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Breast Cancer

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Breast Cancer

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  1. CCO Conference Highlights of SABCS 2018 2018 Annual Meeting of the CTRC-AACR San Antonio Breast Cancer Symposium* *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. Supported by educational grants from Merck & Co., Inc. and Novartis Pharmaceuticals Corporation.

  2. About These Slides • Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients • When using our slides, please retain the source attribution: • These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for details Slide credit: clinicaloptions.com

  3. Faculty Mohammad Jahanzeb, MD, FACPProfessor of Clinical Medicine, Hematology-OncologyMedical Director, UM Sylvester Deerfield CampusAssociate Center Director for Community OutreachSylvester Comprehensive Cancer CenterUniversity of Miami, Miller School of MedicineDeerfield Beach, Florida Mohammad Jahanzeb, MD, FACP, has disclosed that he has received consulting fees from Ipsen, Novartis, Pfizer, and Roche/Genentech and funds for research support from Boehringer Ingelheim, Callisto, and Lilly.

  4. Early-Stage Breast Cancer

  5. KATHERINE: Trastuzumab Emtansine vs Trastuzumab as Adjuvant Therapy for HER2+ EBC • International, randomized, open-label phase III study Stratified by clinical stage, HR status, single vs dual neoadjuvant HER2-targeted therapy, pathological nodal status after neoadjuvant therapy Patients with HER2+ EBC (cT1-4/N0-3/M0) who had residual invasive disease in breast or axillary nodes after neoadjuvant chemotherapy plus HER2-targeted therapy* and surgery (N = 1486) T-DM1† 3.6 mg/kg IV Q3W x 14 cycles (n = 743) Trastuzumab 6 mg/kg IV Q3W x 14 cycles (n = 743) Slide credit: clinicaloptions.com Randomization occurred within 12 wks of surgery; radiotherapy and/or endocrine therapy given per local standards. *Minimum of 9 wks taxane and trastuzumab. †Patients who d/c T-DM1 for toxicity allowed switch to trastuzumab to complete 14 cycles. • Primary endpoint: IDFS • Secondary endpoints including: distant recurrence-free survival, OS, safety Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

  6. KATHERINE: Baseline Characteristics Slide credit: clinicaloptions.com †At definitive surgery. ‡ypTX, n = 1 in trastuzumab arm; ypT1 without further subspecification, n = 5. *Includes North, Central, and South American Indians. Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

  7. KATHERINE: Stratification Factors Slide credit: clinicaloptions.com *Includes afatinib, dacomitinib, lapatinib, neratinib, pertuzumab. †Not a stratification factor; for informational purposes only. Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

  8. KATHERINE: IDFS 100 80 60 • T-DM1 • (n = 743) 91 (12.2) • 88.3 • Trastuzumab • (n = 743) • 165 (22.2) 77.0 IDFS (%) 40 Events, n (%) 3-yr IDFS, % Slide credit: clinicaloptions.com 20 HR: 0.50 (95% CI: 0.39-0.64; P < .001) 0 6 12 18 24 30 36 42 48 54 60 0 Mos Since Randomization Patients at Risk, n T-DM1 Trastuzumab • CNS events: *5.9% vs †4.3%. 707 676 681 635 658 594 633 555 561 501 409 342 255 220 142 119 44 38 4 4 743 743 Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

