卓越引领大道争锋 幻灯2 10 内部学习PAOLA-1

1、3 3期期PAOLA-1/ENGOT-ov25:针对以铂为基础的化疗针对以铂为基础的化疗 和贝伐单抗治疗后的和贝伐单抗治疗后的新诊断的晚期卵巢癌患者， 进行奥拉帕利和贝伐单抗维持治疗的研究 Isabelle Ray-Coquard, Patricia Pautier, Sandro Pignata, David Prol, Antonio Gonzlez-Martin, Paul Sevelda, Keiichi Fujiwara, Ignace Vergote, Nicoletta Colombo, Johanna Menp, Frdric Selle, Jalid Sehouli, Dom

2、enica Lorusso, Eva Maria Guerra Alia, Claudia Lefeuvre-Plesse, Ulrich Canzler, Alain Lortholary, Frederik Marm, Eric Pujade-Lauraine, Philipp Harter ClinicalT identifier: NCT02477644 This study was sponsored by ARCAGY Research 奥拉帕利一线维持治疗卵巢癌尚未在中国获批适应症。本资料仅供医学部/市场部/销售内部学习， 严禁对外展示及推广。所有数据应以最终获

3、批的适应症为准。 CN39986 过期日期 2020-6-4 背景背景 一线贝伐单抗与化疗联合应用，随后进行贝伐单抗维持，已显示可提高肿瘤缓解率,1延长 PFS1,2 ，以及部分高危亚组的OS3,4这是目前大多数新诊断的晚期卵巢癌患者的标准治疗 PARP抑制剂olaparib针对新诊断携带BRCA1/2突变的晚期卵巢癌含铂化疗后维持治疗，显示出 前所未有的PFS获益5 同源重组修复缺陷(HRD)不仅局限于BRCA突变，而且存在于约50%的高级别浆液性卵巢肿瘤6 在铂敏感性复发卵巢癌中，已经观察到PARP抑制剂活性超越BRCA突变7,8 ，与抗血管生成剂联 合使用时，疗效进一步增加9,10 PA

4、OLA-1/ENGOT-ov25, 作为一项学术赞助研究，是第一个评估不考虑BRCA突变状态的，正在接 受包括贝伐单抗在内的一线标准治疗的晚期卵巢癌患者，使用PARP抑制剂维持治疗的有效 性和安全性的三期临床试验 BRCA mutation, BRCA1 and/or BRCA2 mutation; PARP, poly(ADP-ribose) polymerase; PFS, progression-free survival; OS, overall survival 1. Perren et al. N Engl J Med 2011;365:248496; 2. Burger et a

5、l. N Engl J Med 2011;365:247383; 3. Oza et al. Lancet Oncol 2015;16:92836; 4. Tewari et al. J Clin Oncol 2019;26:231728; 5. Moore et al. N Engl J Med 2018;379:2495505; 6. Cancer Genome Atlas Research Network. Nature 2011;474:60915; 7. Ledermann et al. Lancet Oncol 2014;15:85261; 8. Friedlander et al

6、. Br J Cancer 2018;119:107585; 9. Mirza et al. J Clin Oncol 2019;37 (Suppl:abst 5505); 10. Liu et al. Ann Oncol 2019;30:5517. 奥拉帕利一线维持治疗卵巢癌尚未在中国获批适应症。本资料仅供医学部/市场部/销售内部学习，严禁对外展示及推广。所有数据应以最终获批的适应症为准。 研究设计研究设计 一线一线 手术手术 (upfront or interval) 铂类铂类紫杉烷类为基紫杉烷类为基 础化疗础化疗 3 cycles 贝伐单抗贝伐单抗 Randomization NED/C

7、R/PR 分分层 肿瘤组织BRCA突变状态 一线治疗的结果 2:1 N=806 维持治疗维持治疗 新诊断的FIGO III-IV期高级别浆液性/子宫内膜样癌卵巢、输卵管或原发性腹膜癌* 奥拉帕利奥拉帕利(300 mg BID) x2 x2 年年 安慰剂安慰剂 x2 x2 年年 + 贝伐单抗贝伐单抗 + 贝伐单抗贝伐单抗 *Patients with other epithelial non-mucinous ovarian cancer were eligible if they had a germline BRCA1 and/or BRCA2 mutation Bevacizumab: 1

