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Olomorasib

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What are the safety and efficacy results of olomorasib combination treatment with pembrolizumab in the first-line setting in patients with metastatic NSCLC?

Olomorasib plus pembrolizumab showed a 73% ORR (78% in PD-L1 ≥50%) with diarrhea and elevated LFTs as the most common TRAEs. Elevated LFTs were asymptomatic, reversible, and resolved with dose adjustments or corticosteroids.

US_cFAQ_OLO001_1L_NSCLC_PEMBRO_COMBO_v1_0_annotated

Content Overview

Olomorasib: Combination With Pembrolizumab in First-Line Treatment of Advanced/Metastatic NSCLC
- Integrated Analysis Eligibility and Design
- Results
SUNRAY-01: Phase 3 Study in Advanced/Metastatic NSCLC
- Eligibility
- Study Design and Endpoints
LOXO-RAS-20001: Phase 1A/B Study
- Eligibility
- Study Design and Endpoints
References

Olomorasib: Combination With Pembrolizumab in First-Line Treatment of Advanced/Metastatic NSCLC

Olomorasib is a potent, oral, highly selective inhibitor of guanosine diphosphate (GDP)-bound KRAS G12C.¹

The LOXO-RAS-20001 study (NCT04956640) is a first-in-human phase 1 dose escalation/dose expansion study to evaluate safety, tolerability, and preliminary efficacy of olomorasib in patients with KRAS G12C-mutant advanced solid tumors.^1,2

SUNRAY-01 is a pivotal, global, phase 3 study in first-line advanced KRAS G12C-mutated non-small cell lung cancer (NSCLC) (NCT06119581). The study is designed to

optimize the dosing of olomorasib in combination with first-line standard of care (SOC), and
compare efficacy and safety of olomorasib plus SOC vs placebo plus SOC in first-line advanced KRAS G12C-mutated NSCLC.^3,4

An integrated analysis (N=85) combined 43 patients from the LOXO-RAS-20001 phase 1 study and 42 patients from the dose optimization portion of SUNRAY-01 receiving olomorasib and pembrolizumab for KRAS G12C-mutant advanced/metastatic NSCLC in the first-line setting.⁵

Integrated Analysis Eligibility and Design

Patients who were eligible from LOXO-RAS-20001 and SUNRAY-01 for the integrated analysis included patients with

confirmed stage IIIB-IIIC or IV NSCLC
no prior therapy for metastatic disease (one cycle of pembrolizumab prior to enrollment was permitted)
programmed death-ligand 1 (PD-L1) expression 0% to 100%
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and
small (≤1.5 cm), asymptomatic untreated or treated stable brain metastases.⁵

This integrated analysis evaluating the combination of olomorasib and pembrolizumab in first-line NSCLC included patients from part G of the phase 1 LOXO-RAS-20001 study and the dose optimization phase of part A of SUNRAY-01.^4,5

Patients were randomized 1:1 to receive either 50 mg or 100 mg of olomorasib twice daily in combination with pembrolizumab 200 mg every 3 weeks. Stratification was based on PD-L1 status (0% to 49% vs ≥50%).⁵

Results

Baseline Characteristics

Baseline characteristics for the 85 patients included in the integrated analysis (median duration of follow-up, 12.4 months) are summarized in Table 1.

**Table 1.** Patient and Disease Characteristics of Integrated Analysis of LOXO-RAS-20001 and SUNRAY-01⁵
Characteristic^a	Olomorasib and Pembrolizumab (N=85)^b
Age, median, years (range)	69 (44-88)
Sex
Male	41 (48.2)
Female	44 (51.8)
Race^c
White	48 (56.5)
Asian	29 (34.1)
Black or African American	2 (2.4)
Not reported	6 (7.1)
ECOG PS
0	39 (45.9)
1	46 (54.1)
Smoking status
Former or current	80 (94.1)
Never	4 (4.7)
Unknown	1 (1.2)
PD-L1 score
<1%	13 (15.3)
1%-49%	18 (21.2)
≥50%	54 (63.5)
Brain metastases
Yes	7 (8.2)
No	78 (91.8)
Prior neoadjuvant/adjuvant therapy
Anti-PD-(L)1 therapy	1 (1.2)
Received 1 cycle of SOC (pembrolizumab) before enrollment^d
Yes	13 (15.3)
No	72 (84.7)

Abbreviations: anti-PD-(L)1 = anti-programmed cell death protein 1/programmed death-ligand 1; BID = twice daily; ECOG PS = Eastern Cooperative Oncology Group performance status; PD-L1 = programmed death-ligand 1; Q3W = every 3 weeks; SOC = standard of care.