  9. KATHERINE: IDFS by Subgroup • Events/Patients, n/N • HR (95% CI) • 3-Yr IDFS Rate, % Subgroup All patients Age < 40 yrs 40-64 yrs ≥ 65 yrs Clinical stage at presentation Inoperable breast cancer • Operable breast cancer • Hormone-receptor status • ER neg and PgR negative or unknown • ER and/or PgR positive • Preoperative HER2-directed therapy • Trastuzumab alone • Trastuzumab + other HER2-directed agents • Pathologic nodal status after preoperative therapy • Node positive • Node negative/not done • Primary tumor stage at definitive surgery • ypT0, ypT1a, ypT1b, ypT1mic, ypTis • ypT1, ypT1c • ypT2 • ypT3 • ypT4, ypTX • Regional lymph node stage at definitive surgery • ypN0 • ypN1 • ypN2 • ypN3 • ypNX • T-DM1 91/743 20/143 64/542 7/58 42/185 49/558 38/209 53/534 78/600 13/143 62/343 29/400 40/331 14/175 25/174 9/51 3/12 28/344 29/220 16/86 17/37 1/56 • Trastuzumab 165/743 37/153 113/522 15/68 70/190 95/553 61/203 104/540 141/596 24/147 103/346 62/397 52/306 42/184 44/185 21/57 6/11 56/335 50/213 38/103 15/30 6/62 0.50 (0.39-0.64) 0.50 (0.29-0.86) 0.49 (0.36-0.67) 0.55 (0.22-1.34) 0.54 (0.37-0.80) • 0.47 (0.33-0.66) 0.50 (0.33-0.74) 0.48 (0.35-0.67) 0.49 (0.37-0.65) 0.54 (0.27-1.06) 0.52 (0.38-0.71) 0.44 (0.28-0.68) 0.66 (0.44-1.00) 0.34 (0.19-0.62) • 0.50 (0.31-0.82) 0.40 (0.18-0.88) 0.29 (0.07-1.17) • 0.46 (0.30-0.73) • 0.49 (0.31-0.78) • 0.43 (0.24-0.77) • 0.71 (0.35-1.42) • 0.17 (0.02-1.38) • T-DM1 88.3 86.5 88.8 87.4 76.0 92.3 82.1 90.7 87.7 90.9 83.0 92.8 88.3 91.9 88.3 79.8 70.0 91.9 88.9 81.1 52.0 98.1 • Trastuzumab 77.0 74.9 77.1 81.1 60.2 82.8 66.6 80.7 75.9 81.8 67.7 84.6 83.6 75.9 74.3 61.1 30.0 83.9 75.8 58.2 40.6 88.7 Slide credit: clinicaloptions.com 0.50 2.00 0.20 1.00 5.00 Trastuzumab Better T-DM1 Better Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

  10. KATHERINE: Secondary Endpoints Distant Recurrence OS 100 100 80 80 60 60 T-DM1 (n = 743) 42 (5.7) Trastuzumab (n = 743) 56 (7.5) Freedom From Distant Recurrence (%) • T-DM1 • (n = 743) 78 (10.5) • 89.7 Trastuzumab (n = 743) 121 (16.3) 83.0 OS (%) 40 40 Events, n (%) Events, n (%) 3-yr event-free rate, % 20 Slide credit: clinicaloptions.com 20 HR: 0.70 (95% CI: 0.47-1.05; P = .08) HR: 0.60 (95% CI: 0.45-0.79) 0 0 6 12 18 24 30 36 42 48 54 60 0 6 12 18 24 30 36 42 48 54 60 0 Patients at Risk, n T-DM1 Trastuzumab Patients at Risk, n T-DM1 Trastuzumab Mos Since Randomization Mos Since Randomization 719 695 702 677 693 657 668 635 648 608 508 471 345 312 195 175 76 71 12 8 743 743 707 679 682 643 661 609 636 577 564 520 412 359 254 233 143 126 45 41 4 4 743 743 Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

  11. KATHERINE: Safety Slide credit: clinicaloptions.com *Intracranial hemorrhage after a fall with 55,000 platelets/μL. Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

