P1, N=30, Recruiting, Bayer | Not yet recruiting --> Recruiting

P1, N=15, Recruiting, Bayer | Not yet recruiting --> Recruiting

P1, N=21, Recruiting, Bayer

P1, N=15, Recruiting, Bayer | Not yet recruiting --> Recruiting

P1, N=15, Not yet recruiting, Bayer

P1, N=56, Not yet recruiting, Boehringer Ingelheim

P1, N=8, Completed, Bayer | Active, not recruiting --> Completed

P1, N=30, Not yet recruiting, Bayer

P1, N=287, Recruiting, Iambic Therapeutics, Inc | Not yet recruiting --> Recruiting

P1, N=15, Not yet recruiting, Bayer

P1/2, N=240, Not yet recruiting, Boehringer Ingelheim

P1/2, N=460, Recruiting, Bayer | Trial completion date: Jul 2028 --> Nov 2027 | Trial primary completion date: Jul 2028 --> Nov 2027

P1, N=8, Active, not recruiting, Bayer | Recruiting --> Active, not recruiting

P1, N=287, Not yet recruiting, Iambic Therapeutics, Inc

P1, N=8, Recruiting, Bayer | Not yet recruiting --> Recruiting

P1/2, N=460, Recruiting, Bayer | Phase classification: P1 --> P1/2 | N=340 --> 460

P3, N=270, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P1, N=8, Not yet recruiting, Bayer

P1, N=16, Completed, Boehringer Ingelheim | Active, not recruiting --> Completed

P1, N=16, Completed, Boehringer Ingelheim | Active, not recruiting --> Completed

P3, N=270, Not yet recruiting, Boehringer Ingelheim

No abstract available

P1, N=16, Active, not recruiting, Boehringer Ingelheim | Recruiting --> Active, not recruiting

P1, N=16, Recruiting, Boehringer Ingelheim | Not yet recruiting --> Recruiting

P1, N=371, Recruiting, Boehringer Ingelheim | Trial completion date: Dec 2025 --> Dec 2027

P1, N=15, Completed, Boehringer Ingelheim | Active, not recruiting --> Completed

P1, N=16, Not yet recruiting, Boehringer Ingelheim

No abstract available

P1, N=340, Recruiting, Bayer | Trial completion date: Dec 2025 --> Jul 2028 | Trial primary completion date: Dec 2025 --> Jul 2028

Recruitment into phase Ib is ongoing with the QD regimen. Updated phase 1a data, and emerging Phase1b data, will be presented.

In pts with HER2 ex20ins mutant disease, BAY 2927088 showed encouraging preliminary anti-tumour activity. These results warrant further investigation of BAY 2927088 in pts with NSCLC.

These preliminary data indicate that BI 1810631 is well tolerated and shows strong efficacy signals across all dose levels in patients with pre-treated HER2 aberration-positive solid tumors. Recruitment into Phase Ib is ongoing with the QD regimen. Updated Phase Ia data, and emerging Phase Ib data, will be presented.

P1, N=371, Recruiting, Boehringer Ingelheim | N=266 --> 371

These preliminary data indicate that BI 1810631 is well tolerated and shows encouraging anti-tumor activity in pts with HER2 aberration-positive solid tumors. Recruitment into Phase Ia is ongoing. Updated data, including durability endpoints, will be presented.

In addition, trastuzumab and EGFR-TKIs have limited effectiveness for NSCLC patients with HER2 exon 20ins mutation. TAK-788 (mobocertinib) and JNJ6372 (amivantamab-vmjw) are the FDA approvals for NSCLC driven by EGFR exon 20ins mutations. Only T-Dxd is used as a second-line treatment for NSCLC patients with HER2 mutation...In EGFR-related tumor cells and genetically engineered Ba/F3 cell lines, TY-4028 showed similar or better antitumor effects than TAK-788, and better antitumor effects than DZD9008...#Jun Li and Chengshan Niu contributed equally to this work. *They are the correspondent authors.

With the recent approval of fam-trastuzumab deruxtecan-nxki, the first targeted treatment option became available for HER2 mutant NSCLC patients. In addition, the compound was active in a subset of endogenously HER2 mutant cancer cell lines. The in vitro activity of BAY 2927088 was validated in vivo in a patient-derived xenograft model carrying the HER2 exon20 insertion mutation A775insYVMA.The strong preclinical activity of BAY 2927088 in HER2 mutant NSCLC supports clinical evaluation in this indication and might offer a novel targeted therapy option for NSCLC patients that carry HER2 mutations.

These preliminary data indicate that BI 1810631 is well tolerated and shows encouraging anti-tumor activity in pts with HER2 aberration-positive solid tumors. Recruitment into Phase Ia is ongoing.

It was superior to Mobocertinib (IC50 = 27.1 nM for YVMA and IC50 = 3.3 nM for GSP) and comparable with Poziotinib (IC50 = 3.4 nM for YVMA and IC50 = 0.4 nM for GSP). JIN-A04 is highly potent against HER2 exon 20 insertion mutations including YVMA and GSP, while largely sparing HER2 WT activity. Also, JIN-A04 demonstrated effective HER2 pathway inhibition. Based on these robust activities for HER2 exon 20 insertion, JIN-A04 is expected to provide a potent therapeutic opportunity for NSCLC patients with HER2 exon20 insertion mutations.

Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, active CNS metastasis, or leptomeningeal disease. The trial is currently enrolling patients in dose-escalation and backfill parts (NCT05099172).

Agents such as amivantamab and mobocertinib have been approved for treatment of lung cancer patients with exon 20 insertions, but agents with an improved selectivity profile versus wild-type EGFR are still needed. As a parallel approach, we are developing a deep-scanning mutagenesis assay of the EGFR kinase domain to identify mutations that could cause resistance. Understanding these resistance mechanisms will help to identify second-line treatments for exon 20 insertion patients who develop resistance to EGFR inhibition.