Amgen and Mirati Therapeutics may lead the race to develop KRAS inhibitors to treat cancer, but their candidates only target G12C-mutant tumors. Enter Boehringer Ingelheim, which has just advanced its pan-KRAS drug into clinical testing with the hopes of showing it can address around 15% of all metastatic cancers.
Boehringer plans to test the drug, called BI 1701963, both on its own and in combination with Novartis’ MEK inhibitor Mekinist (trametinib), in a phase 1 clinical trial in solid tumors, the company said Tuesday. Preclinical data showed that the drug could block tumor growth for many other G12 mutations beyond G12C as well as the G13 KRAS abnormality, the German drugmaker explained at the International Conference on Molecular Targets and Cancer Therapeutics in Boston.
KRAS, which controls cell proliferation, has long been recognized as a major oncogene, responsible for many human cancer types. It's mutated in 90% of pancreatic cancers, over 40% of colorectal cancers and more than 30% of lung adenocarcinomas.
The two other KRAS contenders, Amgen’s AMG 510 and Mirati’s MRTX849, have produced some promising early clinical results in non-small cell lung cancer (NSCLC). But G12D and G12V mutation subtypes are believed to drive about half of all KRAS-related cancers, leaving room for drug developers that are working on broadening the approach beyond G12C mutations.
Boehringer’s BI 1701963 works by inhibiting the protein SOS1, an activator of KRAS. The KRAS gene normally cycles between “on” and “off” states. But when it’s persistently turned on, several downstream signaling pathways, including the well-characterized KRAS-RAF-MEK-ERK pathway, can be activated, preventing normal cell death and promoting tumor growth. So rather than directly targeting KRAS, which is notoriously hard to drug, blocking SOS1 offers the potential to inhibit KRAS regardless of mutation type.
“Our pan-KRAS inhibitor has been designed to target a broad range of oncogenic KRAS variants, including all major G12 and G13 oncoproteins. Effective targeting of the most prevalent KRAS mutant alleles that have so far proved elusive could enable us to develop much needed new therapy regimens for patients with gastrointestinal and lung cancers who have limited treatment options available,” said Norbert Kraut, Boehringer’s head of global cancer research, in a statement.
In preclinical testing, BI 1701963 blocked tumor growth for many G12 and G13 KRAS mutations, and combining it with MEK inhibition enhanced its anti-tumor activity, according to BI. That’s why the German company just shelled out $20 million upfront and committed more than $700 million in potential milestones to in-license Lupin’s MEK inhibitor LNP3794.
Other research teams are exploring different methods for improving KRAS inhibition. Scientists at the Francis Crick Institute and the Institute of Cancer Research in London recently tried adding Novartis’ mTOR inhibitor Afinitor (everolimus) and Astellas’ anti-IGF1R drug linsitinib to Araxes Pharma’s Johnson & Johnson-partnered KRAS G12C inhibitor ARS1620. In mice and human cells, the combo significantly shrunk lung tumors.
Amgen made waves at this year’s American Society of Clinical Oncology meeting in June, showing that half of 10 evaluable NSCLC patients had a partial response to AMG 510, and four others had stable disease. At the World Conference on Lung Cancer, the data were updated to disease control in all 23 evaluable NSCLC patients.
Mirati followed with news that among six NSCLC patients treated with its MRTX849, three had partial responses. But at the European Society of Medical Oncology meeting a few weeks ago, the drug disappointed in colorectal cancer, with only one of 12 patients taking the highest dose seeing a partial response, while 10 others had stable disease.
Several other companies are also looking into KRAS. Bridgebio is developing BBP-454, and Moderna and Merck & Co. are working on a mRNA KRAS vaccine. In a recent PNAS study, a group of Bayer scientists also examined blocking KRAS activation by inhibiting SOS1.
BI plans to enroll 140 patients with KRAS-mutated solid tumors in the phase 1 trial of its inhibitor. The company expects to complete the study in late 2022.