INAVO120 Trial

[Slide 1] A Overall Survival in the Full Analysis Population 100 96.8 HI Median H 87.0 Overall 90.1 74.3 No. of Survival 75 76.7 Deaths (%) (95% CI) 65.8 Overall Survival (%) mo 67.2 56.5 Inavolisib 50 56.3 72 (44.7) 34.0 (28.4-44.8) (N=161) Inavolisib 46.3 Placebo 82 (50.0) 27.0 (22.8-38.7) (N=164) 25 Placebo Stratified hazard ratio for death, 0.67 (95% CI, 0.48-0.94) P=0.02 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Months No. at Risk Inavolisib 161 155 149 142 131 114 99 88 78 67 54 43 34 22 19 13 7 1 Placebo 164 155 142 127 119 104 90 77 63 48 42 36 32 18 10 4 2 1 B Analysis of Overall Survival in Key Subgroups Subgroup No. of Patients Median Overall Survival Hazard Ratio for Death (95% CI) Inavolisib Placebo Inavolisib Placebo mo All patients 161 164 34.0 27.0 0.76 (0.55-1.04) Age <65 yr 136 130 36.0 26.8 0.65 (0.46-0.92) >65 yr 25 34 14.4 NR 1.65 (0.77-3.51) Geographic region Asia 58 62 32.7 27.0 0.78 (0.45-1.34) North America or western Europe 63 64 30.2 29.3 0.95 (0.56-1.59) Other 40 38 36.0 16.6 0.53 (0.28-0.98) ECOG performance-status score at baseline 0 100 106 39.2 36.0 0.69 (0.45-1.05) 1 60 58 27.1 26.8 0.85 (0.52-1.38) Menopausal status at randomization Premenopausal 52 52 32.7 23.9 0.67 (0.38-1.19) Postmenopausal 104 111 34.0 28.0 0.81 (0.55-1.19) Visceral disease No 29 36 38.0 40.7 1.06 (0.46-2.46) Yes 132 128 33.0 24.1 0.70 (0.50-0.99) Liver metastases at enrollment No 84 73 38.0 36.0 0.87 (0.53-1.44) Yes 77 91 28.8 21.9 0.72 (0.48-1.10) No. of organs with metastases at enrollment 1 21 32 NR 31.9 0.77 (0.28-2.10) 2 58 46 44.8 24.1 0.51 (0.28-0.90) >3 82 86 28.8 24.2 0.86 (0.57-1.30) Resistance to endocrine therapy Primary 54 58 25.9 22.8 0.69 (0.42-1.14) Secondary 107 105 37.7 34.3 0.77 (0.51-1.16) Hormone receptor status ER-positive, PR-negative 45 45 25.9 38.7 1.16 (0.65-2.08) ER-positive, PR-positive 113 113 39.2 24.5 0.60 (0.41-0.88) Previous endocrine therapy Aromatase inhibitor and tamoxifen 18 19 NR NR 1.15 (0.38-3.44) Aromatase inhibitor only 60 71 26.3 24.2 0.89 (0.56-1.41) Tamoxifen only 82 73 44.8 36.0 0.68 (0.42-1.11) 0.10 0.67 1.00 10.00 Inavolisib Better Placebo Better

[Slide 1] San Antonio Breast Cancer Symposium®, December 5-9. 2023 9 Primary endpoint: PFS (investigator-assessed) 6-month 12-month 18-month Inavo+Palbo+Fulv Pbo+Palbo+Fulv 100 (n=161) (n=164) 82.9% No. of events, n (%) 82 (50.9) 113 (68.9) Median (95% CI), mo 15.0 (11.3,20.5) 7.3 (5.6,9.3) 75 Stratified hazard ratio (95% CI) 0.43 (0.32, 0.59) 55.9% 55.9% p<0.0001 46.2% 50 32.6% Inavo+Palbo+Fulv 21.1% 25 Pbo+Palbo+Fulv Censored 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (mo) Patients at risk: Inavo+Palbo+Fulv 161 134 111 92 66 48 41 Median follow-up: 31 22 13 11 5 1 Pbo+Palbo+Fulv 164 113 77 59 40 23 19 16 12 6 3 3 1 21.3 months CCOD: 29th September 2023 CI, confidence interval; Fulv. fulvestrant; Inavo, inavolisib; mo, months: Palbo, palbociclib; Pbo. placebo; PFS, progression-free survival. This presentation is the intellectual property of the authors. Contact jhaverik@mskcc.org for permission to reprint and/or distribute --- [Slide 2] San Antonio Breast Cancer Symposium®, December 5-9, 2023 12 Key