^aData are n (%) unless otherwise indicated.

^bTotal number of patients include 42 patients treated with olomorasib 50 mg BID and 43 patients treated with olomorasib 100 mg BID. All patients (N=85) treated with 200 mg pembrolizumab Q3W.

^cA portion of patients did not report their race at baseline.

^dPatients may have received up to one cycle of standard of care prior to enrollment (defined as one 21-day cycle of pembrolizumab 200 mg).

Efficacy of First-Line Olomorasib and Pembrolizumab

The objective response rate (ORR) in efficacy-evaluable patients (n=84) was 73% (95% CI, 61.8-81.8) in patients with any PD-L1 score. In patients with a PD-L1 score of ≥50% (n=54), the ORR was 78% (95% CI, 64.4-88.0). Efficacy-evaluable patients had at least one post-baseline response assessment or had discontinued treatment before the first post-baseline response assessment. The median duration of follow-up was 12.4 months, and median duration of response (DOR) was not reached.⁵

Safety Profile of First-Line Olomorasib and Pembrolizumab

The safety profile of olomorasib plus pembrolizumab was consistent with known safety data for these therapies. Treatment-related adverse events (TRAEs) were manageable with dose modifications and/or corticosteroids.⁵ The TRAEs in this analysis are summarized in Table 2.

**Table 2.** Treatment-Related Adverse Events^a Occurring in at Least 10% of Patients, and Other Events of Interest, in the Integrated Analysis⁵
	Olomorasib and Pembrolizumab (N=85)^b,c
TRAE^d	Any Grade	Grade 1	Grade 2	Grade 3	Grade 4
Any TRAE	76 (89.4)	14 (16.5)	28 (32.9)	28 (32.9)	6 (7.1)
Diarrhea	26 (30.6)	9 (10.6)	11 (12.9)	6 (7.1)	0
ALT increased	22 (25.9)	5 (5.9)	3 (3.5)	13 (15.3)	1 (1.2)
AST increased	20 (23.5)	4 (4.7)	4 (4.7)	11 (12.9)	1 (1.2)
Nausea	14 (16.5)	8 (9.4)	6 (7.1)	0	0
Fatigue	11 (12.9)	4 (4.7)	7 (8.2)	0	0
Pruritus	11 (12.9)	9 (10.6)	2 (2.4)	0	0
Vomiting	11 (12.9)	6 (7.1)	5 (5.9)	0	0
Decreased appetite	9 (10.6)	5 (5.9)	4 (4.7)	0	0
Other TRAE of interest
Pneumonitis/ILD	2 (2.4)	0	0	1 (1.2)	1 (1.2)

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BID = twice daily; ILD = interstitial lung disease; IQR = interquartile range; TRAE = treatment-related adverse event.

^aTRAEs are olomorasib and/or pembrolizumab related. No patient had grade 5 TRAEs.

^bSafety population consists of 85 patients who received at least one dose of study treatment. Olomorasib dose 50 or 100 mg BID.

^cMedian duration of treatment (IQR) was 10.3 (5.6-13.3) months.

^dData are n (%) unless otherwise indicated.