8、5 mg/kg, every 3 weeks for a total of 15 months, including when administered with chemotherapy; By central labs; According to timing of surgery and NED/CR/PR BID, twice daily; BRCAm, BRCA1 and/or BRCA2 mutation; CR, complete response; NED, no evidence of disease; PR, partial response Ray-Coquard I e

9、t al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain 主要研究终点主要研究终点 研究者评估的PFS (RECIST v1.1) 敏感性分析敏感性分析 独立盲法评估的PFS 次要研究终点次要研究终点 从随机入组至首次应用后续治疗 或死亡时(TFST) PFS2 从随机入组至二次应用后续治疗 或死亡时间(TSST) OS HRQoL 安全性和耐受性 贝伐单抗15mg/kg，每3周一次，共15个月， 包括和化疗联用阶段 患者基线情况

10、患者基线情况 奥拉帕利奥拉帕利+贝伐单抗贝伐单抗 (N=537) 安慰剂安慰剂 + + 贝伐单抗贝伐单抗 (N=269) 年龄年龄, median, years (range)61 (3287)60 (2685) ECOG 评分评分*, n (%)0 1 378 (70) 153 (28) 189 (70) 76 (28) 原发肿瘤部位原发肿瘤部位, n (%)卵巢卵巢 输卵管输卵管 原发性腹膜原发性腹膜 456 (85) 39 (7) 42 (8) 238 (88) 11 (4) 20 (7) 组织学类型组织学类型, n (%)浆液型浆液型 子宫内膜样子宫内膜样 其他其他 519 (97)

11、12 (2) 6 (1) 253 (94) 8 (3) 8 (3) 肿瘤组织肿瘤组织BRCA突变状态突变状态, n (%) 肿瘤组织肿瘤组织BRCA突变突变 无肿瘤组织无肿瘤组织BRCA突变突变/未知未知 157 (29) 380 (71) 80 (30) 189 (70) FIGO 分期分期, n (%)III IV 378 (70) 159 (30) 186 (69) 83 (31) *ECOG performance was missing for six patients in the olaparib arm and four patients in the placebo arm

12、Two patients had low-grade serous carcinoma with a BRCAm; Other includes clear cell, undifferentiated and other histology 33 (4%) patients had an unknown tBRCAm status; 26 patients in the olaparib arm and 7 patients in the placebo arm ECOG, Eastern Cooperative Oncology Group; FIGO, Fdration Internat

13、ionale de Gyncologie et dObsttrique; tBRCAm, tumour BRCA mutation Ray-Coquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain 奥拉帕利奥拉帕利+贝伐单抗贝伐单抗 (N=537) 安慰剂安慰剂+贝伐单抗贝伐单抗 (N=269) 细胞减灭术情况, n (%)初始手术 有肉眼可见残留病灶 无肉眼可见残留病灶 间歇性肿瘤细胞减灭术 有肉眼可见残留

14、病灶 无肉眼可见残留病灶 没有手术 271 (50) 111 (41) 160 (59) 228 (42) 65 (29) 163 (71) 38 (7) 138 (51) 53 (38) 85 (62) 110 (41) 35 (32) 75 (68) 21 (8) 手术/以铂为基础化疗后的 反应情况, n (%) NED CR PR 290 (54) 106 (20) 141 (26) 141 (52) 53 (20) 75 (28) CR, complete response; NED, no evidence of disease; PR, partial response Ray-C

15、oquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain 患者基线情况患者基线情况 患者处置患者处置 奥拉帕利奥拉帕利+贝伐单抗贝伐单抗安慰剂安慰剂+贝伐单抗贝伐单抗 随机化随机化, n537269 治疗治疗, n (%)535 (99.6)267 (99.3) 中断治疗中断治疗, n (%) RECIST评估疾病进展评估疾病进展 非RECIST评估疾病进展评估疾病进展 治疗治疗- -紧急不良事件紧急不良事件(