secondary endpoint: Overall survival (interim analysis) Inavo+Palbo Pbo+Palbo 6-month 12-month 18-month +Fulv (n=161) +Fulv (n=164) No. of events, n (%) 42 (26.1) 55 (33.5) 97.3% 100 85.9% Median (95% CI), mo NE (27.3, NE) 31.1 (22.3, NE) Stratified Hazard 0.64 (0.43, 0.97) 73.7% Ratio (95% CI) p=0.0338 75 89.9% 74.9% 67.5% 50 25 Inavo+Palbo+Fulv Pbo+Palbo+Fulv Censored 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time (mo) Patients at risk: Inavo+Palbo+Fulv 161 143 127 114 101 85 69 56 38 26 17 8 4 1 1 Median follow-up: Pbo+Palbo+Fulv 164 139 120 98 87 72 61 52 33 19 11 5 3 1 0 21.3 months The pre-specified boundary for os (p of 0.0098 or HR of 0.592) was not crossed at this interim analysis CI, confidence interval: Fulv. fulvestrant; Inavo, inavolisib; mo, months: NE, not estimable; OS, overall survival; Palbo, palbociclib; Pbo, placebo. This presentation is the intellectual property of the authors. Contact jhaverik@mskcc.org for permission to reprint and/or distribute --- [Slide 3] San Antonio Breast Cancer Symposium®, December 5-9, 2023 4 INAVO120 study design Key eligibility criteria Enrolment period: December 2019 to September 2023 Enrichment of patients with poor prognosis: N=325 PIK3CA-mutated, HR+, HER2- ABC by central Inavolisib (9 mg QD PO) + palbociclib (125 mg PO QD D1-D21) ctDNA* or local tissue/ctDNA test fulvestrant (500 mg C1D1/15 and Q4W)** Measurable disease R Until PD Progression during/within 12 months of 1:1 or toxicity adjuvant ET completion Placebo (PO QD) SURVIVAL FOLLOW-UP + palbociclib (125 mg PO QD D1-D21) + No prior therapy for ABC fulvestrant (500 mg C1D1/15 and Q4W)** Fasting glucose <126 mg/dL and HbA1c <6.0% Stratification factors: Endpoints Visceral Disease (Yes vs. No) Primary: PFS by Investigator Endocrine Resistance (Primary VS. Secondary) Secondary: OSF, ORR, BOR, CBR, DOR, PROs Region (North America/Western Europe; Asia; Other) . Central testing for PIK3CA mutations was done on ctDNA using FoundationOneLiquid (Foundation Medicine). In China, the central ctDNA test was the PredicineCARE NGS assay (Huidu). : Defined per 4th European School of Oncology (ESO)-European Society for Medical Oncology (ESMO) International Consensus Guidelines for Advanced Breast Cancer.1 Primary: relapse while on the first 2 years of adjuvant ET; Secondary: relapse while on adjuvant ET after at least 2 years or relapse within 12 months of completing adjuvant ET. : OS testing only if PFS is positive; interim OS analysis at primary PFS analysis; .. Pre-menopausal women received ovarian suppression. ctDNA, circulating tumor DNA; R, randomized. 1. Cardoso F, et al. Ann Oncol 2018;29:1634-1657 This presentation is the intellectual property of the authors. Contact jhaverik@mskcc.org for permission to reprint and/or distribute --- [Slide 4] San Antonio Breast Cancer Symposium®, December 5-9, 2023 15 Adverse events with any grade AEs >20% incidence in either treatment group Adverse Events Inavo+Palbo+Fulv Pbo+Palbo+Fulv (N=162) (N=162) All Grades Grade 3-4 All Grades Grade 3-4 Neutropenia 144 (88.9%) 130 (80.2%) 147 (90.7%) 127 (78.4%) Thrombocytopenia 78 (48.1%) 23 (14.2%) 73 (45.1%) 7 (4.3%) Stomatitis/Mucosal inflammation 