PATINA Trial

[Slide 1] SAN ANTONIO BREAST CANCER AFT-38 PATINA Study Design SYMPOSIUM UT Health AACR Men Cancer Center - Registration Key eligibility criteria Palbociclib (125 mg PO QD Histologically confirmed D1-D21) HR+,HER2+ mBC Completion of induction N=518 Trastuzumab I pertuzumab + No prior treatment in the chemotherapy and no endocrine therapy* advanced setting beyond evidence of disease R Until PD or induction treatment progression (i.e., CR, PR, 1:1 toxicity . 6-8 cycles of treatment, or SD) including trastuzumab + Trastuzumab + pertuzumab + endocrine therapy* pertuzumab and taxane/vinorelbine Stratification factors Pertuzumab use (yes vs no) The non-pertuzumab option is limited to up to 20% of the population Prior anti-HER2 therapy in the (neo)adjuvant setting (yes vs no, including de novo) Response to induction therapy (CR or PR vs SD) by investigator assessment Type of endocrine therapy (fulvestrant vs aromatase inhibitor) *Trastuzumab and pertuzumab were administered per SOC. Endocrine therapy options include an aromatase inhibitor or fulvestrant. Factors used in stratified analyses. CR=complete response; D=day; HER2=human epidermal growth factor receptor 2; HR=hormone receptor; mBC=metastatic breast cancer; PD=progressive disease; PO=orally; PR=partial response; QD=once a day; R=randomization; SD=stable disease; SOC=standard of care. --- [Slide 2] SAN ANTONIO BREAST CANCER Conclusions SYMPOSIUM UT Health AACR lan Antonio American Association Care - Mays Cancer Center Our results reinforce the strong scientific rationale for overcoming resistance to anti-HER2 therapy and endocrine therapy by adding CDK4/6 inhibition The addition of palbociclib to anti-HER2 and endocrine therapy demonstrated a statistically significant improvement in PFS in patients diagnosed with HR+,HER2+ advanced breast cancer in the first-line metastatic setting Palbociclib added to anti-HER2 and endocrine therapy had a manageable toxicity profile and without new safety signals CDK4/6=cyclin-dependent kinase 4/6; HER2=human epidermal growth factor receptor 2; HR=hormone receptor; PFS=progression-free survival.

[Slide 1] SAN ANTONIO BREAST CANCER SYMPOSIUM SAN ANTONIO BREAST CANCER Implications to Clinical Practice SYMPOSIUM UT Health AACR - - Ment - The AFT-38 PATINA phase III study demonstrates a clinically meaningful improvement in PFS among patients diagnosed with HR+, HER2+ breast cancer Median PFS increased from 29.1 to 44.3 months (A15.2 months) Manageable toxicity Palbociclib added to anti-HER2 and endocrine therapy may represent a new standard of care for patients diagnosed with HR+, HER2+ advanced breast cancer HER2=human epidermal growth factor receptor 2; HR=hormone receptor; PFS=progression-free survival. This presentation is the intellectual property or the author/presenter. Contact them at Dto for permission to reprint and/or distribute