16、 (TEAE) 患者决定患者决定 死亡 其他* 331 (62) 182 (34) 14 (3) 109 (20) 17 (3) 1 (1) 8 (1) 194 (73) 155 (58) 13 (5) 13 (5) 10 (4) 3 (1) 0 中位治疗持续时间中位治疗持续时间, , 月 (range) 奥拉帕利/安慰剂 贝伐单抗 17.3 (0.0333.0) 11.0 (0.6921.4) 15.6 (0.0726.2) 10.6 (0.6917.1) 中位随访时间中位随访时间, , 月24.022.7 *Other includes lost to follow up, surgery

17、, new comorbidities and other TEAE, treatment-emergent adverse event Ray-Coquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain PAOLA-1作为研究者发起的研究，要求由患者决定是否中断治疗，并鼓励上报AE；与之 对应，SOLO-1并没有采取此归类方案(AE导致中断治疗率20% vs 12%)； 但汇总AE中断治疗和患者决定导致中断治

18、疗率后，两者类似(PAOLA-1 23%,SOLO-1 20%) Patients free from disease progression and death (%) Months since randomization No. at risk Placebo Olaparib537 269 513 252 461 226 433 205 403 172 374 151 279 109 240 83 141 50 112 35 55 15 37 9 12 1 3 100 90 80 70 60 50 40 30 20 10 0 0369121518212427303336394245 1

19、0 0 研究者评估的研究者评估的PFS : ITT 人群 奥拉帕利奥拉帕利 + + 贝伐单抗贝伐单抗 (N=537) 安慰剂安慰剂 + + 贝伐贝伐 单抗单抗 (N=269) Events, n (%) 59% maturity280 (52)194 (72) Median PFS, months22.116.6 HR 0.59(95% CI 0.490.72; P0.0001) 从第一周期化疗到随机化的中位时间= 7 月 ITT, intent-to-treat population Ray-Coquard I et al. Presentation LBA2_PR presented at

20、 ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain PAOLA-1/ENGOT-ov25Biomarker 亚组分析亚组分析 HRD positive n=387; 48% tBRCAm n=235; 29% HRD positive, excluding tBRCAm n=152; 19% HRD negative n=277; 34% HRD status unknown n=142; 18% HRD positive is either tumour BRCA mutation and/or H

21、RD score 42 by Myriad MyChoiceHRD Plus Reasons for HRD status unknown: 4.2% missing; 2.1% fail; 11.3% inconclusive Ray-Coquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain 基于肿瘤组织基于肿瘤组织BRCA突变情况突变情况- -PFS分析分析 Months since randomizat

22、ion Patients free from disease progression and death (%) 100 90 80 70 60 50 40 30 20 10 0 03 No. at risk Placebo Olaparib157 80 154 78 6912 15 18 21 24 27 30 33 36 39 42 45 150 72 148 66 144 59 138 52 117 41 110 36 76 22 58 13 31 7 19 4 7 1 1 1 0 0 奥拉帕利奥拉帕利+ +贝伐单抗贝伐单抗 (N=157) 安慰剂安慰剂+ +贝伐单抗贝伐单抗 (N=80

23、) Events, n (%)41 (26)49 (61) Median PFS, months37.2*21.7 HR 0.31 (95% CI 0.200.47) tBRCAm Months since randomization 03 380 189 359 174 6912 15 18 21 24 27 30 33 36 39 42 45 311 154 285 139 259 113 236 99 162 68 130 47 65 28 54 22 24 8 18 5 5 0 20 奥拉帕利奥拉帕利+ +贝伐单抗贝伐单抗 (N=380) 安慰剂安慰剂+ +贝伐单抗贝伐单抗 (N=18

24、9) 239 (63)145 (77) 18.916.0 HR 0.71 (95% CI 0.580.88) Non-tBRCAm 76% 39% 76% 94% The percentages of patients progression-free at 12 months and 24 months have been calculated based on Kaplan-Meier estimates. *This median is unstable due to a lack of events less than 50% maturity; Includes tBRCA unkn

