A Comprehensive Monograph on Olomorasib (LY3537982): A Second-Generation KRAS G12C Inhibitor

1.0 Executive Summary

Olomorasib (LY3537982) is an investigational, orally available, small-molecule therapeutic agent developed by Eli Lilly and Company. It is engineered as a potent, highly selective, second-generation covalent inhibitor of the Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) protein harboring the G12C mutation. This specific mutation is a key oncogenic driver in a significant subset of solid tumors, most notably non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Preclinical data established Olomorasib's superior potency and target engagement compared to first-generation KRAS G12C inhibitors. A key pharmacological feature is its ability to achieve high ($>90\%$) and sustained target occupancy at low, well-tolerated doses, which has proven critical for its clinical development.

The clinical program for Olomorasib is extensive, headlined by the foundational Phase 1/2 LOXO-RAS-20001 trial and the pivotal Phase 3 SUNRAY-01 and SUNRAY-02 studies. Clinical data have demonstrated a manageable safety profile and compelling anti-tumor activity. As a monotherapy, Olomorasib has shown efficacy in patients with NSCLC who have progressed on prior first-generation KRAS G12C inhibitors, with an objective response rate (ORR) of approximately 40%. In combination regimens, Olomorasib has produced particularly striking results. For the first-line treatment of KRAS G12C-mutant, PD-L1-high ($ \ge 50% $) NSCLC, its combination with the immune checkpoint inhibitor pembrolizumab yielded an ORR of up to 85%. This promising outcome led the U.S. Food and Drug Administration (FDA) to grant the combination Breakthrough Therapy Designation.

The safety profile of Olomorasib is characterized by predominantly low-grade, manageable adverse events, with low rates of treatment discontinuation due to toxicity, even when combined with immunotherapy. This favorable tolerability is a direct enabler of its promising combination strategies. Pending the results of its ongoing pivotal Phase 3 trials, Olomorasib is positioned to potentially become a best-in-class agent and establish a new standard of care in multiple settings for patients with KRAS G12C-mutant cancers.

2.0 Introduction: The Evolving Landscape of KRAS G12C Inhibition

The KRAS gene, a member of the RAS family of oncogenes, is one of the most frequently mutated genes in human cancers, playing a critical role in regulating cell signaling, division, and differentiation.[1] For decades, KRAS was considered an "undruggable" target due to its smooth protein surface and high affinity for its natural ligand, guanosine triphosphate (GTP). However, the discovery of a specific mutation, where glycine at codon 12 is substituted by cysteine (G12C), revealed a druggable pocket, ushering in a new era of targeted therapy.[3] The KRAS G12C mutation is present in approximately 13-14% of patients with NSCLC, 3% of patients with CRC, and 1-3% of patients with other solid tumors, representing a significant patient population with historically poor prognoses.[5]

The paradigm shifted with the regulatory approval of first-generation covalent KRAS G12C inhibitors, sotorasib and adagrasib. These agents validated the therapeutic hypothesis by demonstrating clinical activity, particularly in previously treated NSCLC.[3] Despite this landmark achievement, the clinical utility of these first-generation drugs is constrained by limitations. These include the development of intrinsic and acquired resistance mechanisms, as well as dose-limiting toxicities that can complicate their use in combination with other standard-of-care agents like immunotherapy, which often has an overlapping toxicity profile (e.g., hepatotoxicity).[3]

This clinical context created a clear rationale for the development of second-generation inhibitors designed to overcome these challenges. Olomorasib was specifically engineered to offer enhanced potency, greater selectivity, and more sustained target engagement compared to its predecessors.[3] Its favorable pharmacokinetic properties were intended to achieve high target occupancy at lower systemic exposures, thereby providing a wider therapeutic window and a more manageable safety profile. This profile was hypothesized to be better suited for combination with backbone therapies like immune checkpoint inhibitors, with the ultimate goal of improving clinical outcomes in both treatment-naïve and refractory settings.[7]

3.0 Pharmaceutical Profile and Pharmacology

3.1 Chemical Identity and Physicochemical Properties

Olomorasib is a new molecular entity classified as a small molecule antineoplastic agent.[12] It is identified by its International Nonproprietary Name (INN), Olomorasib, and its development code name, LY3537982.[2] The molecule's chemical structure is complex, comprising multiple heterocyclic ring systems. Its systematic International Union of Pure and Applied Chemistry (IUPAC) name is 4-benzoxazocin-9-yl]-2-amino-7-fluoro-1-benzothiophene-3-carbonitrile.[1] Key chemical and physical identifiers for Olomorasib are consolidated in Table 1.

