Enozertinib (ORIC-114) Program Update

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are being studied. 2

Enozertinib Program Update Agenda Executive Summary

Preclinical Differentiation ESMO Asia Clinical Highlights - 2L EGFR exon 20 - 1L EGFR exon 20 - Pretreated EGFR PACC 1L EGFR PACC (Preliminary Data) Executive Summary and Next Steps ORIC Participants

Jacob Chacko, Chief Executive Officer Lori Friedman, Chief Scientific Officer Pratik Multani, Chief Medical Officer Dominic Piscitelli, Chief Financial Officer Matt Panuwat, Chief Business Officer Keith Lui,

SVP Commercial and Medical Affairs 3

Enozertinib Establishes Potential Best-in-Class Profile in EGFR-Mutated

NSCLC Systemic activity in 2L EGFR exon 20 and pretreated EGFR PACC exceeds competitor benchmarks Highly competitive preliminary 1L systemic activity, with 67% ORR in EGFR exon 20 and 80% ORR in EGFR PACC Convincing 1L CNS

activity, with 100% intracranial ORR in EGFR exon 20 and 100% intracranial ORR in EGFR PACC, including in patients with active brain metastases Competitive safety profile, with no significant off-target toxicity and manageable on-target

toxicity, resulting in low rate of discontinuations 80 mg once-daily selected as recommended dose for potential Phase 3 development Enrollment and follow-up continues in 1L EGFR exon 20 and 1L EGFR PACC with next update (1) expected

mid-2026, ahead of potential initiation of Phase 3 trial(s) Source: John et al. ESMO Asia (2025), Hong et al. ESMO Asia (2025), and ORIC data on file. 5 (1) Enrollment in HER2 exon 20 has been completed with no further development planned in this

Enozertinib Is Pursuing a Significant Commercial Opportunity Across

Patient Populations that Lack an Approved CNS Active Agent Estimated Enozertinib Commercial Opportunity (US Only) 10,000 ~9,000 patients (~5% of NSCLC) diagnosed annually 8,000 EGFR exon 20 mutant NSCLC: no approved CNS-active 5,000

patients therapies 6,000 EGFR PACC mutant NSCLC: no approved therapies 4,000 Potential commercial opportunity of 2,000 4,000 patients ~$3.0 to $3.5 billion in the US annually 0 EGFR Exon 20 EGFR PACC Enozertinib has the potential to address

~9,000 patients with NSCLC annually, representing a commercial opportunity of ~$3.0 to $3.5 billion in the US alone Source: American Cancer Society Cancer Facts & Figures 2025, Heymach et al. WCLC (2018), and Robichaux et al. Nature (2021).

Note: Estimated addressable market assumes 11.4-month treatment duration for EGFR exon 20 based on Girard et al. N Engl J Med (2023), 16.0-month treatment duration based on Le et al. WCLC (2025), and current price of tyrosine kinase 6 inhibitors for

NSCLC. Estimated Annual Incidence in the US

Best-in-Class Profile Yet to Emerge in Treatment Landscape for NSCLC

Patients Harboring EGFR Exon 20 and EGFR PACC Mutations What is a Best-In-Class Target Product Profile for an EGFR Exon 20 and EGFR PACC Inhibitor? Manageable on-target toxicities (e.g., GI and skin) Safety / No significant off-target

toxicities (e.g., cardiac, hematologic and liver) Tolerability Low rate of treatment discontinuations Strong systemic antitumor activity Systemic and CNS Treatment of active brain metastases Activity Prevention of CNS

progression Durability of Strong systemic and CNS activity with a manageable safety profile Response translates to differentiated long-term clinical benefit There remains an unmet need for a highly selective EGFR inhibitor that is also

brain-penetrant to effectively treat and prevent intracranial disease 7

High Burden of CNS Disease in NSCLC Patients with EGFR Mutations Leads

to Disease Progression and Limited Survival with Current Therapies Initial Diagnosis Disease Progression on Treatment CNS Disease Highly ~50% of patients eventually develop Prevalent in EGFR ~30% of patients have known brain metastases, often as the

first (1) CNS disease at diagnosis Mutated NSCLC (2) site of progression (3) (4) Mobocertinib Amivantamab + Chemotherapy Median Progression Free Survival Risk of Progression or Death vs. Control Arm And Patients With Patients Without

8.1 Patients Without 67% Risk CNS Metastases Derive Baseline CNS Mets months History of Brain Mets Reduction Limited Benefit From Non-CNS-Active Drugs 3.7 37% Risk Patients With Patients With months Reduction Baseline CNS Mets History of Brain Mets

An effective, brain-penetrant therapy can potentially drive long-term outcomes and extend survival through durable CNS control (1) Patil et al. Clin Lung Cancer (2021). (2) Wilcox et al. Ann Oncol. (3) Janne et al. ASCO (2019) and Ramalingam et al.