  12. KATHERINE: Treatment Exposure Slide credit: clinicaloptions.com Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

  13. KATHERINE: All-Grade AEs Occurring in ≥ 15% of Patients in Either Arm T-DM1 (n = 740) Trastuzumab (n = 720) 60 Grade 1 Grade 1 Grade 2 Grade 2 Grade ≥ 3 Grade ≥ 3 50 42 40 15 8 34 Patients (%) 29 28 28 7 28 26 Slide credit: clinicaloptions.com 25 6 6 5 23 20 7 22 21 10 33 19 4 2 17 17 11 9 33 5 15 22 3 13 17 23 5 4 19 4 26 11 16 3 18 19 13 8 2 14 7 6 6 13 12 14 4 10 11 2 0 9 5 5 7 5 3 2 Fatigue Nausea Myalgia Epistaxis Headache Arthralgia Constipation Increased AST Increased ALT Decreased PLT count Radiation skin injury Sensory neuropathy Geyer. SABCS 2018. Abstr GS1-10. Reproduced with permission. von Minckwitz. NEJM. 2018;[Epub].

  14. KATHERINE: Conclusions • In patients with HER2+ EBC who had residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy and surgery, T-DM1 significantly prolonged IDFS compared with trastuzumab • HR: 0.50 (95% CI: 0.39-0.64; P < .001) • Benefit with T-DM1 consistent across examined subgroups • No unexpected safety signals • Longer follow-up needed for OS • Study investigators conclude that T-DM1 will likely represent a new standard of care in this population Slide credit: clinicaloptions.com Geyer. SABCS 2018. Abstr GS1-10. von Minckwitz. NEJM. 2018;[Epub].

  15. TAM-01: Low-Dose Tamoxifen vs Placebo as Adjuvant Therapy for EBC • Multicenter, randomized, triple-blind phase III study • Primary endpoint: incidence of invasive breast cancer • Secondary endpoints including: safety, patient-reported outcomes, adherence Women < 75 yrs of age with breast intraepithelial neoplasia (ADH, LCIS, or ER+/unknown DCIS) and prior surgery (N = 500) Tamoxifen 5 mg PO QD for 3 Yrs (n = 253) Follow-up for at least 2 yrs Placebo for 3 Yrs (n = 247) Slide credit: clinicaloptions.com Visit and QoL every 6 mos; mammography every yr. DeCensi. SABCS 2018. Abstr GS3-01. NCT01357772.

  16. TAM-01: Baseline Characteristics Slide credit: clinicaloptions.com DeCensi. SABCS 2018. Abstr GS3-01.

  17. TAM-01: Recurrence • Median follow-up: 5.1 yrs (IQR: 3.9-6.3) *Rate: 11.6 vs 23.9/1000 PY. Slide credit: clinicaloptions.com DeCensi. SABCS 2018. Abstr GS3-01.

  18. TAM-01: On-Study Tumor Development Slide credit: clinicaloptions.com DeCensi. SABCS 2018. Abstr GS3-01.

  19. TAM-01: Safety, QoL • No difference between arms in patient-reported vaginal dryness or pain at intercourse, musculoskeletal pain/arthralgia • Patient-reported frequency of daily hot flashes significantly increased with low-dose tamoxifen vs placebo (P = .05) • Difference disappeared when intensity of hot flash was added to comparison of frequency Slide credit: clinicaloptions.com DeCensi. SABCS 2018. Abstr GS3-01.

  20. TAM-01: Adherence, Treatment Impact *P = .39 Based on 5-yr cumulative incidence of †breast events (6.4% vs 11.0% with PBO) or ‡serious AEs (0.87% vs 0.41% with PBO). Slide credit: clinicaloptions.com DeCensi. SABCS 2018. Abstr GS3-01.

  21. TAM-01: Conclusions • Following surgery in patients with intraepithelial neoplasia, 3 yrs of low-dose tamoxifen (ie, 5 mg/day) halved breast cancer recurrence vs placebo • HR: 0.48 (95 CI: 0.26-0.92; P = .024) • Risk of contralateral breast cancer reduced by 76% with low-dose tamoxifen vs placebo • Similar rates of serious AEs (eg, endometrial cancer, DVT or PE) and most menopausal symptoms between arms • Frequency of self-reported hot flashes higher with tamoxifen vs placebo • Study investigators conclude that low-dose tamoxifen provides a valid preventative option to avoid recurrence in this population Slide credit: clinicaloptions.com DeCensi. SABCS 2018. Abstr GS3-01.