Table 1: Chemical and Physical Identifiers of Olomorasib

Identifier	Value	Source(s)
IUPAC Name	4-benzoxazocin-9-yl]-2-amino-7-fluoro-1-benzothiophene-3-carbonitrile	1
Code Names	LY3537982, LY-3537982	2
Molecular Formula	$C_{25}H_{19}ClF_{2}N_{4}O_{3}S$	13
Molar Mass	528.96 g/mol	13
CAS Registry Number	2771246-13-8	1
UNII (FDA GSRS)	C2VJ83PSN7	1
InChIKey	OZUPICRWMLEFCS-LBPRGKRZSA-N	1
SMILES	C=CC(=O)N1CCN2C@HCCOC3=C(C(=C(C=C3C2=O)F)C4=C5C(=C(SC5=C(C=C4)F)N)C#N)Cl

3.2 Mechanism of Action: Covalent Inhibition and Downstream Signaling

Olomorasib functions as a highly targeted anticancer agent by specifically inhibiting the mutant KRAS G12C oncoprotein. It is administered orally and designed to selectively and irreversibly bind to the unique cysteine residue present in the G12C mutant form of the KRAS protein. This covalent bond formation is crucial, as it locks the KRAS G12C protein in its inactive, guanosine diphosphate (GDP)-bound conformation.

In its active, GTP-bound state, KRAS promotes a cascade of downstream signaling events that are fundamental to cell proliferation and survival. Mutations like G12C cause the protein to become constitutively active, leading to aberrant and uncontrolled activation of key signaling pathways, including the RAS-RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR pathways. This sustained signaling drives tumorigenesis, promoting tumor cell growth, proliferation, invasion, and metastasis. By trapping KRAS G12C in its inactive state, Olomorasib effectively blocks this constitutive signal transduction. This targeted mechanism allows for potent inhibition of tumor cells dependent on the KRAS G12C mutation while minimizing effects on cells with wild-type KRAS, which contributes significantly to its manageable safety profile.

3.3 Pharmacokinetics and Pharmacodynamics (PK/PD)

The pharmacokinetic and pharmacodynamic profile of Olomorasib is a cornerstone of its clinical development strategy and a key differentiator from first-generation inhibitors. It is an orally bioavailable drug designed for competitive PK properties that support its advancement into clinical testing.

A defining feature of Olomorasib, established in preclinical models and supported by early clinical data, is its ability to achieve high ($>90\%$) and sustained target occupancy at relatively low systemic drug exposures. This high efficiency means that a therapeutically effective level of target inhibition can be reached with doses that are well-tolerated by patients. This characteristic is not merely a pharmacological detail but a strategic advantage that directly enables its successful use in combination therapies. First-generation inhibitors can exhibit dose-limiting toxicities that restrict their combination with other agents, particularly immunotherapies that carry their own risk of adverse events. Olomorasib's capacity to achieve profound target inhibition at doses of 50 mg and 100 mg twice daily—which have demonstrated a manageable safety profile in clinical trials—is the direct enabler of the promising combination studies with pembrolizumab. The favorable tolerability observed in these combination regimens is a direct consequence of this efficient PK/PD profile, providing a wider therapeutic index.

Formal characterization of Olomorasib's human pharmacokinetics is ongoing. Several Phase 1 studies in healthy volunteers have been initiated to precisely measure its absorption, distribution, metabolism, and excretion (ADME) properties, including key parameters like the area under the concentration-time curve (AUC) and maximum concentration (Cmax). These studies also aim to evaluate the effect of food on its bioavailability and compare different capsule formulations. Preliminary data from the LOXO-RAS-20001 trial indicated a mean half-life of 2.9 hours and that steady-state exposures at all tested doses exceeded the concentration required for 90% efficacy (EC90) for most of the dosing interval.

4.0 Non-Clinical Studies and Rationale for Development

The advancement of Olomorasib into clinical trials was underpinned by a robust body of non-clinical data that established its potential as a superior second-generation inhibitor. In direct head-to-head preclinical comparisons, Olomorasib demonstrated significantly greater potency and selectivity than the first-generation agents sotorasib (AMG510) and adagrasib (MRTX849).

In kinetic studies, Olomorasib showed a dramatically higher inactivation efficiency, with a $K_{inact}/K_{I}$ value of 248,016 $M^{-1}s^{-1}$, compared to 7,220 $M^{-1}s^{-1}$ for sotorasib and 35,000 $M^{-1}s^{-1}$ for adagrasib. This superior biochemical potency translated to greater cellular activity. In the KRAS G12C-mutant H358 lung cancer cell line, Olomorasib inhibited KRAS-GTP loading with an IC50 value of 3.35 nM and downstream phospho-ERK signaling with an IC50 of 0.65 nM. These values were substantially lower than those for sotorasib (47.9 nM and 13.5 nM, respectively) and adagrasib (89.9 nM and 14 nM, respectively).

In vivo, Olomorasib monotherapy exhibited a range of anti-tumor activity, from significant tumor growth inhibition to complete tumor regression, across multiple xenograft and patient-derived xenograft (PDX) models at well-tolerated oral doses ranging from 3 to 30 mg/kg. Furthermore, preclinical mechanism-based screening identified synergistic activity when Olomorasib was combined with other targeted agents, including the CDK4/6 inhibitor abemaciclib and the anti-EGFR antibody cetuximab, providing a strong scientific rationale for the combination arms subsequently pursued in the clinical development program.