83 (51.2%) 9 (5.6%) 43 (26.5%) 0 Anemia 60 (37.0%) 10 (6.2%) 59 (36.4%) 3 (1.9%) Hyperglycemia 95 (58.6%) 9 (5.6%) 14 (8.6%) 0 Diarrhea 78 (48.1%) 6 (3.7%) 26 (16.0%) 0 Nausea 45 (27.8%) 1 (0.6%) 27 (16.7%) 0 Rash 41 (25.3%) 0 28 (17.3%) 0 Decreased Appetite 38 (23.5%) <2% 14 (8.6%) <2% Fatigue 38 (23.5%) <2% 21 (13.0%) <2% COVID-19 37 (22.8%) <2% 17 (10.5%) <2% Headache 34 (21.0%) <2% 22 (13.6%) <2% Leukopenia 28 (17.3%) 11 (6.8%) 40 (24.7%) 17 (10.5%) Ocular Toxicities 36 (22.2%) 0 21 (13.0%) 0 Key AEs are shown in bold. AES were assessed per CTCAE V5. Neutropenia, thrombocytopenia, stomatitis/mucosal inflammation, anemia, hyperglycemia, diarrhea, nausea and rash were assessed as medical concepts using grouped terms AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Fulv, fulvestrant; Inavo, inavolisib; Palbo, palbociclib; Pbo, placebo. This presentation is the intellectual property of the authors. Contact jhaverik@mskcc.org for permission to reprint and/or distribute

[Slide 1] 2025 ASCO® ANNUAL MEETING --- [Slide 2] INAVO120: A Phase III, randomized, double-blind, placebo-controlled study¹,² Key eligibility criteria Enrollment period: January 2020 to September 2023 Enrichment of patients with poor prognosis: N 325 Inavolisib (9 mg PO QD) PIK3CA-mutated, HR+, HER2- aBC by central + palbociclib (125 mg PO QD D1-D21) ctDNA* or local tissue/ctDNA test + fulvestrant (500 mg C1D1/15 and Q4W)+ R Until PD Measurable disease 1:1 or toxicity Placebo (PO QD) SURVIVAL FOLLOW-UP Progression during/within 12 months of + palbociclib (125 mg PO QD D1-D21) adjuvant ET completion + fulvestrant (500 mg C1D1/15 and Q4W)t No prior therapy for aBC Stratification factors: Fasting glucose <126 mg/dL and HbA1c <6.0% Visceral disease (yes vs. no) Endocrine resistance (primary vs. secondary): Region (North America/Western Europe VS. Asia vs. Other) Primary endpoint: Investigator-assessed PFS Secondary endpoints included: OS; investigator-assessed ORR, BOR, CBR, and DoR; PROs ClinicalTrials gov number, NCT04191499 Adapted from Jhaven KJ, of al. SABCS 2023 (Abstract GS03-13). Central testing for PIK3CA mutations was done on CIDNA using FoundationOneLiquid (Foundation Medicine, Inc.). In China, the central ctDNA test was the PredicineCARE NGS assay (Huidu); Pre-menopausal women received ovarian suppression; Defined per 4th European School of Oncology (ESO)-European Society for Medical Oncology (ESMO) International Consensus Guidelines for Advanced Breast Cancer.3 Primary: Relapse while on the first 2 years of adjuvant ET; secondary: Relapse while on adjuvant ET after at least 2 years or misses within 12 months of completing adjuvant ET. aBC, advanced breast cancer; BOR, best overall response; C, cycle; CBR, clinical benefit rate; ctDNA, circulating tumor DNA D, day: DoR duration of response; ET, endocrine therapy: HbAse glycated hemoglobin; HER2-, HER2-negative; QD, daily; R, randomization HR+, hormone receptor-positive; NGS, next-generation sequencing: ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, by mouth; PRO, patient-reported outcome; Q4W, every 4 weeks; 1. Turner NC, of at. N Engl J Med 2024; 391:1584-1596 2. Jhaven KJ, of al. SABCS 2023 (Abstract GS03-13); 3. Cardoso F, or at Ann Oncol 2018; 29:1634-1657 2025 ASCO #ASCO25 PRESENTED BY: Nicholas Turner, MD, PhD ASCO AMERICAN SOCIETY OF ANNUAL MEETING CLINICAL ONCOLOGY Presentation is property of the author and ASCO. Permission required for reuse, contact -.og KNOWLEDGE CONQUERS CANCER --- [Slide 3] INAVO120 updated PFS Events, n (%) Median, months (95% CI) Inavolisib (n = 161) 103 (64.0) 17.2 (11.6-22.2) Placebo (n = 164) 141 (86.0) 7.3 (5.9-9.2) 100 83.4 Stratified hazard ratio, 0.42 (95% CI = 0.32-0.55) 75 58.0 PFS (%) 49.7 50 41.8 57.9 Inavolisib 25 31.3 20.5 16.7 Placebo 0 Median follow-up: 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 34.2 months Months No. at risk Inavolisib 161 146 129 112 89 73 65 57 46 32 25 19 15 11 10 7 3 1 Placebo 164 125 95 74 50 34 30 24 21 14 11 10 8 4 2 1 1 1 The improvement in PFS was maintained during longer follow-up Data cutoff: November 15, 2024. CI, confidence interval; PFS, progression-free survival. © Copyright 2025. 2025 ASCO PRESENTED BY: Nicholas Turner, MD, PhD ASCO AMERICAN SOCIETY OF #ASCO25 CLINICAL ONCOLOGY ANNUAL MEETING Presentation is property of the author and ASCO. Permission required for reuse, contact permissions@asco.org KNOWLEDGE CONQUERS CANCER --- [Slide 4] INAVO120 key secondary endpoint: os Deaths, n (%) Median, months (95% CI) Inavolisib (n = 161) 72 (44.7) 34.0 (28.4-44.8) Placebo (n = 164) 82 (50.0) 27.0 (22.8-38.7) 96.8 100 87.0 Stratified hazard ratio, 0.67 74.3 (95% CI = 0.48-0.94) 65.8 75 P = 0.0190 90.1 56.5 OS (%) 76.7 50 67.2 Inavolisib 56.3 46.3 25 Placebo 0 Median follow-up: 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 34.2 months Months No. at risk Inavolisib 161 155 149 142 131 114 99 88 78 67 54 43 34 22 19 13 7 1 Placebo 164 155 142 127 119 104 90 77 63 48 42 36 32 18 10 4 2 1 Improvement in median OS: 7 months. The prespecified boundary for statistical significance (p < 0.0469) was crossed Data cutoff: November 15, 2024. CI, confidence interval; OS, overall survival. © Copyright 2025. 2025 ASCO PRESENTED BY: Nicholas Turner, MD, PhD #ASCO25 ASCO AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING Presentation is property of the author and ASCO Permission required for reuse, contact permissions@asco.org KNOWLEDGE CONQUERS CANCER

[Slide 1] Background: INAVO, a highly potent and selective PI3Ka inhibitor that also promotes mutated p110a degradation, is FDA-approved in combination with PALBO + FULV for PIK3CA-mutated, HR+, HER2-, endocrine-resistant aBC, based on the primary analysis of INAV0120 (NCT04191499), which showed a statistically significant and clinically meaningful investigator-assessed progression- free survival (INV-PFS) benefit in the INAVO arm vs. the PBO arm (hazard ratio 0.43; 95% confidence interval [CI] = 0.32-0.59; p < 0.0001). At that analysis, interim OS results were immature. Here we report the final OS analysis, including updated efficacy and safety. --- [Slide 2] Methods: Pts received INAVO (9 mg orally once daily [PO QD]; Days 1-28 of each 28-day cycle)/PBO + PALBO (125 mg PO QD; Days 1-21 of each cycle) + FULV (500 mg intramuscularly; Cycle 1 Days 1 and 15 then every ~4 weeks). OS and