BI 3706674 / Boehringer Ingelheim - LARVOL DELTA

Identifying novel mechanisms of resistance to KRAS-inhibitors in NSCLC (AACR 2025) - "Recent breakthroughs, however, have led to the development of covalent inhibitors such as Sotorasib (AMG510) and Adagrasib (MRTX849), which specifically target the KRAS G12C mutation and have received FDA approval following successful clinical trials...Proteomic profiling using RPPA analysis has identified significant changes in protein expression, with the YAP/TEAD1 and the PDK1 pathways consistently upregulated in cells resistant to MRTX849 (G12Ci), MRTX1133 (G12Di) and the pan-RAS inhibitor BI3706674...We are also trying to understand the molecular crosstalk between the PDK1 and YAP1/TEAD signaling pathways to functionally induce or maintain resistance to MRTX1133. Achieving the objectives of this research project will be instrumental in addressing the critical challenge of overcoming resistance to KRAS inhibitors and enhancing their effectiveness in clinical applications."

Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • PDK1 • TEAD1 • YAP1

KRASmulti inhibitor BI 3706674 shows efficacy in KRAS-driven preclinical models of cancer that supports clinical testing in patients with tumors harboring KRASG12V mutations and KRAS wild-type amplifications. (EORTC-NCI-AACR 2024) - P1 | "Here, we show that BI 3706674, a KRASmulti inhibitor that binds non-covalently to the KRAS wt allele and multiple mutant alleles but spares HRAS and NRAS, has strong anti-tumor activity in KRAS wt-amplified and KRASG12V mutant preclinical models of cancer. A Phase I clinical trial is currently ongoing in patients with advanced solid cancers harboring KRASG12V mutations and KRAS wt amplifications to evaluate safety, tolerability, pharmacokinetics and efficacy of BI 3706674 monotherapy (ClinicalTrials.gov identifier NCT06056024). The deeper responses observed upon combination of BI 3706674 with cetuximab across multiple KRASG12V mutant xenograft models provide a strong rationale for the clinical investigation of this combination therapy."

Preclinical • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Gastroesophageal Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • EGFR • HRAS • KRAS • NRAS

KRASmulti inhibition and checkpoint targeting therapy show strong combination potential in KRAS wild-type and KRASG12V-driven syngeneic mouse models of pancreatic cancer (EORTC-NCI-AACR 2024) - P1 | "Here we provide preclinical data showcasing the potential of combining KRASmulti inhibition with clinically approved immunotherapy. BI 3706674, a KRASmulti inhibitor that binds non-covalently to the KRAS wt allele and multiple mutant alleles but spares HRAS and NRAS, is currently in clinical development for patients with KRAS wild-type amplifications and KRASG12V mutations (ClinicalTrials.gov identifier NCT06056024). Using novel engineered syngeneic mouse tumor models, we have explored the combination potential of BI 3706674 with checkpoint blockade and demonstrate strong combination benefit, leading to long-term complete responses."

IO biomarker • Preclinical • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • HRAS • KRAS • NRAS • TP53

Efficacy of KRAS multi-selective inhibitor BI 3706674 in tumors driven by KRAS mutations and KRAS wild-type allele amplification (EORTC-NCI-AACR 2024) - "Abstract not received."

Clinical • Oncology • KRAS

Identifying Resistant Mechanisms To Direct KRAS-Inhibitors (LUNG-SPORE 2024) - "Recent breakthroughs, however, have resulted in the development of covalent inhibitors capable of selectively targeting the KRAS G12C mutation, like Sotorasib (AMG510) and Adagrasib (MRTX849) which are approved by the FDA due to their encouraging effects in clinical trials. The identification of selective inhibitors of other oncogenic KRAS alleles, such as the noncovalent KRAS-G12D inhibitor, MRTX1133, and a pan-KRAS-inhibitor drug, BI3706674 is also a promising next step in the treatment of KRAS-dependent malignancies...We are currently performing in vitro and In vivo studies to understand the therapeutic efficacy of a TEAD inhibitor (VT107) in combination with KRASi (MRTX849 or MRTX1133) to either reverse or prevent resistance to the direct KRAS inhibitors. Successful completion of this research will help address the urgent need to understand ways to overcome resistance to KRAS inhibitors and increase their clinical efficacy."

Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS • TEAD1 • YAP1

Therapeutic potential of SOS1 and KRAS inhibitors in malignant peripheral nerve sheath tumors (AACR 2024) - "The MEK inihibitor, selumetinib, has received approval for the treatment of PNFs, however some patients who were treated with selumetinib continued to develop MPNSTs suggesting that MEK inhibitors may have limitations in addressing MPNSTs. In conclusion, this study highlights the combined effects of SOS1 (BI 1701963) and KRAS (BI 3706674) inhibition in MPNSTs. The combination therapy of these novel therapeutics may hold promise as a potential treatment strategy for patients with MPNSTs."

Brain Cancer • Neurofibrosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • KRAS • NF1

KRASmulti inhibitor BI 3706674, an orally bioavailable, direct inhibitor of diverse oncogenic KRAS variants drives tumor regression in KRASG12V-driven preclinical models (AACR 2024) - "Clinical combination trials involving KRASG12C inhibitors such as adagrasib and sotorasib and anti-EGFR modalities are further supporting these findings. The deeper response observed upon combination of BI 3706674 with Cetuximab across multiple xenograft models provides a strong rationale for the clinical investigation of this combination therapy. Moreover, based on our in vitro mechanistic studies and ex vivo organoid platform we have identified prospective mechanisms of resistance and opportunity for novel drug combinations with BI 3706674 that can potentially translate into clinical trials."

Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • DUSP6 • KRAS

KRASmulti inhibitor BI 3706674 shows efficacy in KRAS-driven preclinical models of cancer that supports clinical testing in patients with tumors harbouring KRASG12V mutations and KRAS wild-type amplifications (AACR 2024) - "Results of the ongoing pre-clinical analysis will be shared. A Phase I clinical trial is in preparation in patients with advanced solid cancers harboring KRASG12V mutations and KRAS wt amplifications to evaluate safety, tolerability, pharmacokinetic and pharmacodynamic properties, and efficacy of BI 3706674."

Preclinical • Colorectal Cancer • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • DUSP6 • HRAS • KRAS • NRAS

A Study to Test How Well Different Doses of BI 3706674 Are Tolerated by People With Advanced Cancer in the Stomach and Oesophagus (clinicaltrials.gov) - P1 | N=146 | Recruiting | Sponsor: Boehringer Ingelheim | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Monotherapy • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS

A Study to Test How Well Different Doses of BI 3706674 Are Tolerated by People With Advanced Cancer in the Stomach and Oesophagus (clinicaltrials.gov) - P1 | N=146 | Not yet recruiting | Sponsor: Boehringer Ingelheim

Metastases • Monotherapy • New P1 trial • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • KRAS