Dr Loong on Sevabertinib in HER2-Mutant NSCLC: SOHO-01 Trial Insights
Sevabertinib shows promise as a targeted therapy for HER2-mutant non-small cell lung cancer, addressing significant treatment gaps in this area.
Illustration of lungs: © yodiyim - stock.adobe.com
HER2-mutant non–small cell lung cancer (NSCLC) presents a significant unmet need in oncology, particularly concerning targeted therapeutic options. While advancements have been made in other oncogenic drivers like EGFR, ALK, and ROS1, the landscape for HER2 mutations has remained comparatively limited. Current treatment paradigms often rely on cytotoxic chemotherapy, with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) being the only approved agent in the second-line setting.
The phase 1/2 SOHO-01 trial (NCT05099172) investigated sevabertinib (BAY 2927088), a potent and reversible HER2 tyrosine kinase inhibitor (TKI), offering a promising new avenue. At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Herbert H F Loong, MBBS(HK), PDipMDPath(HK), MRCP(UK), FRCP Edin, FHKCP, FHKAM(Medicine), FASCO, presented data demonstrating high and comparable objective response rates with sevabertinib in both pretreated patients naive to HER2-targeted therapy and those who had received no prior treatment for advanced disease.
In an interview with Targeted OncologyTM, Loong, a clinical associate professor in the Department of Clinical Oncology and the deputy medical director of the Phase 1 Clinical Trials Centre at The Chinese University of Hong Kong, as well as an honorary consultant in the Department of Clinical Oncology at the Prince of Wales Hospital/New Territories East Cluster, Hospital Authority, elaborated on the clinical rationale for sevabertinib.
Targeted OncologyTM: Why investigate sevabertinib in HER2-mutant NSCLC? What unmet needs or challenges in this specific molecular subtype does this trial aim to address?
Loong: The rationale for investigating sevabertinib in HER2-mutant NSCLC is because there is an unmet need in this specific population. Whilst we have effective TKIs in EGFR-, ALK- and ROS1-altered NSCLC, there is still a paucity of targeted therapies in the HER2 mutation space. Presently, aside from cytotoxic chemotherapy with or without pembrolizumab [Keytruda], the only approved agent is trastuzumab deruxtecan in the second-line setting. Having identified HER2 mutation as a distinct molecular driver which is now, with medical advancement, targetable, we are hoping to open up a new treatment avenue for this subgroup of [patients with] lung cancer. The ultimate aim is to assess the feasibility of using an oral targeted therapy in the first-line advanced/metastatic setting. This is akin to the approach we have managed to achieve in other molecular subtypes.
How does the mechanism of action of sevabertinib, as a potent and reversible HER2 tyrosine kinase inhibitor, potentially offer advantages or differentiation vs other HER2-targeted approaches in development or already in use for NSCLC?
As opposed to the other established HER2-targeting approach, trastuzumab deruxtecan, an antibody-drug conjugate, sevabertinib has the advantage of being an oral agent which is more convenient and acceptable to patients. The adverse event profile is also very different. Specifically, trastuzumab deruxtecan has been associated with interstitial pneumonitis, which may potentially be a fatal adverse event. This has not been reported in our prior and current studies with sevabertinib.
SOHO-01 included both pretreated and first-line cohorts. What was the importance of evaluating sevabertinib in these distinct patient populations?
This provides us the opportunity to study sevabertinib’s role in different clinical situations and gives us early signals of magnitude and duration of response in the treatment naïve setting. This can then provide a reason estimate of what sevabertinib can achieve as a front line agent to be confirmed with the currently ongoing randomized phase 3 trial, SOHO-02 [NCT06452277]. We also believe that prior treatments may have implications on possible resistance mechanisms against sevabertinib. Thus, having these distinct patient cohorts based on their prior treatment/treatment characteristics can provide us with a clearer understanding of response in specifically homogenous populations.
What were the key patient characteristics for enrollment, and how do these reflect real-world HER2-mutant NSCLC populations?
Patients were recruited into the specific trial cohorts based on their clinical treatment history and characteristics. The majority of patients enrolled had HER2 mutation within the tyrosine kinase domain [TKD]. In cohorts D and F [the 2 cohorts that were reported during ASCO 2025], 88.9% [72 of 81] and 97.4% [38 of 39] had mutations within the TKD in cohorts D and F, respectively.
How do you interpret the efficacy findings, and what do they suggest about the potential of sevabertinib for patients with HER2-mutant NSCLC?
This is a good indication of sevabertinib’s efficacy in HER2-positive NSCLC, both in patients who have not had prior systemic treatments and those who have had prior chemotherapy with and without immunotherapy.
How would you characterize the overall safety and tolerability profile of sevabertinib based on these results, particularly noting the absence of interstitial lung disease (ILD)?
The overall safety profile in this report is compatible with what we have reported previously. The predominant adverse events are diarrhea, skin rash, and paronychia, which are the expected class effect toxicities that we see in agents that have EGFR inhibition. We performed an exploratory analysis on the natural history of patients who experienced CTCAE grade 3 diarrhea, which showed that in this patient population, patients experienced 1 episode of grade 3 diarrhea, and the median time to onset is 1.3 months. Interestingly, only 1 patient [3%] who were recruited into cohort F with no prior systemic therapies, experienced grade 3 diarrhea, as opposed to 24% of patients in cohort D.
We are exploring whether there is any correlation between development of severe diarrhea as a result of prior systemic treatment. In any case, this information provides us with additional safety information that can be used as reference as we continue with our SOHO-02 phase 3 first-line trial.
The absence of ILD is an important distinction of sevabertinib vs trastuzumab deruxtecan, as well as other tyrosine kinase inhibitors being used in other therapeutic indications. This may provide us some confidence in the possibility of combination treatment in the future.
What do you think about sevabertinib's potential clinical positioning within the evolving treatment algorithm for HER2-mutant NSCLC following these data?
My preliminary assessment is that sevabertinib has been proven as an effective treatment in patients with HER2-mutated NSCLC. Its efficacy seen in cohort F [i.e. patients who are treatment naive] provides a good basis for a possible role of sevabertinib in the frontline setting. Whilst this is pending confirmation with the SOHO-02 trial, I remain hopeful that we will see further readout of this data soon. Patients who have had prior cytotoxic chemotherapy with or without immunotherapy have clearly benefited based on the results of cohort D. We also eagerly await report of results from cohort E, [which includes patients that are] pretreated with HER2-targeted [antibody-drug conjugates (ADCs)] and cohort G [which consists of patients in the second-line with] active brain metastases, which can help us further define the most appropriate position for sevabertinib in a patient’s treatment journey.
What are the next steps or further studies needed to fully define the role of sevabertinib in routine clinical practice for patients with advanced HER2-mutant NSCLC?
We shall await the readout of the SOHO-02 trial, which will be able to clearly determine whether sevabertinib can supersede our current standard-of-care treatment of chemotherapy with or without immunotherapy in the first-line setting. At the same time, we are also continuing with our SOHO-01 trial to assess longer time efficacy and toxicities of sevabertinib, as well as being able to assess potential secondary resistance mechanisms against sevabertinib in patients who unfortunately subsequently progress after treatment. Having all this information on hand will help us shape an optimal treatment journey for patients with HER2-mutated NSCLC.
