Immunoconjugates in Both the Adjuvant and Metastatic Setting Mark Pegram, M.D. Director, Stanford Breast Oncology Program Co-Director, Molecular Therapeutics Program
Trastuzumab Treatment of Breast Tumor Cell Lines Blocks G1/S progression only in cells that overexpress erbb2 Low/Normal HER2 Expression (HER2/0) High HER2 Expression (HER2/3+) Pegram, et al. Oncogene, 13:2241 (1997).
SK-BR-3 BT-474 MDA-MB-361 MDA-MB-453 In Vitro Drug Interactions With Trastuzumab Carboplatin Cyclophosphamide Vinorelbine Combination index* 0 1 2 0 1 2 0 1 2 Doxorubicin Epirubicin SK-BR-3 BT-474 MDA-MB-361 MDA-MB-453 Combination index* 0 1 2 0 1 2 Docetaxel Paclitaxel Gemcitabine SK-BR-3 BT-474 MDA-MB-361 MDA-MB-453 Combination index* 0 1 2 0 1 2 0 1 2 *Combination Index = 1.0 denotes additivity Combination Index > 1.0 denotes antagonism Combination Index < 1.0 denotes synergy Pegram et al. J Natl Cancer Inst. 2004;96:739.
Paclitaxel-conjugated Trastuzumab Hydrolysis Gilbert CW, McGowan, EB, Seery GB, Black KS, Pegram, MD J Exp Ther Oncol. 2003 Jan-Feb; 3(10):27-25 4
Preclinical efficacy of Paclitaxel-conjugated Trastuzumab Control Free paclitaxel + Free trastuzumab Paclitaxel-conjugated trastuzumab Gilbert CW, McGowan, EB, Seery GB, Black KS, Pegram, MD J Exp Ther Oncol. 2003 Jan-Feb; 3(10):27-25 5
Structure of trastuzumab (Tmab) maytansinoid conjugates (stability of linker, least to greatest): Tmab-SPDP-DM1, Tmab-SPP-DM1, Tmab-SSNPP-DM3, Tmab-SSNPP-DM4, and Tmab-SMCC-DM1 (nonreducible). Lewis Phillips G D et al. Cancer Res 2008;68:9280-9290 2008 by American Association for Cancer Research
T-DM1: Mechanism of Action HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus Adapted from LoRusso PM, et al. Clin Cancer Res 2011. 7
N Engl J Med. 2012 Nov 8;367(19):1783-91.
EMILIA Study Design HER2-positive LABC or MBC (N=980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic treatment or within 6 months of adjuvant treatment 1:1 Capecitabine 1000 mg/m 2 PO bid, days 1 14, q3w + Lapatinib 1250 mg/day PO qd PD Stratification factors: World region, number of prior chemo regimens for MBC or unresectable LABC, presence of visceral disease Primary end points: PFS by independent review, OS, and safety Key secondary end points: PFS by investigator, ORR, duration of response, time to symptom progression Statistical considerations: Hierarchical statistical analysis was performed in prespecified sequential order: PFS by independent review OS secondary end points Clinical data cutoff: January 14, 2012 (July 31, 2012 for interim OS analysis)
Patient Demographics and Baseline Characteristics (1) Cap + Lap (n=496) T-DM1 (n=495) Median age, years (range) 53 (24 83) 53 (25 84) Race, n (%) White Asian Black/African American Other Not available World region, n (%) United States Western Europe Asia Other ECOG PS, n (%) 0 1 374 (75) 86 (17) 21 (4) 10 (2) 5 (1) 136 (27) 160 (32) 76 (15) 124 (25) 312 (64) 176 (36) 358 (72) 94 (19) 29 (6) 7 (1) 7 (1) 134 (27) 157 (32) 82 (17) 122 (25) 299 (61) 194 (39)
