NATALEE Trial

[Slide 1] The NEW ENGLAND JOURNAL of MEDICINE RESEARCH SUMMARY Ribociclib plus Endocrine Therapy in Early Breast Cancer Slamon D et al. DOI: 10.1056/NEjMoa2305488 CLINICAL PROBLEM Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer Ribociclib + NSAI NSAI alone is the most common subtype of breast cancer, with the (N=2549) Stage II or III (N=2552) HR-positive, majority of cases diagnosed early and treated with cura- HER2-negative early tive intent. Adjuvant endocrine therapy improves out- breast cancer comes in these patients; however, the disease can recur + Ribociclib Endocrine Endocrine up to 20 years after diagnosis. Ribociclib is a cyclin- Therapy Therapy dependent kinase 4 and 6 inhibitor with an established benefit in advanced breast cancer. Whether this benefit extends to early breast cancer is unclear. Invasive Disease-free Survival at 3 Yr CLINICAL TRIAL HR for invasive disease, recurrence, or death, 0.75 Design: A phase 3, international, open-label, randomized (95% CI, 0.62-0.91): P=0.003 trial is examining the efficacy and safety of adjuvant Ribociclib NSAI 100 90.4 ribociclib plus endocrine therapy (a nonsteroidal aromatase 90 inhibitor [NSAI]) as compared with an NSAI alone in 80 NSAI alone 70 87.1 patients with stage II or III HR-positive, HER2-negative early breast cancer. Intervention: 5101 patients were assigned to receive either Percentage of Patients 60 50 40 ribociclib (400 mg per day for 3 weeks, followed by 1 week 30 off, for 3 years) plus an NSAI (letrozole [2.5 mg per day] 20 or anastrozole [1 mg per day] for >5 years) or an NSAI 10 alone. The primary end point was survival free from in- 0 0 6 12 18 vasive disease. 24 30 36 42 48 Months Adverse Events RESULTS 100 97.9 Efficacy: At 3 years, invasive disease-free survival was 87.1 Ribociclib NSAI significantly higher with the addition of ribociclib to an NSAI alone 80 NSAI than with an NSAI alone. Safety: Treatment with ribociclib plus an NSAI was not associated with any new safety signals. The most common Percentage of Patients 62.1 60 42.5 40 36.5 adverse events of any grade were neutropenia, arthralgia, and liver-related events. 25.4 20 10.6 4.5 0 LIMITATIONS AND REMAINING QUESTIONS >1 Adverse Event Neutropenia Arthralgia Liver-Related Events Additional follow-up regarding the long-term efficacy of ribociclib in this population is needed. CONCLUSIONS Patients were younger than the median age at diagnosis Among patients with stage II or III HR-positive, HER2- in the United States, and Black patients were under- represented. negative early breast cancer, the addition of ribociclib to adjuvant endocrine therapy significantly improved 3-year invasive disease-free survival. Links: Full Article I NEJM Quick Take Copyright © 2024 Massachusetts Medical Society.

[Slide 1] NOVARTIS Novartis Kisqali® Phase III NATALEE trial meets primary endpoint at interim analysis demonstrating clinically meaningful benefit in broad population of patients with early breast cancer

[Slide 1] 100 Ribociclib+NSAI No. of Patients 3-Yr Invasive 90 with Event/ Disease-free 80 NSAI alone Total No. (%) Survival 70 Percentage of Patients percent 60 Ribociclib+ NSAI 189/2549 (7.4) 90.4 50 NSAI alone 237/2552 (9.3) 87.1 40 Hazard ratio for invasive disease, recurrence, 30 or death, 0.75 (95% CI, 0.62-0.91) Two-sided P=0.003 20 10 Median follow-up for invasive disease- free survival, 27.7 mo 0 0 6 12 18 24 30 36 42 48 Months No. at Risk Ribociclib+NSAI 2549 2350 2274 2193 1718 1111 311 12 0 NSAI alone 2552 2240 2166 2071 1631 1067 286 13 0

