Emerging Agents in HER2-positive Disease. Mary Cianfrocca, DO Director, Breast Oncology Program Banner MD Anderson Cancer Center Gilbert, AZ
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1 Emerging Agents in HER2-positive Disease Mary Cianfrocca, DO Director, Breast Oncology Program Banner MD Anderson Cancer Center Gilbert, AZ
2 Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab Hudis C. N Engl J Med 2007;357:39-51
3 AVEREL: Study Design Previously untreated HER2-positive LR/MBC Centrally confirmed IHC 3+ or IHC 2+ and FISH/CISH+ Measurable or evaluable disease ECOG PS 0/1 No CNS metastases Stratification variables Prior (neo)adjuvant taxane (yes vs no [no chemotherapy/relapse <12 months vs 12 months since last chemotherapy]) Adjuvant H (yes vs no) ER/PgR status (positive vs negative) Measurable disease (yes vs no) R H: 8 6 mg/kg DOC: 100 mg/m 2 both q3w H: 8 6 mg/kg DOC: 100 mg/m 2 BEV: 15 mg/kg all q3w H and BEV continued to PD or unacceptable toxicity DOC given until PD or unacceptable toxicity (planned minimum of 6 cycles) BEV, bevacizumab; CISH, chromogenic in situ hybridization; DOC, docetaxel; ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; FISH, fluorescence in situ hybridization; H, trastuzumab; IHC, immunohistochemistry; MBC, metastatic breast cancer; PD, progressive disease; PgR, progesterone receptor. Gianni L, et al. Cancer Res. 2011;71(24 Suppl):Abstract S4-8.
4 Estimated probability AVEREL: IRC-Assessed PFS (Stratified, Censored for Non-Protocol Therapy a ) H + DOC (n=208) H + DOC + BEV (n=216) Events, n (%) 114 (54.8) 111 (51.4) Median PFS, months (95% CI) HR, stratified a (95% CI) 13.9 ( ) 0.72 ( ) Log - rank P - value ( ) Time (months) No. at risk: BEV, bevacizumab; CI, confidence interval; DOC, docetaxel; H, trastuzumab; IRC, Independent Review Committee; PFS, progression-free survival. a Prespecified in the statistical analysis plan for US regulatory purposes. Gianni L, et al. Cancer Res. 2011;71(24 Suppl):Abstract S4-8.
5 Estimated probability AVEREL: Interim Overall Survival H + DOC (n=208) H + DOC + BEV (n=216) Events, n (%) 78 (37.5%) 81 (37.5%) Median OS, months (95% CI) 38.3 (34.3 NR) 38.5 (32.1 NR) HR, unstratified (95% CI) 1.01 ( ) p= HR, stratified (95% CI) 0.94 ( ) p= Time (months) No. at risk: BEV, bevacizumab; CI, confidence interval; DOC, docetaxel; H, trastuzumab; NR, not reached; OS, overall survival. Gianni L, et al. Cancer Res. 2011;71(24 Suppl):Abstract S4-8.
6 Conclusions and Perspectives AVEREL demonstrated improved PFS when BEV was combined with H + DOC in patients with HER-positive LR/MBC Investigator-assessed PFS (primary endpoint): HR 0.82 (P =.0775) IRC-assessed PFS: HR 0.72 (P =.0162) No difference in OS (immature data) was observed No new safety signals were observed In AVEREL, exploratory analyses of plasma VEGF-A suggest a potentially predictive effect (greater benefit with high VEGF-A levels), consistent with observations in HER2-negative LR/MBC BEV, bevacizumab; DOC, docetaxel; H, trastuzumab; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; LR, locally recurrent; MBC, metastatic breast cancer; OS, overall survival; PFS, progression-free survival; VEGF-A, vascular endothelial growth factor A. Gianni L, et al. Cancer Res. 2011;71(24 Suppl):Abstract S4-8.
