Pembrolizumab联合Axitinib获批一线晚期RCC
神速啊，PDUFA date是2019-6-20啊
Label上已经更新,2月15号才Grants Priority Review
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514Orig1s054lbl.pdf
今年GU上披露的data，同期NEJM在线，基于KN-426，联合组降低47%的死亡风险和39%的进展风险
详细描述可以关注前期关于GU19的报道：KEYNOTE-426@GU19
Pem+Axi对比Suntinib一线治疗mRCC，入组标准：透明细胞癌+先前未系统治疗+KPS≥70%
预设的优效性假设：P = 0.0001 for OS, 0.0013 for PFS, and 0.025 for ORR
详细结果
对的 没有看错 批的不是Avelumab+Axitinib
主要看几家的比较
可以这样看
可以这样看
也可以这样看
Ave+Axi和Nivo+Ipi分别只针对PD-L1+和中高危群体，Pembro针对ITT且PFS和OS均达到预设终点，唯一遗憾的就是这几个一线基本只入组ccRCC，虽然这部分占了整个晚期RCC的~80%
GU19上几项non-ccRCC的研究的结果
周末愉快，我去睡个回笼觉了
官网还没更新，就看下2月份的数据披露的新闻
KEYTRUDA® (pembrolizumab) in Combination with Inlyta® (axitinib) Reduced Risk of Death by Nearly Half Compared to Sunitinib as First-Line Treatment for Advanced Renal Cell Carcinoma (RCC)
Results from Phase 3 KEYNOTE-426 Study Presented Today at the 2019 Genitourinary Cancers Symposium (ASCO GU) and Published in the New England Journal of Medicine Also Showed Risk of Progression or Death Reduced by 31 Percent
Data Consistent Across all IMDC Risk Groups and Regardless of PD-L1 Expression
Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced presentation of the full results from the pivotal Phase 3 KEYNOTE-426 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with Inlyta (axitinib), a tyrosine kinase inhibitor, for the first-line treatment of advanced renal cell carcinoma (RCC) at the 2019 Genitourinary Cancers Symposium (ASCO GU) (Abstract #543). These data were also simultaneously published in the New England Journal of Medicine. This is the first combination regimen to significantly improve overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) compared to sunitinib. Results were consistent across all IMDC subgroups, including favorable, intermediate and poor risk groups, and regardless of PD-L1 expression.
As previously announced, the U.S. Food and Drug Administration (FDA) has granted priority review for a supplemental Biologics License Application (sBLA) for KEYTRUDA in combination with axitinib for the first-line treatment of patients with advanced RCC based on the results of KEYNOTE-426, and has set a Prescription Drug User Fee Act (PDUFA), or target action, date of June 20, 2019.
“Historically, patients with advanced RCC have faced five-year survival rates of less than 10 percent. Given the aggressive nature of this disease and the poor long-term prognosis, these new survival data with KEYTRUDA in combination with axitinib from KEYNOTE-426 offer the potential of a new treatment option for patients with advanced renal cell carcinoma,” said Dr. Thomas Powles, lead investigator for KEYNOTE-426, professor of genitourinary oncology, lead for Solid Tumor Research at Barts Cancer Institute, director of Barts Cancer Centre.
Findings from the first interim analysis showed KEYTRUDA in combination with axitinib reduced the risk of death by 47 percent – significantly improving OS compared to sunitinib (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001). For the dual primary endpoint of PFS, the KEYTRUDA combination showed a reduction in the risk of progression of disease or death of 31 percent compared to sunitinib (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). In the study, the ORR was 59.3 percent for patients who received KEYTRUDA in combination with axitinib (95% CI, 54.5-63.9) and 35.7 percent for those who received sunitinib (95% CI, 31.1-40.4) (p<0.0001), with a complete response rate of 5.8 percent (n=25) and 1.9 percent (n=8) and a partial response rate of 53.5 percent (n=231) and 33.8 percent (n=145), for patients receiving the KEYTRUDA combination or sunitinib, respectively. Median duration of response was not reached in the KEYTRUDA combination arm (range, 1.4+ to 18.2+ months) and was 15.2 months (range, 1.1+ to 15.4+) in the sunitinib arm. The results for OS, PFS and ORR were consistent across all IMDC risk groups and seen regardless of PD-L1 expression. The observed adverse event profile was as expected based on the known profiles of KEYTRUDA and axitinib. There was a higher incidence of grade 3 or 4 liver enzyme elevation with KEYTRUDA plus axitinib than previously observed with each agent as monotherapy.
“With a reduction in the risk of death by nearly half, these findings are particularly impressive considering the benefit was not limited to one subgroup of patients – we observed an overall survival improvement across all IMDC risk groups and regardless of PD-L1 expression,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “We are pleased that these findings have been accepted for priority review by the FDA, and hopeful that they will be viewed positively by regulatory authorities worldwide. In the meantime, we are grateful to the investigators and patients for their involvement in this important study.”
"These data build on the single-agent activity of pembrolizumab and axitinib, and represent the first time a kidney cancer regimen has improved overall survival, progression-free survival and objective response rate versus sunitinib. More importantly, they offer patients with this aggressive form of kidney cancer a potential new first-line treatment option,” said Dr. Brian Rini, lead author for the New England Journal of Medicine publication of KEYNOTE-426, medical oncologist at Cleveland Clinic Cancer Center and professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. As reported by the Cleveland Clinic, Dr. Rini reports consulting and research funding from Merck.