This enhanced preclinical potency provides a clear explanation for the clinical activity later observed in patients who were refractory to first-generation inhibitors. A critical test for any next-generation therapeutic is its ability to overcome resistance to the prior standard of care. The data from the LOXO-RAS-20001 trial, which showed a meaningful ORR of 39-41% in NSCLC patients who had progressed on a prior KRAS G12C inhibitor, serves as a direct clinical validation of this preclinical promise. This demonstrates a clear link between the superior molecular potency observed in laboratory models and tangible clinical benefit for patients with advanced, resistant disease, solidifying Olomorasib's credentials as a true second-generation agent.

5.0 The Olomorasib Clinical Development Program

The clinical development of Olomorasib is being conducted by its originator, Eli Lilly and Company, through a comprehensive and strategically designed series of trials aimed at establishing its efficacy and safety across multiple tumor types and treatment settings. The program is anchored by three key studies: LOXO-RAS-20001, SUNRAY-01, and SUNRAY-02. A summary of these trials is provided in Table 2.

LOXO-RAS-20001 (NCT04956640): This is the foundational Phase 1/2 "pan-tumor" basket trial that has provided the initial safety, pharmacokinetic, and efficacy data for Olomorasib. Its multi-part, open-label design includes a Phase 1a dose-escalation component for monotherapy, followed by Phase 1b dose-expansion and dose-optimization cohorts, and a Phase 2 component. This study is evaluating Olomorasib both as a single agent and in combination with various partners (e.g., pembrolizumab, cetuximab, chemotherapy) across a wide range of KRAS G12C-mutant advanced solid tumors, including NSCLC, CRC, and pancreatic cancer.

SUNRAY-01 (NCT06119581): This is the pivotal, global, randomized, double-blind, placebo-controlled Phase 3 study designed to support regulatory approval in the first-line treatment of metastatic KRAS G12C-mutant NSCLC. The trial has a seamless design that includes a dose-optimization phase followed by two main parts. Part A will randomize patients with high PD-L1 expression ($\ge 50\%$) to receive Olomorasib plus pembrolizumab versus placebo plus pembrolizumab. Part B will randomize patients, regardless of PD-L1 status, to receive Olomorasib plus chemoimmunotherapy (pembrolizumab, pemetrexed, platinum) versus placebo plus chemoimmunotherapy. The primary endpoint for both parts is progression-free survival (PFS) as assessed by blinded independent central review.

SUNRAY-02 (NCT06890598): This second pivotal Phase 3 study extends the investigation of Olomorasib into earlier stages of NSCLC, aiming to improve outcomes in the curative-intent setting. This trial is also a randomized, double-blind, placebo-controlled study with two distinct parts. Part A is evaluating Olomorasib in the adjuvant setting in combination with pembrolizumab for patients with resected Stage II-IIIB NSCLC. Part B is assessing Olomorasib as a consolidation therapy in combination with durvalumab for patients with unresectable Stage III NSCLC who have completed concurrent chemoradiotherapy.

Table 2: Overview of Key Clinical Trials in the Olomorasib Development Program

6.0 Analysis of Clinical Efficacy

The clinical efficacy of Olomorasib has been evaluated extensively in the LOXO-RAS-20001 trial, with data presented at major oncology conferences. The results have been promising across multiple settings, particularly in combination therapies for NSCLC.

6.1 Monotherapy Activity in Advanced Solid Tumors

As a single agent, Olomorasib has demonstrated meaningful anti-tumor activity, most notably in patients with NSCLC who had previously been treated with a first-generation KRAS G12C inhibitor. In this heavily pre-treated, refractory population, Olomorasib achieved an ORR of 39-41% and a median PFS of 6.0 to 8.1 months. This level of activity in a resistant setting is clinically significant and underscores its enhanced potency. In KRAS G12C inhibitor-naïve NSCLC patients, monotherapy yielded a median PFS of 7.9 to 9.0 months. A particularly promising finding has been the observation of preliminary central nervous system (CNS) activity, with CNS responses seen in patients with active, untreated brain metastases, addressing a critical unmet need in this population.

Across a range of other KRAS G12C-mutant solid tumors (excluding CRC), monotherapy produced an ORR of 35-40%. Consistent with the known biology of CRC and the experience with other KRAS inhibitors, monotherapy activity in this indication was modest, with an ORR of 9%. This finding reinforced the necessity of combination strategies in CRC. Efficacy data for monotherapy is summarized in Table 3.