[Slide 1] Distant Disease-Free Survival 100 90 . The absolute DDFSᵃ benefit with 80 ribociclib plus NSAI was 2.7% at 3 years Distant disease-free survival, % 70 . The risk of distant disease was reduced 60 by 25.1% with ribociclib plus NSAI VS 50 NSAI alone at the final analysis 40 RIB + NSAI NSAI alone 30 Events/n (%) 204/2549 (8.0) 256/2552 (10.0) 20 3-Year DDFS rate, % 92.9 90.2 Hazard ratio (95% CI) 0.749 (0.623-0.900) 10 Nominal 1-sided P value 0010 0 0 6 12 18 24 30 36 42 48 54 Months No. at risk RIB + NSAI 2549 2352 2280 2212 2113 1704 1119 369 21 0 NSAI alone 2552 2245 2171 2091 1990 1609 1080 356 26 0 DOFS distant disease free survival *DDFS is the time from randomization to the date of the list event of listant recurrence death by any cause or second primary nonbreast INVESAGE cancer (excluding basal and squarious cell caronomes of the skin) --- [Slide 2] iDFS by Anatomical Stage Stage II Stage III 100 100 90 90 80 80 Invasive disease-free survival, % 70 40 NSAI alone Invasive disease-free survival, % 70 60 60 50 Median follow-up: 38.6 mo Median follow-up: 33.1 mo 50 RIB + NSAI RIB + NSAI NSAI alone 40 30 Events/n (%) 55/1011 (5.44) 80/1034 (7.74) 30 Events/n (%) 170/1528 (11.1) 203/1512 (13.4) 20 3-Year iDFS rate, % 94.2 92.6 20 3-Year iDFS rate, % 88.1 83.8 10 Hazard ratio (95% CI) 0.700 (0.496-0.986) 10 Hazard ratio (95% CI) 0.755 (0.616-0.926) 0 0 0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54 Months Months No. at risk No. at risk RIB + NSAI 1011 929 902 883 859 841 611 194 15 0 RIB + NSAI 1528 1411 1362 1312 1232 844 496 174 6 0 NSAI alone 1034 948 924 893 872 840 609 203 18 0 NSAI alone 1512 1289 1241 1183 1099 753 456 151 8 0 The risk of invasive disease was reduced by 30.0% for stage II and by 24.5% for stage III disease with ribociclib plus NSAI vs NSAI alone --- [Slide 3] iDFS Across Key Prespecified Subgroups RIB NSAI NSAI alone Subgroup Events/n 3-y IDFS rate, % Events/n 3.y iDFS rate, % Hazard ratio 95% CI Menopausal status Men and premenopausal women 83/1125 91.8 114/1132 88.2 0.688 0.519-0.913 Postmenopausal women 143/1424 89.7 169/1420 87.1 0.806 0.645-1.007 AJCC stage Stage II 55/1101 94.2 80/1034 92.6 0.700 0.496-0.986 Stage III 170/1528 88.1 203/1512 83.8 0.755 0.616-0.926 Prior CT Yes 203/2249 90.5 255/2245 87.1 0.746 0.620-0.897 No 23/300 92.0 28/307 91.2 0.852 0.491-1.479 Region North America/Westem Europe/Oceania 131/1563 91.1 166/1565 87.5 0.748 0.595-0.941 Rest of world 95/986 90.1 117/987 87.6 0.774 0.591-1.015 Histological grade at time of surgery Grade 1 9/213 95.1 13/217 93.1 0.708 0.303-1.657 Grade 2 118/1460 91.5 155/1432 88.0 0.696 0.548-0.885 Grade 3 80/684 87.5 89/702 85.9 0.890 0.658-1.204 Ki-67 status Ki-67 ≤20% 93/1199 91.8 117/1236 89.8 0.794 0.605-1.042 Ki-67 >20% 98/920 89.0 125/937 84.9 0.743 0.570-0.988 Nodal status NO 20/285 93.2 31/328 90.6 0.723 0.412-1.288 N1-N3 206/2261 90.3 251/2219 87.1 0.759 0.631-0.912 Prior ET Yes 150/1826 91.4 186/1805 88.4 0.755 0.609-0.936 No 76/723 88.9 97/747 85.8 0.771 0.571-1.040 0.0 0.5 1.0 1.5 2.0 2.5 3.0 AJCC, American Joint Committee on Cancer, CT, chemotherapy Hazard ratio a From archival tumor tissue b Nodal status classification according to AJCC staging Nodal status is from the worst stage derived per surgical specimen or at diagnosis Favors RIB + NSAI Favors NSAI alone --- [Slide 4] Invasive Disease-Free Survival 100 93.5% 90.7% 90 92.0% The median follow-up for iDFS was 33.3 87.6% 80 months (maximum, 51 months)-an 1.5% additional 5.6 months from the second 3.1% Invasive disease-free survival, % 70 interim efficacy analysis¹ 60 The absolute iDFS benefit with ribociclib 50 plus NSAI was 3.1% at 3 years 40 RIB + NSAI NSAI alone The risk of invasive disease was 30 Events/n (%) 226/2549 (8.9) 283/2552 (11.1) reduced by 25.1% with ribociclib plus 20 3-Year iDFS rate, % 90.7 87.6 NSAI vs NSAI alone 10 Hazard ratio (95% CI) 0.749 (0.628-0.892) Nominal 1-sided P value .0006 0 0 6 12 18 24 30 36 42 48 54 Months No. at risk RIB + NSAI 2549 2350 2273 2204 2100 1694 1111 368 21 0 NSAI alone 2552 2241 2169 2080 1975 1597 1067 354 26 0 1 Slamon D. et al ASCO 2023 Oral LBA500