A total of 29 patients (34.1% of the safety population) experienced dose reductions of olomorasib due to TRAEs. Reasons for dose reductions included

alanine aminotransferase/aspartate aminotransferase (ALT/AST) increased (n=9)
diarrhea (n=8)
hepatitis (n=2), and
liver disorder, dysphagia, cholecystitis, fatigue, rash, pneumonitis, lung injury, myalgia, peripheral edema, and rhabdomyolysis (all n=1).⁵

A total of 10 patients (11.8%) discontinued the treatment regimen of olomorasib and pembrolizumab due to TRAEs. The most common reason for permanent discontinuation was hepatitis (n=3). One patient each discontinued due to

ALT increased
AST increased followed by ALT increased
diarrhea followed by ALT/AST increased
diabetic ketoacidosis followed by diarrhea
rash
pulmonary toxicity, and
pneumonitis.⁵

The median time to onset of grade ≥3 hepatic events was 61 days (range, 23-302), and the median duration of grade ≥3 hepatic events was 7 days. All grade ≥3 hepatic events resolved to grade 1 or baseline after dose modifications and/or corticosteroids. No concurrent clinical symptoms were observed.⁵

At an updated analysis (median duration of follow-up, 20.1 months), TRAEs of any grade occurred in 77 patients (90.6%) of the safety population (n=85). TRAEs were

grade 1 in 11 patients (12.9%)
grade 2 in 29 patients (34.1%)
grade 3 in 31 patients (36.5%), and
grade 4 in 6 patients (7.1%).⁷

No grade 5 TRAEs were reported. Olomorasib in combination with pembrolizumab continued to demonstrate a manageable safety profile in the safety population across all PD-L1 expression levels.⁷

Results in Patients Who Received One Prior Cycle of SOC or No Prior SOC Treatment Before Enrollment

A subgroup analysis of the 85 patients treated with olomorasib and pembrolizumab in the integrated analysis evaluated efficacy and safety outcomes by prior receipt of one cycle of SOC before enrollment (defined as one 21-day cycle of pembrolizumab 200 mg), with a median duration of follow-up of 20.7 months.⁶

Baseline characteristics of patients who did (n=14) and did not (n=71) receive one prior cycle of SOC were comparable. In efficacy-evaluable patients, the

ORR was 71.4% (95% CI, 41.9-91.6) with one prior cycle of SOC (n=14) and 72.9% (95% CI, 60.9-82.8) with no prior SOC (n=70)
disease control rate (DCR) was 100.0% (95% CI, 76.8-100.0) with one prior cycle of SOC and 88.6% (95% CI, 78.7-94.9) with no prior SOC, and
6-month progression-free survival (PFS) rates were 71.4% with one prior cycle of SOC and 78.0% with no prior SOC (12-month PFS rates were 71.4% and 63.7%, respectively).⁶

Any-grade TRAEs occurred in 100% (n=14) of patients with one prior cycle of SOC and 88.7% (n=63) of patients with no prior SOC; grade ≥3 TRAEs occurred in 35.7% (n=5) and 45.1% (n=32), and treatment regimen discontinuations due to TRAEs occurred in 14.3% (n=2) and 11.3% (n=8), respectively. No grade 5 TRAEs were reported.⁶

Prior receipt of one cycle of SOC appeared to have no detrimental effect on the safety and efficacy of olomorasib plus pembrolizumab, though the analysis was limited by small sample sizes.⁶

Results in Patients With PD-L1 Expression Level of 0% to 49%

An integrated analysis from the dose optimization cohorts of LOXO-RAS-20001 and SUNRAY-01 (median duration of follow-up, 20.1 months) evaluated first-line olomorasib and pembrolizumab in 31 patients with PD-L1 expression 0% to 49% (13 with PD-L1 <1% and 18 with PD-L1 1%-49%).⁷

In efficacy-evaluable patients (n=30), the

ORR was 63.3% (19/30)
DCR was 90.0% (27/30)
median time to response was 1.5 months (95% CI, 1.3-2.9), and
median DOR was 12.6 months (95% CI, 6.2 to not evaluable [NE]).⁷

In the PD-L1 <1% subgroup (n=12), the

ORR was 58.3% (7/12)
DCR was 91.7% (11/12), and
median DOR was 9.9 months (95% CI, 4.4-NE).⁷

