LY3537982 for Cancer

Recruiting at 67 trial locations

Overseen By There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Eli Lilly and Company

Must not be taking: Steroids, KRAS inhibitors

Disqualifiers: Infection, Cardiac condition, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

540 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called LY3537982 in cancer patients with the KRAS G12C mutation. It targets this mutation to stop cancer cells from growing. The study includes patients who haven't responded to other treatments or cannot tolerate them. LY3537982 is a new drug targeting the KRAS G12C mutation, similar to previously approved drugs like sotorasib and adagrasib.

Will I have to stop taking my current medications?

The trial requires that participants have discontinued all previous cancer treatments and resolved any significant ongoing side effects before joining. However, the protocol does not specify if you need to stop other non-cancer medications, so it's best to discuss this with the trial team.

What evidence supports the effectiveness of the drug LY3537982 for cancer?

KRAS G12C inhibitors, like LY3537982, have shown promising results in early clinical trials for certain cancers, such as lung cancer, by targeting a specific mutation in the KRAS gene. Similar drugs, like sotorasib, have been approved for use and have demonstrated improved survival and quality of life in patients with KRAS G12C mutations. ^{1 2 3 4 5}

Is LY3537982 safe for humans?

The safety profile of divarasib (another name for LY3537982) combined with cetuximab was consistent with the safety of each drug alone, with some patients needing dose reductions but no treatment withdrawals, suggesting it is generally manageable. ^{1 2 3 6 7}

What makes the drug LY3537982 unique for cancer treatment?

LY3537982 is a KRAS G12C inhibitor, which targets a specific mutation in the KRAS gene that was previously considered untreatable. This drug works by covalently binding to the G12C mutation, blocking its activity and preventing cancer cell growth, offering a targeted approach for cancers driven by this mutation. ^{1 3 7 8 9}

Research Team

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Eligibility Criteria

This trial is for cancer patients with a KRAS G12C mutation who've tried or can't tolerate standard treatments. It's open to those with certain cancers, like pancreatic and lung, if they have measurable disease, good organ function, an ECOG status of 0 or 1, and agree to use contraception. Some untreated NSCLC patients may join under specific conditions.

Inclusion Criteria

I have advanced NSCLC, haven't had treatment for it, and may start some treatments soon.

My cancer has a KRAS G12C mutation.

My organs are functioning well.

Exclusion Criteria

I have not received a live vaccine in the last 30 days.

I have an autoimmune disease treated with medication in the last 2 years.

I have a serious heart condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1a Dose Escalation

Participants receive escalating doses of LY3537982 to determine the recommended phase 2 dose

21 days

Phase 1b Dose Expansion

Participants receive LY3537982 to assess safety and tolerability

Estimated up to 2 years

Phase 1b Dose Optimization

Participants receive LY3537982 to determine the optimal dose in combination with pembrolizumab

Estimated up to 2 years

Phase 2

Participants receive LY3537982 to evaluate preliminary efficacy

Estimated up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• LY3537982

Trial Overview The study tests LY3537982's safety and effectiveness in treating various cancers with the KRAS G12C mutation. Patients will also receive other drugs like Pemetrexed and Pembrolizumab depending on their condition. The trial aims to include participants for up to four years.

Participant Groups

Group I: LY3537982 (Dose Optimization) Experimental Treatment 3 Interventions

LY3537982 administered orally either alone or with another investigational agent

Group II: LY3537982 (Dose Expansion) Experimental Treatment 6 Interventions

LY3537982 administered orally either alone or with another investigational agent.

Group III: LY3537982 (Dose Escalation) Experimental Treatment 1 Intervention

LY3537982 administered orally.

Who Is Running the Clinical Trial?

Eli Lilly and Company

Lead Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Loxo Oncology, Inc.

Industry Sponsor

Trials

72

Recruited

11,600+

Jacob Van Naarden

Loxo Oncology, Inc.

Chief Executive Officer since 2019

A.B. in Molecular Biology from Princeton University

Dr. Jennifer Low

Loxo Oncology, Inc.

Chief Medical Officer since 2014

MD and PhD from Georgetown University; Undergraduate degree from California Institute of Technology

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Findings from Research

KRAS is a challenging oncogene to target, but recent subtype-specific inhibitors like adagrasib and sotorasib have shown promising early efficacy in clinical trials for patients with KRASG12C mutations.