7 Pertuzumab: Dimerization Inhibitor HER2 EGFR HER-2 specific monoclonal antibody binds HER2 at the dimerization domain II Disrupts ligand-dependant HER2 heterodimerization and signaling Pre-clinical activity in non-her2 overexpressing tumors Activity in trastuzumab-refractory cell lines In vitro synergy with trastuzumab
8 Hubbard S. Cancer Cell.2005;7(4): Trastuzumab and Pertuzumab Bind to Distinct Epitopes on HER2 Extracellular Domain Trastuzumab Pertuzumab Activates antibody-dependent cellular cytotoxicity Enhances HER2 internalization Inhibits angiogenesis Activates antibody-dependent cellular cytotoxicity Prevents receptor dimerization Potent inhibitor of HER-mediated signaling pathways
9 Phase II Trial of Pertuzumab and Trastuzumab in HER2+ Patients Progressing on Trastuzumab HER2+ Breast Cancer Heavily Pretreated (up to 3 prior therapies) LVEF 55%, no drop <50% during prior trastuzumab a T: 4 mg/kg loading dose 2 mg/kg qw or 8 mg/kg loading dose 6 mg/kg q3w; P: 840 mg loading dose 420 mg q3w IDSMB, International Data and Safety Monitoring Board Gelmon, ASCO 2008, Abstract 1026
10 Phase II Study of Pertuzumab Monotherapy in Patients with Metastatic Breast Cancer Progressing on Trastuzumab Data on 1 st and 2 nd cohort receiving pertuzumab and trastuzumab in combination has previously been reported 3 rd cohort enrolled to evaluate activity of pertuzumab monotherapy (trastuzumab could be added if progression) Efficacy Pertuzumab + Trastuzumab (n=66) Pertuzumab (n=29) ORR 16 (24%) 2 (7%) CR 5 (8%) 0 PR 11 (17%) 2 (7%) SD 17 (26%) 1 (4%) *Asymptomatic failing LVEF (< 50% absolute value and by 10%-points) in 3 patients; 2 on pertuzumab monotherapy and 1 on pertuzumab and trastuzumab Gelmon et al. Paper presented at: 44 th Annual Meeting of the American Society of Clinical Oncology; May 30-June 3, 2008; Chicago, IL. Abstract Cortes et al. Paper presented at : 45 th Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2009; Orlando, FL. Abstract 1022.
11 Pertuzumab and Trastuzumab have Complementary Mechanisms of Action HER2 Pertuzumab Trastuzumab HER1/3/4 Subdomain IV Dimerization domain Trastuzumab: Inhibits ligand-independent HER2 signaling Activates ADCC Prevents HER2 ECD shedding Pertuzumab: Inhibits ligand-dependent HER2 dimerization and signaling Activates ADCC ADCC, antibody-dependent cell-mediated cytotoxicity; EDC, extracellular domain; HER2, human epidermal growth factor receptor 2. Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5.
12 CLEOPATRA: Study Design n = 406 Placebo + trastuzumab PD Patients with HER2-positive MBC centrally confirmed (N = 808) 1:1 Docetaxel* 6 cycles recommended Pertuzumab + trastuzumab PD n = 402 Docetaxel* 6 cycles recommended * <6 cycles allowed for unacceptable toxicity or PD; >6 cycles allowed at investigator discretion Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not) Study dosing q3w: Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance Docetaxel: 75 mg/m 2, escalating to 100 mg/m 2 if tolerated MBC, metastatic breast cancer; PD, progressive disease Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
13 CLEOPATRA: Prior Breast Cancer Therapy Prior (neo)adjuvant chemotherapy, n (%) Yes No Components of (neo)adjuvant therapy a, n (%) Anthracycline Hormones Taxane Trastuzumab Placebo + trastuzumab + docetaxel (n = 406) 192 (47.3) 214 (52.7) 164 (40.4) 97 (23.9) 94 (23.2) 41 (10.1) Pertuzumab + trastuzumab + docetaxel (n = 402) 184 (45.8) 218 (54.2) 150 (37.3) 106 (26.4) 91 (22.6) 47 (11.7) a Numbers add up to more than 100% because patients could have received more than one therapy. Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
14 Progression-free survival (%) CLEOPATRA: Independently Assessed PFS n = 433 PFS events n at risk Ptz + T + D Pla + T + D Ptz + T + D: median 18.5 months Pla + T + D: median 12.4 months Time (months) = 6.1 months Hazard ratio = % CI P<.0001 CI, confidence interval; D, docetaxel; PFS, progression-free survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab. Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
15 CLEOPATRA: PFS in Predefined Subgroups Favors pertuzumab Favors placebo n HR 95% CI Prior (neo)adjuvant chemotherapy Region Age group Race All No Yes Europe North America South America Asia <65 years 65 years <75 years 75 years White Black Asian Other Disease type ER/PgR status HER2 status Visceral disease Non-visceral disease Positive Negative Unknown IHC 3+ FISH-positive CI, confidence interval; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; PFS, progression-free survival. Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
