VIC-1911 With/Without Sotorasib Under Investigation in KRAS G12C Inhibitor–Resistant and –Naïve NSCLC

The selective, reversible, orally active, small molecule, aurora kinase A (AUKRA) inhibitor, VIC-1911, showed preclinical activity as both monotherapy and in combination with sotorasib (Lumakras) in non–small cell lung cancer (NSCLC) models with intrinsic or acquired KRAS G12C resistance, supporting its investigation in a phase 1 trial (NCT05374538) in patients with KRAS G12C–mutant NSCLC.

Sarah Goldberg, MD, MPH, expanded on the details of this ongoing study at the 2023 ASCO Annual Meeting. In the nonrandomized, open label, dose-escalation phase of the study, patients will be assigned to cohort 1a or cohort 1b. Cohort 1a consists of patients with relapsed/refractory disease who will receive VIC-1911 monotherapy. Cohort 1b is comprised of patients with relapsed/refractory disease who were previously treated with a KRAS G12C inhibitor, or patients who are naïve to prior KRAS G12C inhibitor therapy. Patients in this cohort will be treated with VIC-1911 plus sotorasib.

In the dose expansion phase, patients will be enrolled onto cohorts 2a, 2b, or 2c. Cohort 2a will include patients with relapsed/refractory disease who will receive VIC-1911 monotherapy. Patients in cohort 2b with relapsed/refractory disease who received a prior KRAS G12C inhibitor will be treated with the combination of VIC-1911 and sotorasib. Lastly, patients naïve to a KRAS G12C inhibitor in cohort 2c will be treated with the combination regimen.

“This first generation of KRAS G12C inhibitors set the stage for us to be confident that we can inhibit KRASG12C–mutant tumors, and it's possible to [target] this mutation. Therefore, it's exciting that we know there can be effects [with this regimen],” Goldberg explained in an interview with OncLive®.

In the interview, Goldberg highlighted the mechanism of action of VIC-1911, expanded on its ongoing investigation in the phase 1 trial, and shed light on next steps planned for the agent’s investigation in KRASG12C–mutant NSCLC. Goldberg is an associate professor of Internal Medicine in the section of Medical Oncology at Yale School of Medicine. She is also associate director of the Medical Oncology-Hematology Program, research director for the Center of Thoracic Cancers, and division chief of Thoracic Oncology at Yale Cancer Center in New Haven, Connecticut.

OncLive: What is the mechanism of action of VIC-1911?

Goldberg: VIC-1911 is an AUKRA inhibitor. AUKRA is involved in mitosis during the cell cycle, and it's important in a lot of different cancers, including lung cancer. There are also some data [indicating] that AUKRA is relevant in KRAS G12C–mutant NSCLC. It may be part of the reason why some tumors are not responding to KRAS inhibition, and may [play a role in] the mechanism of resistance to KRAS inhibition.

What preclinical data supported the investigation of VIC-1911 in KRAS G12C–mutant NSCLC?

VIC-1911 is different from other aurora kinase inhibitors [because of its selectivity for AUKRA], so the idea is that it may have less toxicity. The preclinical data that led to the rationale for this study [were generated] in part by Barbara Burtness, MD, of the Yale School of Medicine. Burtness and her colleagues found that the combination of VIC-1911 and sotorasib appeared to be effective in cell and animal models of KRAS G12C–mutant NSCLC.

Moreover, [the combination] seemed to overcome resistance to sotorasib alone. It also looked to be effective as up-front therapy in treatment-naïve KRAS G12C models. Additionally, VIC-1911 appeared to be effective, even as a single agent, at the time of progression on prior KRAS G12C inhibitors. There was a rationale for studying VIC-1911 in patients with either treatment-naive or previously treated, resistant KRAS G12C–mutant NSCLC.

What unmet needs currently exist for patients with KRAS G12C–mutant NSCLC?

In recent years, there have been exciting data [on] drugs for this subset of patients with lung cancer. Approximately 12% of [patients with] lung adenocarcinoma have KRAS G12C mutations, and we've seen some great results with single-agent KRAS G12C inhibition [in this population]. We've seen data with sotorasib and adagrasib [Krazati], [along with] several other agents. These 2 drugs are now approved for use [in KRASG12C–mutant NSCLC] by the FDA. However, many patients don't experience responses with those drugs. Even those who do respond eventually develop resistance, and the [duration of response] is variable; some have very durable responses, and others have a short-lived response. This creates a huge unmet need.

[Moreover,] the duration of response is shorter than what we have come to expect with many other targeted therapies. There is a huge [opportunity] to study combinations at the time of resistance and to think about what can be used up-front to improve response rates and durability.

Could you expand on the design of this phase 1 trial?

We designed the study based on preclinical data showing that the combination of VIC-1911 and sotorasib can overcome resistance to prior KRAS G12C inhibitor therapy. There are a few different cohorts of patients that we're looking at.

One is patients who have been previously treated with KRAS G12C inhibitors; they will receive the combination of VIC-1911 and sotorasib. Because we did see [favorable] preclinical data for single-agent VIC-1911 in the resistant setting, we're also evaluating single-agent VIC-1911 [in patients with resistance to a prior KRAS G12C inhibitor]. Finally, there's a cohort that's looking at KRAS G12C inhibitor–naive patients, and they will receive the combination of VIC-1911 and sotorasib.

We're looking broadly at whether VIC-1911 has activity up-front, and whether it has activity at the time of resistance.

What next steps will be taken with this research?

This trial just opened, and we've accrued a few patients thus far. We are excited to see these results based on our preclinical findings. The next steps are to continue accrual to the study and get a good sense of whether the preclinical data will translate into a clinical benefit for patients.

We also are looking at biopsy material and blood samples from these patients. Understanding which patients are benefiting, which may not benefit, and why, [will give us] a sense of the biology of these tumors. This will help us understand what's happening at the time of resistance and how that may affect outcomes with this combination.

Disclosures: Dr Goldberg reports serving as a consultant or in an advisory role for AstraZeneca/ MedImmune, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Genentech/Roche, Genzyme, Janssen, Merck, Mirati Therapeutics, Regeneron, Summit Therapeutics, Takeda; she received research funding from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Merck, Mirati Therapeutics, Pfizer, Spectrum Pharmaceuticals; she received honoraria from Amgen.

Reference

Bar Y, Dedeoglu AS, Fell GG, et al. A phase 1a/1b study of aurora kinase A inhibitor VIC-1911 as monotherapy and in combination with sotorasib for the treatment of KRAS G12C-mutant non–small-cell lung cancer. J Clin Oncol. 2023;41(suppl 16):TSPS9140. doi:10.1200/JCO.2023.41.16_suppl.TPS9140