Small molecule inhibitors, such as the investigational CDK9 inhibitor KB-0742, are laying the groundwork for continued research into optimal strategies for targeting the biology of solid tumors, according to Brian Van Tine, MD, PhD.

An ongoing phase 1 dose-escalation and cohort-expansion trial (NCT04718675) is evaluating KB-0742 in patients with MYC-amplified or MYC-overexpressed relapsed or refractory solid tumors, such as lung cancer, triple-negative breast cancer, ovarian cancer, and soft tissue sarcoma, or non-Hodgkin lymphoma (NHL). The primary end points of this trial include the incidence of adverse effects, the rate of dose-limiting toxicities, and the determination of the maximum tolerated dose (MTD) and recommended phase 2 dose of the agent.¹

“The influences of MYC in driving cancer progression can’t be under appreciated,” Van Tine said. “It’s an important transcription factor in cancer.”

In an interview with OncLive®, Van Tine discussed key considerations for understanding the biology of MYC, the rationale for the phase 1 study, and patient characteristics that may signal their eligibility for participation in this trial.

Van Tine is a professor of medicine in the Division of Oncology in the Section of Medical Oncology at Washington University School of Medicine in St. Louis, Missouri.

OncLive: What is the role of MYC as a cancer driver, and in which tumor types can MYC amplification occur?

Van Tine: MYC is a transcription factor that is often amplified in solid tumors and in all sorts of lymphomas. There are several solid tumors, [such as] small cell lung cancer [SCLC], where MYC gets amplified. This drives transcriptional programming of MYC. There’s also a MYC-amplified subset of osteosarcoma.

As we [do more research] into MYC, [we may find] MYC-amplified subsets of almost every solid tumor, which is why trying to drive MYC has been a goal of science for a long time. It’s also a master metabolic regulator.

What challenges arise during testing for and detecting MYC amplification or overexpression in patients with solid tumors?

There are a few challenges in understanding MYC biology. MYC, as a transcription factor, is important when it’s in the nucleus but may have different biology in the cytoplasm. If MYC ends up sequestered in the cytoplasm, MYC transcriptional programming [may not occur]. [MYC] is a shuttling protein. It’s an elegant molecule that does much to help proliferation or induce cell death through disrupting [cell] biology.

[We] think about nuclear MYC, but if you do a western blot for MYC, you don’t know where it came from. If you just have [MYC-amplified tumors per] Tempus, Caris, or Sanger [tests], you don’t necessarily know if you have the high concentration of nuclear MYC that [treatment is] dependent on. Often, [that high concentration is] assumed, but some of the challenges of understanding MYC biology have to do with its short half-life and where it’s located.

How is CDK9 related to the expression and function of MYC?

CDK9 is a cyclin-dependent kinase that has had several small molecule inhibitors developed for it. It’s involved in the regulation of MYC transcription. If you inhibit CDK9, you disrupt RNA polymerase II, and then you alter the MYC biology [of the] tumor. MYC is often associated with transcription factor fusions. We’re quickly beginning to learn the importance of CDK9 biology, which, until now has been underappreciated within the MYC realm of transcription factors. CDK9 is becoming an exciting target within EWS-driven tumors, especially.

What is the mechanism of action of the CDK9 inhibitor KB-0742?

KB-0742 is an orally bioavailable CDK9 inhibitor that prevents the phosphorylation of RNA polymerase II, thus leading to inhibition of gene transcription. That leads, at least in preliminary models, to apoptosis because [the cells] can’t drive the MYC transcription factor.

What has been observed in preclinical studies of KB-0742?

Preclinical studies have shown that inhibiting CDK9 can lead to cell cycle arrest and apoptosis. In small animal models, [KB-0742] shows great tumor control. From a clinical translational standpoint, a rich body of evidence shows that this [finding] needs to be clinically translated.

Could you highlight the rationale and design of the phase 1 trial evaluating KB-0742 in patients with relapsed/refractory solid tumors or NHL?

I’ve been privileged to participate in the phase 1 dose-escalation trial trying to determine the MTD of KB-0742. We have gone through several steps, and now we’re looking in various expansions to determine [the drug’s] activity. One arm is investigating [the agent’s activity in] MYC-amplified solid tumors, and another is evaluating [the activity of the drug in] transcription factor– and translocation-driven tumors with MYC biology.

What are the key enrollment criteria for patients in this trial, and what challenges may arise when enrolling patients?

The key inclusion criteria are different in each arm. If a patient has, for example, SCLC that’s MYC amplified by their genomics report, they need [further testing] to make sure they have activated MYC transcription. [If so, they can] enroll on the trial. There’s a bit of [eligibility] screening in that arm, but it’s an important screen because it predicts for success with the drug mechanistically. In the other arm, we’re looking at transcription factor–driven sarcomas, such as myxoid round cell sarcoma and Ewing sarcoma, [diseases which], when the fusion comes together, such as in solitary fibrous tumors, make a transcription factor fusion that shouldn’t be there because many of these are associated with MYC and CDK9 biology. We’re looking for signals in both arms right now.

The challenges involve finding patients with MYC-amplified solid tumors. Whereas in the sarcoma arm, we have a rich repertoire because we know what the transcription factor fusions are, a concerted effort to find more, say, SCLC that has MYC amplification to test this drug would be important for its development.

What is your main message for colleague regarding the development of KB-0742 and its exploration in this phase 1 trial?

[MYC is] an interesting target, and if a patient has a MYC-amplified tumor and is willing to go on a phase 1 trial, [this may] be a promising avenue for exploration, especially if they’re a patient who helps us identify [further] avenues to go down.

Clinical trials are the most important patient-centric thing we do. It’s not about drug development. Now, in 2023, it’s about [agents that are] ultra-targeted to the biology of tumors. We’ve come a long way from chemotherapy now to these ultra-targeted agents. The opportunity for patients to get these nicely targeted agents that have much less toxicity than classic chemotherapy into their treatment paradigms is a patient-centric view of what we’re doing and needs to be thought through because we’re now at a level where we’re mixing and matching genomics with biology. These small molecule inhibitors are a neat opportunity to try, especially if [a patient has] the right biology.