16 CLEOPATRA: Independently Assessed PFS by Prior Trastuzumab Therapy in Patients who Received Neoadjuvant Therapy Prior (neo)adjuvant trastuzumab treatment (n = 88) No prior (neo)adjuvant trastuzumab treatment (n = 288) Median PFS, months Placebo + trastuzumab + docetaxel Pertuzumab + trastuzumab + docetaxel HR (95% CI) 0.62 ( ) 0.60 ( ) CI, confidence interval; HR, hazard ratio; PFS, progression-free survival. Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
17 CLEOPATRA: Independently Reviewed Objective Response In Patients With Measurable Disease at Baseline Objective response rate, n (%) Complete response rate, n (%) Partial response rate, n (%) Placebo + trastuzumab + docetaxel (n = 336) 233 (69.3) 14 (4.2) 219 (65.2) Pertuzumab + trastuzumab + docetaxel (n = 343) 275 (80.2) 19 (5.5) 256 (74.6) P =.0011 a Stable disease, n (%) 70 (20.8) 50 (14.6) Progressive disease, n (%) 28 (8.3) 13 (3.8) Unable to assess or no assessment, n (%) 5 (1.5) 5 (1.5) a The statistical test result is deemed exploratory. Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
18 Overall survival (%) CLEOPATRA: Overall Survival (Interim Analysis) n at risk Median follow-up: 19.3 mos; n = 165 OS events Pertuzumab + T + D Placebo + T + D Ptz + T + D: 69 events Pla + T + D: 96 events Time (months) CI, confidence interval; D, docetaxel; OS, overall survival; Pla, placebo; Ptz, pertuzumab; T, trastuzumab. a The interim OS analysis did not cross the prespecified O Brien-Fleming stopping boundary (HR 0.603; p ). Hazard ratio = 0.64 a 95% CI P =.0053 a Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
19 CLEOPATRA: Cardiac Tolerability Percentage of patients Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Investigator-assessed symptomatic LVSD a Independently adjudicated symptomatic LVSD a Fall in LVEF to <50% and by 10 percentage points from baseline LVEF, left ventricular ejection fraction; LVSD, left ventricular systolic dysfunction. a LVSD was defined as New York Heart Association class III/IV. Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
20 CLEOPATRA: Adverse Events (All Grades) 25% Incidence or >5% Difference Between Arms Adverse event, n (%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Diarrhea 184 (46.3) 272 (66.8) Alopecia 240 (60.5) 248 (60.9) Neutropenia 197 (49.6) 215 (52.8) Nausea 165 (41.6) 172 (42.3) Fatigue 146 (36.8) 153 (37.6) Rash 96 (24.2) 137 (33.7) Decreased appetite 105 (26.4) 119 (29.2) Mucosal inflammation 79 (19.9) 113 (27.8) Asthenia 120 (30.2) 106 (26.0) Peripheral edema 119 (30.0) 94 (23.1) Constipation 99 (24.9) 61 (15.0) Febrile neutropenia 30 (7.6) 56 (13.8) Dry skin 17 (4.3) 43 (10.6) Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
21 CLEOPATRA: Grade 3 Adverse Events (Incidence >5%) Adverse event, n (%) Placebo + trastuzumab + docetaxel (n = 397) Pertuzumab + trastuzumab + docetaxel (n = 407) Neutropenia 182 (45.8) 199 (48.9) Febrile neutropenia 30 (7.6) 56 (13.8) Leukopenia 58 (14.6) 50 (12.3) Diarrhea 20 (5.0) 32 (7.9) Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
22 Summary and Conclusions CLEOPATRA met its primary endpoint and demonstrated a statistically significant and clinically meaningful improvement in PFS (HR 0.62) Median PFS by 6.1 months from 12.4 to 18.5 months The PFS improvement was consistent across subgroups and supported by the secondary endpoints of ORR and OS (immature) The combination of pertuzumab, trastuzumab and docetaxel diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin rates These adverse events were primarily grades 1 2, manageable, and occurred during docetaxel therapy There was no increase in cardiac adverse events or LVSD This regimen may be practice-changing as first-line therapy in HER2+ MBC HER2, human epidermal growth factor receptor 2; HR, hazard ratio; LVSD, left ventricular systolic dysfunction; MBC, metastatic breast cancer; ORR, objective response rate; OS, overall survival; PFS; progression-free survival. Baselga J, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-5. Baselga J, et al. N Engl J Med December 7. [Epub ahead of print].