objective response rate (ORR) were formally tested; updated INV-PFS and safety analyses are descriptive. --- [Slide 3] Results: Data cut-off was Nov 15, 2024, at 34.2 months (mo) of median follow-up. Median OS was 34.0 mo (95% CI = 28.4-44.8) in the INAVO arm and 27.0 mo (95% CI = 22.8-38.7) in the PBO arm (stratified hazard ratio 0.67; 95% CI = 0.48-0.94; p = 0.0190 [boundary = 0.0469]). The os benefit was consistent across key subgroups. The survival probability at 6, 12, 18, 24, and 30 mo was 96.8%, 87.0%, 74.3%, 65.8%, and 56.5% in the INAVO arm and 90.1%, 76.7%, 67.2%, 56.3%, and 46.3% in the PBO arm. ORR was 62.7% (95% CI = 54.8-70.2) and 28.0% (95% CI = 21.3-35.6), respectively (p < 0.0001). Median time to chemotherapy (TTC) was 35.6 mo (95% CI = 25.4-not reached) in the INAVO arm and 12.6 mo (95% CI = 10.4-16.1) in the PBO arm (stratified hazard ratio 0.43; 95% CI = 0.30- 0.60). Updated median INV-PFS was 17.2 mo (95% CI = 11.6-22.2) in the INAVO arm and 7.3 mo (95% CI = 5.9-9.2) in the PBO arm (stratified hazard ratio 0.42; 95% CI = 0.32-0.55), with landmark --- [Slide 4] analyses supporting durable benefit. 90.7% of pts in the INAVO arm and 84.7% in the PBO arm had grade 3/4 adverse events (AEs); there were no new grade 5 AEs; 63.4% and 13.5% experienced any-grade hyperglycemia (grouped term); and AEs led to INAVO and PBO discontinuation in 6.8% and 0.6% of pts, respectively. Conclusions: INAVO + PALBO + FULV demonstrated a statistically significant and clinically meaningful os benefit compared with PBO + PALBO + FULV. Improvement in INV-PFS was maintained during longer follow-up, along with a substantial and statistically significant improvement in ORR. TTC was also substantially delayed (by ~2 years) by the addition of INAVO to PALBO + FULV. With longer exposure to INAVO, no new safety signals, nor changes in the safety profile, were noted, supporting good tolerability (reflected in low discontinuation due to AEs).

[Slide 1] Table S1. Key Post-progression Therapies. Patients — no. (%) Inavolisib Placebo Second line Third line Second line Third line or later or later Discontinued 111/161 (68.9) 144/164 (87.8) treatment No subsequent 17/161 (10.6) 22/164 (13.4) therapy — death Received 109/144 subsequent 83/111 (74.8) 48/111 (43.2) 56/144 (38.9) (75.7) therapy* Chemotherapy (any) 46/83 (55.4) 41/48 (85.4) 79/109 (72.5) 49/56 (87.5) Capecitabine 26/83 (31.3) 14/48 (29.2) 37/109 (33.9) 24/56 (42.9) Paclitaxel 12/83 (14.5) 17/48 (35.4) 20/109 (18.3) 16/56 (28.6) Eribulin 1/83 (1.2) 11/48 (22.9) 6/109 (5.5) 17/56 (30.4) Antibody-drug 1/83 (1.2) 8/48 (16.7) 1/109 (0.9) 20/56 (35.7) conjugate (any) Trastuzumab 0 6/48 (12.5) 1/109 (0.9) 16/56 (28.6) deruxtecan Sacituzumab 0 2/48 (4.2) 0 8/56 (14.3) govitecan PI3K inhibitor (any) 5/83 (6.0) 2/48 (4.2) 11/109 (10.1) 3/56 (5.4) Alpelisib 5/83 (6.0) 2/48 (4.2) 9/109 (8.3) 2/56 (3.6) mTOR kinase inhibitor 8/83 (9.6) 4/48 (8.3) 10/109 (9.2) 9/56 (16.1) (everolimus) 8 Original Article CDK4/6 inhibitor 8/83 (9.6) 3/48 (6.2) 5/109 (4.6) 3/56 (5.4) (any) Ribociclib 1/83 (1.2) 1/48 (2.1) 5/109 (4.6) 0 Abemaciclib 2/83 (2.4) 2/48 (4.2) 0 2/56 (3.6) Other (any) 6/83 (7.2) 0 3/109 (2.8) 5/56 (8.9)