In the PD-L1 1% to 49% subgroup (n=18), the

ORR was 66.7% (12/18)
DCR was 88.9% (16/18), and
median DOR was NE (95% CI, 4.1-NE).⁷

At the time of analysis, 29% of patients with PD-L1 expression of 0% to 49% had received treatment for at least 12 months and remained on treatment.⁷

Safety was not assessed specifically in the subgroup of patients with PD-L1 expression of 0% to 49%. Safety across all treated patients (PD-L1 expression 0%-100%) is presented in the Safety Profile of First-Line Olomorasib and Pembrolizumab section above.⁷

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SUNRAY-01: Phase 3 Study in Advanced/Metastatic NSCLC

SUNRAY-01 (NCT06119581) is a global, phase 3 study evaluating olomorasib, a KRAS G12C inhibitor, plus pembrolizumab with or without chemotherapy in first-line advanced KRAS G12C-mutant NSCLC.⁴

The SUNRAY-01 study design incorporates pragmatic elements including

the allowance of one cycle of SOC prior to enrollment in cases where immediate treatment is clinically indicated, while awaiting screening results and/or considering treatment options
flexible enrollment using local biomarker testing (tissue or liquid), and
^a reduced operational burden by consolidating patient populations under a single trial protocol.⁸

As of August 2026, recruitment for the phase 3 trial is ongoing.³

Eligibility

Eligible patients for the SUNRAY-01 trial must

be ≥18 years of age with ECOG PS of 0-1
have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
have stage IIIB-IIIC or IV NSCLC not suitable for curative intent radical surgery or radiation therapy, and
have KRAS G12C mutation in tumor or blood and known PD-L1 expression (0%-100%; ≥50% in part A only).^3,4

Participants with asymptomatic (lesion ≤1.5 cm) or previously treated radiographically and clinically stable brain metastases are eligible.⁴

Prior systemic therapy for advanced or metastatic NSCLC is not permitted; however, patients who had received one cycle of SOC treatment prior to enrollment are allowed if immediate treatment is clinically indicated.⁴

Study Design and Endpoints

Part A

Following dose optimization for olomorasib (50 mg vs 100 mg twice daily) in combination with pembrolizumab, patients (n=384) will be randomized 1:1 to receive either olomorasib plus pembrolizumab or placebo plus pembrolizumab. Participants with PD-L1 expression ≥50% are eligible to be enrolled at the discretion of the investigator.⁴

The primary objective of part A of the phase 3 study is to compare the efficacy of olomorasib plus pembrolizumab based on PFS per RECIST version 1.1 as assessed by blinded independent central review (BICR).⁴

Part B

Following confirmation of the optimal dose of olomorasib in the safety lead-in portion, patients (n=552) will be randomized 1:1 to receive either olomorasib or placebo in combination with pembrolizumab, pemetrexed, and a platinum agent (for 4 cycles). Participants with PD-L1 expression 0% to 100% are eligible to be enrolled at the discretion of the investigator.⁴

The primary objective of part B of the phase 3 study is to compare the efficacy of olomorasib with pembrolizumab, pemetrexed, and platinum based on PFS per RECIST version 1.1 as assessed by BICR.⁴

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LOXO-RAS-20001: Phase 1A/B Study

The LOXO-RAS-20001 study (NCT04956640) is an open-label, multicenter, phase 1 study to evaluate safety, tolerability, and preliminary efficacy of olomorasib in patients with KRAS G12C-mutant tumors. This study is being conducted in multiple parts including dose escalation and dose expansion, which will evaluate olomorasib as monotherapy and in combination with other drugs.^1,2

Eligibility

Eligible patients for the phase 1a dose escalation portion must

be ≥18 years of age
have an ECOG PS of 0-1
have measurable disease per RECIST version 1.1
have locally advanced/metastatic solid tumor, and
have locally assessed KRAS G12C mutation.¹

Study Design and Endpoints

The key objectives of this study are to

evaluate safety and tolerability
determine the maximum tolerated dose and recommended phase 2 dose
evaluate pharmacokinetics, and
evaluate ORR and DOR per RECIST version 1.1.¹

