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

Olomorasib plus chemoimmunotherapy showed an ORR of 61% across PD-L1 subgroups and demonstrated a manageable safety profile, with common grade ≥3 TRAEs including neutropenia, anemia, and ALT/AST elevations.

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Content Overview

Olomorasib: Combination with Chemoimmunotherapy 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 Chemoimmunotherapy in First-Line Treatment of Advanced/Metastatic NSCLC

Olomorasib (LY3537982) is a potent, oral, highly selective inhibitor of guanosine diphosphate-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=77) combined 37 patients from the LOXO-RAS-20001 phase 1 study and 40 patients from the safety lead-in portion of SUNRAY-01 receiving olomorasib plus chemoimmunotherapy for KRAS G12C-mutant advanced/metastatic NSCLC in the first-line setting.⁵

Integrated Analysis Eligibility and Design

Eligibility criteria for the integrated analysis from LOXO-RAS-20001 and SUNRAY-01 included

confirmed stage IIIB-IIIC or IV non-squamous NSCLC
no prior therapy for advanced or metastatic NSCLC (patients could have received up to one cycle of SOC prior to enrollment)
all programmed death-ligand 1 (PD-L1) expression levels permitted
Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (with one exception of ECOG PS 2 after screening), and
small (≤1.5 cm), asymptomatic untreated or treated stable brain metastases.⁵

The integrated analysis evaluating the combination of olomorasib and chemoimmunotherapy in first-line NSCLC included patients from cohort B9 of the LOXO-RAS-20001 study and the safety lead-in phase for part B of SUNRAY-01.^4,5

Patients received olomorasib 50 mg or 100 mg twice daily, pembrolizumab 200 mg every 3 weeks (Q3W), pemetrexed 500 mg/m² Q3W, and a platinum agent (either cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min Q3W [maximum dose: 750 mg]).⁵

Results

Baseline Characteristics

Baseline characteristics for the 77 patients included in the integrated analysis are summarized in Table 1.

**Table 1.** Patient and Disease Characteristics of Integrated Analysis of LOXO-RAS-20001 and SUNRAY-01⁵
Characteristic^a	Olomorasib + Pembrolizumab + Pemetrexed + Platinum (N=77)^b
Age, median, years (range)	66.0 (45-83)
Sex
Male	45 (58.4)
Female	32 (41.6)
Race
White	42 (54.5)
Asian	23 (29.9)
Black	5 (6.5)
Not reported	7 (9.1)
ECOG PS^c
0	27 (35.1)
1	49 (63.6)
2	1 (1.3)
Smoking status
Former or current	69 (89.6)
Never	6 (7.8)
Not reported	2 (2.6)
PD-L1 score^d
<1%	26 (33.8)
1%-49%	31 (40.3)
≥50%	18 (23.4)
Unknown	2 (2.6)
Brain metastases
Yes	14 (18.2)
No	63 (81.8)
Prior neoadjuvant/adjuvant therapy
Anti-PD-(L)1 therapy	2 (2.6)
Received 1 cycle of SOC prior to enrollment^e
Yes	23 (29.9)
No	54 (70.1)

Abbreviations: BID = twice daily; ECOG PS = Eastern Cooperative Oncology Group performance status; PD-(L)1 = programmed death-ligand 1; SOC = standard of care.

^aData are presented as n (%) unless otherwise specified.

^bTotal number of patients includes 32 patients treated with olomorasib 50 mg BID, and 45 patients treated with olomorasib 100 mg BID. Total % may be different from the individual components due to rounding.

^cOne patient had a change in ECOG PS from 1 at screening to 2 by cycle 1 day 1.

^dLocal testing allowed for PD-L1 expression.

^ePatients may have received up to 1 cycle of standard of care prior to enrollment (defined as one 21-day cycle of any combination of pembrolizumab, pemetrexed, and carboplatin or cisplatin).

Efficacy of First-Line Olomorasib and Chemoimmunotherapy

The objective response rate (ORR) was 61% (95% CI, 49.2-72.0) for all patients (N=77), with ORRs of 50%, 68%, and 67% observed in patients with PD-L1 <1%, 1% to 49%, and ≥50%, respectively.⁵ The results are summarized in Table 2.