Table 3: Summary of Efficacy of Olomorasib Monotherapy in Advanced Solid Tumors (from LOXO-RAS-20001)

Patient Population	N (Evaluable)	ORR (%)	DCR (%)	mPFS (months)	Source(s)
NSCLC (Prior G12Ci)	26-39	39 - 41	73	6.0 - 8.1
NSCLC (G12Ci-Naïve)	N/A	N/A	N/A	7.9 - 9.0
CRC	32	9	84	4.0
Non-CRC Solid Tumors (G12Ci-Naïve)	88-105	35 - 40	90	7.1

6.2 Combination Therapy in First-Line Non-Small Cell Lung Cancer

The most compelling efficacy data for Olomorasib has emerged from its use in combination regimens for first-line metastatic NSCLC, based on integrated analyses from the LOXO-RAS-20001 and SUNRAY-01 dose-optimization cohorts. These results were the basis for the FDA's Breakthrough Therapy Designation.

When combined with the anti-PD-1 antibody pembrolizumab, Olomorasib demonstrated a remarkably high ORR of 70-77% across all PD-L1 expression levels. In the patient subset with high PD-L1 expression ($\ge 50\%$), the ORR reached 82-85%. The disease control rate (DCR) was outstanding at 90-100%. Responses were also durable, with a 6-month PFS rate of 77-80% and the median duration of response (DOR) not yet reached at the time of data reporting. These response rates represent a potential paradigm shift. The current standard of care for this patient population (first-line, KRAS G12C-mutant, PD-L1 $\ge 50\%$ NSCLC) is often pembrolizumab monotherapy, which typically yields an ORR in the range of 45%. The near-doubling of this response rate with the Olomorasib combination, if confirmed in the pivotal SUNRAY-01 trial, would be a practice-changing advancement. The FDA's designation formally acknowledges this potential for substantial improvement over available therapy.

In combination with chemoimmunotherapy (pembrolizumab plus platinum-based chemotherapy), Olomorasib also showed strong efficacy, with an ORR of 59-61% and a DCR of 90%. This regimen yielded a median PFS of 11.6 months, providing another promising option for first-line therapy.

6.3 Combination Therapy in Advanced Colorectal Cancer

To address the limited efficacy of monotherapy in CRC, Olomorasib was studied in combination with cetuximab, an anti-EGFR monoclonal antibody. This strategy is based on the biological rationale that inhibiting both KRAS G12C and EGFR signaling simultaneously can overcome intrinsic resistance mechanisms in CRC. Data from the LOXO-RAS-20001 trial showed that this combination produced an ORR of 42-44% and a median PFS of 7.5 months in patients with previously treated KRAS G12C-mutant CRC. This result is a marked improvement over the 9% ORR observed with Olomorasib monotherapy and is competitive with other KRAS G12C inhibitor plus anti-EGFR combinations in this setting.

7.0 Comprehensive Safety and Tolerability Assessment

A central element of Olomorasib's clinical profile is its manageable safety and tolerability, which underpins its potential for use in combination therapies and in patients who are intolerant to other inhibitors.

7.1 Safety Profile of Olomorasib Monotherapy

When administered as a single agent, treatment-related adverse events (TRAEs) associated with Olomorasib were predominantly Grade 1 in severity. Across studies, the most frequently reported any-grade TRAEs were gastrointestinal, including diarrhea (23-24%), nausea (10-11%), and fatigue (10%). The incidence of serious adverse events was very low; Grade $\ge 3$ TRAEs occurred in only 5% of patients, and the rate of treatment discontinuation due to TRAEs was exceptionally low at 1-2%. Importantly, the safety profile remained favorable in patients who had discontinued a prior first-generation KRAS G12C inhibitor due to toxicity, suggesting a differentiated and improved tolerability profile.

7.2 Safety Profile of Olomorasib in Combination Regimens

The safety profile of Olomorasib in combination with other anticancer agents has been well-characterized and deemed manageable.

• With Pembrolizumab: The most common TRAEs for this combination included diarrhea (23-30%), increased alanine aminotransferase (ALT) (20-33%), increased aspartate aminotransferase (AST) (16-30%), pruritus (11-19%), and fatigue (14-16%). While Grade 3 elevations in liver enzymes were observed (ALT 18-26%, AST 14-16%), these events were generally manageable with dose modifications or corticosteroids and did not typically lead to treatment cessation. Immune-related events such as pneumonitis were reported in a small number of patients (3-4% of cases).
• With Chemoimmunotherapy: When combined with chemotherapy and pembrolizumab, the adverse event profile was consistent with the known toxicities of the individual agents. Common TRAEs included nausea, anemia, fatigue, and diarrhea, with Grade $\ge 3$ TRAEs being primarily hematologic (e.g., anemia, decreased neutrophil count).
• With Cetuximab: The safety profile of the Olomorasib plus cetuximab combination was dominated by the known class effects of EGFR inhibitors. The most common TRAEs were dermatologic, including dermatitis acneiform (58%), dry skin (31%), paronychia (28%), and rash (26%), along with hypomagnesemia (26%). The majority of these events were Grade 1-2, with Grade $\ge 3$ TRAEs occurring in 24% of patients.

