ABC1 - I.E. Krop, US - New and future therapies for HER-2+ advanced breast cancer
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ABC1 - I.E. Krop, US - New and future therapies for HER-2+ advanced breast cancer
- 1. New and future therapies for HER-2+ advanced breast cancer Ian Krop Dana-Farber Cancer Institute Harvard Medical School November 2011
- 7. HER2:HER3 dimers may provide an escape mechanism from trastuzumab + + + + + + + + + + + Signaling activity + + + + Homodimers Heterodimers HER1:HER1 HER2:HER2 HER3:HER3 HER4:HER4 HER1:HER2 HER1:HER3 HER1:HER4 HER2:HER3 HER2:HER4 HER3:HER4 Tzahar, et al. Mol Cell Biol 1996. Sergina et al. Nature 2007, 445:437-441
- 8. Pertuzumab Activity 1. Baselga J et al. J Clin Oncol. 2010;28:1138-1144. 2. Cortés J et al. ASCO 2009 Annual Meeting. Abstract 1022. With Trastuzumab 1 n = 66 Monotherapy 2 n = 29 % % Best objective response CR 8 0 PR 17 7 SD-6 months 26 4 ORR 24 7 Clinical benefit rate 50 11
- 9. NeoSphere: Study Design THP (n=107) Docetaxel + Herceptin + Pertuzumab HP (n=107) Herceptin + Pertuzumab TP (n=96) Docetaxel + Pertuzumab S U R G E R Y Study dosing: q3w x 4 TH (n=107) Docetaxel + Herceptin Patients with operable or locally advanced /inflammatory* HER2-positive BC Chemo-naïve & primary tumours >2cm (N=417 ) BC, breast cancer; FEC, 5-fluorouracil, epirubicin and cyclophosphamide *Locally advanced=T2–3, N2–3, M0 or T4a–c, any N, M0; operable=T2–3, N0–1, M0; inflammatory = T4d, any N, M0 3 Docetaxel q3w x 4-> FEC q3w x 3 Herceptin q3w cycles 5–17 FEC q3w x 3 Herceptin q3w cycles 5–17 FEC q3w x 3 Herceptin q3w cycles 5–17 FEC q3w x 3 Herceptin q3w cycles 5–21
- 10. NeoSphere pCR Rates: ITT population summary pCR, % 95% CI Treatment 29.0% 45.8% 16.8% 24.0% 6 p = 0.0141 50 40 30 20 10 0 TH THP HP TP p = 0.0198 p = 0.003
- 15. T-DM1 selectively delivers DM1 to HER2-positive tumor cells Receptor-T-DM1 complex is internalized into HER2-positive cancer cell Potent antimicrotubule agent is released once inside the HER2-positive tumor cell T-DM1 binds to the HER2 protein on cancer cells HER2
- 18. Phase II Study (TDM4374g): Common Adverse Events Krop et al. Presented at: 32nd Annual SABCS Meeting. December 10–13, 2009; San Antonio, TX. Poster 710. AST=aspartate aminotransferase. Adverse event, % Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 All grades Fatigue 30.0 26.4 2.7 0 0 59.1 Nausea 26.4 10.0 0.9 0 0 37.3 Thrombocytopenia 10.9 12.7 3.6 1.8 0 29.1 AST increased 10.9 10.9 2.7 0 0 24.5 Pyrexia 12.7 8.2 0.9 0 0 21.8 Constipation 17.3 2.7 0.9 0 0 20.9 Dry mouth 17.3 3.7 0 0 0 20.0 Headache 17.3 2.7 0 0 0 20.0 Back pain 13.6 1.8 2.7 0.9 0 19.1 Hypokalemia 16.4 0.9 0.9 0 0 18.2 Anemia 5.5 10.0 1.8 0 0 17.3 Decreased appetite 10.9 6.4 0 0 0 17.3 Cough 12.7 4.5 0 0 0 17.3 Epistaxis 13.6 2.7 0.9 0 0 17.3
- 19. Phase II Study (TDM4374g): LVEF (Local Assessment) Baselga et al. Discussion of Krop et al poster 710. Presented at 32nd Annual SABCS Meeting. December 10–13, 2009; San Antonio, TX. Lowest post-baseline value, n (%) N=110 ≥ 45% 107 (97.3) ≥ 40 – <45% 0 (0) <40% 0 (0) Missing 3 (2.7) Maximum decrease from baseline, n (%) Increase 25 (22.7) 0 – <15% 80 (72.7) ≥ 15 – <25% 2 (1.8) ≥ 25% 0 (0) Missing 3 (2.7)