  22. AERAS: Extended Adjuvant Therapy With Anastrozole for Postmenopausal Women With HR-Positive EBC • Prospective, multicenter, randomized, open-label phase III study • Primary endpoint: DFS • Secondary endpoints including: OS, distant DFS, safety Stratified by nodal status, prior adjuvant chemotherapy, choice of tamoxifen or anastrozole, institution Continue Anastrozole† for up to 5 Additional Yrs (n = 840) Postmenopausal women with stage I-III HR+ breast cancer who were disease free after adjuvant anastrozole therapy* (N = 1683) Slide credit: clinicaloptions.com No Further Adjuvant Therapy (n = 843) *As monotherapy for 4 yrs 9 mos to 5 yrs 2 mos or for > 2 yrs after tamoxifen for a total of 5 yrs adjuvant therapy. †1 mg PO QD. Ohtani. SABCS 2018. Abstr GS3-04. JPRN-UMIN000000818.

  23. AERAS: Baseline Characteristics Slide credit: clinicaloptions.com Ohtani. SABCS 2018. Abstr GS3-04.

  24. AERAS: Patient Disposition Slide credit: clinicaloptions.com Ohtani. SABCS 2018. Abstr GS3-04.

  25. AERAS: Disease-Free Survival 100 80 Stop Therapy (n = 828) Continue Anastrozole (n = 831) 60 DFS (%) 40 Slide credit: clinicaloptions.com 84.4 91.9 5-yr DFS rate, % 20 Events, n 51 98 HR: 0.548, P = .0004 0 1000 2000 3000 4000 0 Days From Randomization to First Event Patients at Risk, n Continue Stop 831 828 755 773 687 728 600 643 522 570 228 257 Ohtani. SABCS 2018. Abstr GS3-04. Reproduced with permission.

  26. AERAS: DFS by Subgroup • Events/Patients, n/N (%) HR (95% CI) Subgroup Overall • Prior endocrine therapy • Anastrozole • Tamoxifen, then anastrozole Age < 60 yrs ≥ 60 yrs BMI • < 25 • ≥ 25 T-stage • T1 • ≥ T2 N-stage • N0 • ≥ N1 Hormone status ER+PgR+ Any negative Prior chemotherapy No Yes Continue 51/831 (6.1) 47/757 (6.2) 4/74 (5.4) 8/200 (4.0) 43/631 (6.8) 40/598 (6.7) 11/233 (4.7) 21/427 (4.9) 30/375 (8.0) 36/621 (5.8) 15/181 (8.3) 39/580 (6.7) 12/222 (5.4) 27/488 (5.5) 24/313 (7.7) Stop 97/829 (11.7) 89/753 (11.8) 8/76 (10.5) 18/204 (8.8) 79/625 (12.6) 72/599 (12.0) 25/230 (10.9) 36/415 (8.7) 61/384 (15.9) 76/634 (12.0) 21/165 (12.7) 67/587 (11.4) 30/212 (14.2) 50/487 (10.3) 47/311 (15.1) 0.55 (0.39-0.77) 0.55 (0.39-0.78) 0.60 (0.18-1.99) 0.46 (0.20-1.06) 0.57 (0.40-0.83) 0.58 (0.40-0.86) 0.47 (0.23-0.96) 0.60 (0.35-1.04) 0.52 (0.34-0.81) 0.51 (0.34-0.76) 0.69 (0.35-1.33) 0.64 (0.43-0.95) 0.38 (0.19-0.73) 0.58 (0.36-0.92) 0.53 (0.32-0.86) P Value* .0006 .5677 .0487 .3088 .0005 .2881 .6668 .0205 Slide credit: clinicaloptions.com 3 1 1.5 2 0.25 0.5 *Test of interaction between treatment and each subgroup unadjusted for multiplicity. Stop Better Continue Better Ohtani. SABCS 2018. Abstr GS3-04. Reproduced with permission.

