AST-008 Plus PD-1 Blockade Shows Early Synergy in Merkel Cell Carcinoma, CSCC

Mohammed M. Milhem, MBBS

AST-008 in combination with a PD-1 inhibitor, such as pembrolizumab (Keytruda) or cemiplimab (Libtayo), in patients with PD-1–refractory Merkel cell carcinoma and cutaneous squamous cell carcinoma (CSCC) might represent an additional treatment approach for a population with an unmet need, according to Mohammed M. Milhem, MBBS.

In an open-label, multicenter phase 1b/2 dose-escalation/expansion study presented during the 2020 ASCO Virtual Scientific Program, investigators examined the efficacy of AST-008 in combination with either pembrolizumab or cemiplimab in patients with advanced/metastatic Merkel cell carcinoma or CSCC.

The phase 1b dose-escalation portion of the study used a 3+3 design that examined increasing doses of AST-008 plus a standard dose of pembrolizumab. The combination was found to be very well-tolerated, Milhem said, with no notable dose-limiting toxicities reported. The phase 2 dose-expansion portion is using the recommended dosage of AST-008 plus a standard dose of pembrolizumab or cemiplimab in the 2 patient cohorts.

“The ultimate goal of the research is to show that AST-008 is safe for use in combination with an anti–PD-1 agent in both Merkel cell carcinoma and CSCC,” said Milhem, Holden Chair of Experimental Therapeutics and associate director of Clinical Research at Holden Comprehensive Cancer Center. “This is a space where very few options are available for patients, so the hope is to show that this approach improves the immune environment to [eliminate] these tumors [and can] provide these patients [with an additional option in the future]."

In an interview with OncLive, Milhem, who is also the director of the Melanoma Program, chief of the Section of Oncology in the Department of Internal Medicine, and clinical professor at the University of Iowa Hospital and Clinics, discussed the promise of the AST-008 combination in patients with Merkel cell carcinoma and CSCC who do not achieve a response with PD-1 inhibitors alone.

OncLive: What makes AST-008 unique? How does this molecule fit into the landscape for Merkel cell carcinoma and CSCC?

Milhem: AST-008 is a spherical nucleic acid TLR9 agonist. It consists of single-stranded CpG oligonucleotides presented in a dense radial arrangement. CpG oligonucleotides actually come from bacteria. The interesting thing about this [agent] is the spherical structure; it has a bacterial signature that actually activates the TLR9 antigen on presenting cells to stimulate downstream immune responses and convert tumors that are believed to be inert to the immune system, so cold tumors, into those that are much more responsive to the microenvironment, so hot tumors. This then allows the immune system to recognize the tumor and potentially kill it. That is the unique structure of this spherical molecule.

What was the rationale to examine this AST-008 with PD-1 blockade in these diseases?

Patients who initially respond to anti–PD-1 blockade therapy, do not need more therapy; however, for patients who are progressing on those treatments, it’s sort of an immune desert. We don't have drugs that really help these patients, so this is an unmet need. CSCC and Merkel cell carcinoma [are] 2 rare tumors types. It’s important to always consider tumors that are incredibly rare [because we need] to find good treatments [for patients who have them]. AST-008 [could potentially] add value to those patients who are not responding to anti–PD-1 therapy.

What was the design of the study examining this approach?

The phase 1b [portion of this research] was a dose-escalation study. [Patients receiving] AST-008 started off [by receiving] 2 mg [of the molecule], which was injected directly into their tumor; this was combined with pembrolizumab, which is an anti–PD-1 agent. [The dose for AST-008] escalated from 2 mg all the way to 32 mg. The safety data [for that portion of the trial] were presented at several meetings and showed no real dose-limiting toxicities; patients tolerated this very well. Patients with different tumor types, such sarcomas, melanomas, CSCC, and Merkel cell carcinoma tumors [were permitted to participate] in the phase 1b dose-escalation trial.

For the first 2 weeks, AST-008 was given by itself, and that [helped us] define its dose-limiting toxicity. Then, [the molecule] was combined with an anti–PD-1 agent for another 3 weeks; that was another [way to] define dose-limiting toxicity. If no dose-limiting toxicities were observed in both of those 2 periods, the next dose escalation was [identified]. The final dose that was accepted into the phase 2 portion of this research was the 32 mg.

Two specific cohorts were selected for exceptional responses and those were the Merkel cell carcinoma and the CSCC groups, and the phase 2 trial [examining the approach in these subgroups] is currently ongoing. The plan is to enroll 10 patients first to see whether any develop a partial response or a complete response to the treatment. If they do, then they will expand [enrollment] to a total of 29 patients in each of those 2 cohorts.

Do you expect to see synergy with AST-008 and cemiplimab in the CSCC cohort?

Having been involved in the earlier portion of the phase 1 trial, [I had] the privilege of actually seeing what's being [achieved]. Yes, I do believe there is synergy; I have seen very nice responses with patients [who were exposed] to this particular molecule. My expectation is, yes, we will hopefully see a positive result in these patient populations.

What are some additional areas of research that you feel are helping to move the needle forward?

The concept of injecting tumors is something that is becoming very common now. Trying to understand what tumors look like when they get injected, how to define whether the tumor is responding or not to treatment, understanding when to do a biopsy, [and gathering] information on what’s being done with regard to patients] immune profiles [are all areas of interest]. [These are] all exciting [areas of research] and [what comes out of these efforts is] probably going to be very informative; this information can help us make better decisions for our patients in the long run. This is an opportunity for us to understand how the immune system engages, more specifically, which is great.

Is there anything else that you would like to add?

If you look broadly in the immune world, we are slowly, hopefully, tackling what could potentially be different areas of interest. One of [these areas] has to do with these injectables in the TLR9 space, which I'm very interested in. I've had the liberty of working with other TLR9 agonists and there are some other agents that are being injected that [are being examined in] these 2 patient populations.

Reference

Milhem MM, Perez CA, Hanna GJ, et al. AST-008: A novel approach to TLR9 agonism with PD-1 blockade for anti-PD-1 refractory Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (CSCC). J Clin Oncol. 2020;38(suppl 15):TPS3164. doi:10.1200/JCO.2020.38.15_suppl.TPS316