[Slide 1] Invasive Disease-free Survival at 3 Yr HR for invasive disease, recurrence, or death, 0.75 (95% CI, 0.62-0.91): P=0.003 Ribociclib + NSAI 100 90.4 90 80 NSAI alone 87.1 Percentage of Patients 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 48 Months Adverse Events 100 97.9 87.1 Ribociclib + NSAI NSAI alone 80 Percentage of Patients 62.1 60 42.5 40 36.5 25.4 20 10.6 4.5 0 ≥1 Adverse Event Neutropenia Arthralgia Liver-Related Events

[Slide 1] monarchE NATALEE Study drug abemaciclib ribociclib Dosing 150 mg twice daily 400 mg 3 wk on, 1 wk off Duration of therapy 2y 3y ET anastrozole, letrozole, exemestane, tamoxifen, +/- OFS anastrozole, letrozole, +/- OFS Eligible patients 4+ LN or Any LN+ or 1 to 3+ LN and tumor > 2 cm and tumor size 2 5 cm or G3 or histologic grade 3 or G2 and Ki-67 > 20% or Ki-67 > 20% G2 and high genomic risk (oncotype RS > 26, MammaPrint high) 2-y invasive disease-free survival A 3.5%, 92.2% abemaciclib VS 88.7% ET. A 3.3%, 90.4% ribociclib VS 87.1% ET. HR 0.75, P= .012 HR 0.748, P= 0014 Proportion who had completed treatment period 707 (12.5%) 2-y treatment period 515 (20%) 3-y treatment period 4-y invasive disease-free survival 6.4% (85.8% VS 79.4%) Not reported Proportion who had completed treatment period 100% (2,794 treated, including 510 early discontinuation) N/A Any grade noutropenia (z G3) 44.6% (18.0%)2 62.1% (43.8%)1 Liver-related AE (z G3) ALT: 9.5% (2.1%)2 25.4% (8.3%)' Diarrhea (z G3) 82.2% (7.6%)2 14.2% (0.6%) QT prolongation (z G3) 0.0% (0.0%)? 5.3% (1.0%)' ILD pneumonitis (> G3) 2.7% (0.3%)2 1.5% (0.0%)1