  27. AERAS: Distant Disease–Free Survival and OS DDFS OS 100 100 80 80 Continue Anastrozole (n = 831) Stop Therapy (n = 828) Continue Anastrozole (n = 831) Stop Therapy (n = 828) 60 60 DDFS (%) OS (%) 5-yr DDFS rate, % 97.2 94.3 5-yr OS rate, % 99.5 99.6 40 40 Events, n 23 47 Events, n 4 3 HR: 0.514 (P = .0077) HR: 1.389 (P = .665) 20 20 Slide credit: clinicaloptions.com 0 0 Patients at Risk, n Days Continue Stop 831 828 755 773 687 728 600 643 522 570 228 257 Days Patients at Risk, n 1000 1000 2000 2000 3000 3000 4000 4000 0 0 Continue Stop 831 828 755 773 687 728 600 643 522 570 228 257 Ohtani. SABCS 2018. Abstr GS3-04. Reproduced with permission.

  28. AERAS: Safety, Event Overview Slide credit: clinicaloptions.com Ohtani. SABCS 2018. Abstr GS3-04.

  29. AERAS: Conclusions • In postmenopausal women with primary HR+ breast cancer who were disease free after 5 yrs of adjuvant endocrine therapy, an additional 5 yrs of anastrozole significantly prolonged DFS compared with patients who stopped therapy • 5-yr DFS rate: 91.9% vs 84.4%, respectively (HR: 0.548; P = .0004) • DDFS also significantly prolonged with anastrozole extension vs discontinuation • 5-yr DDFS rate: 97.2% vs 94.3%, respectively (HR: 0.514; P = .0077) • 5-yr OS rates comparable between arms • Local and distant recurrence, second primary cancers numerically less frequent with anastrozole extension vs discontinuation • AE rates numerically higher with anastrozole extension vs discontinuation Slide credit: clinicaloptions.com Ohtani. SABCS 2018. Abstr GS3-04.

  30. Locally Advanced/Metastatic Breast Cancer

  31. SOLAR-1: Alpelisib + Fulvestrant for Men and Postmenopausal Women With HR-Positive ABC • International, randomized, double-blind phase III study Stratified by presence of liver/lung metastases, prior CDK4/6 inhibitor treatment Alpelisib† + Fulvestrant‡ (n = 169) PIK3CA mutant* (n = 341) Men or postmenopausal women with HR+/HER2- advanced breast cancer and recurrence/progression on or after prior aromatase inhibitor therapy; ECOG PS 0/1; measurable disease or ≥ 1 predominantly lytic bone lesion (N = 572) Placebo + Fulvestrant‡ (n = 172) *By tumor tissue. †300 mg PO QD. ‡500 mg IM on Days 1, 15 of first 28-day cycle, then on Day 1 in subsequent cycles. Alpelisib† + Fulvestrant‡ (n = 115) Slide credit: clinicaloptions.com PIK3CA non-mutant* (n = 231) Placebo + Fulvestrant‡ (n = 116) • Primary endpoint: PFS in PIK3CA-mutant cohort (locally assessed) • Secondary endpoints including: OS, PFS in PIK3CA non-mutant cohort, PFS by PIK3CA status as evaluated with ctDNA, ORR/CBR, safety Juric. SABCS 2018. Abstr GS3-08.

  32. SOLAR-1: PFS in PIK3CA-Mutant Cohort (Locally Assessed) Slide credit: clinicaloptions.com • Similar PFS outcome for alpelisib + fulvestrant vs placebo + fulvestrant in retrospective analysis of PIK3CA mutation status via ctDNA testing • Median PFS: 10.9 vs 3.7 mos, respectively; HR: 0.55 • More patients with BL measurable disease experienced decreases in tumor burden with alpelisib + fulvestrant vs placebo + fulvestrant (75.9% vs 43.5%, respectively) Juric. SABCS 2018. Abstr GS3-08. André. ESMO 2018. Abstr LBA3_PR.

