乳腺癌tki治疗课件

复旦大学附属肿瘤医院 乳腺癌TKI治疗 2010ASCO 胡夕春 内容 Sunitinib in Combination with Docetaxel vs. Docetaxel Alone for the First-line Treatment of Advanced Breast Cancer Phase 3 Trial of Sunitinib in Combination with Capecitabine vs. Capecitabine in Previously Treated Advanced Breast Cancer 多靶点TKI治疗 Sunitinib in Combination with Docetaxel vs. Docetaxel Alone for the First-line Treatment of Advanced Breast Cancer Rationale Sunitinib inhibits multiple RTKs These RTKs may be of importance in the pathogenesis, microvascular support, and metastatic progression of BC Sunitinib alone and in combination with docetaxel inhibited tumor growth and increased survival in preclinical BC models1 An exploratory clinical study suggested that sunitinib in combination with docetaxel had promising antitumor activity in patients with HER2- negative ABC (N=22):2 ORR: 74% Duration of response: 7.2 months PFS: 8.7 months 1Abrams TJ, et al. Mol Cancer Ther 2003;2:1011 2Mariani G, et al. J Clin Oncol 2008;26:suppl (abstr 14534) SUN 1064 Design Stratification 2/2 metastatic sites Estrogen receptor status Disease-free interval /12 months Key eligibility criteria HER2-negative ABC Measurable or bone-only disease Disease-free 12 months after neo/adjuvant taxane No prior chemotherapy for ABC Docetaxel 75 mg/m2 IV day 1 q3w + Sunitinib 37.5 mg po days 215 q3w N=296 Docetaxel 100 mg/m2 IV q3w N=297 1:1 R A N D O M I Z A T I O N Trial funded and conducted by Pfizer Inc. Europe AsiaPacific North America South America Africa United Kingdom France Germany Italy Spain Turkey Australia Korea Columbia Argentina Canada SUN 1064 was funded by Pfizer Inc. Editorial support was provided by Wendy Sacks at ACUMED (Tytherington, UK) and funded by Pfizer Inc. 593 patients; 127 centers; 27 countries Austria Belgium Czech Republic Finland Hungary Ireland Netherlands Panama Poland Portugal Romania Russian Federation Slovakia Sweden Ukraine USA Endpoints and Statistical Hypothesis Primary endpoint: PFS Hypothesis: 50% increase in median PFS (from 6 to 9 months) in ITT population (independent central review), based on 285 events, power of 90%, alpha error 0.025, one sided log-rank test Secondary endpoints PFS (investigator assessment) ORR, duration of response OS Safety Median follow-up: 18.0 months (95% CI: 17.618.4) Patient Characteristics (ITT Population) Characteristic SU + DOC N=296 DOC N=297 Median age, years (range)54 (3184)56 (2878) ECOG performance status 0/1, %56/4254/46 Prior neoadjuvant/adjuvant chemotherapy, %8382 Anthracycline7774 Taxane1925 No prior chemotherapy, %1717 Estrogen receptor-positive, % 7470 Triple-negative disease, %2023 2 metastatic sites, %4748 Disease-free interval 12 months, %2828 Treatment Administration (AT Population) SU + DOC N=295 DOC N=293 SUDOCDOC Median dose per cycle (range) 37.5 mg* (2641) 73 mg/m2 (3987) 96 mg/m2 (65112) Median relative dose intensity, % (range) 94 (14142) 92 (52108) 93 (57112) Median duration of treatment, weeks (range) 26 (2329) 18 (1721) 18 (1619) Cycles started, median (range) 8 (132) 7 (123) 6 (126) AT = as-treated *Median daily dose Objective Response in Patients with Measurable Disease P=0.001 P=0.016 55% 42% 58% Investigator assessment Central review Median duration of response (months): 70 60 50 40 30 20 10 0 Objective responses (%) SU + DOC n=269 7.5 DOC n=269 7.2 SU + DOC n=269 6.9 DOC n=269 5.8 48% CR PR Patients at