Sevabertinib Exhibits Activity in Treatment-Naïve HER2-Mutant NSCLC

ORRs were consistent across all subgroups, including stratification by the number of prior systemic treatments, as well as the presence of brain metastasis at baseline, and those had HER2 TKD mutations.

Sevabertinib (BAY 2927088) exhibited high and comparable objective response rates (ORRs) among patients with HER2-mutant non–small cell lung cancer (NSCLC) who received prior treatment excluding a HER2-targeted therapy, or who were treatment-naïve for advanced disease, according to phase 1/2 SOHO-01 trial (NCT05099172) results presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

“Sevabertinib showed meaningful and durable responses assessed by blinded, independent review that were consistent with previously reported investigator-associated responses in pretreated patients with advanced HER2-mutant non–small cell lung cancer,” Herbert H. Loong, FASCO, FRCP, MBBS, 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, in China, said during a presentation at the meeting, where he reported safety and efficacy data from expansion/extension cohort D (n = 81; patients who were naive to HER2-targeted therapies) and expansion cohort F (n = 39; patients who were naive to systemic therapy for advanced disease) of the ongoing, open-label, multicenter study.

“[Further,] preliminary analysis of an ongoing cohort of first-line patients showed an objective response rate which is comparable to that among pretreated patients, despite the shorter follow-up,” he added.

The data cutoff date from both cohorts that were presented at ASCO was October 14, 2024.

Pretreated HER2-Mutant NSCLC

After a median follow-up of 7.3 months, ORRs by investigator assessment and blinded independent central review (BICR) were 59.3% (95% CI, 47.8%-70.1%) and 60.5% (95% CI, 49.0%-71.2%), respectively. Investigator- and BICR-assessed response rates included a complete response (CR) rate of 1.2% for both assessments, partial response (PR) rates of 58% and 59.3%, respectively, a stable disease (SD) rate of 27.2% for both assessments, and progressive disease (PD) rates of 12.3% and 8.6%.

The investigator-assessed disease control rate (DCR) was 84.0% (95% CI, 74.1%-91.2%), and was 81.5% (95% CI, 71.3%-89.2%) per BICR.

ORRs were consistent across all subgroups, including stratification by the number of prior systemic treatments, as well as the presence of brain metastasis at baseline (64.7%; 95% CI, 38.3%-85.8%), and those had HER2 TKD mutations (65.3%; 95% CI, 53.1%-76.1%)

At the time of cutoff, 41 patients (50.6%) had ongoing treatment with sevabertinib. Overall, 16 patients (19.8%) had a treatment duration longer than 12 months, with a median duration of treatment of 6.2 months (range, 0.2-24.4).

In the expansion cohort (n = 44), median duration of response (DOR) was 9.2 months (range, 2.6-21.5). Further, treatment with sevabertinib led to a 12-month DOR rate of 49.3%.

Treatment-Naive HER2-Mutant NSCLC

After a median follow-up of 5.6 months, investigator-assessed ORR in expansion cohort F was 59.0% (95% CI, 42.1%-74.4%), which included no CRs, a PR rate of 59.0%, SD rate of 30.8%, and PD rate of 7.7%. The DCR was 84.6% (95% CI, 69.5%-94.1%).

At the time of data cutoff, 32 patients (82.1%) were ongoing with sevabertinib treatment. The median duration of treatment was 5.6 months (range, 0.3-6.9).

Safety and Tolerability

Loong noted that, in cohort D, the safety profile was consistent with those previously reported. Treatment-related grade 3 diarrhea was reported in 24% of patients, with a median of 1 episode (IQR, 1-1) across patients at a median time to onset of 1.3 months (interquartile range, 0.5-3.6).

In cohort F, treatment-related grade 3 diarrhea was reported in 1 patient (3%).

Overall, no grade 4 diarrhea was reported. In addition, investigators saw no reports of interstitial lung disease or pneumonitis.

Lastly, 4 patients in cohort D (4.9%) and 1 patient in cohort F (2.6%) discontinued treatment as a result of treatment-related adverse events (TRAEs).