  33. SOLAR-1: PFS by Prior Therapy in PIK3CA-Mutant Cohort Slide credit: clinicaloptions.com *PD > 1 yr after (neo)adjuvant ET; excluded later per protocol amendment. †PD ≤ 1 yr after (neo)adjuvant ET. ‡PD > 1 yr after (neo)adjuvant ET and while on/after 1 line of ET for ABC or newly diagnosed ABC with PD on/after 1 line of ET. Juric. SABCS 2018. Abstr GS3-08.

  34. SOLAR-1: Interim OS in PIK3CA-Mutant Cohort • Data cutoff (June 12, 2018) included 52% of planned events for final OS analysis • Median follow-up: 15.9 mos (range: 0.4-31.7) Slide credit: clinicaloptions.com Juric. SABCS 2018. Abstr GS3-08.

  35. SOLAR-1: AEs Occurring in ≥ 20% of Patients in Either Arm Slide credit: clinicaloptions.com Juric. SABCS 2018. Abstr GS3-08.

  36. SOLAR-1: Hyperglycemia in Alpelisib-Containing Arm • Glucose > 160 mg/dL typically observed by Day 15 • Median duration: 10 days • Fasting plasma glucose and A1C spikes highest in alpelisib recipients who were diabetic (4%) or prediabetic (56%) at BL • 87% with hyperglycemia received antidiabetic medication, typically metformin Slide credit: clinicaloptions.com Juric. SABCS 2018. Abstr GS3-08.

  37. SOLAR-1: Conclusions • In patients with HR+/HER2- PIK3CA-mutant advanced breast cancer and recurrence/progression on or after prior aromatase inhibitor therapy, addition of alpelisib to fulvestrant significantly prolonged PFS vs placebo plus fulvestrant • PIK3CA-mutant assessed by tissue (HR: 0.65; 95% CI: 0.50-0.85; P = .00065) • Benefit evident regardless of line of therapy and/or prior CDK4/6 inhibitor treatment; for PIK3CA-mutant determined by ctDNA • OS data not yet mature • Hyperglycemia common on-target adverse event with alpelisib, typically observed early in treatment and transient • Manageable with oral antidiabetic therapy Slide credit: clinicaloptions.com Juric. SABCS 2018. Abstr GS3-08.

  38. IMpassion130: Biomarker Analysis in TNBC Patients Receiving Frontline Atezolizumab + Nab-Paclitaxel • International, randomized, double-blind phase III study[1,2] Stratified by prior taxane use, liver metastases, and PD-L1 expression on IC Atezolizumab† + Nab-Paclitaxel‡ (n = 451) Patients with previously untreated* metastatic or unresectable locally advanced triple-negative breast cancer (N = 902) Until PD or unacceptable toxicity Placebo + Nab-Paclitaxel‡ (n = 451) Slide credit: clinicaloptions.com *Prior chemo in curative setting permitted if tx-free for ≥ 12 mos. †840 mg IV Q2W. ‡100 mg/m2 IV on D1, 8, and 15 of 28-day cycle. • Coprimary endpoints: PFS, OS in ITT population and PD-L1+ subgroup (≥ 1% on tumor infiltrating IC)[1] • Exploratory analysis: efficacy by PD-L1 expression on TC, intratumoral CD8+ T-cells, sTILs, BRCA1/2 status[2] 1. Schmid. NEJM. 2018;379:2108. 2. Emens. SABCS 2018. Abstr GS1-04.

  39. IMpassion130: PD-L1 Expression Slide credit: clinicaloptions.com *IC0: < 1%; IC1: ≥ 1% and < 5%; IC2: ≥ 5% and < 10%; IC3: ≥ 10%. †TC-negative: < 1%; TC-positive: ≥ 1%. Emens. SABCS 2018. Abstr GS1-04.

