Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial
Key notes
Type: Phase 3 trial, RCT
Conclusion: Pembrolizumab plus axitinib is a better therapy than sunitinib monotherapy for treatment-naive, advanced renal cell carcinoma. 对于未接受治疗的晚期肾细胞癌，帕博丽珠单抗+阿西替尼比舒尼替尼单药治疗效果好
Measurements/Results: hazard ratio [HR] 0·68 [95% CI 0·55–0·85], p=0·0003
DOI: https://doi.org/10.1016/S1470-2045(20)30436-8
Total Review
Sample
129 cites in 16 coountries
stage IV or recurrent + clear cell histology
REGIST v1.1 + Karnofsky socre 70+
-= hypertension -= ischaemic cardiovascular event -= CHF congestive heart failure class III or IV -= have any kind of therapy before
FULL Sample Exclusion
had inadequate organ function
had and active CNS metastases or carcinomatous meningitis, or both
did not have a histologically confirmed diagnosis of RCC with a clear-cell component
had a his tory or current evidence of an intercurrent condition that might confound the results of the study, interfere with participation for the full study duration, or it was not in the best interest of the patient to participate the opinion of the treating investigator
did not have measureable disease assessed per RECIST version 1.1
were unable to provide tumour tissue from a non-irradiated site
had a Karnofsky performance status socre < 70
had a history of deep vein thrombosis or pulmonary embolism in the previous 6 months
were unwilling to provide wirtten, informed consent
had a known additional malignancy that progressed or required active treatment in the previous 3 years
had major surgery in the previous 4 weeks, radiotherapy in the previous 2 weeks or did not recover from adverse events of previous therapy
had poorly controlled hypertension defined as systolid blood pressure >= 150mm Hg or diastolic blood pressure >= 90 mm Hg
did not have locally adcanced (metastatic) or recurrent disease
did not meet other inclusion criteria or did meet other exclusion criteria ??
withdrew consent
Randomization & Masking
Stratified by risk group (high, norm, poor) and geological regions
No Masking
Treatments 【待完善】
In both groups, a similar proportion of
patients received subsequent VEGF or VEGFR inhibitors,
which accounted for 153 (49%) of 312 patients who
discontinued study treatment from the pembrolizumab
plus axitinib group and 159 of (46%) 349 who discontinued
study treatment from the sunitinib group. Only 25 (8%) of
312 patients in the pembrolizumab plus axitinib group
received subsequent PD-1 or PD-L1 inhibitors, compared
with 169 of (48%) 349 in the sunitinib group.
Measurements
Baseline CT/MRI
response evaluations done in 12 to 54 per 6 weeks and every 12 weeks after 54 weeks
response evaluation: blind image central review (BICR)
survival status update every 12 weeks
blood test every 3 weeks for adverse events and laboratory tests
End Point Event for progression-free: Disease Progression, unacceptable toxicity, participants’(investigators’) decision
End Point Event for overall: Death after randomisation
Statisticall Analysis
power 80%
ITT
Cox proportional hazard (stratified)
Kaplan-Meier
Efron’s method of tie handling -> magnitude of treatement difference (HR) between treatment groups
stratified factors for randomisation are also used in log-rank test and stratified cox model.
Miettien and Nurmen’s method with weights compare patients with objective response and others in treatment group
Univariate for overall survival and progress free survival (var: risk group, region, PD-L1 status, age, gender)
post-hoc analysis association between depth of response and overall survival (2 methods here: stratified cox and landmark analysis)
SAS 9.4
Results
| Pembrolizumab plus axitinib group (n=432) | Sunitinib group (n=429) | |
|---|---|---|
| Age, years | ||
| Median | 62 (55–68) | 61 (53–68) |
| <65 | 260 (60%) | 278 (65%) |
| Sex | ||
| Male | 308 (71%) | 320 (75%) |
| Female | 124 (29%) | 109 (25%) |
| Region of enrolment | ||
| North America | 104 (24%) | 103 (24%) |
| Western Europe | 106 (25%) | 104 (24%) |
| Rest of the world | 222 (51%) | 222 (52%) |
| IMDC prognostic risk | ||
| Favourable | 138 (32%) | 131 (31%) |
| Intermediate | 238 (55%) | 246 (57%) |
| Poor | 56 (13%) | 52 (12%) |
| Sarcomatoid features | ||
| Yes | 51 (12%) | 54 (13%) |
| No | 234 (54%) | 239 (56%) |
| Unknown or missing | 147 (34%) | 136 (32%) |
| PD-L1 combined positive score | ||
| ≥1 | 242 (56%) | 253 (59%) |
| <1 | 165 (38%) | 156 (36%) |
| Missing or unknown | 25 (6%) | 20 (5%) |
| Number of organs of metastases | ||
| 1 | 114 (26%) | 96 (22%) |
| ≥2 | 315 (73%) | 331 (77%) |
| Missing | 3 (1%) | 2 (<1%) |
| Most common sites of metastasis | ||
| Lung | 312 (72%) | 309 (72%) |
| Lymph node | 199 (46%) | 197 (46%) |
| Bone | 103 (24%) | 103 (24%) |
| Adrenal gland | 67 (16%) | 76 (18%) |
| Liver | 66 (15%) | 71 (17%) |
| Previous radiotherapy | 41 (9%) | 40 (9%) |
| Previous nephrectomy | 359 (83%) | 359 (84%) |
Criticize
Vocabulary
treatment-naive 未接受治疗的
renal cell carcinoma 肾细胞癌
inhibitor 抑制剂
advanced 晚期的
Immunotherapy 免疫疗法
durable 持久的 耐用的
hallmark 标志性
efficacy 功效
malignancies 恶性肿瘤
malignancy 恶性肿瘤
granular 颗粒状（粒度更小）
spectrum 波谱
regimens 疗程
recurrent 循环性
ischaemic 缺血
Allocation 拨款
intravenously 静脉地
corticosteroids 皮质类固醇
disease progression 病情恶化
Adverse Events 不良反应
haematology 血液学
active CNS metastases (癌症)活动性中枢神经系统转移
carcinomatous meningitis 癌性脑膜炎
irradiated 经辐照的
embolism 栓塞
thrombosis 血栓形成