Non-small cell lung cancer (NSCLC) dominates the lung cancer landscape, representing over 85% of cases, with activating HER2 mutations detected in 2% to 4% of advanced NSCLC patients. Currently, ENHERTU (trastuzumab deruxtecan) is the approved therapy for previously treated NSCLC with HER2 mutations, underscoring the importance of targeting HER2 alterations in this context.

Significant strides have been made in understanding HER2-driven NSCLC and evaluating therapeutic strategies. Platinum-based chemotherapy with or without immunotherapy remains the standard first-line treatment for advanced or metastatic HER2-mutant NSCLC. With HER2 mutations, particularly exon 20 insertions, accounting for a notable proportion of NSCLC cases, the market for HER2-targeted therapies continues to expand. According to the DelveInsight analysis, the total market size of HER2 NSCLC was ~USD 120 million in the US in 2023.

BAY 2927088, an oral tyrosine kinase inhibitor, has shown promising results in preclinical models by effectively inhibiting mutant HER2 and EGFR. Encouraging objective responses were witnessed in NSCLC patients harboring HER2-activating mutations during the Phase I/II SOHO-01 trial. Notably, the recent FDA designation of Breakthrough Therapy status for BAY 2927088 in previously treated advanced NSCLC with activating HER2 mutations highlights its potential as a game-changing therapeutic option. The results presented at ASCO 2024 were the following:

Efficacy outcomes 

As of February 19, 2024, 34 patients were treated with BAY 2927088, with a median follow-up of 8 months. The median duration of treatment with BAY 2927088 was 7.1 months

• Objective response rate was 70%, and disease control rate was 82% 

• Of the 17 patients remaining on treatment, 3 had stable disease and 14 had a partial response

• Responses were rapid and durable (median duration of response not reached). 

• Median progression-free survival was 8.1 months 

• In a subset of 20 patients with successful paired blood NGS and detectable HER2 ctDNA at baseline, 95% had a decrease in ctDNA and one patient with progressive disease had an increase in ctDNA; 75% had no detectable ctDNA after 6 weeks of treatment 

Safety result: 

• The most common adverse events were diarrhea and rash (Grade 1-2).

• Drug-related Grade 3 TEAEs were reported in 12 patients, and there were no drug-related Grade 4 TEAES

• Ten patients had a dose reduction, eight had dose interruptions, and three discontinued study treatment due to a drug-related adverse event

• Grade 5 (death) TEAEs occurred in two patients and were deemed to be drug-related in the patient with dyspnea

KOL insights

“Early clinical evidence suggests that BAY 2927088 has the potential to benefit patients with NSCLC harboring a HER2 mutation that has progressed on a prior systemic therapy and currently has no other approved treatment available.” – Ph.D., Head of Research and Early Development for Oncology.

“BAY 2927088 led to rapid, substantial, and durable responses in patients with pretreated HER2-mutant NSCLC. The safety profile was consistent with previously reported data”– Professor, National Cancer Center.

Conclusion-

Biomarkers in non-small cell lung cancer (NSCLC), ranging from mutations to protein overexpression, offer a diverse landscape for targeted therapies. Currently, ENHERTU (T-DXd) is an approved option for previously treated NSCLC with HER2 mutations. The development of HER2-specific TKIs, exemplified by BAY2927088, is actively progressing.

In a Phase I/II study, BAY2927088 demonstrated promising results in adult patients with advanced NSCLC harboring HER2 or EGFR mutations. Recent data presentation highlighted its safety, anti-tumor activity, and longitudinal circulating tumor DNA (ctDNA) dynamics. Notably, BAY2927088 elicited rapid, substantial, and durable responses in pretreated HER2-mutant NSCLC patients, with a safety profile consistent with prior findings. These compelling findings underscore the rationale for advancing the clinical development of BAY2927088 in HER2-mutant NSCLC patients.