LY3537982 for Cancer
Recruiting in Palo Alto (17 mi)
+67 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Eli Lilly and Company
Must not be taking: Steroids, KRAS inhibitors
Disqualifiers: Infection, Cardiac condition, Autoimmune, others
No Placebo Group
Breakthrough Therapy
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.12345
Is LY3537982 safe for humans?
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.13789
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.
See 7 more
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.
See 9 more
Trial 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 (Small Molecule Inhibitor)
Trial OverviewThe 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
3Treatment groups
Experimental Treatment
Group I: LY3537982 (Dose Optimization)Experimental Treatment3 Interventions
LY3537982 administered orally either alone or with another investigational agent
Group II: LY3537982 (Dose Expansion)Experimental Treatment6 Interventions
LY3537982 administered orally either alone or with another investigational agent.
Group III: LY3537982 (Dose Escalation)Experimental Treatment1 Intervention
LY3537982 administered orally.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
NYU Langone Health- Long IslandMineola, NY
AdventHealth OrlandoOrlando, FL
Novant Health Cancer Institute - ElizabethCharlotte, NC
Florida Cancer SpecialistsSarasota, FL
More Trial Locations
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Who Is Running the Clinical Trial?
Eli Lilly and CompanyLead Sponsor
Loxo Oncology, Inc.Industry Sponsor
Merck Sharp & Dohme LLCIndustry Sponsor
References
Mechanisms of Resistance to KRASG12C Inhibitors. [2021]KRAS is one of the most common human oncogenes, but concerted efforts to produce direct inhibitors have largely failed, earning KRAS the title of "undruggable". Recent efforts to produce subtype specific inhibitors have been more successful, and several KRASG12C inhibitors have reached clinical trials, including adagrasib and sotorasib, which have shown early evidence of efficacy in patients. Lessons from other inhibitors of the RAS pathway suggest that the effect of these drugs will be limited in vivo by the development of drug resistance, and pre-clinical studies of G12C inhibitors have identified evidence of this. In this review we discuss the current evidence for G12C inhibitors, the mechanisms of resistance to G12C inhibitors and potential approaches to overcome them. We discuss possible targets of combination therapy, including SHP2, receptor tyrosine kinases, downstream effectors and PD1/PDL1, and review the ongoing clinical trials investigating these inhibitors.
KRAS G12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma. [2022]Label="PURPOSE"> KRAS G12C is the most common KRAS mutation in primary lung adenocarcinoma. Phase I clinical trials have demonstrated encouraging clinical activity of KRAS G12C inhibitors in the metastatic setting. We investigated disease-free survival (DFS) and tumor genomic features in patients with surgically resected KRAS G12C-mutant lung adenocarcinoma.
A Breakthrough Brought about by Targeting KRASG12C: Nonconformity Is Punished. [2022]KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRASG12C mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable-that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRASG12C-selective inhibitors, e.g., the FDA-approved AMG510 and MRTX849, have demonstrated potent clinical efficacy and selectivity in patients with KRASG12C-driven cancers only, which spares other driver KRAS mutations (e.g., G12D/V/S, G13D, and Q61H) and has ushered in an unprecedented breakthrough in the field in recent decades. However, accumulating evidence from preclinical and clinical studies has shown that G12C-targeted therapeutics as single agents are inevitably thwarted by drug resistance, a persistent problem associated with targeted therapies. A promising strategy to optimize G12C inhibitor therapy is combination treatments with other therapeutic agents, the identification of which is empowered by the insightful appreciation of compensatory signaling pathways or evasive mechanisms, such as those that attenuate immune responses. Here, we review recent advances in targeting KRASG12C and discuss the challenges of KRASG12C inhibitor therapy, as well as future directions.