ASCO (2021). (4) Girard et al. ESMO Presentation (2023). 8

Enozertinib Phase 1b Data Establishes Potential Best-in-Class Profile in

EGFR Exon 20 and PACC Mutated NSCLC Enozertinib Updated Phase 1b Data Highlights 2L EGFR Exon 20 Median 3L EGFR PACC 45% 36% ORR ORR Enozertinib Enozertinib Previously Treated 22% 40% Benchmark ORR Benchmark ORR 1L EGFR Exon 20 (Preliminary Data) 1L

EGFR PACC (Preliminary Data) 80% ORR 67% ORR Enozertinib Enozertinib Treatment- Na ve (1L) Intracranial ORR Enozertinib 100% Intracranial ORR Enozertinib 100% Enozertinib data in previously treated patients with EGFR exon 20 and PACC mutations

exceed competitor benchmarks; preliminary 1L systemic and intracranial activity establishes potential best-in-class profile Source: John et al. ESMO Asia (2025), Hong et al. ESMO Asia (2025), and ORIC data on file. Benchmark ORR: Piotrowska et al. J

Clin Oncol (2025) and Udagawa et al. WCLC (2025). Note: All data in previously treated patients represent confirmed ORR. All data in 1L patients represent best ORR, due to preliminary nature of data. 1L EGFR exon 20 intracranial ORR data in all

patients with measurable CNS disease by BICR-RANO 9 and 1L EGFR PACC intracranial ORR data in all patients with measurable CNS disease by investigator assessment using RECIST.

Preclinical Differentiation

Enozertinib Is a Promising Candidate for NSCLC Patients with EGFR Exon

20 and PACC Mutations, Including Those with Brain Metastases Enozertinib Target Candidate Profile Differentiated Profile Validated in Phase 1b in Patients with Strong potency against EGFR exon 20 and EGFR Exon 20 and PACC Mutations atypical

mutations; superior to competitors Tumor regressions in multiple in vivo models Robust Mutant Potency Exquisite selectivity with limited potential for off-target activity Potency responses in breadth of Kinome

selectivity superior to competitors Exquisite Selectivity EGFR mutants Selectivity minimized off-target tox High unbound (free) brain exposures in vivo Brain-penetrance robust Substantial tumor

regression in intracranial intracranial responses efficacy studies Highly Brain Penetrant Enozertinib is a potential best-in-class inhibitor of EGFR exon 20 and PACC mutations, with superior potency and selectivity, and excellent brain-penetrance

driving intracranial responses 11

Enozertinib Best-in-Class Potency Across Breadth of EGFR Exon 20 and

Atypical Mutations In Vitro Potency Comparison EC50 (nM) >100 Zipalertinib Firmonertinib Silevertinib Enozertinib 100 L858R Classical del19 763_FQEA 769_ASV Exon 20 770_NPG Insertion 770_SVD 80 773_NPH E709A E709K L718Q L718V 60 G719A G719C G719S

G724S Atypical L747P PACC L747S 40 S768I E709A/ G719S G719A/ L861Q del19 / L792H del19 / G796S L858R / L718V 20 L858R / L718Q M277E A289V Atypical A289T Other L861Q Enozertinib displays superior potency across EGFR exon 20 and atypical mutations in

vitro, including PACC singleton and complex mutations Source: Junttila et al. Cancer Research 2025. 12

Enozertinib Was Designed to Selectively Target EGFR with High Potency

Against Exon 20 and Atypical Mutations Kinome Selectivity Comparison Zipalertinib Firmonertinib Silevertinib Enozertinib Off-target Wildtype Kinases Inhibited 80% at 1 M Enozertinib Zipalertinib Firmonertinib Silevertinib 0 7 4

25 Enozertinib has demonstrated an exquisitely clean kinome panel, mitigating the potential for off-target toxicities Source: Junttila et al. Cancer Research 2025. Note: Kinase binding profiles across 468 kinases at 1 M assessed using

KINOMEscan. Red circles indicate kinases impacted within 10% of control. Table reports the number of off-target (non-EGFR/HER2) wildtype kinases inhibited 80% or more. 13

Superior Brain Penetration of Enozertinib Differentiates from

Comparator Agents Enozertinib Exhibits High Ratio of Free (Unbound) Enozertinib CNS Efficacy vs. Mobocertinib in Intracranial Brain/Plasma Exposure in Mice NSCLC EGFR Mutant In Vivo Model 9 10 10 Vehicle 8 10 1 7 10 0.1 Mobocertinib 6 (30 mg/kg QD)

10 0.01 5 10 Enozertinib (2.5 mg/kg QD) BQL 4 10 0.001 0 5 10 15 Osimertinib Mobocertinib Zipalertinib Enozertinib Days After Treatment Enozertinib preclinical profile demonstrates superior CNS properties and strong tumor regressions in an

intracranial NSCLC model, with potential to treat patients with brain metastases and delay CNS progression Source: Junttila et al. Cancer Research 2025. Note: BQL - below quantifiable limits. 14 Bioluminescence (photons/sec)