7.3 Management of Key Adverse Events and Discontinuation Analysis

Across all clinical settings, a key finding has been the low rate of treatment discontinuation due to adverse events. For the critical combination with pembrolizumab, only 3-5% of patients discontinued Olomorasib due to a TRAE, and only 5-9% discontinued both drugs. This reinforces the conclusion that the combination is well-tolerated and the associated toxicities are manageable for the majority of patients, allowing them to remain on therapy to derive clinical benefit. A comparative summary of key adverse events is provided in Table 4.

Table 4: Comparative Summary of Common Treatment-Related Adverse Events (TRAEs)

Adverse Event	Monotherapy (Any Grade %)	Monotherapy (Grade ≥3 %)	+ Pembrolizumab (Any Grade %)	+ Pembrolizumab (Grade ≥3 %)	+ Cetuximab (Any Grade %)	+ Cetuximab (Grade ≥3 %)
Diarrhea	23 - 24	<1	23 - 30	7 - 16	38	2
Nausea	10 - 11	<1	14	<1	N/A	N/A
Fatigue	10	<1	14 - 16	<1	N/A	N/A
ALT Increased	N/A	N/A	20 - 33	18 - 26	N/A	N/A
AST Increased	N/A	N/A	16 - 30	14 - 16	N/A	N/A
Pruritus	N/A	N/A	11 - 19	<1	N/A	N/A
Dermatitis Acneiform	N/A	N/A	N/A	N/A	58	<5
Dry Skin	N/A	N/A	N/A	N/A	31	<1
Hypomagnesemia	N/A	N/A	N/A	N/A	26	<5
Note: Data compiled from multiple trial reports and presentations. N/A indicates not reported as a top adverse event in the available source.

8.0 Dosage and Administration in Clinical Trials

The optimal dose of Olomorasib was determined through the dose-escalation and dose-optimization phases of the LOXO-RAS-20001 trial. The study evaluated oral doses ranging from 50 mg to 200 mg, administered twice daily (BID).

During dose optimization for the combination with pembrolizumab, it was observed that the 150 mg BID dose level was associated with an increased incidence of Grade $\ge 3$ liver function test elevations, which precluded further evaluation of this higher dose. In contrast, the 50 mg and 100 mg BID dose levels demonstrated both promising anti-tumor activity and a more favorable and manageable safety profile. Based on an integrated assessment of efficacy and safety data, the 100 mg BID oral dose was selected as the optimal dose for the pivotal Phase 3 SUNRAY-01 trial and for the combination with cetuximab in CRC. The drug is administered in capsule form, which patients must be able to swallow.

9.0 Regulatory Status and Future Directions

9.1 Current U.S. FDA Designations and Implications

Olomorasib has achieved two significant regulatory milestones with the U.S. FDA, underscoring its clinical promise and potential to address an unmet medical need.

• Breakthrough Therapy Designation: On September 4, 2025, the FDA granted this designation to Olomorasib in combination with pembrolizumab for the first-line treatment of patients with unresectable or metastatic KRAS G12C-mutant NSCLC with high PD-L1 expression ($\ge 50\%$). This designation is intended to expedite the development and review of drugs that demonstrate the potential for substantial improvement over available therapies on a clinically significant endpoint. The decision was based on the encouraging efficacy and safety data from the LOXO-RAS-20001 and SUNRAY-01 dose-optimization cohorts.
• Orphan Drug Designation: On June 24, 2025, the FDA granted Orphan Drug Designation to Olomorasib for the treatment of KRAS G12C-mutant NSCLC. This status provides incentives to encourage the development of drugs for rare diseases, including potential market exclusivity upon approval, tax credits for clinical trials, and exemption from certain FDA fees.

As of the latest reports, Olomorasib is not yet approved by the FDA for any indication.

9.2 Status with Other Global Regulatory Agencies (EMA, TGA)

The provided research materials do not contain information regarding specific regulatory filings or approvals for Olomorasib with the European Medicines Agency (EMA) or Australia's Therapeutic Goods Administration (TGA). However, the global nature of the clinical development program is evident from the inclusion of European trial sites, as indicated by the assignment of EU Trial (CTIS) Numbers to the key studies, such as 2024-512302-25-00 for SUNRAY-02 and 2022-502756-31-00 for LOXO-RAS-20001. This global trial footprint is a necessary precursor to future regulatory submissions in these regions.

9.3 Outlook Based on Ongoing Pivotal Trials

The future regulatory and clinical trajectory of Olomorasib is critically dependent on the outcomes of the ongoing pivotal Phase 3 trials. Positive results from the SUNRAY-01 study could establish the combination of Olomorasib and pembrolizumab (with or without chemotherapy) as a new first-line standard of care for patients with metastatic KRAS G12C-mutant NSCLC. Success in the SUNRAY-02 trial would further expand its use into earlier, curative-intent settings, including adjuvant therapy for resected disease and consolidation therapy for unresectable Stage III disease. These trials have the potential to significantly reshape the treatment landscape for this molecularly defined subset of lung cancer.