**Table 2.** Objective Response Rates and Best Overall Response in Patients Receiving Olomorasib and Chemoimmunotherapy in the Integrated Analysis⁵
	Efficacy Evaluable Patients Receiving Olomorasib + Pembrolizumab + Pemetrexed + Platinum^a
Efficacy Measure	All Patients (PD-L1 0%-100%) (N=77)	PD-L1 <1% (n=26)	PD-L1 1%-49% (n=31)	PD-L1 ≥50% (n=18)
ORR^b,c (%) (95% CI)	61 (49.2-72.0)	50 (29.9-70.1)	68 (48.6-83.3)	67 (41.0-86.7)
BOR, n (%)
CR	1 (1)	0	1 (3)	0
PR^d	46 (60)	13 (50)	20 (65)	12 (67)
SD	22 (29)	9 (35)	8 (26)	5 (28)
PD	3 (4)	2 (8)	0	0
NE	5 (7)	2 (8)	2 (7)	1 (6)
DCR (%) (95% CI)	90 (80.6-95.4)	85 (65.1-95.6)	94 (78.6-99.2)	94 (72.7-99.9)

Abbreviations: BOR = best overall response; CR = complete response; DCR = disease control rate; NE = not evaluable; ORR = objective response rate; PD = progressive disease; PD-L1 = programmed death-ligand 1; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease.

^aEfficacy evaluable patients are those who had at least one postbaseline response assessment or had discontinued treatment before the first postbaseline response assessment.

^bORR includes patients with a best response of PR (confirmed, and pending confirmation and ongoing).

^cInvestigator-assessed response per RECIST version 1.1.

^dOne patient has unconfirmed PR pending confirmation and ongoing.

The median follow-up time was 9.7 months and 64% of patients had at least 6 months of ongoing treatment. Most patients responded early to treatment with a median time to response of 1.4 months (95% CI, 1.4-2.6). Durable responses were seen in populations with PD-L1 0% to 49% and ≥50%.⁵

Safety Profile of First-Line Olomorasib and Chemoimmunotherapy

The combination of olomorasib, pembrolizumab, pemetrexed, and platinum demonstrated a manageable safety profile, with treatment-related adverse events (TRAEs) reported in 96.1% of patients (any grade) and no grade 5 TRAEs.⁵ The TRAEs in this analysis are summarized in Table 3.

**Table 3.** Treatment-Related Adverse Events Occurring in at Least 10% of Patients, and Other Events of Interest, in the Integrated Analysis⁵
	Olomorasib^a + Pembrolizumab + Pemetrexed + Platinum (N=77)
Adverse Event, n (%)	Any Grade	Grade 1	Grade 2	Grade 3	Grade 4
Any TRAE	74 (96.1)	7 (9.1)	29 (37.7)	26 (33.8)	12 (15.6)
Nausea	34 (44.2)	18 (23.4)	13 (16.9)	3 (3.9)	0
Anemia	31 (40.3)	6 (7.8)	14 (18.2)	10 (13.0)	1 (1.3)
Fatigue	29 (37.7)	15 (19.5)	13 (16.9)	1 (1.3)	0
AST increased	24 (31.2)	10 (13.0)	6 (7.8)	7 (9.1)	1 (1.3)
Diarrhea	24 (31.2)	12 (15.6)	8 (10.4)	4 (5.2)	0
Neutropenia	22 (28.6)	2 (2.6)	4 (5.2)	6 (7.8)	10 (13.0)
ALT increased	21 (27.3)	7 (9.1)	5 (6.5)	9 (11.7)	0
Platelet count decreased	13 (16.9)	3 (3.9)	2 (2.6)	3 (3.9)	5 (6.5)
Blood creatinine increased	11 (14.3)	7 (9.1)	4 (5.2)	0	0
Constipation	11 (14.3)	7 (9.1)	4 (5.2)	0	0
Vomiting	11 (14.3)	5 (6.5)	5 (6.5)	1 (1.3)	0
WBC count decreased	11 (14.3)	3 (3.9)	1 (1.3)	4 (5.2)	3 (3.9)
Decreased appetite	9 (11.7)	5 (6.5)	3 (3.9)	1 (1.3)	0
Pneumonitis/ILD	8 (10.4)	0	6 (7.8)	2 (2.6)	0
Pruritus	8 (10.4)	4 (5.2)	4 (5.2)	0	0
Rash	8 (10.4)	4 (5.2)	3 (3.9)	1 (1.3)	0
Other TRAE of interest
Pancytopenia	2 (2.6)	0	0	1 (1.3)	1 (1.3)

