LY3537982 for Cancer

Recruiting at 75 trial locations

Overseen By Physicians interested in becoming principal investigators please contact

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new drug, LY3537982 (a KRAS G12C inhibitor), to determine its safety and effectiveness for individuals with cancers featuring a specific genetic change called KRAS G12C. The trial consists of three phases, testing the drug alone or with other treatments. It seeks participants whose cancer has advanced and who have not succeeded with standard treatments. Participants must be able to swallow pills and have cancers that cannot be treated with surgery or radiation. Those who meet these criteria may consider learning more about joining the trial. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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.

Is there any evidence suggesting that LY3537982 is likely to be safe for humans?

Research has shown that LY3537982 is generally safe. In earlier studies, patients tolerated the drug well, with no reports of serious liver problems. This indicates that patients did not experience major liver issues while taking LY3537982. The treatment is being tested on individuals with a specific genetic change in their cancer and has been well-tolerated at various doses. This suggests that LY3537982 is generally safe for participants in these trials. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about LY3537982 for cancer because it offers a fresh approach to treatment. Unlike traditional chemotherapy, LY3537982 is taken orally and is designed to work either on its own or alongside another investigational drug. This flexibility means it could potentially enhance its effectiveness while possibly reducing side effects. Additionally, its unique mechanism of action may target cancer cells differently, providing new hope for patients who haven't responded to existing therapies.

What evidence suggests that LY3537982 might be an effective treatment for cancer?

Research has shown that LY3537982 may effectively treat cancers with the KRAS G12C mutation. This drug has shown effectiveness in patients with non-small cell lung cancer and colorectal cancer. In colorectal cancer, combining LY3537982 with another drug resulted in a 34% overall response rate (ORR) and an 85% disease control rate (DCR). LY3537982 is generally well-tolerated, with no serious liver problems reported. Early evidence suggests it could be a strong option for people with this specific genetic mutation. ^{3 6 7 8 9}

Who Is on the Research Team?

Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 8 AM - 8 PM Eastern time (UTC/GMT - 5 hours, EST)

Principal Investigator

Eli Lilly and Company

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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 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]

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 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]

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]

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]

Citations

1. aacrjournals.org aacrjournals.org/cancerres/article/83/8_Supplement/CT028/725327/Abstract-CT028-A-first-in-human-phase-1-study-of

Abstract CT028: A first-in-human phase 1 study of LY3537982 ... Conclusions: LY3537982 demonstrated a favorable safety profile, including the absence of high-grade liver toxicity, and tolerance in pts ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12037499/

Current status of KRAS G12C inhibitors in NSCLC and the ... In KRAS G12C-mutated colorectal cancer, combining MRTX849 with the anti-EGFR antibody cetuximab achieved an ORR of 34%, a DCR of 85%, and a ...

3. onclive.com onclive.com/view/novel-kras-g12c-inhibitor-shows-early-signs-of-efficacy-across-solid-tumors-pretreated-nsclc

Novel KRAS G12C Inhibitor Shows Early Signs of Efficacy ... LY3537982, an investigative KRAS G12C inhibitor, demonstrated clinical efficacy across patients with non–small cell lung cancer (NSCLC), colorectal cancer (CRC ...

4. jto.org jto.org/article/S1556-0864(24)00762-7/fulltext

Efficacy and Safety of KRAS G12C Inhibitor IBI351 ... IBI351 was well-tolerated in patients with advanced solid tumors harboring KRAS G12C mutation, demonstrating promising efficacy and durable ...

5. wjso.biomedcentral.com wjso.biomedcentral.com/articles/10.1186/s12957-024-03449-8

Efficacy and toxicity of KRAS G12C inhibitors in advanced ... KRAS G12C inhibitors have good ORR, DCR, PFS rate, OS rate, tolerable trAEs, and early response with long duration in advanced solid tumors.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.3007

Pan-tumor activity of olomorasib (LY3537982), a second- ... Conclusions: Olomorasib demonstrates efficacy across a range of KRAS G12C-mutant solid tumors with a favorable safety profile including in pts ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12035108/

Potency and Safety of KRAS G12C Inhibitors in Solid Tumors In this study, we comprehensively evaluate the effectiveness and toxicity of relevant KRAS G12C inhibitors (Sotorasib, Adagrasib, Garsorasib, and Divarasib)

8. onclive.com onclive.com/view/ly3537982-demonstrates-tolerability-and-preliminary-efficacy-in-kras-g12c-mutated-advanced-solid-tumors

LY3537982 Demonstrates Tolerability and Preliminary ... The favorable safety and preliminary efficacy demonstrated by the LY3537982 at multiple dose levels in patients with KRAS G12C–mutated advanced solid tumors

9. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0169500224005002

Safety assessment of KRAS (G12C) inhibitors based on the ... This study revealed the potential adverse events (AEs) of KRAS (G12C) inhibitors, as well as comparing AE in sotorasib and adagrasib.