23 Trastuzumab-DM1 (TDM-1): HER2 antibody-drug conjugate Trastuzumab modified using a covalent linker to attach DM-1 DM-1, derivative of microtubule destabilizer maytansine Naturally occurring antitumor antibiotic Significant preclinical activity, but significant clinical toxicity as free drug Trastuzumab-DM1 is designed to preferentially deliver DM1 to HER2+ tumor cells Improve therapeutic index of DM1 Maintain biological effect of trastuzumab Burris et al, 2006; Beeram et al, 2008; Holden et al, 2008.
24 T-DM1: Mechanism of Action HER2 T-DM1 Emtansine release Inhibition of microtubule polymerization Lysosome P P P Internalization Nucleus LoRusso PM, et al. Clin Cancer Res. 2011;17(20): Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1.
25 Single agent T-DM1:Phase 2 study; previously treated with an anthracycline, a taxane, capecitabine, lapatinib and trastuzumab Complete response 0% Partial response 33% Overall response rate 33% Clinical benefit rate 45% PFS 7.3 months Kropp et al, SABCS 2009, Abstract 5090
26 EMILIA Study Design HER2+ (central) LABC or MBC (N = 980) T-DM1 3.6 mg/kg q3w IV PD Prior taxane and trastuzumab Progression on metastatic tx or within 6 mos of adjuvant tx 1:1 Capecitabine 1000 mg/m 2 orally bid, days 1 14, q3w + Lapatinib 1250 mg/day orally 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 Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1.
27 Statistical Considerations for Efficacy End Points Hierarchical statistical analysis: performed in prespecified sequential order Progression-free Survival (PFS) by Independent Review Final PFS analysis: Targeted number of events: % power to detect HR = 0.75; 2-sided alpha 5% Overall Survival Overall Survival (OS) Interim OS analysis: Efficacy stopping boundary determined using Lan-DeMets alpha spending function with O Brien-Fleming boundary and number of death events observed Final OS analysis: Targeted number of events: % power to detect HR = 0.80; 2-sided alpha 5% Secondary End Points Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1.
28 Proportion Surviving Overall Survival: Interim Analysis 84.7% 77.0% 65.4% Median, mos No. events Cap + Lap T-DM1 NR 94 Stratified HR = (95% CI, 0.48, 0.81) P =.0005 Efficacy stopping boundary P =.0003 or HR = % Time, months No. at risk: Cap + Lap T-DM Unstratified HR = 0.63 (P =.0005). Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1. NR=not reached.
29 Proportion Progression-Free Progression-Free Survival by Independent Review Median, months No. events Cap + Lap T-DM Stratified HR = (95% CI, 0.55, 0.77) P< Time, months No. at risk by independent review: Cap + Lap T-DM Unstratified HR = 0.66 (P<.0001) Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1.