Despite their potential, resistance to G12C inhibitors is a concern, and the review discusses strategies for combination therapies to enhance effectiveness, targeting pathways such as SHP2 and PD1/PDL1 to overcome this resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of Resistance to KRASG12C Inhibitors. Dunnett-Kane, V., Nicola, P., Blackhall, F., et al.[2021]

In a study of 604 patients with surgically resected lung adenocarcinoma, those with KRASG12C mutations experienced worse disease-free survival (DFS) compared to patients with other KRAS mutations, indicating a more aggressive disease course.

KRASG12C tumors exhibited higher rates of lymphovascular invasion and a greater tumor mutation burden, suggesting that these tumors have distinct and more aggressive genomic features, highlighting the need for targeted therapies like KRASG12C inhibitors to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KRAS G12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma. Jones, GD., Caso, R., Tan, KS., et al.[2022]

KRAS mutations, particularly KRASG12C, are common in lung cancer, and new inhibitors like AMG510 and MRTX849 effectively target this mutation, showing strong clinical efficacy in patients with KRASG12C-driven cancers.

Despite their effectiveness, KRASG12C inhibitors face challenges with drug resistance, suggesting that combining these inhibitors with other therapies could enhance treatment outcomes by addressing compensatory signaling pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished. Ning, W., Yang, Z., Kocher, GJ., et al.[2022]

The KRASp.G12C mutation, found in 12% of advanced non-small cell lung cancer (NSCLC) cases, is a promising biomarker for selecting patients who may benefit from targeted therapies like sotorasib, which has shown significant efficacy in improving progression-free survival and quality of life compared to traditional treatments.

Despite the potential of KRAS inhibitors, the presence of co-mutations and resistance mechanisms in KRAS mutant NSCLC complicates treatment, highlighting the need for combination therapies and the identification of predictive biomarkers to personalize treatment strategies for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting KRASp.G12C Mutation in Advanced Non-Small Cell Lung Cancer: a New Era Has Begun. Bungaro, M., Novello, S., Passiglia, F.[2023]

KRAS mutations, particularly the G12C variant, are common in lung adenocarcinoma, and new targeted inhibitors have shown promising response rates of 32% to 46% in clinical trials, leading to FDA approvals for treatment.

Despite these advancements, rapid tumor resistance to G12C inhibitors poses challenges, highlighting the need for combination therapies and further research to understand and overcome resistance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg. Rosen, JC., Sacher, A., Tsao, MS.[2023]

The combination of divarasib and cetuximab in treating KRAS G12C-positive colorectal cancer showed a manageable safety profile, with only 13.8% of patients experiencing treatment-related adverse events that required dose reductions, and no treatment withdrawals.

This combination therapy demonstrated promising antitumor activity, achieving a 62.5% objective response rate in previously untreated patients, with a median progression-free survival of 8.1 months, indicating its potential effectiveness in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Desai, J., Alonso, G., Kim, SH., et al.[2023]

The study identified multiple mechanisms that cancer cells use to resist treatment with direct inhibitors targeting the KRAS G12C mutation, which is important for developing more effective therapies.

Understanding these resistance mechanisms is crucial for improving treatment strategies and overcoming challenges in targeting KRAS G12C in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiple Mechanisms Underlie the Acquired Resistance to KRAS G12C Inhibition. [2022]

Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that showed promising efficacy in patients with advanced solid tumors, achieving a confirmed response rate of 53.4% in non-small-cell lung cancer (NSCLC) and 29.1% in colorectal cancer, with median progression-free survival of 13.1 months and 5.6 months, respectively.

The treatment was generally well-tolerated, with no dose-limiting toxic effects or treatment-related deaths reported, although 93% of patients experienced treatment-related adverse events, mostly low-grade.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. Sacher, A., LoRusso, P., Patel, MR., et al.[2023]

KRASG12C inhibitors are effective in targeting KRASG12C-mutant cancer cells, but these cells can rapidly develop resistance or enter a quiescent state after treatment.

This suggests that while KRASG12C inhibitors may initially work, their long-term efficacy could be limited due to the adaptive responses of the cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Newly Synthesized KRASG12C Mediates Escape from KRASG12C Inhibition. [2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Mechanisms of Resistance to KRASG12C Inhibitors. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

KRAS G12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Targeting KRASp.G12C Mutation in Advanced Non-Small Cell Lung Cancer: a New Era Has Begun. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Multiple Mechanisms Underlie the Acquired Resistance to KRAS G12C Inhibition. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Newly Synthesized KRASG12C Mediates Escape from KRASG12C Inhibition. [2020]