- 20. Antitumor Activity in Treated Patients IRF - Independent Review Facility Objective Response - CR or PR determined by two consecutive tumor assessments at least 28 days apart. Clinical Benefit - objective response or SD maintained for at least 6 months. *Including unconfirmed PRs. Krop et al, ESMO 2010 Tumor Response IRF (N=110) Investigator (N=110) Objective Response Rate, % (95% CI) CR PR SD* PD 34.5 (26.1–43.9) 0 34.5 44.5 18.2 32.7 (24.1–42.1) 4.5 28.2 50.9 14.5 Clinical Benefit Rate, % (95% CI) 48.2 (38.8–57.9) 46.4 (37.1–56.1)
- 21. Pro gressio n-Free Survival Krop et al, SABCS 2009 Progression-Free Survival Rate Time on Study (months) T-DM1 (N=110) Median PFS: 7.3 mo 95% CI: (4.2- ) 25–75 percentile: 2.6–9.7 Range: 0.0+ – 11.7+ N 110 Number progressed 50 (45.5%) Number censored 60 (54.5%) 0 2 4 6 8 10 12 14 16 0.0 0.20 0.4 0.6 0.8 1.0 110 82 58 33 19 1 0 0 0 Number at risk T-DM1
- 23. Pharmacokinetics of T-DM1 at q3wk MTD
- 24. Platelet counts at the MTD: consistent effects over time Platelet count by study day for 3.6 mg/kg cohort T – DM1 administered on Day 21 of each cycle. Krop et al, JCO 2010:2698
- 25. Patterns of thrombocytopenia with T-DM1 Stable effects over time ≈ 80% of patients Cumulative loss of platelets ≈ 20% of patients Bender et al, SABCS 2010
- 28. Objective Response by Investigator Patients With Measurable Disease at Baseline a One patient was not included in the efficacy analysis due to study site withdrawal. b Defined as complete or partial response based on RECIST 1.0 determined on 2 consecutive tumor assessments at least 4 weeks apart. c Defined as objective response any time during the study or maintained stable disease for at least 6 months from randomization. Hurvitz et al, ESMO 2011 Trastuzumab + docetaxel (n=69) a T-DM1 (n=67) Patients with an objective response, b n (%) 40 (58.0) 43 (64.2) 95% CI 45.5–69.2 51.8–74.8 Objective responses, n (%) Complete response 3 (4.3) 7 (10.4) Partial response 37 (53.6) 36 (53.7) Stable disease 23 (33.3) 13 (19.4) Progressive disease 4 (5.8) 8 (11.9) Unable to evaluate or missing 2 (2.9) 3 (4.5) Patients with clinical benefit, c n (%) 56 (81.2) 50 (74.6) 95% CI 70.7–89.1 63.2–84.2
- 29. Time (months) Proportion progression-free 1.0 0.8 0.6 0.4 0.2 0.0 0 2 4 6 8 10 12 14 16 18 20 Number of patients at risk T+D 70 66 63 53 43 27 12 4 2 2 0 T-DM1 67 60 51 46 42 35 22 15 6 3 0 Trastuzumab + docetaxel (n=70) T-DM1 (n=67) Progression-Free Survival by Investigator Randomized Patients Median PFS, mos Hazard ratio 95% CI Log-rank P value 9.2 14.2 0.594 0.364– 0.968 0.0353
- 30. Duration of objective response (months) Proportion progression-free Number of patients at risk T+D 40 40 38 32 19 8 2 1 1 0 T-DM1 43 41 38 33 27 19 12 6 3 0 0 2 4 6 8 10 12 14 16 18 1.0 0.8 0.6 0.4 0.2 0.0 Trastuzumab + docetaxel (n=40) T-DM1 (n=43) Duration of Response by Investigator Patients with Measurable Disease at Baseline with an Objective Response Median DOR, mos 95% CI 9.5 NR 6.6–10.6 –
- 31. Summary of Adverse Events Safety Evaluable Patients a Two patients mistakenly received a dose of T-DM1 and were thus included in the T-DM1 arm for safety analyses. b Includes 3 patients who received at least 1 dose of trastuzumab alone or trastuzumab plus docetaxel. c Due to cardiopulmonary failure. d Due to sudden death. Hurvitz et al, ESMO 2011 No clinically significant cardiac events reported Trastuzumab + docetaxel (n=66) a , n (%) T-DM1 (n=69) a,b , n (%) Any grade ≥3 AE 59 (89.4) 32 (46.4) AE leading to discontinuation of any study treatment component (any grade) 19 (28.8) 5 (7.2) AE leading to death 1 (1.5) c 1 (1.4) d Serious AEs (any grade) 17 (25.8) 13 (18.8)