30 Percent Proportion Progression-Free Objective Response Rate (ORR) and Duration of Response (DOR) in Patients with Measurable Disease ORR DOR 50 Difference: 12.7% (95% CI, 6.0, 19.4) P = % 1.0 Median, mos (95% CI) Cap + Lap 6.5 (5.5, 7.2) T-DM (8.4, 20.8) % /389 Cap + Lap 173/397 T-DM No. at risk Cap + Lap T-DM Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1.
31 Patient-Reported Outcomes Time to Symptom Progression The FACT-Breast Trial Outcome Index 1 evaluates Physical well-being Functional well-being Breast cancer-specific symptoms Symptom progression defined as 5-point decrease from baseline Time to Symptom Progression Cap + Lap (n = 445) T-DM1 (n = 450) Median, mos HR (95% CI) P value 0.80 (0.67, 0.95) Brady MJ, et al. J Clin Oncol. 1997;15(3): Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1.
32 Overview of Adverse Events Cap + Lap (n = 488) T-DM1 (n = 490) All-grade AE, n (%) 477 (97.7) 470 (95.9) Grade 3 AE, n (%) 278 (57.0) 200 (40.8) AEs leading to treatment discontinuation (for any study drug), n (%) 52 (10.7) 29 (5.9) AEs leading to death on treatment, n (%) a 5 (1.0) 1 (0.2) LVEF <50% and 15-point decrease from baseline, % b 7 (1.6) 8 (1.7) a Cap + Lap: CAD, multiorgan failure, coma, hydrocephalus, ARDS a T-DM1: metabolic encephalopathy b Evaluable pts: 445 (Cap + Lap); 481 (T-DM1) Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1.
33 Nonhematologic 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, % Diarrhea Hand-foot syndrome Vomiting Hypokalemia Fatigue Nausea Mucosal inflammation Increased AST Increased ALT ALT, alanine aminotransferase; AST, aspartate aminotransferase. Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1.
34 Hematologic Adverse Events Adverse Event All Grade, % Cap + Lap (n = 488) Grade 3, % Grade 4, % All Grade, % T-DM1 (n = 490) Grade 3, % Grade 4, % Neutropenia Febrile neutropenia Anemia Thrombocytopenia Blackwell K, et al. J Clin Oncol. 2012;30(Suppl): Abstract LBA1.
35 Conclusions T-DM1 demonstrated improved efficacy over capecitabine + lapatinib T-DM1 demonstrated a significant improvement in PFS HR = 0.650; P<.0001 Interim overall survival favored T-DM1 but did not cross the efficacy stopping boundary HR = 0.621; P =.0005 Safety and secondary efficacy end points favored T-DM1 T-DM1 should offer an important therapeutic option in the treatment of HER2-positive metastatic breast cancer
36 Phase 2, Randomized, Open-Label Study of Neratinib vs Lapatinib + Capecitabine for 2 nd /3 rd -Line Tx of HER2+ MBC Phase II, open-label trial in HER2+ locally advanced or metastatic BC patients R A N D O M I Z E Neratinib 240 mg/day n = 117 L + C L 1250 mg/day + C 2000 mg/m 2 per day n = 116 Randomization is stratified based on geographical regions Patients were randomized 1:1 to neratinib or L + C Neratinib was administered orally at 240 mg/day continuously L 1,250 mg/day was administered orally continuously; C 2,000 mg/m 2 was administered orally on Days 1 to 14 of each 21-day cycle BC, breast cancer; C, capecitabine; HER2, human epidermal growth factor receptor 2; L, lapatinib. Martin M, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-7.
37 Treatment-Related Grade 3/4 Adverse Events Reported for 2% of Patients (Safety Population) Neratinib L + C Adverse Event, % (n = 116) (n = 115) Diarrhea PPE 0 14 Nausea 4 4 Vomiting 4 2 Neutropenia 2 4 Hyperbilirubinemia 0 4 Fatigue 3 3 Increased AST 3 3 Dehydration 3 2 Increased ALT 3 1 Rash 0 3 Stomatitis 0 3 Asthenia 3 0 Pruritis 2 1 ALT, alanine aminotransferase; AST, aspartate aminotransferase; C, capecitabine; L, lapatinib ; PPE, palmar-plantar erythrodysesthesia. Martin M, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-7.