25、own Ray-Coquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain 基于基于HRD类型类型- - PFS分析分析 Months since randomization 03 No. at risk Placebo Olaparib255 132 252 128 6912 15 18 21 24 27 30 33 36 39 42 45 242 117 236 103 223 91 213 79 169

26、54 155 44 103 28 85 18 46 8 29 5 11 1 30 10 100 90 80 70 60 50 40 30 20 10 0 Patients free from disease progression and death (%) HRD 阳性阳性, 包括包括tBRCAm Months since randomization 03 97 55 96 54 6912 15 18 21 24 27 30 33 36 39 42 45 90 48 86 41 79 37 75 32 54 19 48 15 30 11 29 8 16 3 12 2 4 0 20 03 Mo

27、nths since randomization 282 137 261 124 6912 15 18 21 24 27 30 33 36 39 42 45 219 109 197 102 180 81 161 72 110 55 85 39 38 22 27 17 9 7 8 4 1 0 0 HRD 阳性阳性, 排除排除tBRCAmHRD 阴性阴性/ /未知未知 奥拉帕利奥拉帕利+ +贝伐单抗贝伐单抗 (N=97) 安慰剂安慰剂+ +贝伐单抗贝伐单抗 (N=55) 43 (44)40 (73) 28.1*16.6 HR 0.43 (95% CI 0.280.66) 奥拉帕利奥拉帕利+ +贝伐

28、单抗贝伐单抗 (N=282) 安慰剂安慰剂+ +贝伐单抗贝伐单抗 (N=137) 193 (68)102 (74) 16.916.0 HR 0.92 (95% CI 0.721.17) 66% 52% 29% 26% 89% 71% 83% 69% 奥拉帕利奥拉帕利+ +贝伐单抗贝伐单抗 (N=255) 安慰剂安慰剂+ +贝伐单抗贝伐单抗 (N=132) Events, n (%)87 (34)92 (70) Median PFS, months37.2*17.7 HR 0.33 (95% CI 0.250.45) The percentages of patients progression

29、-free at 12 months and 24 months have been calculated based on Kaplan-Meier estimates. HRD positive is an HRD score 42. *This median is unstable due to a lack of events less than 50% maturity Ray-Coquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October

30、, Barcelona, Spain 主要研究终点的敏感性分析和次要研究终点主要研究终点的敏感性分析和次要研究终点 HR 0.59 (95% CI 0.490.72, P0.0001) HR 0.63 (95% CI 0.510.77, P0.0001) HR 0.59 (95% CI 0.490.71, P0.0001) HR 0.86 (95% CI 0.691.09) 在第二线治疗中，奥拉帕利组的 30/537(6%)患者和安慰剂组的 55/269(20%)患者接受了PARP抑制剂的 治疗 数据未成熟数据未成熟 30.1 18.5 18.3 16.6 32.3 24.8 26.1 22.

31、1 05101520253035 OS* Interim PFS2* TFST PFS by BICR PFS Months since randomization 安慰剂+贝伐单抗奥拉帕利+贝伐单抗 *These results are immature: PFS2 39% mature and OS 26% mature Ray-Coquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain Subgroup奥

32、拉帕利奥拉帕利+ +贝伐单抗贝伐单抗安慰剂安慰剂+ +贝伐单抗贝伐单抗HR (95% Cl) No. of events/no. of patients (%) All280/537 (52)194/269 (72)0.59(0.490.72) 年龄年龄 65 岁171/332 (52)126/182 (69)0.61(0.490.77) 65 岁109/205 (53)68/87 (78)0.55(0.410.75) FIGO 分期分期 III184/378 (49)125/186 (67)0.64(0.510.80) IV96/159 (60)69/83 (83)0.49(0.360.67