- 35. Th3RESA: Study Schema Study treatment continues until disease progression or unmanageable toxicity HER2 positive (Centrally confirmed) Unresectable locally advanced/recurrent or Metastatic breast cancer Prior trastuzumab, lapatinib, anthracycline, taxane, and capecitabine Treatment of physician ’ s choice N = 795 2:1 randomization 2 1 T-DM1 q3w
- 36. HER1/2 TKI Lapatinib, HKI-272, BIBW 2992, PKI-166, EKB-569 Pan HER TKI Canertinib, BMS-599626 HER1/2/VEGFR TKI XL647, AEE788 HER2 dimerization inhibitor Pertuzumab Bispecific antibody Ertumaxomab Conjugated antibodies Trastuzumab-MCC-DM1, trastuzumab-A-Z-CINN, 310-paclitaxel HSP90 inhibitors Tanespimycin, alvespimycin, CNF2024, IPI-504, AUY922, SNX5422 IGF-1R inhibitors (mAb, TKI) CP-751871, EM164, IMC-A12, NVP-ADW742, INSM-18 HDAC inhibitors Vorinostat, LBH589, PXD101, NVP-LAQ824, depsipeptide, CI-994, MS-275 PI3K inhibitors SF1126, BEZ235, XL147, XL765 Akt inhibitors Perifosine, XL418 mTOR inhibitors Rapamycin (sirolimus), temsirolimus, everolimus, deforolimus HER2 vaccines Other Novel HER2 targeted Agents
- 39. NeoALTTO: Pathologic CR Rates Baselga J et al. SABCS 2010. Abstract S3-3. No difference in proportion of patients undergoing breast conservation Path CR (Breast Only) Path CR (Breast and LN) Lapatinib + Paclitaxel 25% 20% Trastuzumab + Paclitaxel 29% 28% Trastuzumab + Lapatinib + Paclitaxel 51% 47%
- 40. Lapatinib +/- Trastuzumab in HER2+ MBC Progressing on Trastuzumab: Updated Overall Survival in ITT Blackwell KL et al. J Clin Oncol . 2010;28:1124. Time From Random Assignment (weeks) Patients at Risk L + T 148 L 148 106 121 30 40 3 4 L N = 145 L+T N = 146 Died, n 69 56 Median, wk 39.0 51.6 Hazard ratio (95% CI) 0.75 (0.53, 1.07) P value 0.106 Survival (%) L + T L 100 80 60 40 20 0 0 20 60 40 80 45 70 36 6 Months OS 12 Months OS
- 41. Trastuzumab+lapatinib in HER2+ MBC Lin et al. ASCO 2011 Best Overall Response (n=76) Response 1 st Line (n=36) N (%) 2 nd /3 rd line (n=40) N (%) Confirmed response Complete response Partial response 16 (44%) 3 13 9 (23%) 0 9 Unconfirmed response Complete response Partial response 3 (8%) 0 3 5 (13%) 0 5 Stable disease 5 (14%) 16 (40%) Progressive disease 10 (28%) 10 (25%) Unknown 2 (6%) 0 (0%) Clinical Benefit Rate (confirmed CR or PR + SD > 24 weeks) 17 (47%) 14 (35%)
Notas del editor
- Add isakoff slide for pertuz Find # of priors for pertuz Find exposure data for tdm1 weekly
- by selectively delivering drugs to overexpressed antigens on tumor cells than could be achieved by administration of either antibody or chemotherapy as free agents
- T-DM1 Mechanism of Action T-DM1 is a unique ADC because it provides intracellular delivery of the highly potent cytotoxic agent DM1 to HER2-overexpressing cells, in addition to the antitumor activities of trastuzumab. Trastuzumab biological activity is retained by T-DM1; trastuzumab MOAs include: Antibody-dependent cellular cytotoxicity (ADCC) Inhibition of cell signaling through the PI3K/AKT pathway Inhibition of HER2 shedding • It is thought that once T-DM1 binds HER2, the receptor–ADC complex is internalized, then degraded by proteolytic digestion in lysosomes. This allows for the release of DM1 into the cytoplasm and the subsequent inhibition of microtubule assembly, resulting in cell death DM1 is a highly potent microtubule inhibitor 20-100 times more potent than vincristine and 25-500 fold more potent than paclitaxel in cytotoxic assays
- .