Merck has filed these data with regulatory authorities worldwide. Merck has an extensive clinical development program in RCC and is advancing multiple potential registration-enabling studies with KEYTRUDA, as monotherapy and in combination with other treatments, including KEYNOTE-564 and KEYNOTE-581.
Study Design and Additional Data from KEYNOTE-426
KEYNOTE-426 is a randomized, double-arm, Phase 3 trial (ClinicalTrials.gov, NCT02853331) evaluating the safety and efficacy of KEYTRUDA in combination with axitinib as first-line treatment for advanced or metastatic RCC compared to sunitinib monotherapy. The dual primary endpoints of the study were OS and PFS; key secondary endpoints include ORR, safety, duration of response, PFS at 12, 18 and 24 months and OS at 12, 18 and 24 months. The primary outcome measures were further evaluated based on PD-L1 tumor expression (combined positive score [CPS] <1 [n=325] and ≥1 [n=497]). In the trial, 861 patients determined to be favorable-, intermediate- or poor-risk by IMDC criteria (n=269, n=484, n=108, respectively) were randomly assigned to receive KEYTRUDA 200 mg intravenously every three weeks plus axitinib 5 mg orally twice daily for up to 24 months (n=432), or sunitinib 50 mg orally once daily for four weeks followed by no treatment for two weeks (n=429).
At the first interim analysis, after a median follow-up of 12.8 months, overall survival was significantly longer in the KEYTRUDA combination arm than in the sunitinib arm (HR=0.53 [95% CI, 0.38-0.74]; p<0.0001). Estimated 12-month survival rates were 89.9 percent (95% CI, 86.4-92.4) in the KEYTRUDA combination arm compared to 78.3 percent (95% CI, 73.8-82.1) in the sunitinib arm; the 18-month survival estimates were 82.3 percent (95% CI, 77.2-86.3) and 72.1 percent (95% CI, 66.3-77.0), respectively. Median survival was not reached in either group. Progression-free survival was also significantly longer in the KEYTRUDA combination arm than in the sunitinib arm (HR=0.69 [95% CI, 0.57-0.84]; p=0.0001). The 12-month PFS rate was 59.6 percent in the KEYTRUDA combination arm and 46.2 percent in the sunitinib arm; the 18-month PFS rate was 41.1 percent in the KEYTRUDA combination arm and 32.9 percent in the sunitinib arm. Median PFS was 15.1 months (95% CI, 12.6-17.7) in the KEYTRUDA combination arm compared to 11.1 months (95% CI, 8.7-12.5) in the sunitinib arm.
Analysis of the OS endpoint based on patient subgroups showed consistent results across each of the IMDC risk categories (favorable, intermediate and poor) (HR=0.64 [95% CI, 0.24-1.68]; HR=0.53 [95% CI, 0.35-0.82]; and HR=0.43 [95% CI, 0.23-0.81], respectively), and regardless of PD-L1 expression (PD-L1 combined positive score [CPS <1 [HR=0.59 (95% CI, 0.34-1.03)] and PD-L1 CPS ≥1 [HR=0.54 (95% CI, 0.35-0.84]). Results were also consistent for PFS across these same IMDC risk categories (HR=0.81 [95% CI, 0.53-1.24]; HR=0.70 [95% CI, 0.54-0.91]; and HR=0.58 [95% CI, 0.35-0.94], respectively), as well as for tumors with PD-L1 CPS <1 (HR=0.87 [95% CI, 0.62-1.23]) and PD-L1 CPS ≥1 (HR=0.62 [95% CI, 0.47-0.80]). Subgroup analyses were not controlled for multiplicity.
Grade 3-5 treatment-related adverse events (TRAEs) occurred in 62.9 percent of the 429 treated patients in the KEYTRUDA combination arm and 58.1 percent of the 425 treated patients in the sunitinib arm. TRAEs resulting in discontinuation of any treatment occurred in 25.9 percent of patients in the KEYTRUDA combination arm and 10.1 percent of patients in the sunitinib arm; 8.2 percent of patients discontinued both KEYTRUDA and axitinib. The most common grade 3-5 TRAEs (occurring in ≥10% of patients) were hypertension (22.1%) and increased alanine aminotransferase (ALT) (13.3%) in the KEYTRUDA combination arm and hypertension (19.3%) in the sunitinib arm.
Immune-mediated adverse events and infusion reactions of any grade occurred in 51.3 percent of patients in the KEYTRUDA combination arm and 36.2 percent of patients in the sunitinib arm. The most common immune-mediated adverse events (occurring in ≥10% of patients) were hypothyroidism (35.4%) and hyperthyroidism (12.8%) in the KEYTRUDA combination arm and hypothyroidism (31.5%) in the sunitinib arm. Treatment-related deaths occurred in four patients in the KEYTRUDA combination arm (myasthenia gravis, myocarditis, necrotizing fasciitis, pneumonitis [n=1 each]), and seven patients in the sunitinib arm (acute myocardial infarction, cardiac arrest, fulminant hepatitis, gastrointestinal hemorrhage, intracranial hemorrhage, malignant neoplasm progression, pneumonia [n=1 each]).
About Renal Cell Carcinoma (RCC)
Renal cell carcinoma is by far the most common type of kidney cancer; about 9 out of 10 kidney cancers are RCCs. Renal cell carcinoma is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. There were approximately 403,000 cases of kidney cancer diagnosed worldwide in 2018 and about 175,000 deaths from the disease. In the U.S. alone, there will be an estimated 74,000 new cases of kidney cancer diagnosed in 2019 and about 15,000 people will die from the disease.