10.0 Expert Synthesis and Conclusion

Olomorasib represents a significant and sophisticated advancement in the targeted therapy of KRAS G12C-mutant cancers. It has progressed beyond being merely another entrant in the class to a strong candidate for a best-in-class designation. Its development was rationally designed to improve upon the limitations of first-generation inhibitors, and the accumulating clinical data suggest this goal has been largely achieved.

The key differentiating strengths of Olomorasib are threefold. First, its superior preclinical potency has been clinically validated by its meaningful activity in patients whose disease has progressed on prior KRAS G12C inhibitors, a setting of high unmet need. Second, its favorable pharmacokinetic profile, which allows for high target occupancy at well-tolerated doses, has unlocked the potential of combination therapy. The manageable safety profile, even when combined with immunotherapy, is a critical advantage that has enabled its successful investigation in the first-line setting. Third, the resulting clinical efficacy, particularly the high response rates seen with the pembrolizumab combination in first-line NSCLC, is compelling and has been recognized by the FDA with a Breakthrough Therapy Designation. If these results are confirmed in the SUNRAY-01 trial, they are poised to be practice-changing.

In conclusion, Olomorasib has demonstrated a compelling profile of high efficacy and manageable tolerability across multiple clinical contexts. It has shown promise as a monotherapy in refractory disease and transformative potential as a combination partner in the front-line setting. The ongoing pivotal Phase 3 program will be definitive, but the current body of evidence strongly positions Olomorasib to become a cornerstone of treatment for patients with KRAS G12C-mutant NSCLC and potentially other solid tumors.

