Texas MD Anderson Cancer Center and principal investigator of the phase 1b/2 clinical trial of the agent, added in the release.

References

1. Exicure granted two fast track designations for cavrotolimod (AST-008) from the US Food and Drug Administration. News release. Exicure, Inc. January 11, 2021. Accessed January 11, 2021. http://bwnews.pr/2LHDWLY.
2. Pipeline: Cavrotolimod (AST-008). Exicure, Inc. website. Accessed January 11, 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 January 11, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03684785.