38 Probability of PFS (%) Progression-Free Survival (ITT Population) Time since randomization (mo) Neratinib L + C n Median PFS 95% CI P value Neratinib mo mo L + C mo mo C, capecitabine; CI, confidence interval; L, lapatinib; PFS, progression-free survival. Martin M, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-7.
39 Summary and Conclusions Neratinib did not demonstrate noninferiority vs L+C in terms of PFS The median PFS was numerically superior in L+C arm vs neratinib (6.8 months vs 4.5 months) The antitumor activity of neratinib monotherapy in heavily pretreated patients with advanced or metastatic HER2+ BC was robust (ORR 29%) and consistent with results from the preceding single-arm trial Compared with L+C, neratinib was well tolerated with fewer dose reductions, dose delays, or discontinuations due to adverse events Diarrhea was the most frequently reported adverse event, but was typically transient and manageable with loperamide These findings support the continued development of neratinib as monotherapy and in combination with other agents for treatment of recurrent HER2+ BC BC, breast cancer; C, capecitabine; HER2, human epidermal growth factor receptor 2; L, lapatinib; ORR, objective response rate; PFS, progression-free survival. Martin M, et al. Cancer Res. 2011;71(24 Suppl):Abstract S5-7.
40 Phase II Trial of Afatinib in HER2+ Patients Progressing After Trastuzumab Oral, ErbB family blocker, irreversible TKI 41 heavily pretreated patients Median of 3 prior chemotherapy regimens 68% had received trastuzumab for > 1 yr. Afatinib 50 mg/day 4 PR (10%); 15 SD (37%); 19 CB (46%) Median PFS=15.1 weeks Most frequent Gr3 toxicities: diarrhea (24.4%) and rash (9.8%) Lin, NU, et al. Br Cancer Res Treat 133:157-65, 2012
41 PI3K/AKT/mTOR pathway mtor, a serine/threonine protein kinase is a key regulator of cell growth, proliferation, motility, and survival protein synthesis transcription metabolism in response to environmental and nutritional cues Regulation of pathway is complex with feedback loops and horizontal cross-talks with parallel signaling axes
42 Mammalian Target of Rapamycin (mtor) Amplification PI3K PTEN Loss Ribosome synthesis P70-S6K1 Akt mtor Activation associated with loss of both apoptotic and cell cycle regulatory molecules 4E-PB1 Translation Cyclin D1 overexpression C-MYC overexpression HIF-1α, HIF2α overexpression
43 RAD001 (everolimus): mtor Pathway Inhibitor RAD001 binding FKBP-12 protein RAD001 Active rapamycin derivitive Orally bioavailable Broad activity vs human cancer cell lines and tumor xenografts Preclinically, enhances activity of cytotoxics, hormonal agents, radiation, and targeted agents Oral once-daily dosing Half life = 30 hours Generally well tolerated (<5% patients with grade 3 toxicity) Recently approved for ER+, HER2- negative BC
44 Phase I/II Study of Trastuzumab (T)+ Everolimus (E) in HER2+ Patients Who Have Progressed on Trastuzumab Pooled analysis from 2 concurrent trials MD Anderson Beth Israel Deaconess and Dana-Farber Patients with HER2-overexpressing BC who had progressed on T-based therapy received T every 3 weeks with daily E. T dose was constant, E dose varied 47 patients Morrow PK, et al. J Clin Oncol 29: , 2011
45 Phase I/II Study of Trastuzumab (T)+ Everolimus (E) in HER2+ Patients Who Have Progressed on Trastuzumab PR=15%; SD=19%; CBR=34% Among the 16 patients who had clinical benefit: 9 (56%) relapsed w/in a year of adjuvant T 6 (38%) had received > 2 lines of metastatic therapy 2 (13%) had received prior lapatinib Median PFS =4.1 mos Morrow PK, et al. J Clin Oncol 29: , 2011
46 Summary HER2 overexpression defines a unique subset of breast cancer HER2 targeting is possible with a growing number of novel agents HER2 remains a viable treatment target even after progression on trastuzumab and lapatinib
47 Thank You!
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