[Slide 1] BRINGING THE WORLD OF EP TOGETHER SAN ANTONIO BREAST CANCER SYMPOSIUM Secondary endpoint: Overall Survival SAN ANTONIO BREAST CANCER SYMPOSIUM (interim analysis) UT Health AACR - - - 100 90 80 70 60 Final overall survival 50 analysis requires 247 Palbociclib Anti- Anti-HER2 and 40 HER2 and ET ET events. Only 119 Events 58/261 61/257 30 Median in mos (95% CI) NE (71.6 NE) 77 (72-NE) observed thus far. 3-yr os, %. 95% CI 87 (82.8-91.2) 84.7 (80-89.3) 20 5-yr OS, %. 95% CI 74.3 (67.7-80.9) 69.8 (62.4-77.2) 10 Hazard ratio (95% CI) 0.86 (0.6-1.24) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time (months) "Kaplan- Patients at-Risk Meier method: Unstratified Palbo HER2 ET 261 255 248 239 229 220 207 187 146 101 60 22 7 I 0 Cox model; Cl=confidence HER2 ET 257 235 228 221 215 197 188 167 125 90 49 22 6 0 interval: NE=not evaluable; OS=overall survival; DECEMBER 10-14,2024 * SAN ANTONIO --- [Slide 2] BRINGING THE WORLD OF EP TOGETHER 2 SAN ANTONIO BREAST CANCER SYMPOSIUM SAN ANTONIO BREAST CANCER AFT-38 PATINA SYMPOSIUM UT Health AACR Key eligibility criteria Palbociclib (125 mg PO QD D1- Pre-Study D21) Histologically confirmed Completion of induction N=518 Trastuzumab + Pertuzumab + HR+HER2+ MBC chemotherapy and no Endocrine therapy R* Until PD No prior treatment in the evidence of disease or advanced setting beyond progression (i.e. , CR, PR, 1:1 toxicity induction treatment or SD) Trastuzumab * Pertuzumab + 6-8 cycles of treatment, Endocrine therapy including trastuzumab I pertuzumab and taxane Start of Study AFTER Induction Patients who experienced disease progression during induction or screening were not included in study. Patients with de novo resistance were eliminated Metzger o et al. SABCS 2024 DECEMBER 10 14, 2024 * SAN ANTONIO

[Slide 1] & SAN ANTONIO BREAST CANCER SYMPOSIUM SAN ANTONIO BREAST CANCER Implications to Clinical Practice SYMPOSIUM UT Health AACR - MayCamerCom The AFT-38 PATINA phase III study demonstrates a clinically meaningful improvement in PFS among patients diagnosed with HR+,HER2+ breast cancer Median PFS increased from 29.1 to 44.3 months (A15.2 months) Manageable toxicity Palbociclib added to anti-HER2 and endocrine therapy may represent a new standard of care for patients diagnosed with HR+,HER2+ advanced breast cancer HER2=human epidermal growth factor receptor 2: HR=hormone receptor PFS=progression-free survival. This presentation is the intelectual property of the author/presenter Contact them at Other CL for permission to reprint and/or distribute --- [Slide 2] SAN ANTONIO BREAST CANCER Conclusions SYMPOSIUM UT Health AACR Sex Annoid American Association Mays Cancer Center for Cancer Research Our results reinforce the strong scientific rationale for overcoming resistance to anti-HER2 therapy and endocrine therapy by adding CDK4/6 inhibition The addition of palbociclib to anti-HER2 and endocrine therapy demonstrated a statistically significant improvement in PFS in patients diagnosed with HR+,HER2+ advanced breast cancer in the first-line metastatic setting Palbociclib added to anti-HER2 and endocrine therapy had a manageable toxicity profile and without new safety signals CDK4/6=cyclin-dependent kinase 4/6; HER2=human epidermal growth factor receptor 2; HR=hormone receptor; PFS=progression-free survival. --- [Slide 3] Primary Endpoint: PFS SAN ANTONIO BREAST CANCER SYMPOSIUM (Investigator-Assessed) UT Health AACR San Americ Mays Cancer Center for Cancer Research 100 93.6% Palbo + anti-HER2 Anti-HER2 and ET 90 and ET 84.9% 87.9% Events 126/261 136/257 80 Median PFS, months (95% CI) 44.3 (32.4-60.9) 29.1 (23.3-38.6) 73.4% 70 Hazard ratio (95% CI) 0.74 (0.58-0.94) 65.4% Nominal 1-sided P value 0.0074 60 55.2% 50 46.9% 43.2% 40 38.2% HH 30 33.4% 20 10 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time (months) Cl=confidence interval; ET=endocrine therapy; Patients-at-Risk HER2=human epidermal growth factor receptor 2; Palbo + HER2 261 231 203 168 146 128 113 94 78 55 33 14 4 1 0 palbo=palbociclib. HER2 ET 257 198 159 137 116 102 87 68 51 29 14 6 1 0 --- [Slide 4] SAN ANTONIO BREAST CANCER AFT-38 PATINA Study Design SYMPOSIUM UT Health AACR Sen Antonio American Association for Cancer Research Mays Cancer Center Registration Key eligibility criteria Palbociclib (125 mg PO QD Histologically confirmed D1-D21) HER2+ mBC Completion of induction N=518 Trastuzumab + pertuzumab + No prior treatment in the chemotherapy and no endocrine therapy* advanced setting beyond R Until PD evidence of disease or induction treatment progression (i.e., CR, PR, 1:1 toxicity SURVIVAL FOLLOW-UP 6-8 cycles of treatment, or SD) including trastuzumab + Trastuzumab + pertuzumab + pertuzumab and endocrine therapy* taxane/vinorelbine Stratification factors Pertuzumab use (yes VS no) The non-pertuzumab option is limited to up to 20% of the population Prior anti-HER2 therapy in the (neo)adjuvant setting (yes VS no, including de novo)+ Response to induction therapy (CR or PR VS SD) by investigator assessment Type of endocrine therapy (fulvestrant VS aromatase inhibitor) *Trastuzumab and pertuzumab were administered per SOC. Endocrine therapy options include an aromatase inhibitor or fulvestrant. Factors used in stratified analyses. CR=complete response; D=day; HER2=human epidermal growth factor receptor 2; HR=hormone receptor; mBC=metastatic breast cancer; PD=progressive disease; PO=orally; PR=partial response; QD=once a day; R=randomization; SD=stable disease; SOC=standard of care.