Selected Patient Demographics and Baseline Characteristics Cap + Lap (n=496) T-DM1 (n=495) Measurable disease by independent review, n (%) 389 (78) 397 (80) Metastatic involvement, n (%) Visceral Nonvisceral Metastatic sites, n (%) <3 3 Unknown ER/PR status, n (%) ER+ and/or PR+ ER and PR Unknown 335 (68) 161 (32) 307 (62) 175 (35) 14 (3) 263 (53) 224 (45) 9 (2) 334 (67) 161 (33) 298 (60) 189 (38) 8 (2) 282 (57) 202 (41) 11 (2)
Prior treatment type, n (%) Taxanes Anthracyclines Endocrine agents Prior therapy for MBC, n (%) Yes No Prior Systemic Treatment Prior trastuzumab treatment, n (%) Early breast cancer only Duration of trastuzumab treatment, n (%) <1 yr 1 yr Cap + Lap (n=496) 494 (100) 302 (61) 204 (41) 438 (88) 58 (12) 495 (100) 77 (16) 212 (43) 284 (57) T-DM1 (n=495) 493 (100) 303 (61) 205 (41) 435 (88) 60 (12) 495 (100) 78 (16) 210 (42) 285 (58) Median time since last trastuzumab, months (range) 1.5 (0 98) 1.5 (0 63)
Drug Exposure Cap (n=487) Lap (n=488) T-DM1 (n=490) Median dose intensity, % 77.2 93.4 99.9 Pts with dose reduction, n (%) 260 (53.4) 133 (27.3) 80 (16.3) T-DM1 decreased to 3.0 mg/kg, n (%) 58 (11.8) T-DM1 decreased to 2.4 mg/kg, n (%) 22 (4.5)
Patients, % Proportion progression-free Objective Response Rate (ORR) and Duration of Response (DOR) in Patients with Measurable Disease 50 ORR Difference: 12.7% (95% CI, 6.0, 19.4) P=.0002 43.6 1.0 DOR Median, months (95% CI) Cap + Lap 6.5 (5.5, 7.2) T-DM1 12.6 (8.4, 20.8) 40 30.8 0.8 30 0.6 20 0.4 10 0.2 0 120/389 Cap + Lap 173/397 T-DM1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk Cap + Lap 120 105 77 48 32 14 9 8 3 3 1 1 0 0 0 0 T-DM1 173 159 126 84 65 47 42 33 27 19 12 8 2 0 0 0 0 0 0 0 0 0 14 14
Proportion progression-free Progression-Free Survival by Independent (IRC) and Investigator (INV) Review 1.0 0.8 0.6 IRC INV Cap + Lap T-DM1 Cap + Lap T-DM1 HR=0.650 (95% CI, 0.55, 0.77) P<0.0001 HR=0.658 (95% CI, 0.56, 0.77) P<0.0001 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Time (mos) No. at risk by independent review: Cap + Lap 496 404 310 176 129 73 53 35 25 14 9 8 5 1 0 0 T-DM1 495 419 341 236 183 130 101 72 54 44 30 18 9 3 1 0 Unstratified HR by independent review=0.66 (P<0.0001).
Progression-Free Survival Subgroup Analyses Baseline Total Characteristic n Stratification factors All patients 991 World region United States 270 Western Europe 317 Other 404 Number prior chemotherapy regimens for MBC or unresectable LABC 0 1 609 >1 382 Presence of visceral disease Yes No 669 322 HR (95% CI) 0.66 (0.56, 0.78) 0.70 (0.51, 0.98) 0.56 (0.41, 0.74) 0.73 (0.56, 0.94) 0.68 (0.55, 0.85) 0.63 (0.49, 0.82) 0.55 (0.45, 0.67) 0.96 (0.71, 1.30) Other characteristics Age <65 years 65 74 years 853 113 0.62 (0.52, 0.74) 0.88 (0.53, 1.45) 75 years 25 3.51 (1.22, 10.13) ER and PR status ER+ and/or PR+ ER and PR 545 426 0.72 (0.58, 0.91) 0.56 (0.44, 0.72) Line of therapy a First Second Third 118 361 512 0.51 (0.30, 0.85) 0.69 (0.53, 0.91) 0.69 (0.55, 0.86) T-DM1 Better Cap + Lap Better HRs from unstratified analysis. Hazard ratio a 0.2 0.5 1 2 5 Defined as any systemic therapy, including endocrine or chemotherapy.