Works cited

1. Olomorasib | C25H19ClF2N4O3S | CID 156472638 - PubChem, accessed October 19, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Olomorasib
2. Definition of olomorasib - NCI Drug Dictionary - NCI, accessed October 19, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/olomorasib
3. Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with KRAS G12C-mutant advanced solid tumors. | Request PDF - ResearchGate, accessed October 19, 2025, https://www.researchgate.net/publication/381499651_Pan-tumor_activity_of_olomorasib_LY3537982_a_second-generation_KRAS_G12C_inhibitor_G12Ci_in_patients_with_KRAS_G12C-mutant_advanced_solid_tumors
4. Preclinical pharmacodynamics and pharmacokinetics of KRAS G12C inhibitors | Download Scientific Diagram - ResearchGate, accessed October 19, 2025, https://www.researchgate.net/figure/Preclinical-pharmacodynamics-and-pharmacokinetics-of-KRAS-G12C-inhibitors_tbl1_380559414
5. olomorasib (ly3537982) - Lilly Oncology Pipeline Database, accessed October 19, 2025, https://www.lillyoncologypipeline.com/flashcards/Olomorasib_KRASFlashcard_Apr_2025.pdf
6. FDA Grants Breakthrough Therapy Designation to Olomorasib With Pembrolizumab for NSCLC | Pharmacy Times, accessed October 19, 2025, https://www.pharmacytimes.com/view/fda-grants-breakthrough-therapy-designation-to-olomorasib-with-pembrolizumab-for-nsclc
7. Updated Data from the Phase 1/2 Study of Olomorasib in KRAS G12C-Mutant Advanced Solid Tumors Presented at the, accessed October 19, 2025, https://investor.lilly.com/node/50826/pdf
8. KRAS G12C inhibitor combination therapies: current evidence and challenge - PMC, accessed October 19, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11097198/
9. Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with KRAS G12C-mutant advanced solid tumors. - ASCO, accessed October 19, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT440004
10. Abstract 1259: Preclinical characterization of LY3537982, a novel ..., accessed October 19, 2025, https://www.researchgate.net/publication/352917813_Abstract_1259_Preclinical_characterization_of_LY3537982_a_novel_highly_selective_and_potent_KRAS-G12C_inhibitor
11. Abstract CT202: A first-in-human phase 1 study of LY3537982, a ..., accessed October 19, 2025, https://aacrjournals.org/cancerres/article/82/12_Supplement/CT202/704447/Abstract-CT202-A-first-in-human-phase-1-study-of
12. Olomorasib - Eli Lilly and Company - AdisInsight, accessed October 19, 2025, https://adisinsight.springer.com/drugs/800064203
13. OLOMORASIB - gsrs, accessed October 19, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/C2VJ83PSN7
14. Olomorasib - Wikipedia, accessed October 19, 2025, https://en.wikipedia.org/wiki/Olomorasib
15. OLOMORASIB - precisionFDA, accessed October 19, 2025, https://precision.fda.gov/ginas/app/ui/substances/C2VJ83PSN7
16. Olomorasib - Drug Targets, Indications, Patents - Patsnap Synapse, accessed October 19, 2025, https://synapse.patsnap.com/drug/1ea9c6b4fae94410871d28f73ce30a01
17. Olomorasib Receives FDA Breakthrough Therapy Designation for KRAS G12C-Mutant NSCLC - OncoDaily, accessed October 19, 2025, https://oncodaily.com/fda-approvals/olomorasib-fda-aprove-kras-g12c-nsclc
18. oncodaily.com, accessed October 19, 2025, https://oncodaily.com/fda-approvals/olomorasib-fda-aprove-kras-g12c-nsclc#:~:text=Olomorasib%20binds%20covalently%20to%20the,minimizing%20effects%20on%20normal%20cells.
19. What is Olomorasib used for? - Patsnap Synapse, accessed October 19, 2025, https://synapse.patsnap.com/article/what-is-olomorasib-used-for
20. KRAS G12C Inhibitor - LY3537982 Molecule Summary For HCPs | Lilly Oncology, accessed October 19, 2025, https://www.lillyoncologypipeline.com/molecule/kras-g12c-inhibitor/
21. Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC. - ASCO, accessed October 19, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT440014
22. NCT07044271 | A Study of Multiple Olomorasib (LY3537982) Capsules in Healthy Participants | ClinicalTrials.gov, accessed October 19, 2025, https://clinicaltrials.gov/study/NCT07044271
23. Impact of food on the pharmacokinetics of olomorasib in healthy, accessed October 19, 2025, https://www.cochranelibrary.com/central/doi/10.1002/central/CN-02871789/full
24. NCT07124013 | A Study of Olomorasib (LY3537982) in Healthy Japanese Participants, accessed October 19, 2025, https://clinicaltrials.gov/study/NCT07124013
25. LY3537982 Demonstrates Tolerability and Preliminary Efficacy in ..., accessed October 19, 2025, https://www.onclive.com/view/ly3537982-demonstrates-tolerability-and-preliminary-efficacy-in-kras-g12c-mutated-advanced-solid-tumors
26. Olomorasib | MedChemExpress, accessed October 19, 2025, https://file.medchemexpress.com/batch_PDF/HY-132980/Olomorasib-DataSheet-MedChemExpress.pdf
27. Olomorasib (Synonyms: KRAS G12C inhibitor 19) - MedchemExpress.com, accessed October 19, 2025, https://www.medchemexpress.com/kras-g12c-inhibitor-19.html
28. Updated Data from the Phase 1/2 Study of Olomorasib in KRAS G12C-Mutant Advanced Solid Tumors Presented at the 2024 ASCO® Annual Meeting - BioSpace, accessed October 19, 2025, https://www.biospace.com/updated-data-from-the-phase-1-2-study-of-olomorasib-in-kras-g12c-mutant-advanced-solid-tumors-presented-at-the-2024-asco-annual-meeting
29. NCT06890598 | Study of Olomorasib (LY3537982) in Combination With Standard of Care in Participants With Resected or Unresectable KRAS G12C-mutant Non-Small Cell Lung Cancer | ClinicalTrials.gov, accessed October 19, 2025, https://www.clinicaltrials.gov/study/NCT06890598
30. NCT04956640 | Study of LY3537982 in Cancer Patients With a Specific Genetic Mutation (KRAS G12C) | ClinicalTrials.gov, accessed October 19, 2025, https://clinicaltrials.gov/study/NCT04956640
31. Lilly's olomorasib receives U.S. FDA's Breakthrough Therapy designation for the treatment of certain newly diagnosed metastatic KRAS G12C-mutant lung cancers - PR Newswire, accessed October 19, 2025, https://www.prnewswire.com/news-releases/lillys-olomorasib-receives-us-fdas-breakthrough-therapy-designation-for-the-treatment-of-certain-newly-diagnosed-metastatic-kras-g12c-mutant-lung-cancers-302545643.html