Targeting KRASp.G12C Mutation in Advanced Non-Small Cell Lung Cancer: a New Era Has Begun. [2023]KRASp.G12C mutation occurs in 12% of newly diagnosed advanced NSCLC and has recently emerged as a positive predictive biomarker for the selection of advanced NSCLC patients who may respond to novel KRASp.G12C inhibitors. The recent discovery of a new binding pocket under the effector region of KRAS G12C oncoprotein has made direct pharmacological inhibition of the KRASp.G12 mutation possible, leading to the clinical development of a new series of direct selective inhibitors, with a potential major impact on patients' survival and quality of life. Promising efficacy and tolerability data emerging from the early phase CodeBreak trial have already supported the regulatory approval of sotorasib as first in class targeted treatment for the second-line treatment of KRASp.G12C-positive NSCLC population, following immunotherapy-based first-line therapies, while the randomized phase III CodeBreak 200 clinical study has recently confirmed a significant superiority of sotorasib over docetaxel in terms of progression-free survival and quality of life. However, KRAS mutant NSCLC is a high heterogeneous disease characterized by a high rate of co-mutations, most frequently involving P53, STK11, and KEAP1 genes, which significantly modulate the composition of the tumor microenvironment and consequently affect clinical responses to both immunotherapy and targeted inhibitors now available in clinical practice. Both pre-clinical and clinical translational series have recently revealed a wide spectrum of resistance mechanisms occurring under selective KRASG12C inhibitors, including both on-target and off-target molecular alterations as well as morphological switching, negatively affecting the antitumor activity of these drugs when used as single agent therapies. The understanding of such biological background along with the emergence of pre-clinical data provided a strong rational to investigate different combination strategies, including the inhibition of SHP2, SOS1, and KRAS G12C downstream effectors, as well as the addition of immunotherapy and/or chemotherapy to targeted therapy. The preliminary results of these trials have recently suggested a promising activity of SHP2 inhibitors in the front-line setting, while toxicity issues limited the concurrent administration of immune-checkpoint inhibitors and sotorasib. The identification of predictive genomic/immunological biomarkers will be crucial to understand how to optimally sequencing/combining different drugs and ultimately personalize treatment strategies under clinical investigation, to definitively increase the survival outcomes of KRASp.G12C mutant advanced NSCLC patients.
Direct GDP-KRASG12C inhibitors and mechanisms of resistance: the tip of the iceberg. [2023]Kirsten rat sarcoma viral oncogene homolog mutations are observed in 25% of lung adenocarcinoma and 40% of these are G12C mutations. Historically, no approved targeted agents were available for patients with any KRAS mutation, and response rates to standard-of-care therapies were suboptimal. Newly developed inhibitors directed toward KRASG12C have been successful in clinical trials with overall response rates ranging between 32% and 46%, and two FDA approvals were granted in May 2021 and December 2022 as second-line or later monotherapies. However, rapid tumor resistance complicates their use as a monotherapy. With the rapid development of this novel class of inhibitors, it is important to discern the different types of tumor resistance that may arise and how each can differently contribute to tumor growth and survival. G12C inhibitor resistance is under investigation and combinations of therapies with G12C inhibitors have been proposed. Much of this insight is gleaned from preclinical investigations, as our knowledge of clinical resistance is in its infancy. In this review, we summarize the preclinical development of KRASG12C inhibitors, their clinical evaluations, different types of resistance mechanisms to these compounds, and ways of overcoming them. Finally, we underscore the importance of basic and translational investigations of these molecules in a landscape where their clinical evaluations garner the most attention, and we set the stage for what is to come.
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. [2023]KRAS G12C mutation is prevalent in ~4% of colorectal cancer (CRC) and is associated with poor prognosis. Divarasib, a KRAS G12C inhibitor, has shown modest activity as a single agent in KRAS G12C-positive CRC at 400 mg. Epidermal growth factor receptor has been recognized as a major upstream activator of RAS-MAPK signaling, a proposed key mechanism of resistance to KRAS G12C inhibition in CRC. Here, we report on divarasib plus cetuximab (epidermal growth factor receptor inhibitor) in patients with KRAS G12C-positive CRC (n = 29) from arm C of an ongoing phase 1b trial. The primary objective was to evaluate safety. Secondary objectives included preliminary antitumor activity. The safety profile of this combination was consistent with those of single-agent divarasib and cetuximab. Treatment-related adverse events led to divarasib dose reductions in four patients (13.8%); there were no treatment withdrawals. The objective response rate was 62.5% (95% confidence interval: 40.6%, 81.2%) in KRAS G12C inhibitor-naive patients (n = 24). The median duration of response was 6.9 months. The median progression-free survival was 8.1 months (95% confidence interval: 5.5, 12.3). As an exploratory objective, we observed a decline in KRAS G12C variant allele frequency associated with response and identified acquired genomic alterations at disease progression that may be associated with resistance. The manageable safety profile and encouraging antitumor activity of divarasib plus cetuximab support the further investigation of this combination in KRAS G12C-positive CRC.ClinicalTrials.gov identifier: NCT04449874.
Multiple Mechanisms Underlie the Acquired Resistance to KRAS G12C Inhibition. [2022]Numerous mechanisms of resistance to direct KRAS G12C inhibition were revealed.
Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. [2023]Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity.
Newly Synthesized KRASG12C Mediates Escape from KRASG12C Inhibition. [2020]KRAS G12C-mutant cells treated with KRASG12C inhibitors quickly became either quiescent or resistant.