Immunoconjugates in Both the Adjuvant and Metastatic Setting

Transcription

1 Immunoconjugates in Both the Adjuvant and Metastatic Setting Mark Pegram, M.D. Director, Stanford Breast Oncology Program Co-Director, Molecular Therapeutics Program

2 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).

3 SK-BR-3 BT-474 MDA-MB-361 MDA-MB-453 In Vitro Drug Interactions With Trastuzumab Carboplatin Cyclophosphamide Vinorelbine Combination index* Doxorubicin Epirubicin SK-BR-3 BT-474 MDA-MB-361 MDA-MB-453 Combination index* Docetaxel Paclitaxel Gemcitabine SK-BR-3 BT-474 MDA-MB-361 MDA-MB-453 Combination index* *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.

4 Paclitaxel-conjugated Trastuzumab Hydrolysis Gilbert CW, McGowan, EB, Seery GB, Black KS, Pegram, MD J Exp Ther Oncol Jan-Feb; 3(10):

5 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 Jan-Feb; 3(10):

6 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: by American Association for Cancer Research

7 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

8 N Engl J Med Nov 8;367(19):

9 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)

10 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 (%) (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)

11 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)

12 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)

13 Drug Exposure Cap (n=487) Lap (n=488) T-DM1 (n=490) Median dose intensity, % 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)

14 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= DOR Median, months (95% CI) Cap + Lap 6.5 (5.5, 7.2) T-DM (8.4, 20.8) /389 Cap + Lap 173/397 T-DM Time (months) No. at risk Cap + Lap T-DM

15 Proportion progression-free Progression-Free Survival by Independent (IRC) and Investigator (INV) Review IRC INV Cap + Lap T-DM1 Cap + Lap T-DM1 HR=0.650 (95% CI, 0.55, 0.77) P< HR=0.658 (95% CI, 0.56, 0.77) P< Time (mos) No. at risk by independent review: Cap + Lap T-DM Unstratified HR by independent review=0.66 (P<0.0001).

16 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 >1 382 Presence of visceral disease Yes No 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 years (0.52, 0.74) 0.88 (0.53, 1.45) 75 years (1.22, 10.13) ER and PR status ER+ and/or PR+ ER and PR (0.58, 0.91) 0.56 (0.44, 0.72) Line of therapy a First Second Third (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 Defined as any systemic therapy, including endocrine or chemotherapy.

17 Proportion surviving Overall Survival: Second Interim Analysis % 85.2% Median (months) No. of events Cap + Lap T-DM Stratified HR=0.682 (95% CI, ) P=.0006 Efficacy stopping boundary P=.0037 or HR= % 64.7% Time (months) No. at risk: Cap + Lap T-DM Data cutoff July 31, 2012; Unstratified HR=0.70 (P=.0012).

18 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 Diarrhea Hand-foot syndrome Vomiting Neutropenia Hypokalemia Fatigue Nausea Mucosal inflammation Thrombocytopenia Increased AST Increased ALT Anemia 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).

19 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

20 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= cycles trastuzumab T-DM1 70% 76.5% HR = 0.75 MDD = 74.7% HR = Primary Endpoint: DFS Secondary Endpoints: OS, Safety MDD = Minimal Detectable Difference.

21 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

22 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-DM 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

23 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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