Proportion surviving Overall Survival: Second Interim Analysis 1.0 0.8 0.6 0.4 78.4% 85.2% Median (months) No. of events Cap + Lap 25.1 182 T-DM1 30.9 149 Stratified HR=0.682 (95% CI, 0.548 0.849) P=.0006 Efficacy stopping boundary P=.0037 or HR=0.727 51.8% 64.7% 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk: Cap + Lap 496 471 453 435 403 368 297 240 204 159 133 110 86 63 45 27 17 7 4 T-DM1 495 485 474 457 439 418 349 293 242 197 164 136 111 86 62 38 28 13 5 Data cutoff July 31, 2012; Unstratified HR=0.70 (P=.0012).
Adverse Events Grade 3 AEs With Incidence 2% Cap + Lap (n=488) T-DM1 (n=490) Adverse Event All Grades, % Grade 3, % All Grades, % Grade 3, % Total 97.7 57.0 95.9 40.8 Diarrhea 79.7 20.7 23.3 1.6 Hand-foot syndrome 58.0 16.4 1.2 0.0 Vomiting 29.3 4.5 19.0 0.8 Neutropenia 8.6 4.3 5.9 2.0 Hypokalemia 8.6 4.1 8.6 2.2 Fatigue 27.9 3.5 35.1 2.4 Nausea 44.7 2.5 39.2 0.8 Mucosal inflammation 19.1 2.3 6.7 0.2 Thrombocytopenia 2.5 0.2 28.0 12.9 Increased AST 9.4 0.8 22.4 4.3 Increased ALT 8.8 1.4 16.9 2.9 Anemia 8.0 1.6 10.4 2.7 ALT, alanine aminotransferase; AST, aspartate aminotransferase. There was no increase in cardiotoxicity (LVEF <50% and 15-point decrease from baseline): Cap + Lap, 1.6% (445 evaluable patients); T-DM1, 1.7% (481 evaluable patients).
1 st Line mbc Phase III MARIANNE Study: BO22589/TDM4788g HER2-positive, first-line, metastatic breast cancer N=1092 Trastuzumab + taxane (until PD) n=364 T-DM1 + pertuzumab (until PD) n=364 T-DM1 + pertuzumab placebo (until PD) n=364 Primary endpoints: PFS as assessed by IRF; Safety Secondary endpoints: OS; PFS by investigator; patient reported outcomes analysis; biomarkers 19 Perez EA, et al. Abstr LBA3. ESMO 2010
Post Neo-adjuvant T-DM1: Trial Schema Target 3-year DFS HER2+ ebc Preoperative chemo (taxane ± anthracycline) + trastuzumab S U R G E R Y Residual invasive tumor (breast or nodes) N=1484 14 cycles trastuzumab T-DM1 70% 76.5% HR = 0.75 MDD = 74.7% HR = 0.816 Primary Endpoint: DFS Secondary Endpoints: OS, Safety MDD = Minimal Detectable Difference.
Adjuvant T-DM1: Trial Schema AC/FEC-T N = 1750 Node + or HR- Trastuzumab + Pertuzumab AC/FEC-T T-DM1 + Pertuzumab Primary Endpoint: DFS Second Endpoints: OS, Safety AC: adriamycin/cyclophosphamide; FEC: 5FU/epirubicin/cyclophosphamide; T: docetaxel Q3W or paclitaxel QW
Summary/Conclusion T-DM1 demonstrates improved efficacy over capecitabine + lapatinib Significant improvement in PFS Median PFS: Cap + Lap 6.4 mo; T-DM1 9.6 mo HR=0.650; P<.0001 Significant improvement in OS Median OS: Cap + Lap 25.1 mo; T-DM1 30.9 mo HR=0.682; P=.0006 Safety and secondary efficacy endpoints also favored T-DM1 T-DM1 offers an important therapeutic option in the treatment of HER2-positive metastatic breast cancer FDA approval, February 22, 2013 Future T-DM1 studies are underway in first line MBC, and are planned in early stage disease
Thanks To all of the patients who participated in the trial and their families To the investigators, clinicians and research staff at the 213 sites in 26 countries 23 23
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