[Slide 1] QUESTIONS AHEAD OF DESTINY-Breast09 AT ASCO 2025 1. How strong will the benefit be? 1. PATINA vs. CLEOATRA 2. Is sequential T-Dxd use an option? 1. os differential between 1st line - 2nd line 3. What to give after T-Dxd? 4. Proionged T-Dxd use and managing ILD risk

[Slide 1] SAN ANTONIO Primary Endpoint: PFS BREAST CANCER SYMPOSIUM UT Health AACR (Investigator-Assessed) butes - I I I 100 Palbo + anti-HER2 Anti-HER2 93.6% and ET and ET 90 84.9% Events 126/261 136/257 87.9% so Median PFS, months (95% CI) 44.3 (32.4-60.9) 29.1 (23.3-38.6) 73.4% Hazard ratio (95% CI) 0.74 (0.58-0.94) 70 Percent alive and disease-free 65.4% Nominal 1-sided P value 0.0074 60 55.2% 46.9% 50 43.2% 40 38.2% 33.4% 30 20 10 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time (months) Cl=confidence Interval; ET=endocrine therapy; Patients-at-Risk HER2=human epidermal growth factor receptor 2; Pabo . HER2 ET 261 231 203 168 146 128 113 94 78 55 33 14 4 I 0 palbo=palbociclib. HER2 ET 257 198 159 137 116 102 87 68 51 29 14 6 I 0 This presentation is the intellectual property of the authoripresenter Contact them at Offe for permission to reprint and/or distribute i , ,

[Slide 1] HR-Positive or -Negative and HER2-Positive See BINV-Q 1 of 15 for Considerations for systemic HER2-targeted therapy. Setting Regimen Docetaxel + Pertuzumab + Trastuzumab (category 1, preferred) with maintenance Pertuzumab + Trastuzumab If HR-positive: Aromatase inhibitor + Palbociclib + Pertuzumab + Trastuzumab First Line Paclitaxel + Pertuzumab + Trastuzumab (preferred) with maintenance Pertuzumab + Trastuzumab If HR-positive: Aromatase inhibitor + Palbociclib + Pertuzumab + Trastuzumab Fam-trastuzumab deruxtecan-nxki° + Pertuzumab (other recommended)