ESMO Asia Clinical Highlights EGFR Exon 20 Mutant NSCLC

Enozertinib Phase 1b Trial Enrolled Patients with Previously Treated

and Treatment- Na ve NSCLC with EGFR Exon 20 Mutations Enozertinib Phase 1b Trial Design in EGFR Exon 20 Mutations Key Eligibility Criteria: Enozertinib 2L post-chemotherapy 1:1 Randomization 80 mg QD Locally advanced or Primary

endpoint: Patients with advanced metastatic NSCLC Selection of recommended NSCLC and EGFR Enozertinib phase 2 dose (RP2D) with EGFR exon 20 exon 20 mutation 120 mg QD mutation Secondary endpoints: Investigator assessed

Untreated, stable, objective response rate asymptomatic brain (ORR) metastases allowed 1L treatment-na ve BICR-RANO CNS response Enozertinib Enozertinib Patients with advanced (1L) Treatment-na ve or NSCLC

and EGFR 120 mg QD 80 mg QD Safety received 1L exon 20 mutation platinum-based chemotherapy Enrolled 1L and 2L NSCLC patients with EGFR exon 20 mutations, including those with active untreated brain metastases Note: Tumor restaging,

including with brain MRI, performed at 4 weeks and every 8 weeks thereafter. BICR - blinded independent central review; QD - once-daily. 16

Phase 1b Trial Patient Demographics and Baseline Characteristics 2L

post-chemotherapy, advanced NSCLC with EGFR exon 20 mutations 80 mg 120 mg (n=24) (n=21) Age, years, median (range) 63 (44-75) 70 (28-86) Female, n (%) 17 (71) 16 (76) Non-smoker, n (%) 22 (92) 21 (100) Race: Asian / White / Other, % 42 / 50 / 8 57

/ 43 / 0 ECOG performance: 0 / 1, % 29 / 71 19 / 81 Brain metastases at baseline*, n (%) 10 (42) 7 (33) Prior chemotherapy 24 (100) 21 (100) Prior EGFR targeted therapies 0 2 (10) 38% of 2L patients had brain metastases at study entry,

including those with active CNS disease Source: John et al. ESMO Asia (2025). Note: Data as of August 29, 2025. * Patients with brain metastases at study entry, including active brain metastases. One patient each received prior erlotinib or

Enozertinib Has Been Generally Well Tolerated Despite Enrolling

Heavily-Pretreated Patients and a Less Stringent Enrollment Criteria for Baseline CNS Disease 2L post-chemotherapy, advanced NSCLC with EGFR exon 20 mutations Treatment-Related Adverse Events (TRAEs) in 20% of Patients 80 mg 120 mg 80 mg 120

mg Event, n (%) Event, n (%) (n=24) (n=21) (n=24) (n=21) Preferred term, n (%) Grade 1-2 Grade 3 Grade 1-2 Grade 3 TRAEs Grade 3 10 (42) 7 (33) Diarrhea 19 (79) 2 (8) 12 (57) 5 (24) Dose reduction due to 8 (33) 12 (57) TRAE Paronychia 20 (83)

0 14 (67) 0 Discontinued due to 3 (13) 0 Stomatitis 10 (42) 0 12 (57) 1 (5) TRAE Dermatitis acneiform 9 (38) 1 (4) 4 (19) 0 Well tolerated safety profile with TRAEs Rash 9 (38) 1 (4) 12 (57) 1 (5) predominantly Grades 1-2 Nausea 8 (33) 0 9

(43) 0 One Grade 4 TRAE (pneumonitis at 120 mg); no Grade 5 TRAEs Decreased appetite 6 (25) 0 6 (29) 0 No significant off-target toxicities (e.g., cardiac, Mucosal inflammation 6 (25) 0 3 (14) 0 hematologic and liver) Alopecia 6 (25)

0 5 (24) 0 Low rate of discontinuations due to TRAEs Dysgeusia 8 (33) 0 2 (10) 0 Enozertinib was generally well tolerated with mainly Grade 1 or 2 adverse events and no significant off-target toxicities; 80 mg cohort experienced lower rate

of dose reductions compared to 120 mg cohort Source: John et al. ESMO Asia (2025). Note: Data as of August 29, 2025. 18

Enozertinib Achieved Robust Circulating Tumor DNA (ctDNA) Responses 2L

post-chemotherapy, advanced NSCLC with EGFR exon 20 mutations Patients with Available ctDNA (n=25) 40 80 mg 120 mg 20 0 ctDNA clearance rate of 69% (11/16) at 80 -20 mg and 67% (6/9) at 120 mg -40 -60 -80 -100 Enozertinib achieved robust