32. NCT06119581 | A Study of First-Line Olomorasib (LY3537982) and Pembrolizumab With or Without Chemotherapy in Patients With Advanced KRAS G12C-Mutant Non-small Cell Lung Cancer | ClinicalTrials.gov, accessed October 19, 2025, https://clinicaltrials.gov/study/NCT06119581
33. SUNRAY-01, a pivotal, global study of olomorasib (LY3537982) in ..., accessed October 19, 2025, https://ascopubs.org/doi/10.1200/JCO.2024.42.23_suppl.TPS218
34. Study of Olomorasib (LY3537982) in Combination With Standard of Care in Participants With Resected or Unresectable KRAS G12C-mutant Non-Small Cell Lung Cancer (SUNRAY-02) - Lilly Trials, accessed October 19, 2025, https://trials.lilly.com/en-US/trial/585993
35. SUNRAY-02 - UF Health Jacksonville, accessed October 19, 2025, https://www.ufhealthjax.org/clinical-trials/sunray-02
36. Lilly to present new clinical data for Verzenio and multiple novel pipeline programs at the 2025 European Society for Medical Oncology Annual Meeting - Investing News Network, accessed October 19, 2025, https://investingnews.com/lilly-to-present-new-clinical-data-for-verzenio-and-multiple-novel-pipeline-programs-at-the-2025-european-society-for-medical-oncology-annual-meeting/
37. Updated Data from the Phase 1/2 Study of Olomorasib in KRAS G12C-Mutant Advanced Solid Tumors Presented at the 2024 ASCO® Annual Meeting - PR Newswire, accessed October 19, 2025, https://www.prnewswire.com/news-releases/updated-data-from-the-phase-12-study-of-olomorasib-in-kras-g12c-mutant-advanced-solid-tumors-presented-at-the-2024-asco-annual-meeting-302160829.html
38. Lilly Announces Updated Data From Phase 1/2 Study Of Olomorasib In Advanced Solid Tumors | Nasdaq, accessed October 19, 2025, https://www.nasdaq.com/articles/lilly-announces-updated-data-phase-1-2-study-olomorasib-advanced-solid-tumors
39. Olomorasib Combo Elicits Favorable Efficacy in NSCLC | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways, accessed October 19, 2025, https://www.targetedonc.com/view/olomorasib-combo-elicits-favorable-efficacy-in-nsclc
40. Safety and efficacy of olomorasib + immunotherapy in first-line ..., accessed October 19, 2025, https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8519
41. FDA Grants Breakthrough Therapy Designation to Olomorasib in KRAS G12C NSCLC | Targeted Oncology - Immunotherapy, Biomarkers, and Cancer Pathways, accessed October 19, 2025, https://www.targetedonc.com/view/fda-grants-breakthrough-therapy-designation-to-olomorasib-in-kras-g12c-nsclc
42. Safety and efficacy of olomorasib + immunotherapy in first-line treatment of patients with KRAS G12C-mutant advanced NSCLC: Update from the LOXO-RAS-20001 trial. - ResearchGate, accessed October 19, 2025, https://www.researchgate.net/publication/392306349_Safety_and_efficacy_of_olomorasib_immunotherapy_in_first-line_treatment_of_patients_with_KRAS_G12C-mutant_advanced_NSCLC_Update_from_the_LOXO-RAS-20001_trial
43. Promising Trial Data Leads to Breakthrough Designation for Eli Lilly's Investigational KRAS G12C Inhibitor in Advanced, Metastatic Non-Small Cell Lung Cancer, accessed October 19, 2025, https://www.appliedclinicaltrialsonline.com/view/promising-trial-data-leads-breakthrough-designation-eli-lilly-investigational-kras-g12c-inhibitor-advanced-metastatic-non-small-cell-lung-cancer
44. WCLC 2025: Combination therapy achieves durable response in ..., accessed October 19, 2025, https://www.mdanderson.org/newsroom/research-newsroom/wclc-2025--combination-therapy-achieves-durable-response-in-adva.h00-159779601.html
45. Efficacy and safety of olomorasib, a second-generation KRAS G12C inhibitor, plus cetuximab in KRAS G12C-mutant advanced colorectal cancer. - ASCO, accessed October 19, 2025, https://www.asco.org/abstracts-presentations/ABSTRACT482740
46. Evaluating first-line olomorasib and chemo-IO in KRAS G12C NSCLC - YouTube, accessed October 19, 2025, https://www.youtube.com/watch?v=Ds9f-FFjeKA
47. olomorasib (LY3537982) / Eli Lilly - LARVOL DELTA, accessed October 19, 2025, https://delta.larvol.com/Products/?ProductId=65d97bf4-8b77-442d-af72-27d99b9c59ac
48. FDA Grants Breakthrough Therapy Designation to Lilly's Olomorasib for KRAS G12C-Mutant NSCLC - Voice Of HealthCare, accessed October 19, 2025, https://vohnetwork.com/news/precision-medicine/fda-grants-breakthrough-therapy-designation-to-lillys-olomorasib-for-kras-g12c-mutant-nsclc
49. FDA Grants Breakthrough Therapy to Olomorasib in Lung Cancer Subset - CURE, accessed October 19, 2025, https://www.curetoday.com/view/fda-grants-breakthrough-therapy-to-olomorasib-in-lung-cancer-subset
50. Search Orphan Drug Designations and Approvals - FDA, accessed October 19, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=1059424
51. Eli Lilly's Olomorasib Receives FDA Orphan Drug Designation for KRAS G12C-Mutated NSCLC Treatment - MedPath, accessed October 19, 2025, https://trial.medpath.com/news/ca5778db64759acb/eli-lilly-s-olomorasib-receives-fda-orphan-drug-designation-for-kras-g12c-mutated-nsclc-treatment
52. Medicines | European Medicines Agency (EMA), accessed October 19, 2025, https://www.ema.europa.eu/en/medicines
53. Lilly gains FDA breakthrough status for olomorasib in advanced lung cancer, accessed October 19, 2025, https://www.worldpharmaceuticals.net/news/lilly-gains-fda-breakthrough-status-for-olomorasib-in-advanced-lung-cancer/
54. Krazati | European Medicines Agency (EMA), accessed October 19, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/krazati
55. Lilly's Kisunla receives marketing authorization by European Commission for the treatment of early symptomatic Alzheimer's disease - Investing News Network, accessed October 19, 2025, https://investingnews.com/lilly-s-kisunla-receives-marketing-authorization-by-european-commission-for-the-treatment-of-early-symptomatic-alzheimer-s-disease/