pan-KRAS SOS1 inhibitor (BI 1701963)

pan-KRAS SOS1 inhibitor (BI 1701963)

SOS1::KRAS inhibitor (BI 1701963)

BI 1701963: a pan-KRAS SOS1 inhibitor

BI 1701963* is a first-in-class, small-molecule pan-KRAS inhibitor that prevents the association of KRAS with a key regulator, Son of sevenless homolog 1 (SOS1).1

Clinical trials: BI 1701963 is currently being investigated in Phase I trials involving patients with KRAS G12C mutation-positive solid tumors, KRAS-mutant advanced colorectal cancer, and KRAS-mutant advanced solid tumors that failed previous chemotherapy.2-6

Role of KRAS and SOS1

KRAS is one of the most frequently mutated oncogenes with high prevalence of alterations in pancreatic, colorectal and non-small cell lung tumors.1 KRAS functions as a molecular switch,  existing in two states: the guanosine diphosphate-(GDP-)bound ‘off’ state, or the guanosine triphosphate-(GTP-)bound ‘on’ state. Active KRAS–GTP activates downstream effector pathways, including the RAF/MEK/ERK signaling pathway that regulates gene expression and prevents apoptosis.7

SOS1 is one of the guanine nucleotide exchange factors that regulates the KRAS GDP–GTP cycle and promotes nucleotide exchange and formation of ‘active’ KRAS–GTP.7

About BI 1701963

Mechanism of action

BI 1701963, a pan-KRAS SOS1 inhibitor, is a first-in-class, small-molecule pan-KRAS inhibitor that prevents the association of KRAS with a key regulator, SOS1.1 BI 1701963 has shown broad activity against G12, G13 mutant KRAS alleles, including the most prevalent G12C, G12D and G12V oncogenic variants.1 pan-KRAS SOS1 inhibitors bind to SOS1 and inhibit the interaction between KRAS and SOS1 proteins, reducing the formation of GTP-loaded KRAS.7 SOS1 inhibitors also antagonize the negative feedback relief induced by RAF/MEK/ERK pathway inhibitors.1 

pan-KRAS SOS1 inhibitor mechanism of action1

pan-KRAS SOS1 Inhibitor mechanism of action
ERK, extracellular signal-regulated kinases; GDP, guanosine diphosphate; GTP, guanosine triphosphate; KRAS, Kirsten rat sarcoma; MEK, mitogen-activated protein kinase kinase; SOS1, Son of sevenless homolog 1.

Watch the pan-KRAS SOS1 inhibitor mechanism of action animation

Watch the pan-KRAS SOS1 inhibitor mechanism of action animation

Combination Therapy

While SOS1 inhibition yields cytostasis in cancer cells addicted to KRAS signaling, the synergistic combination of SOS1 inhibitor with a MAPK pathway inhibitor results in a more profound blockade of KRAS signaling. This provides a strong rationale for development in combination with a MAPK pathway inhibitor. BI 1701963 in combination with MEK inhibition has shown strong in vivo efficacy in a broad range of tumor mouse models of KRAS-driven cancers and time- and dose-dependent modulation of transcriptional target genes in the MAPK pathway.1

Monotherapy with a KRAS G12C inhibitor may not be sufficient to achieve durable responses, whereas combination therapy may lead to enhanced anti-tumor efficacy and may address resistance mechanisms as well. Preclinical data identified strong synergistic anti-proliferative activity with BI 1701963, a pan-KRAS SOS1 inhibitor, and this combination will be tested in the clinic.8

SOS1 inhibition also sensitizes KRAS mutant cancer cells to the effect of irinotecan; BI 1701963 in combination with irinotecan also showed in vivo efficacy in tumor mouse models.1

Clinical development

BI 1701963 is currently being investigated as a monotherapy and in combination with the MEK inhibitor trametinib in clinical trials in patients with KRAS mutation-positive solid tumors who progressed despite appropriate prior standard therapies,2 in combination with irinotecan in patients with KRAS-mutated advanced CRC,3 in combination with BI 3011441 in advanced or metastatic ­KRAS-mutant solid tumors,4 and in combination with BI 1701963 in advanced or metastatic solid tumors that express the KRAS G12C mutation.5

Boehringer Ingelheim has also entered into a clinical trial collaboration with Mirati Therapeutics to study BI 1701963 in combination with adagrasib, a KRAS G12C selective inhibitor, in patients with solid tumors that harbor the KRAS G12C mutation.6,9

More information about Boehringer Ingelheim oncology clinical trials can be found on the MyStudyWindow website. Relevant trials for our pan-KRAS SOS1 inhibitor include: BI 1432-0001 and BI 1432-0008.

pan-KRAS SOS1 inhibitor (BI 1701963) clinical trials

KRAS, Kirsten rat sarcoma; MAPK, mitogen-activated protein kinase kinase.
Trial number Phase Treatment Patient population Status

NCT041114582 (1432.1)

I

BI 1701963 alone and in combination with a MAPK pathway inhibitor (trametinib)

KRAS-mutant solid tumors that have progressed despite appropriate prior standard therapies

Recruiting

NCT046271423 (1432.8)

I

BI 1701963 alone and in combination with irinotecan

Advanced colorectal cancer with a KRAS mutation

Recruiting

NCT04835714(1432.6)

I

BI 1701963 as monotherapy and in combination with BI 3011441

Advanced or metastatic solid tumors with KRAS mutation

Recruiting

NCT04973163(1472.1)

I

BI 1823911 as monotherapy and in combination with BI 1701963

Patients with advanced or metastatic solid tumors expressing KRAS G12C mutation

Recruiting

NCT04975256(Mirati sponsored)

I

BI 1701963 in combination with MRTX849 (adagrasib)

Advanced solid tumors with KRAS G12C mutation

Recruiting

Explore our latest pan-KRAS SOS1 inhibitor data

Our latest data on the pan-KRAS SOS1 inhibitor (BI 1701963) were presented at the American Associated for Cancer Research Congress 2021.

 

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References

1

Hofmann MH, et al. Cancer Discov 2021;11:142–57.

2

ClinicalTrials.gov. NCT04111458. https://clinicaltrials.gov/ct2/show/NCT04111458 (Accessed: September 2021).

3

ClinicalTrials.gov. NCT04627142. https://clinicaltrials.gov/ct2/show/NCT04627142 (Accessed: September 2021).

4

ClinicalTrials.gov. NCT04835714. https://clinicaltrials.gov/ct2/show/NCT04835714 (Accessed: September 2021).

5

ClinicalTrials.gov. NCT04973163. https://clinicaltrials.gov/ct2/show/NCT04973163 (Accessed: September 2021.

6

ClinicalTrials.gov. NCT04975256. https://clinicaltrials.gov/ct2/show/NCT04975256 (Accessed: September 2021).

7

Evelyn CR, et al. Chem Biol 2014;21:1618‒28.

8

Boehringer Ingelheim, data on file.

9

Boehringer Ingelheim. Press release. https://www.boehringer-ingelheim.com/press-release/clinicalcollaborationwithmirati (Accessed: September 2021).

10

Lin C, et al. Poster presented at the 80th Annual Meeting of the Japanese Cancer Association 2021.

*This is an investigational compound and has not been approved. Its safety and efficacy have not been established.

 

© 2021 Boehringer Ingelheim International GmbH. All rights reserved.

 

Last updated: September 2021