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BID = twice daily; ILD = interstitial lung disease; TRAE = treatment-related adverse event; WBC = white blood cell.

^aOlomorasib 50 mg or 100 mg BID.

A total of 14 patients (18.2%) experienced a TRAE that led to dose reduction of olomorasib. Most commonly these were due to increased alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) (n=8), and neutrophil count decreased (n=2). There were 6 patients (7.8%) requiring discontinuation of the treatment regimen. Reasons for discontinuation included

pancytopenia (n=2)
pneumonitis (n=1)
interstitial pneumonia (n=1)
neutropenia followed by diarrhea (n=1), and
anemia followed by declining kidney function (n=1).⁵

The median time to onset of grade ≥3 hepatic events was 43 days (range, 13-145) with a median duration of grade ≥3 hepatic events of 4 days. There were no total bilirubin elevations >1.5 × upper limit of normal or concurrent clinical symptoms observed, and all grade ≥3 hepatic events resolved to grade 1 or baseline with dose modifications and/or corticosteroids, with no patients discontinuing the treatment regimen due to hepatic events.⁵

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

A subsequent analysis of LOXO-RAS-20001 and SUNRAY-01 compared outcomes according to whether patients had received one cycle of SOC before enrollment (defined as one 21-day cycle of pemetrexed-platinum chemotherapy ± pembrolizumab or pembrolizumab monotherapy). The median follow up time for this analysis was 20.7 months. Of the 77 patients treated with olomorasib + chemoimmunotherapy, 25 had received one prior cycle of SOC and 52 had not. Demographic and disease characteristics at baseline were comparable across these 2 subgroups.⁶

Among efficacy-evaluable patients, the

ORR was 72.0% (95% CI, 50.6-87.9) with one prior cycle of SOC and 55.8% (95% CI, 41.3-69.5) with no prior SOC
disease control rates were 92.0% (95% CI, 74.0-99.0) with one prior cycle of SOC and 86.5% (95% CI, 74.2-94.4) with no prior SOC
median time to response was 1.4 months for both subgroups, and
6-month progression-free survival (PFS) rates were 76.0% with one prior cycle of SOC and 72.9% with no prior SOC (12-month PFS rates were 45.2% and 47.8%, respectively).⁶

Any-grade TRAEs were reported for 23 patients (92.0%) who had received one prior cycle of SOC and 51 patients (98.1%) who had not, and grade ≥3 TRAEs were reported for 11 patients (44.0%) and 30 patients (57.7%), respectively. Neither subgroup had a grade 5 TRAE. Discontinuation of the treatment regimen occurred in no patients who had received one prior cycle of SOC and in 6 patients (11.5%) who had not.⁶

Receipt of one cycle of SOC before enrollment did not appear to compromise either efficacy or safety with olomorasib plus chemoimmunotherapy, although the small number of patients in each subgroup limits interpretation of these findings.⁶

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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.⁷

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 chemotherapy 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.⁸

A pan-tumor analysis was also performed that includes patients from the phase 1a monotherapy portion and phase 1b portion with various tumor types.⁹

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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 September 21, 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 September 8, 2026. Accessed September 21, 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.
Negrao MV, Uyeki JV, Cicin I, et al. Efficacy and safety of 1L olomorasib + chemoimmunotherapy 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.
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 KH, 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: September 16, 2026

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