图解ASCO19 day3 / 四六文摘

昨天网络出了点问题，最后两天可能晚更

POLO：Olaparib在gBRCAm的晚期胰腺癌患者接受一线含铂化疗后的维持治疗

主要终点BICR PFS：7.4 vs. 3.8 mo [HR0.53; 95% CI 0.35, 0.82; p = 0.0038] 达到预设值：这种降低与对含铂化疗的应答没有相关性：CR/PR HR 0.62; SD HR 0.50

6mo的PFS率翻了1倍多：53% vs 23%
OS数据还不成熟
安全方面：≥3级 AE 40% vs 23%，分别5.5%和1.7%因AE终止治疗

NEJM已经online，First biomarker-driven treatment in pancreatic cancer

https://www.nejm.org/doi/full/10.1056/NEJMoa1903387%C2%A0%E2%80%A6

一线化疗后4-8周随机分别接受olaparib和安慰剂的维持治疗直至进展或不可耐受的毒性

除了65y以上患者，绝大多数亚组都能从olparib维持治疗中降低进展风险

3级以上AE40% vs 23%，olaparib组更高的是贫血11% vs 3%和疲劳5% vs 2%

这里提到要在数据成熟69%时候再次进行OS分析

Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial.

Background: Pancreatic cancer (PC) pts with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) have shown response to the PARP inhibitor olaparib (Kaufman 2015). POLO is the first phase III trial to evaluate efficacy of maintenance treatment with a PARP inhibitor in PC.

Methods: POLO is an international, randomized, double-blind, placebo-controlled trial of pts with a gBRCAm and pancreatic adenocarcinoma who had received ≥16 weeks of first-line PBC for metastatic disease without progression. Pts were randomized 3:2 to maintenance olaparib (O) tablets (300 mg bid) or placebo (P). Treatment began 4–8 weeks after last PBC dose, continuing until investigator-assessed progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by blinded independent central review (modified RECIST 1.1).

Results: We screened 3315 pts, identified 247 with a gBRCAm（也就是说gBRCAm在mPC中占 7-8%）, randomized 154 (O 92, P 62), and treated 151 (O 90, P 61). Pt characteristics (O/P): age, median (range) 57 (37–84)/57 (36–75); male, 58%/50%; ECOG performance status 0, 71%/61%. With 104 events, PFS was significantly improved with O vs. P (hazard ratio [HR] 0.53; 95% CI 0.35, 0.82; p = 0.0038; median PFS was 7.4 vs. 3.8 months [mo], respectively) and consistent irrespective of response to prior PBC (complete/partial HR 0.62; stable disease HR 0.50). From 6 mo, the % of pts progression-free in the O arm was more than twice that in the P arm (Table). At the interim overall survival analysis (46% maturity), HR was 0.91 (95% CI 0.56, 1.46; p = 0.68). Grade ≥3 adverse events (AE) occurred in 40% of O- and 23% of P-treated pts; 5.5% and 1.7% of pts, respectively, discontinued treatment due to an AE.

Conclusions: Maintenance olaparib provided a statistically significant and clinically meaningful improvement in PFS in mPC pts with a gBRCAm who had not progressed on PBC. Safety was consistent with the known profile for olaparib. POLO is the first phase III trial to validate a biomarker-driven treatment in PC. Clinical trial information: NCT02184195

ANNOUBNCE failed：Olaratumab一线治疗STS的3期临床

另一个就是之前礼亲王失败了的ANNOUBNCE研究，olaratumab一线治疗STS也因此申请退市

二期结果亮瞎狗眼后开的三期

主要终点是总的软组织肉瘤(tSTS)和平滑肌肉瘤(LMS)中的OS

主要终点tSTS和LMS中的OS：Olaratumab不仅没有带来统计学意义的改善，连临床意义上的提升趋势都没有

根绝Olaratumab的靶点PDGFα的表达做了探索性分析，在数值反倒是PDGFα neg的OS更长

事后诸葛亮一下，当时看到2期的这个结果也是奇怪，不知道为何反倒是PDGFα neg的患者能从Olaratumab中获益，当然没过多久就看到公告称3期失败

Olaratumab的加入反倒使得ORR和PFS有恶化的趋势

两组任意级别和≥3级TEAE十分接近——从这个角度看，不良事件还真是预判疗效的晴雨表

1b/2期与3期的比较

另外2期在后续治疗上的差异可能也最终影响了OS

毕竟本身2期PFS获益程度小于OS

ANNOUNCE: A randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS).

Background:Dox is standard therapy in STS. In a Ph 2 trial, olaratumab (a human IgG1 antibody targeting PDGFRα) + dox improved overall survival (OS) and progression-free survival (PFS) vs dox. ANNOUNCE aimed to confirm the OS benefit in advanced STS.Methods:Adult pts with unresectable locally advanced or metastatic STS, anthracycline-naïve, and ECOG PS 0-1 were eligible. Pts were randomized 1:1 to olaratumab (20mg/kg Cycle 1, 15mg/kg subsequent cycles) or PBO on Days 1 and 8 of each 21-day cycle combined with dox (75mg/m2) on Day 1 for up to 8 cycles. After 8 cycles, pts with disease control continued olaratumab or PBO until progression or toxicity. Randomization was stratified by histology, prior systemic therapy, ECOG PS, and geographic region. Dexrazoxane use was allowed to mitigate dox-related cardiotoxicity. Primary endpoints were OS in the intent-to-treat (ITT) population and/or leiomyosarcoma (LMS) subset of the ITT population; the study was designed to be positive if either primary endpoint was met. Secondary endpoints included PFS, response/disease control rates, safety, and pharmacokinetics.Results:509 pts were randomized: 258 in the investigational and 251 in the control arm. Baseline pt characteristics were well balanced. Dexrazoxane was received by 63.0% vs 65.1% of pts (investigational vs control arm, respectively, for all data). In the ITT population, median OS was 20.4 vs 19.8 months (m) (HR=1.05, 95% CI: 0.84-1.30; p = 0.69) and was 21.6 vs 21.9 m in LMS pts (HR=0.95, 95% CI: 0.69-1.31; p = 0.76). Median PFS was lower in the investigational arm in the ITT population (5.4 vs 6.8 m; HR=1.23, 95% CI: 1.01-1.50; p = 0.04) and in LMS pts (4.3 vs 6.9 m, HR=1.22, 95% CI: 0.92-1.63; p = 0.17). Median dox exposure was 6 vs 7 cycles. Safety was similar between arms. Olaratumab serum concentrations reached levels expected from prior trials. Additional subgroup/biomarker results will be presented.Conclusions:ANNOUNCE did not confirm that olaratumab + dox, followed by olaratumab monotherapy, improves OS over dox in pts with advanced STS. Further analyses are warranted to explore the inconsistent outcomes between the Ph 3 and Ph 2 studies. Clinical trial information: NCT02451943

KEYNOTE-240

最后看KN024的2L HCC研究，这个结果还是挺可惜的，不过将来Pembro+Lenva问世，2L其实也没多大的发挥余地