33、) ECOG 基线基线 0193/378 (51)132/189 (70)0.63(0.500.78) 185/153 (56)61/76 (80)0.51(0.370.71) 肿瘤细胞减灭术后结果肿瘤细胞减灭术后结果 手术后无肉眼可见残留病灶 135/323 (42)104/160 (65)0.54(0.420.71) 手术后有肉眼可见残留病灶113/176 (64)71/88 (81)0.63(0.470.85) 不进行手术 32/38 (84)19/21 (90)0.56(0.321.01) 肿瘤细胞减灭术时机肿瘤细胞减灭术时机 初始手术 116/271 (43)92/138 (67)0

34、.52(0.400.69) 间歇性肿瘤细胞减灭术 132/228 (58)83/110 (75)0.66(0.500.87) 不进行手术 32/38 (84)19/21 (90)0.57(0.321.02) 对一线化疗的反应对一线化疗的反应 NED119/290 (41)92/141 (65)0.53(0.400.70) CR54/106 (51)42/53 (79)0.44 (0.290.66) PR107/141 (76)60/75 (80)0.86(0.631.19) PFS 亚组分析亚组分析 210.50.2 安安慰剂慰剂+ +贝伐单抗更优贝伐单抗更优奥拉帕利奥拉帕利+ +贝伐单抗更优

35、贝伐单抗更优 Ray-Coquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain AEs情况总结情况总结 奥拉帕利奥拉帕利+ +贝伐单抗贝伐单抗 (N=535) 安慰剂安慰剂+ +贝伐单抗贝伐单抗 (N=267) 所以级别所以级别TEAEs, n (%)531 (99)256 (96) 3级级 TEAEs, n (%)303 (57)136 (51) 严重不良事件严重不良事件, n (%)167 (31)83

36、(31) 死亡死亡, n (%)1 (1)4 (1) 由于由于AEs导致的剂量中断导致的剂量中断, n (%)291 (54)65 (24) 由于由于AEs导致的药物减量导致的药物减量, n (%)220 (41)20 (7) 由于由于AEs导致的中断治疗导致的中断治疗, n (%)109 (20)15 (6) Dose interruptions, reductions and discontinuations reported are for olaparib and placebo SAE, serious adverse event Ray-Coquard I et al. Prese

37、ntation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain 在“患者处置”-中断治疗的归类中已经解释 15 18 18 18 19 22 22 24 41 46 53 53 奥拉帕利奥拉帕利+ +贝伐单抗贝伐单抗(N=535)安慰剂安慰剂+ +贝伐单抗贝伐单抗(N=267) Adverse events (%) 10075502500255075100 所有级别(频率 15%) 所有级别(频率 15%) 3级 3级 呕吐 腹痛 白细胞减少* 恶心 疲乏/

38、虚弱* 高血压 淋巴细胞减少症* 腹泻 贫血* 中性白细胞减少症* 尿路感染 关节痛 10 10 16 17 20 11 24 9 10 60 22 32 1 3 2 1 1 1 2 2 1 1 30 1 1 2 6 2 1 1 1 7 17 19 2 5 最常见的最常见的AEs *Grouped terms. All-grade thrombocytopenia (grouped term) occurred in 8% of patients in the olaparib group and 3% of patients in the placebo group, grade 3 thr

39、ombocytopenia occurred in 2% of patients in the olaparib group and 1% of patients in the placebo group Ray-Coquard I et al. Presentation LBA2_PR presented at ESMO Annual Conference 2019, 27 September - 1 October, Barcelona, Spain 奥拉帕利特别关注的不良事件奥拉帕利特别关注的不良事件 奥拉帕利奥拉帕利+ +贝伐单抗贝伐单抗 (N=535) 安慰剂安慰剂+ +贝伐单抗贝伐单抗 (N=267) 骨髓增生异常综合征/急性髓系白血 病/再生障碍性贫血, n (%) 6 (1.1)1 (0.4) 新的原发性恶性肿瘤, n (%) 急性淋巴细胞白血病 乳腺癌 肺癌 骨髓瘤 胰腺癌 鳞状皮肤癌 甲状腺癌 7 (1.3) 1 2 1 1 1 1 0 3 (1.1) 0 2 0 0 0 0 1 肺炎/间质性肺疾病, n (%)6 (1.1)0 AA,再