Clinical activity, safety and predictive biomarkers results from a phase Ia atezolizumab (atezo) trial in extensive-stage small cell lung cancer (ES-SCLC)
L.V. Sequist, A. Chiang, J. Gilbert, M. Gordon, P.R. Conkling, D. Thompson, J.P. Marcoux, S.J. Antonia, B. Liu, D.S. Shames, A. Lopez-Chavez, C. O’Hear, M. Fasso, S. Gettinger
Background: Most patients ( pts) with ES-SCLC receive platinum-based chemotherapy with etoposide, however median survival is <1 y, and new options are needed. Here we
assess the safety and clinical activity of the cancer immunotherapy atezo (anti-PDL1)
as monotherapy in ES-SCLC.
Methods: ES-SCLC pts received atezo IV q3w at 15 mg/kg or 1200 mg as part of a Ph Ia study (NCT01375842). Due to protocol amendments the first 5 pts were PD-L1 selected and the subsequent 12 were not PD-L1 selected. Initially treatment was to last up to 1 y though retreatment at PD was allowed. Later pts were treated until loss of clinical benefit. RECIST v1.1 and irRC assessments were used. PD-L1 expression was centrally evaluated using the VENTANA SP142 IHC assay. Teffector (Teff ) gene signature (CD8A, GZMA, GZMB, EOMES, CXCL9, CXCL10, TBX21) and PD-L1 mRNA was measured (iChip).
Results: As of Dec 15, 2015, 17 pts with a minimum follow-up of 6.7 mo, were safety/efficacy evaluable. 65% were male; 88% were ECOG PS 1. Median age was 63 y (range 44-80), and pts were heavily pretreated (65% ≥ 3 prior therapies). 65% pts had all grade (1-5) treatment-related AEs most often fatigue (24%). There were 8 related G3-5 AEs in 3 pts, including 1 G3 pneumonitis leading to treatment discontinuation and 1 G5 hepatic failure. Confirmed ORR by RECIST was 6% (1 PR with DOR of 7 mo, also irPR by irRC) and 24% by irRC. 4/17 pts received atezo for ≥ 6 mo, 2 of these for ≥ 12 mo. 1 irPR pt stopped atezo per protocol after 1 y and remained in irPR for an additional 1 y until PD. Upon retreatment, the patient again derived benefit and is still on atezo as of data cutoff, 2.6 y from first dose. mPFS by RECIST was 1.5 mo (95% CI: 1.2, 2.7), and mOS was 5.9 mo (95% CI: 4.3, 20.1). PD-L1 expression was low overall, consistent with published data. A trend toward greater clinical benefit was seen for Teff gene signature and PD-L1 mRNA.
Conclusions: These initial results in ES-SCLC demonstrate a tolerable safety profile with no new safety signals for atezo. Atezo also showed encouraging single-agent activity, based on the duration of clinical benefit in a subset of patients. Further studies of atezo in ES-SCLC are planned.
Clinical trial identification: NCT01375842
Legal entity responsible for the study: F. Hoffmann-La Roche Ltd.
Funding: F. Hoffmann-La Roche Ltd.
在Ia期临床试验（NCT01375842）中，广泛期小细胞肺癌患者接受atezo 15mg/kg或1200mg静脉推注治疗，每三周重复。由于治疗流程修改的原因，最初5个接受治疗的患者为PD-L1选择性，但后续的12个患者并未进行PD-L1状态选择。最初的治疗持续一年，其中疾病进展的患者也允许继续接受治疗。之后的患者都接受治疗直至没有临床获益为止。评估通过RECIST V1.1和irRC。PD-L1的表达通过VENTANA SP142 IHC检测。Teffector基因状态（CD8A,GZMA,GZMB,EOMES,CXCL9,CXCL10,TBX21）及PD-L1的Mrna都进行了检测。
Phase II study of roniciclib in combination with cisplatin/etoposide or carboplatin/etoposide as first-line therapy in subjects with extensive-disease small cell lung cancer (ED-SCLC)
M. Reck, L. Horn, S. Novello, F. Barlesi, I. Albert, E. Juhasz, J. Chung, A. Fritsch, U. Drews, M. Rutstein, A. Wagner, R. Govindan.
Background: Patients with ED-SCLC have a poor prognosis.We conducted a phase II study to evaluate the efficacy and safety of roniciclib (R), an oral pan-cyclin-dependent kinase inhibitor, in combination with standard first-line platinum-based chemotherapy in subjects with ED-SCLC (NCT02161419).
Methods: Chemotherapy-naïve ED-SCLC patients were randomized 1:1 to receive 5 mg R or placebo (P) BID, 3d-on/4d-off, and standard chemotherapy (etoposide with either cisplatin or carboplatin) on a 21-day schedule for 6 cycles after which R/P was continued as monotherapy. Treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary objectives included overall survival (OS), time to progression (TTP), and objective response rate (ORR) and safety.
Results: A total of 140 patients with ED-SCLC started treatment with R plus chemotherapy (R-Chemo) or P-Chemo (70 in each arm). Baseline characteristics were balanced between R-Chemo and P-Chemo: male patients 61 vs 62%, ECOG status (0/1) 35/65% vs 28/72%, median age 62 vs 63 years. Median number of cycles during combination treatment was 4 vs 6 (R-Chemo vs P-Chemo), and dose reductions/ treatment discontinuations due to AEs were 44/23% vs 13/6%. No significant differences in favor of R-Chemo were seen in the efficacy endpoints (R-Chemo vs P-Chemo): median PFS 4.9 mo vs 5.5 mo [HR 1.242 (CI: 0.82, 1.88), p-value 0.865]; median OS 10.7 mo vs 10.7 mo [HR 1.430 (CI: 0.79, 2.61), p-value 0.869]; median TTP 5.4 mo vs 5.5 mo [HR 1.047 (CI: 0.67, 1.65), p-value 0.590]; and ORR 61% vs 75% [p-value0.968 ]. Incidence of notable adverse events (AEs) higher in the R-Chemo arm included vomiting, diarrhea, hypomagnesemia, thromboembolic events, sepsis and acute kidney injury. There were 9 fatal AEs in the R-Chemo arm compared to one in the P-Chemo arm, with 2 attributed to R (sepsis and bronchopulmonary hemorrhage). Study treatment was discontinued for all ongoing patients.
Conclusions: Addition of R to platinum-based first-line chemotherapy in ED-SCLC patients increased toxicity without improving efficacy.
Clinical trial identification: NCT02161419
Legal entity responsible for the study: Bayer AG
Funding: Bayer AG
总数为140例患者入组该实验，roniciclib及安慰剂组各70例。两组患者的基本特征平均，其中男性患者两组分别为61%vs62%；ECOG评分0-1分患者35例（65%）vs 28例（72%）；中位年龄62 vs 63。所有患者接收治疗的中位周期R药物组为6周期，安慰剂组为4周期；副作用相关导致的药物剂量减少或治疗终止在R药物组为13例（6%），安慰剂组44例（23%）。结果显示R药物联合化疗组没有显示出明显的获益，R药物联合化疗组与安慰剂联合化疗组相比，中位PFS 4.9个月vs5.5个月，中位OS 10.7个月vs10.7个月，中位TTP5.4个月vs5.5个月。R药物联合化疗组不良反应发生较多，包括呕吐、腹泻、低镁、血栓栓塞事件、脓毒症及急性肾损伤。在R药物联合组有9例出现了致死性的不良反应，安慰剂联合组1例出现了致死性不良反应，其中2例不良反应为R药物相关——脓毒症及支气管肺出血。所有的患者研究治疗均已经停止。