risk SU + DOC296241162804019820 DOC29722496432316622 Progression-free Survival (Central Review; ITT Population) SU + DOC N=296 DOC N=297 PFS events, n (%)147 (50)109 (37) Median, months8.68.3 HR (95% CI)0.92 (0.721.19) 0.265 P value (1-sided) 0369121518212427 Time (months) 100 80 60 40 20 0 PFS probability (%) Overall Survival (ITT Population) SU + DOC N=296 DOC N=297 OS events, n (%)107 (36)91 (31) Median, months24.825.5 HR (95% CI)1.21 (0.911.60) P value (1-sided )0.904 0369121518212427303336 Time (months) 100 80 60 40 20 0 OS probability (%) Patients at risk SU + DOC 296284264235213164955026832 DOC2972902692462221731045223610 Common All-Causality AEs (AT Population) Patients (%) SU + DOC N=295 DOC N=293 AEAny gradeGrade 3/4Any gradeGrade 3/4 Neutropenia56464944 Handfoot syndrome4117*91 Fatigue4312348 Diarrhea6010384 Asthenia339307 Stomatitis325261 Decreased appetite324241 Hypertension12210 Nausea401392 Dysgeusia302 metastatic sites Triple-negative disease vs. all others 1/1 prior chemotherapy regimen 1:1 R A N D O M I Z A T I O N CAP 2,500 mg/m2 po days 114 q3w N=221 SU 37.5 mg po CDD + CAP 2,000 mg/m2 po days 114 q3w N=221 Optional “crossover“ to SU 37.5 mg po CDD Disease progression Trial funded and conducted by Pfizer Inc. Romania Europe AsiaPacific North America South America Africa United Kingdom France Germany Italy Spain Canada SUN 1099 was funded by Pfizer Inc. Editorial support was provided by Wendy Sacks at ACUMED (Tytherington, UK) and funded by Pfizer Inc. Austria Belgium Czech Republic Ireland Netherlands Poland Russian Federation USA Greece Denmark Norway Endpoints and Statistical Hypothesis Primary endpoint: PFS Hypothesis: 50% increase in median PFS (from 4 to 6 months) in ITT population (independent blinded central review) Secondary endpoints PFS (investigator assessment) ORR, duration of response OS Safety Planned enrollment: 430 patients Patient Characteristics (ITT Population) Characteristic SU + CAP N=221 CAP N=221 Median age, years (range)52 (2779)54 (3177) ECOG performance status 0/1, %59/4057/42 HER2-positive disease, % 1311 Triple-negative disease, %2727 2 metastatic sites, %5050 1 prior chemotherapy regimen, %5555 Prior chemotherapy regimens, % Neoadjuvant/adjuvant only2321 1 for ABC6362 2 for ABC1415 Treatment Administration (AT Population) SU + CAP N=217 CAP N=215 SUCAPCAP Median daily dose given37.5 mg 1,727 mg/m2 2,286 mg/m2 Median relative dose intensity, %898489 Median duration of treatment, wks161720 Median no. of cycles started556 Dose reductions, % of pts447165 Cycle delays, % of ptsNA*6655 Dosing interruptions within cycles, % of pts 612816 AT = as-treated *Not applicable since sunitinib was dosed daily Hematologic AEs (All-causality; AT Population) Percentage (%) of patients SU + CAP N=217 CAP N=215 AEAny gradeGrade 3/4Any gradeGrade 3/4 Neutropenia4832184 Leucopenia23481 Thrombocytopenia481770 Anemia257175 *20% in SU + CAP arm On-study grade 5 events: n=14; n=9 Most Common* Non-hematologic AEs (All-Causality; AT Population) Percentage (%) of patients SU + CAP (N=217)CAP (N=215) AEAny gradeGrade 3/4Any gradeGrade 3/4 Asthenia/fatigue6523476 Nausea/vomiting649474 Diarrhea5894510 Handfoot syndrome54166124 Decreased appetite302201 Stomatitis283122 Dysgeusia27080 Headache261140 Mucosal inflammation243121 Upper abdominal pain232140 Hypertension22241 Most Common AEs Leading to Tx Discontinuations/ Dosing Modifications in Either Arm (AT Population) *Dosing delays/interruptions or dose reductions Percentage (%) of patients SU + CAP (N=217)CAP (N=215) SU or CAPCAP ReasonDiscMod*DiscMod* Any AE (% of patients)48881866 Neutropenia937011 Thrombocytopenia62601 Handfoot syndrome525335 Diarrhea220114 Chest pain1011 Progression-free Survival (Central Review; ITT Population) SU + CAP N=221 CAP N=221 PFS events, n (%)132 (60)116 (53) Median, months5.55.9 HR (95% CI)1.22 (0.951.58) 0.941 P value (1-sided) Patients at risk SU + CAP221124572813743200 CAP2211256438181053221 03691215182124273033 Time (months) 100 80 60 40 20 0 PFS probability (%) Progression-free Survival (Investigator Assessment; ITT Population) SU + CAP N=221 CAP N=221 PFS events, n (%)160 (72)152 (69) Median, months5.45.5 HR (95% CI)1.11 (0.881.39) 0.812 P value (1-sided) 03691215182124273033 Time (months) 100 80 60 40 20 0 PFS probability (%) Patients at risk SU + CAP22112867281775320 CAP22112370411894221 Overall Survival (ITT Population) SU + CAP N=221 CAP N=221 OS events, n (%)117 (53)108 (49) Median, months16.416.5 HR (95% CI)0.99 (0.761.30) P value (1-sided )0.484 Patients at risk SU + CAP2212031781511177737261790 CAP221200175151106653923941 03691215182124273033 Time (months) 100 80 60 40 20 0 OS probability (%) Overall Response in Patients with Measurable Disease (Central Review) Response parameter SU + CAP n=206 CAP n=201 Objective response rate,* % 95% exact CI 19 1425 18 1324 Complete response, %00 Partial response,%1918 Stable disease, %5459 Stable disease 26 weeks, %1414 Median duration of response, months, 95% CI 9.0 5.720.7 8.8 5.713.8 *% CR + PR Overall Response in Patients with Measurable Disease (Investigator Assessment) Response parameter SU + CAP n=206 CAP n=201 Objective response rate,* % 95% exact CI 27 2134 22 1729 Complete response, %01 Partial response,%2721 Stable disease, %4650 Stable disease 26 weeks, %1314 Median duration of response, months, 95% CI 5.7 4.36.9 7.6 6.59.9 *% CR + PR Conclusions The study did not meet its primary endpoint Sunitinib in combination with capecitabine did not improve efficacy compared with capecitabine alone The frequency of AEs was higher with sunitinib and capecitabine than with capecitabine alone Treatment discontinuations and dosing modifications occurred more frequently in the combination arm The sunitinibcapecitabine regimen evaluated in this study is not recommended for second- or third-line treatment of patients with ABC 多靶点TKI治疗 拉帕替尼 Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2 Blocks signaling through EGFR and HER2 homodimers and heterodimers May also prevent signaling between ErbB1/ErbB2 and other ErbB family members PTEN Lapatinib P13K pAkt Ras Raf pErk Shc Grb2 So8 Phospholipid cell membrane 到疾病进展时间（ITT Population） 70 20 40 60 80 0 100 1020304050600 Time (weeks) Patients Progression Free* (%) Lap + CapCap 病例数, n160161 Median TTP, wk36.919.7 HR (95% CI)0.51 (0.350.74) P value (log-rank, 1-sided)0.00016 Lap + Cap Cap EGF100151 Geyer CE, et al. N Engl J Med 2006 ;355(26):2733-2743. Event-free survival Was Significantly Prolonged in HER2+ Patients Treated With Lapatinib Letrozole 2.5 mg daily + Lapatinib 1500 mg daily Phase III, Randomized, Double-Blind Controlled Trial: Study Design Patient Population ER+ and/or PgR+ Postmenopausal HER2+ , HER2-ve / Unknown Stage IIIb/IIIc/IV No prior treatment for