BI 1701963 / Boehringer Ingelheim - LARVOL DELTA

A Study to Test Different Doses of BI 1701963 Alone and Combined With Trametinib in Patients With Different Types of Advanced Cancer (Solid Tumours With KRAS Mutation) (clinicaltrials.gov) - P1 | N=71 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Apr 2025 ➔ Dec 2025 | Trial primary completion date: Apr 2025 ➔ Dec 2025

Monotherapy • Trial completion date • Trial primary completion date • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Trial completion date: Mar 2028 ➔ Dec 2027

Monotherapy • Trial completion date • Brain Cancer • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Adagrasib in Combination With BI 1701963 in Patients With Cancer (KRYSTAL 14) (clinicaltrials.gov) - P1 | N=7 | Terminated | Sponsor: Mirati Therapeutics Inc. | Completed ➔ Terminated; The decision was made to terminate this study to further enrollment, as of 08 March 2022. The decision was made primarily due to a change in development strategy.

Combination therapy • Metastases • Trial termination • Colon Cancer • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Trial completion date: Jun 2029 ➔ Mar 2028 | Trial primary completion date: Jan 2027 ➔ Apr 2026

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Trial completion date: Mar 2028 ➔ Jun 2029 | Trial primary completion date: Sep 2025 ➔ Jan 2027

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study to Test Different Doses of BI 1823911 Alone and Combined With Other Medicines in People With Different Types of Advanced Cancer With KRAS Mutation (clinicaltrials.gov) - P1 | N=30 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Dec 2024 ➔ Dec 2025 | Trial primary completion date: Nov 2024 ➔ Nov 2025

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Cholangiocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study to Test Different Doses of BI 1701963 Alone and Combined With Trametinib in Patients With Different Types of Advanced Cancer (Solid Tumours With KRAS Mutation) (clinicaltrials.gov) - P1 | N=71 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Oct 2024 ➔ Apr 2025 | Trial primary completion date: Oct 2024 ➔ Apr 2025

Trial completion date • Trial primary completion date • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Trial primary completion date: Dec 2026 ➔ Sep 2025

Combination therapy • Metastases • Monotherapy • Trial primary completion date • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1 | N=1200 | Recruiting | Sponsor: Amgen | Phase classification: P1/2 ➔ P1

Combination therapy • Metastases • Monotherapy • Phase classification • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1/2 | N=1126 | Recruiting | Sponsor: Amgen | Trial primary completion date: Sep 2026 ➔ Dec 2026

Combination therapy • Metastases • Monotherapy • Trial primary completion date • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study to Test Different Doses of BI 1701963 Alone and Combined With Trametinib in Patients With Different Types of Advanced Cancer (Solid Tumours With KRAS Mutation) (clinicaltrials.gov) - P1 | N=71 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial primary completion date: Mar 2024 ➔ Oct 2024

Combination therapy • Metastases • Monotherapy • Trial primary completion date • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

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

A Study to Test Different Doses of BI 1701963 Alone and Combined With Trametinib in Patients With Different Types of Advanced Cancer (Solid Tumours With KRAS Mutation) (clinicaltrials.gov) - P1 | N=71 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Mar 2024 ➔ Oct 2024

Combination therapy • Metastases • Monotherapy • Trial completion date • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1/2 | N=1143 | Recruiting | Sponsor: Amgen | Phase classification: P1b/2 ➔ P1/2

Phase classification • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1/2 | N=1143 | Recruiting | Sponsor: Amgen | Trial primary completion date: Jun 2026 ➔ Sep 2026

Trial primary completion date • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

A Study to Test Different Doses of BI 1823911 Alone and Combined With Other Medicines in People With Different Types of Advanced Cancer With KRAS Mutation (clinicaltrials.gov) - P1 | N=30 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Phase classification: P1a/1b ➔ P1

Combination therapy • Metastases • Monotherapy • Phase classification • Cholangiocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1b/2 | N=1143 | Recruiting | Sponsor: Amgen | Trial completion date: Jul 2027 ➔ Oct 2027