  40. IMpassion130: PFS by PD-L1 Expression 100 80 60 *For interaction (treatment x PD-L1 IC). PFS (%) Slide credit: clinicaloptions.com Atezolizumab + nab-P (PD-L1 IC+) 40 Atezolizumab + nab-P (PD-L1 IC-) Placebo + nab-P (PD-L1 IC+) Placebo + nab-P (PD-L1 IC-) 20 0 0 3 6 9 12 15 18 21 24 27 30 33 Mos Emens. SABCS 2018. Abstr GS1-04. Reproduced with permission.

  41. IMpassion130: OS by PD-L1 Expression 100 80 60 *For interaction (treatment x PD-L1 IC). OS (%) Slide credit: clinicaloptions.com Atezolizumab + nab-P (PD-L1 IC+) 40 Atezolizumab + nab-P (PD-L1 IC-) Placebo + nab-P (PD-L1 IC+) Placebo + nab-P (PD-L1 IC-) 20 0 36 0 3 6 9 12 15 18 21 24 27 30 33 Mos Emens. SABCS 2018. Abstr GS1-04. Reproduced with permission.

  42. IMpassion130: Survival by PD-L1 IC Subgroup PFS OS Median, mos Median, mos HR(95% CI) 0.93(0.77-1.12) 0.59(0.44-0.78) 0.64(0.42-0.97) 0.79(0.68-0.92) HR(95% CI) 1.02(0.79-1.31) 0.56(0.38-0.82) 0.71(0.39-1.30) 0.83(0.68-1.02) • Atezo 18.9 23.4 25.0 21.3 PD-L1 Status IC0 IC1 IC2/3 All • Atezo • 5.6 7.4 9.3 7.2 • PBO • 18.4 14.4 21.1 17.6 • PBO 5.6 3.9 5.7 5.5 P Value .47 ≤ .005 .03 • ≤ .005 P Value .90 ≤ .005 .26 • .07 n 532 243 125 900 Neg Pos Slide credit: clinicaloptions.com 2 2 0.2 0.2 1.0 1.0 • Atezo + Nab-P Better Placebo + Nab-P Better • Atezo + Nab-P Better Placebo + Nab-P Better Emens. SABCS 2018. Abstr GS1-04. Reproduced with permission.

  43. IMpassion130: Survival by PD-L1 Expression and CD8 Expression, sTIL, or BRCA1/2 Mutation Status Slide credit: clinicaloptions.com *N = 720; 0.5% cutoff for positive vs negative CD8. †N = 893; 10% cutoff for low vs intermediate/high sTILs. ‡N = 612. Emens. SABCS 2018. Abstr GS1-04.

  44. IMpassion130: Conclusions • In patients with untreated metastatic or unresectable locally advanced triple-negative breast cancer, PD-L1 IC positivity (≥ 1%) predicted survival benefit with atezolizumab vs placebo addition to nab-paclitaxel • Subgroups positive for intratumoral CD8+ T-cells, sTILs, or BRCA1/2 mutations demonstrated prolonged OS and/or PFS with atezolizumab only when simultaneously PD-L1 IC+ • Study investigators suggest that PD-L1 IC testing should be routine in this population to identify individuals who would most benefit from combination treatment Slide credit: clinicaloptions.com Emens. SABCS 2018. Abstr GS1-04.