In the phase 1a monotherapy escalation portion, the study uses a modified toxicity probability interval 2 design. Patients will be dosed in a 21-day cycle with a dose-limiting toxicity evaluation period, allowing for intrapatient dose escalation. In patients with any KRAS G12C-mutant advanced tumors, the dose of olomorasib could be escalated from 50 mg twice daily up to 200 mg twice daily.¹

The phase 1b combination expansion is further split into several arms to study various combinations and tumor types.⁹

A pan-tumor analysis was also performed that includes patients from the phase 1a monotherapy portion and phase 1b portion with various tumor types.¹⁰

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References

The published reference below is available by contacting 1-800-LillyRx (1-800-545-5979).

Murciano-Goroff YR, Heist RS, Kuboki Y, et al. A first-in-human phase 1 study of LY3537982, a highly selective and potent KRAS G12C inhibitor in patients with KRAS G12C-mutant advanced solid tumors. Poster presented at: 114th Annual Meeting of the American Association for Cancer Research (AACR); April 14-19, 2023; Orlando, FL.
Study of LY3537982 in cancer patients with a specific genetic mutation (KRAS G12C). ClinicalTrials.gov identifier: NCT04956640. Updated May 29, 2026. Accessed August 14, 2026. https://clinicaltrials.gov/study/NCT04956640
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 (SUNRAY-01). ClinicalTrials.gov identifier: NCT06119581. Updated July 20, 2026. Accessed August 14, 2026. https://clinicaltrials.gov/study/NCT06119581
Negrao MV, Arbour KC, Burns TF, et al. SUNRAY-01, a pivotal, global study of olomorasib (LY3537982) in combination with pembrolizumab with or without chemotherapy for 1L treatment in KRAS G12C-mutant advanced NSCLC (trial in progress). Poster presented at: 60th Annual Meeting of the American Society of Clinical Oncology (ASCO); May 31-June 4, 2024; Chicago, IL.
Johnson ML, Mateos LL, Yamada T, et al. Efficacy and safety of 1L olomorasib plus pembrolizumab in KRAS G12C-mutant NSCLC: results from LOXO-RAS-20001 and SUNRAY-01. Poster presented at: 26th World Conference on Lung Cancer (WCLC); September 6-9, 2025; Barcelona, Spain.
Burns TF, Fujiwara Y, Lin VTG, et al. First-line olomorasib plus pembrolizumab ± chemotherapy in KRAS G12C-mutant NSCLC patients ± a prior cycle of SOC: results from LOXO-RAS 20001 and SUNRAY-01. Poster presented at: 62nd Annual Meeting of the American Society of Clinical Oncology (ASCO); May 29-June 2, 2026; Chicago, IL.
Chan BA, Peters S, Mateos LL, et al. First-line olomorasib plus pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC, and PD-L1 expression 0-49%, from the dose optimization cohorts of LOXO-RAS-20001 and SUNRAY-01. Poster presented at: 62nd Annual Meeting of American Society of Clinical Oncology (ASCO); May 29-June 2, 2026; Chicago, IL.
Hochmair MJ, Arbour KC, Negrao MV, et al. Enhancing enrollment to 1L NSCLC trials by allowing 1 prior cycle of standard of care (SOC): SUNRAY-01 experience. J Thorac Oncol. 2025;20(3 suppl 1):S78-S79. International Association for the Study of Lung Cancer abstract 109P. https://doi.org/10.1016/S1556-0864(25)00304-1
Burns TF, Dragnev K, Fujiwara Y, et al. 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. Poster presented at: 60th Annual Meeting of the American Society of Clinical Oncology (ASCO); May 31-June 4, 2024; Chicago, IL.
Heist RS, Koyama T, Murciano-Goroff YR, et al. Pan-tumor activity of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in patients with KRAS G12C-mutant advanced solid tumors. Poster presented at: 60th Annual Meeting of the American Society of Clinical Oncology (ASCO); May 31-June 4, 2024; Chicago, IL.

Date of Last Review: August 14, 2026

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