BAY 2927088 Shows Promise in HER2-Mutant NSCLC

Xiuning Le, MD, PhD

BAY 2927088, an oral, reversible tyrosine kinase inhibitor (TKI) that potently inhibits mutant HER2, led to promising response rates when used for the treatment of patients with pretreated HER2-mutant non–small cell lung cancer (NSCLC), according to findings from cohort D of the phase 1 SOHO-01 trial (NCT05099172).¹

Data from the study were recently presented at the 2024 IASLC World Conference on Lung Cancer (WCLC). A total of 44 patients with NSCLC with HER2 activating mutations and HER2 exon 20 insertions and those who were naive to other targeted treatments were included in the efficacy analysis of cohort D. Investigators assessed the recommended dose of BAY 2927088 given orally at a dose of 20 mg twice daily.

The objective response rate in this cohort was 72.1% (95% CI, 56.3%-84.7%), with a complete response rate of 2.3% and a partial response rate of 69.8%. The stable disease rate was 16.3%, and the progressive disease rate was 11.6%. The disease control rate was 83.7% (95% CI, 69.3%-93.2%).

For safety, 95.5% of patients had any-grade treatment-related adverse effects (TRAEs), and 43.2% had grade 3 or higher TRAEs.

In an interview with Targeted Oncology^TM, Xiuning Le, MD, PhD, associate professor in the Department of Thoracic/Head and Neck Medical Oncology, Division of Internal Medicine at The University of MD Anderson Cancer Center, delved into the background, findings, and next steps of the SOHO-01 study.

3D rendered Medical Illustration of Male Anatomy - Lung Cancer:© Sebastian Kaulitzki- stock.adobe.com

Targeted Oncology: Could you elaborate on the mechanism of action of BAY 2927088, and how it differs from or improves upon existing TKIs?

Le: BAY 2927088 is a small molecule oral medication. This molecule is smartly designed to target either EGFR or HER2 mutations, especially the ones that are difficult to treat. The preclinical study indicated excellent preclinical efficacy. That is why the SOHO-01 study has moved to the patient phase, including expansion cohorts.

Can you provide an overview of the design of theSOHO-01 study?

The SOHO-01 study is a phase 1/2 global, multicenter study. In fact, this is the first-in-human study of the drug. The study mostly has 2 big parts. The first part is dose escalation, and the second part is dose expansion. In the dose-escalation part, which has already been completed and reported before, we identified BAY 2927088 at 20 mg twice a day to be the recommended dose. In the expansion parts, we have multiple cohorts evaluating patients with lung cancer with different mutations, subtypes, different prior treatment, and with different tumor characteristics. We are trying to identify which patient population we can serve better with BAY 2927088.

What are the inclusion and exclusion criteria for patient enrollment in this study? Are there specific characteristics of HER2 mutations that are being targeted?

Each cohort is designed very differently. Some cohorts will allow more prior treatment. Some cohorts will allow less prior treatment. For the cohort D that I [discussed at the 2024 World Conference on Lung Cancer], we enrolled patients who have HER2 mutations. Their cancer is advanced or metastatic, and those patients have all received prior chemotherapy but have not received any targeting HER2 treatment, neither an [antibody-drug conjugate] or targeted therapy.

What end points are being evaluated?

This is still a relatively early phase of the understanding of this medicine, so we use both safety and feasibility and tolerability as one key end point. The other key efficacy end point is response rate. Here we used the investigator-evaluated response rate.

Have there been any early indications of efficacy in the data presented so far, such as objective response rates or progression-free survival?

[Our] report is quite exciting. We reported in cohort D [that the] response rate was 72%, including 1 patient who had a complete response. The disease control rate, basically, for patients who did not have tumor progression, is 84%, so again, very impressive response data. The duration of response was 8.7 months, and the median progression-free survival was 7.5 months.

How is the safety profile of BAY 2927088?

In cohort D with BAY 2927088 at 20 mg twice a day dosing, we did not find anything that is a new safety issue, which is reassuring. We still see diarrhea being a common toxicity that we need to manage, and most of the diarrhea is in grade 1 to 2. Patients also have other toxicities, but overall, we have a very low discontinuation rate, only at 6.8%.

What are the most promising aspects of BAY 2927088’s performance in this study? Are there particular subgroups of patients who seem to benefit more?

Our patient is never cookie cutter, but we want to try to identify the high-risk patient population, or the patient population we can serve better. We performed a field subgroup analysis. One that I reported more in detail is the molecular subgroup of patients having YVMA insertions. This is the most common HER2 mutation in lung cancer, so it is a large unmet need in prior studies, including prior TKI analysis. This is also a population that is harder to treat, so we were excited that we reported a response rate of 90% and disease control rate of 97% in this population. The progression-free survival is also very long, nearly 10 months. We are encouraged by this group. The other group I want to highlight is the patients who had brain metastasis at the start of the trial. We saw that in those patients, they derive a similar magnitude of benefit. We have ongoing studies evaluating, more specifically, a brain metastasis patient population.

What are the next steps for this research?

The data are encouraging, so we are going to continue to move forward. There is a [NCT06452277] that has been activated. This study is going to serve as a confirmatory analysis. It is going to be a randomized, global, large, phase 3 study to compare BAY 2927088 in treatment-naive [patients with HER2 mutations] compared with the current standard of care of chemoimmunotherapy.

What potential challenges do you foresee in translating the results of this study into broader clinical practice?

Even before we go into clinical practice, oftentimes when we go from a phase 2 study to a randomized phase 3, the efficacy continues to have a little bit difference. Oftentimes, it is a little bit declined. For BAY 2927088, I also feel that toxicity management is important so that we can maintain the efficacy. For example, we need to teach our patients how to manage their diarrhea, how to manage their rash, and how to work together with a study team so that each patient can get a good treatment with high quality –of life for as long as possible.

REFERENCE:

Le X, Girard N, Janne PA, et al. Safety and efficacy of BAY 2927088 in patients with HER2-mutant NSCLC: expansion cohort from the phase I/II SOHO-01 study. Presented at the 2024 IASLC World Conference on Lung Cancer; San Diego, CA, September 7-10, 2024. PL04.03.