  45. KEYNOTE-173: Pembrolizumab + Chemotherapy as Neoadjuvant Therapy for TNBC • Multicohort, open-label phase Ib study • Primary endpoint: safety/tolerability • Secondary endpoints including: pCR rate, ORR, EFS, OS Cycle 1 Cycle 9 Cycle 5 Cohort A Pembro Pembro + Nab-P 125 mg/m2 Pembro + AC Adult women with untreated, locally advanced TNBC; ECOG PS 0/1; adequate organ function (N = 60) Cohort B Pembro Pembro + Nab-P 100 mg/m2 + Carboplatin AUC 6 D1 Pembro + AC Cohort C Pembro Pembro + Nab-P 125 mg/m2 + Carboplatin AUC 5 D1 Pembro + AC Cohort D Pembro Pembro + Nab-P 125 mg/m2 + Carboplatin AUC 2 D1, 8, 15 Pembro + AC Slide credit: clinicaloptions.com Cohort E Pembro Pembro + Paclitaxel 80 mg/m2 + Carboplatin AUC 5 D1 Pembro + AC Cohort F Pembro Pembro + Paclitaxel 80 mg/m2 + Carboplatin AUC 2 D1, 8, 15 Pembro + AC All tx given IV. Cyclophosphamide: 600 mg/m2 Q3W. Doxorubicin: 60 mg/m2 Q3W. Nab-P, Pac: Days 1, 8, 15 Q3W. Pembro: 200 mg Day 1 in cycle 1, then Q3W. Definitive surgery per local standards and tissue collection for pCR 3-6 wks following completion of neoadjuvant therapy. Schmid. SABCS 2018. Abstr PD5-01. NCT02622074.

  46. KEYNOTE-173: Baseline Characteristics Slide credit: clinicaloptions.com Schmid. SABCS 2018. Abstr PD5-01.

  47. KEYNOTE-173: Dose-Limiting Toxicities • Overall DLTs: 22/60 (36.7%) • 0% in cohort E • 20% in cohort A • 40% in cohorts B/F • 60% in cohorts C/D • Dosing and regimens from cohorts A/E deemed acceptable • All other cohorts failed to meet RP2D threshold • Most frequent DLTs • Febrile neutropenia, n = 9 • Neutropenia, n = 7 • DLT severity • Grade 4, n = 11 • Grade 5, n = 1 • Death due to chemotherapy-related septic shock in cohort D Slide credit: clinicaloptions.com Schmid. SABCS 2018. Abstr PD5-01.

  48. KEYNOTE-173: Treatment-Related AEs • 100% of patients experienced treatment-related AEs • Grade ≥ 3 events reported in 90% • Led to pembrolizumab discontinuation in 18% • 30% of patients experienced immune-related AEs Slide credit: clinicaloptions.com Schmid. SABCS 2018. Abstr PD5-01.

  49. KEYNOTE-173: Efficacy • Overall pCR rate at definitive surgery[1] • ypT0/Tis ypN0: 60% (range: 30% to 80%) • ypT0 ypN0: 57% (range: 20% to 80%) • Highest rates observed in cohorts B-D (ie, patients receiving nab-paclitaxel and carboplatin in cycles 2-5) • Patients achieving pCR showed better 12-mo and 24-mo EFS compared with those who did not[1] • Better EFS (and OS) rates with vs without carboplatin • Higher pretreatment sTILs and PD-L1 CPS and on-treatment sTILs were associated with higher pCR rates[2] Slide credit: clinicaloptions.com 1. Schmid. SABCS 2018. Abstr PD5-01. 2. Loi. SABCS 2018. Abstr P3-10-09.

  50. KEYNOTE-173: Conclusions • In patients with untreated, locally advanced TNBC, preliminary data suggest promising antitumor activity and manageable toxicity with neoadjuvant pembrolizumab + chemotherapy according to investigators[1] • DLTs in 36.7% of patients • Higher pCR and extended EFS and OS in cohorts receiving carboplatin • Exploratory analyses suggest that higher pretreatment sTIL level or PD-L1 CPS may predict higher pCR/ORR[2] • Phase III KEYNOTE-522 examining neoadjuvant pembrolizumab + chemotherapy in patients with high-risk, early-stage TNBC ongoing[3] Slide credit: clinicaloptions.com 1. Schmid. SABCS 2018. Abstr PD5-01. 2. Loi. SABCS 2018. Abstr P3-10-09. 3. NCT03036488.

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