P863 KEYNOTE-022 parts 4 and 5: pembrolizumab plus trametinib for patients with solid tumors or BRAF wild-type melanoma

Michele Maio, Matteo Carlino, Anthony Joshua, Elaine McWhirter, Antoni Ribas, P. Ascierto, Wilson Miller, Marcus Butler, Pier Ferrucci, Robert Zielinski, Michele Del Vecchio, E. Gasal, R. Ghori, S. Diede, E. Croydon, Omid Hamid
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Abstract

Background Pembrolizumab+dabrafenib+trametinib demonstrated promising antitumor activity and acceptable tolerability in BRAF-mutant melanoma in phase 1/2 KEYNOTE-022 parts 1 and 2 (NCT02130466). Pembrolizumab+dabrafenib+trametinib numerically prolonged PFS and DOR versus placebo+dabrafenib+trametinib but had a higher grade 3-5 TRAE rate in part 3. KEYNOTE-022 parts 4 and 5 evaluated pembrolizumab+trametinib. Methods In part 4 (open-label, 3+3 dose-finding) patients with advanced solid tumors (irrespective of BRAF status) or unresectable/metastatic BRAF wild-type melanoma received pembrolizumab 200 mg Q3W with trametinib as concurrent (2 or 4 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD]) or intermittent dosing (2 weeks of trametinib run-in [1.5 or 2 mg QD], then pembrolizumab+trametinib [1.5 or 2 mg QD; 1 week off/2 weeks on]). Interim MTDs identified in part 4 were confirmed in part 5 using a modified toxicity probability interval design. The primary objectives were safety, tolerability, and ORR by investigator assessment per RECIST v1.1 of the maximum administered or tolerated dose (MAD/MTD) of pembrolizumab+trametinib. Safety was analyzed for all patients who received ≥1 dose of study drug; patients treated during the trametinib run-in who discontinued study before receiving pembrolizumab were included; patients who did not complete trametinib run-in or receive ≥66% of planned doses during the 6-week dose-limiting toxicity (DLT) evaluable period were not included for DLT evaluation. AEs were graded per NCI CTCAE v4. Results Of 42 enrolled patients, most were female (61.9%); median age was 55.0 years; 57.1% had received ≥2 prior lines of therapy. At database cutoff (June 26, 2019), median follow-up was 9.0 months (range, 1.4-25.6 months). Of 38 DLT-evaluable patients, 10 had DLTs (table 1). Dosing regimens were selected for confirmation in part 5 based on safety data. Any-grade TRAEs occurred in 39 (92.9%) patients; grade 3-4 TRAEs occurred in 19 (45.2%), none were grade 5. TRAEs led to discontinuation in 8 (19.0%) patients. Immune-mediated AEs occurred in 12 (28.6%) patients, most commonly severe skin reactions (n=6; 14.3%), pneumonitis (n=3; 7.1%), hypothyroidism (n=2; 4.8%). The MTD of concurrent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 1.5 mg with 2 weeks of trametinib run-in (ORR, 0/16; 0%) and the MTD of intermittent pembrolizumab+trametinib was pembrolizumab 200 mg Q3W plus trametinib 2 mg with 2 weeks of run-in (ORR, 4/15; 26.7%). Abstract P863 Table 1 DLT, TRAE, and ORR in KEYNOTE-022 parts 4 and 5 Conclusions Both concurrent or intermittent pembrolizumab+trametinib dosing were feasible and the combination showed antitumor activity in patients with advanced solid tumors or advanced BRAF wild-type melanoma.
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P863 KEYNOTE-022 part 4和part 5: pembrolizumab + trametinib治疗实体瘤或BRAF野生型黑色素瘤
在KEYNOTE-022 part 1和part 2 (NCT02130466)的1/2期研究中,Pembrolizumab+dabrafenib+trametinib在braf突变黑色素瘤中显示出有希望的抗肿瘤活性和可接受的耐受性。与安慰剂+达非尼+曲美替尼相比,派姆单抗+达非尼+曲美替尼在数字上延长了PFS和DOR,但在第3部分具有更高的3-5级TRAE率。KEYNOTE-022 part 4和part 5评估派姆单抗+曲美替尼。方法在第4部分(开放标签,3+3剂量发现)中,晚期实体瘤(无论BRAF状态)或不可切除/转移BRAF野生型黑色素瘤患者接受派姆单抗200mg Q3W与曲美替尼同时服用(2或4周曲美替尼[1.5或2mg QD],然后派姆单抗+曲美替尼[1.5或2mg QD])或间歇性给药(2周曲美替尼[1.5或2mg QD],然后派姆单抗+曲美替尼[1.5或2mg QD;休息1周/休息2周])。在第4部分中确定的临时MTDs在第5部分中使用改进的毒性概率区间设计进行确认。研究的主要目标是通过研究者根据RECIST v1.1评估派姆单抗+曲美替尼的最大给药或耐受剂量(MAD/MTD)的安全性、耐受性和ORR。对所有接受≥1剂量研究药物的患者进行安全性分析;包括在曲美替尼治疗期间在接受派姆单抗前停止研究的患者;未完成曲美替尼磨合或在6周剂量限制毒性(DLT)可评估期间接受≥66%计划剂量的患者未纳入DLT评估。ae按NCI CTCAE v4分级。结果42例入组患者中,女性居多(61.9%);中位年龄55.0岁;57.1%的患者既往接受过≥2条治疗线。在数据库截止日期(2019年6月26日),中位随访时间为9.0个月(范围1.4-25.6个月)。在38名可评估dlt的患者中,10名患者接受了dlt(表1)。在第5部分中,根据安全性数据选择给药方案进行确认。39例(92.9%)患者发生任何级别trae;3 ~ 4级trae 19例(45.2%),5级无一例。8例(19.0%)患者停药。12例(28.6%)患者发生免疫介导的不良反应,最常见的是严重的皮肤反应(n=6;14.3%),肺炎(n=3;7.1%),甲状腺功能减退(n=2;4.8%)。同时使用派姆单抗+曲美替尼的MTD为派姆单抗200 mg Q3W +曲美替尼1.5 mg,曲美替尼磨合2周(ORR, 0/16;0%),间歇派姆单抗+曲美替尼的MTD为派姆单抗200 mg Q3W +曲美替尼2 mg,磨合2周(ORR, 4/15;26.7%)。KEYNOTE-022 part 4和part 5的DLT、TRAE和ORR结论同时或间歇给药派姆单抗+曲美替尼都是可行的,联合用药对晚期实体瘤或晚期BRAF野生型黑色素瘤患者显示出抗肿瘤活性。
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