- “ A novel exploitation of HER2 biology” The green fluorophore Alexa-488 was conjugated to trastuzumab BT474 cells incubated with 488trastuzumab +/- were incubated 1 micromolar GA for 3h and then imaged by fluorescence microscopy
- Thrombocytopenia at the MTD (3.6 mg/kg) was generally Grade ≤ 1 and non-cumulative, without significant lowering of nadirs or increase in time to recovery after repeated administration. 1 Platelet nadirs were observed on approximately Day 8; recovery was rapid (by approximately Day 15). Reference Krop IE, Beeram M, Modi S, Rabbee N, Girish S, Tibbitts J, et al. A Phase I study of trastuzumab – DM1, a first-in-class HER2 antibody – drug conjugate (ADC), in patients with HER2+ metastatic breast cancer. San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, December 13–16, 2007 (Abstract 310).
- In the T-DM1 arm dose delays (up to 3 weeks) and dose reductions (3.0 mg/kg and 2.4 mg/kg) may occur for toxicity. In the trastuzumab-plus-docetaxel arm standard dose modifications apply Patients in the trastuzumab-plus-docetaxel arm may crossover to T-DM1 therapy upon radiographic progression. All patients will be followed for subsequent therapy until death. Reference A study of the efficacy and safety of T-DM1 vs. trastuzumab (Herceptin ® ) and docetaxel (Taxotere ® ) in patients with metastatic HER2-positive breast cancer who have not received prior chemotherapy for metastatic disease. ClinicalTrials.gov [Website]. http://www.clinicaltrials.gov/ct2/show/NCT00679341?term=T-DM1+docetaxel&rank=1. Updated October 9, 2009. Accessed October 22, 2009.
- Secondary Endpoints: ORR by investigator were very similar between control arm and experimental T-DM1 arm Stable disease includes 11 patients with unconfirmed partial response (5 in T-DM1 arm and 6 in the trastuzumab + docetaxel arm) QOL data to be presented at a future congress (SABCS) QOL Background: Trial Outcome Index–Physical/Functional/Breast (TOI-PFB) subset of the Functional Assessment of Cancer Therapy Breast (FACT-B) provides a summary measure of physical and functional well-being and breast cancer–specific symptoms. QOL analyses were based on patients who had a FACT-B assessment at cycle 1 and at least one FACT-B assessment after cycle 1; a change of 5 points in the FACT-B TOI-PFB is considered clinically meaningful, which may reflect changes of QOL due to treatment side effects and/or disease burden. The worsening of health-related QOL, as measured by the first 5 points drop from baseline for TOI-PFB, was significantly delayed in patients treated with T-DM1 relative to patients treated with docetaxel plus trastuzumab. RECIST, Response Evaluation Criteria In Solid Tumors.
- Clear differences were seen between study arms in terms of Grade 3 or greater AEs (89% for control arm vs. 46% for T-DM1) AEs led to treatment discontinuation more frequently in the control arm than T-DM1 arm Serious AEs were numerically more common in control arm Note that the discontinuation for AE any drug for control arm means that any treatment had to be stopped (docetaxel) due to AE. Therefore 28.8% is higher than the 5.7% seen in disposition slide because both docetaxel and trastuzumab were discontinued for those AEs. AEs leading to death (1 each on control and experimental T-DM1 arm were not attributed to study treatment by investigator ) Death on T-DM1: this is the event of sudden death occurred after one dose of T-DM1 due to medication error. However, this pt had episodes of syncope while on trastuzumab + docetaxel (prior to the dose of T-DM1) and the etiology of syncope was being investigated prior to the event (without conclusions). Death on trastuzumab + docetaxel: this pt had Grade 5 ACUTE cardiopumonary FAILURE; right before this reported event, pt experienced DVT, A-fib, and renal failure. Pt also had history of HTN, ISCHAEMIC HEART DISEASE, and aortic insufficiency. AE, adverse event Serious AEs = AEs that result in death, are life-threatening, require inpatient hospitalization or prolongation of existing hospitalization, result in persistent or significant disability/incapacity, or are congenital anomalies/birth defects
- In the T - DM1 arm dose delays and reductions are allowed per protocol toxicity guidelines. In the control arm (lapatinib + capecitabine), dosing modifications are by prescribing guidelines. All patients will be followed with tumor assessments until progression and for subsequent therapy until death. Independent committees: data monitoring committee are to monitor overall safety data; cardiac review committee to review potential cases of left ventricular systolic dysfunction. Reference An open-label study of trastuzumab-MCC-DM1 (T-DM1) vs. capecitabine + lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer. ClinicalTrials.gov [Website]. http://www.clinicaltrials.gov/ct2/show/NCT00829166? term=T-DM1&rank=2. Updated October 5, 2009. Accessed October 23, 2009 .
- No crossover allowed for control arm to T-DM1 after PD (OS)