Combination therapy • Metastases • Monotherapy • Trial completion date • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1b/2 | N=1143 | Recruiting | Sponsor: Amgen | Trial primary completion date: Jan 2025 ➔ May 2026

Trial primary completion date • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

A Study to Test Different Doses of BI 1701963 Alone and Combined With Trametinib in Patients With Different Types of Advanced Cancer (Solid Tumours With KRAS Mutation) (clinicaltrials.gov) - P1 | N=71 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Trial completion date: Sep 2023 ➔ Mar 2024 | Trial primary completion date: Sep 2023 ➔ Mar 2024

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - P1b/2 | N=1143 | Recruiting | Sponsor: Amgen | Trial completion date: Jan 2029 ➔ Jul 2027 | Trial primary completion date: Jul 2026 ➔ Jan 2025

Combination therapy • Metastases • Monotherapy • Trial completion date • Trial primary completion date • Brain Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • KRAS

A Study to Test Different Doses of BI 1823911 Alone and Combined With Other Medicines in People With Different Types of Advanced Cancer With KRAS Mutation (clinicaltrials.gov) - P1a/1b | N=29 | Active, not recruiting | Sponsor: Boehringer Ingelheim | Recruiting ➔ Active, not recruiting

Enrollment closed • Cholangiocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Study to Test Different Doses of BI 1823911 Alone and Combined With Other Medicines in People With Different Types of Advanced Cancer With KRAS Mutation (clinicaltrials.gov) - P1a/1b | N=29 | Recruiting | Sponsor: Boehringer Ingelheim | N=72 ➔ 29 | Trial completion date: Jul 2024 ➔ Dec 2024

Enrollment change • Trial completion date • Cholangiocarcinoma • Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A novel ex vivo platform, 3D-EXpress, to rapidly assess the efficacy of KRAS targeting drugs alone and in combination with nivolumab using a biorepository of fresh patient tumoroids with intact tumor microenvironment (AACR 2023) - "3D tumoroids were treated with vehicle only, a SOS1::KRAS inhibitor, BI 1701963, apotent, selective, and covalent KRASG12C inhibitor, MRTX849, and a KRAS G12C inhibitor, sotorasib,alone and in combination with nivolumab for 72h. Our data demonstrate that the 3D-Express platform, using cryopreserved 3D tumoroidswith intact TME, is an effective tool to assess the efficacy of KRAS and immune checkpoint inhibitorstargeting drugs to identify rational combination therapies and to develop clinically relevant biomarkersfor individualized patients in the future."

Combination therapy • IO biomarker • Preclinical • Tumor microenvironment • Oncology • CCL4 • CSF2 • GZMA • GZMB • IFNG • IL10 • IL13 • IL2 • IL4 • IL5 • IL6 • KRAS • PD-1 • TNFA

SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer (AACR 2023) - "The recent development of novel SOS1 inhibitors, including BI-3406 and BI-1701963, that block interaction between SOS1 and RAS, presents a potential therapy for SOS1-driven cancers. Tumor-suppressive effects of SOS1i in these models were comparable to or stronger than the effects of SHP2i or MEKi. Thus, our results suggest that SOS1 inhibition could be an effective therapeutic approach in RAS wild-type cancer patients with SOS1 mutations."

Acute Myelogenous Leukemia • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Targeting of SOS1: from SOS1 Activators to Proteolysis Targeting Chimeras. (PubMed, Curr Pharm Des) - "The most frequent mutated oncogene KRAS in lung cancer is targeted by KRAS G12C-directed drugs, such as Sotorasib and Adagrasib...High throughput screenings resulted in the detection of SOS1 inhibitors Bay-293 and BI-3406 comprising amino quinazoline scaffolds optimized for binding to the pocket by various substituents. The first inhibitor, BI-1701963, is in clinical studies alone or in combination with a KRAS inhibitor, a MAPK inhibitor or chemotherapeutics...This PROTAC exhibited the highest SOS1-directed activity due to target destruction, recycling and removal of SOS1 as a scaffolding protein. Although other first PROTACs have entered clinical trials, each conjugate must be meticulously adapted as an efficient clinical drug."

Journal • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • Targeted Protein Degradation • KRAS