The most common TRAEs of any grade across cohorts D and F included diarrhea (84% and 82%, respectively), rash (49% and 56%), paronychia (25% and 18%), stomatitis (19% and 23%), nausea (19% and 15%), hypokalemia (16% and 21%), vomiting (16% and 21%), anemia (14% and 21%), decreased weight (17% and 10%), increased alanine aminotransferase (15% each), dry skin (17% and 8%), increased aspartate aminotransferase (16% and 10%), pruritis (16% and 10%), decreased appetite (15% and 10%), increased amylase (15% and 8%), lipase increase (10% and 15%), and mouth ulceration (6% and 18%).

SOHO-01 Study Background

Dose escalation and backfill comprised patients with advanced NSCLC with HER2 or EGFR mutations who were treated with increasing oral doses of sevabertinib to identify the recommended dose for expansion (20 mg sevabertinib twice daily in 21-day cycles).

In the expansion/extension phase, investigators aimed to evaluate the safety, tolerability, and efficacy to characterize the pharmacokinetics of the agent at its recommended dose for expansion.

Safety and tolerability, as well as pharmacokinetics, served as the study’s primary end points. Secondary end points included ORR per investigator assessment and BICR by RECIST v1.1, as well as DOR, DCR, and progression-free survival all assessed per investigator and BICR.

Additional cohorts in the study, which were not presented at ASCO, include those who were pretreated with HER2-targeted antibody drug conjugates (cohort E) and those with second-line, active brain metastases (cohort G). In addition, data from extension cohort F were also not presented.

Patient Characteristics

Among cohorts D and F, the majority were female (61.7% and 64.1%, respectively), Asian (70.4% and 71.8%), and were median ages of 60 years (range, 29-82) and 65 years (range, 31-80). Most had an ECOG performance status of 1 (61.7% and 76.9%, respectively), and 61.7% and 79.5% reported never smoking. NSCLC histology was primarily adenocarcinoma (95.1% and 100%, respectively), with 84% and 94.9% with HER2 exon 20 insertion mutations and 88.9% and 97.4% with HER2 TKD mutations.

Median time since most recent progression or relapse to first administration of the study drug was 1.2 months (range, 0-14) for cohort D and 1.4 months (range, 0-3) for cohort F.

The majority of both cohorts (cohort D, 79.0%; cohort F, 94.9%) did not have brain metastases.

In cohort D, the majority of patients previously received 1 prior systemic anti-cancer therapy (56.8%), with 96.3% having received chemotherapy (platinum only, 24.7%; platinum plus immunotherapy, 69.1%).

Next Steps for Sevabertinib

Based on this study’s results, the FDA recently accepted and granted priority review to a new drug application for sevabertinib as a treatment for this patient population, according to a press release from the drug’s developer, Bayer.²

“If approved, sevabertinib will provide an additional treatment option for previously treated patients with advanced NSCLC harboring a HER2-activating mutation,” said Christine Roth, executive vice president, global product strategy and commercialization and member of the Pharmaceuticals Leadership Team at Bayer, in the release.

Loong noted that the safety and efficacy of sevabertinib as a first-line therapy for patients with locally advanced or metastatic NSCLC with HER2 mutations is being investigated in the ongoing, randomized phase 3 SOHO-02 trial (NCT06452277).

References

1. Loong HH, Li L, Wu L, et al. SOHO-01: Safety and efficacy of BAY 2927088 in patients with advanced HER2-mutant non-small cell lung cancer (NSCLC) who were pretreated but naïve to HER2-targeted therapy or had not received any treatment for advanced disease. J Clin Oncol. 2025;43(16):abstract 8504. doi:10.1200/JCO.2025.43.16_suppl.8504
2. U.S. FDA accepts new drug application under priority review for sevabertinib (BAY 2927088) in HER2-mutant non-small cell lung cancer. News release. Bayer. May 28, 2025. Accessed May 29, 2025. https://tinyurl.com/2t5vb5ky