"ALL Hard"-K drug strong "ALL-IN" digestive tract tumors

*Only for medical professionals to read and refer to those studies on which medicine K enters gastrointestinal tumors-2021 ASCO at a glance.
In the past few years, the PD-1 immune checkpoint inhibitor pembrolizumab (commonly known as "K medicine" in China) is As a leader in tumor immunotherapy, multiple research results of its KEYNOTE research series have been published in the American Society of Clinical Oncology (ASCO) over the years, and have also marked the annual ASCO event with a deep KEYNOTE brand
.

 At this year’s ASCO conference, drug K has made a comprehensive attack in the field of gastrointestinal tumor treatment.
The KEYNOTE research series is in metastatic colorectal cancer (KEYNOTE-177), unresectable locally advanced or metastatic esophageal cancer (KEYNOTE-590), and advanced gastric cancer.
Both (KEYNOTE-811) and unresectable advanced hepatocellular carcinoma (KEYNOTE-240) have been released.
The first time on the ASCO stage as an "ALL-IN" posture to show its digestion to the field of tumor treatment "ALL- Hard” data results
.

 It is worth noting that in the field of gastrointestinal cancer treatment, the KEYNOTE research series has strong Asian/Chinese “characteristics”.
Therefore, for more than 17 million new gastrointestinal cancer patients (colorectal cancer, esophageal cancer, gastric cancer and liver cancer) in 2020 ) For China, the significance of these studies is extraordinary
.

 Set up a milestone and sound the "Charge"-KEYNOTE-177, which reshapes the treatment pattern of colorectal cancer.
At the ASCO conference in 2020, the results of the first interim analysis of KEYNOTE-177 were selected as one of the five most important studies Release [1]
.

The results of the study showed for the first time that PD-1 monoclonal antibody single-agent treatment of MSI-H/dMMR metastatic colorectal cancer, pressure 6 kinds of chemotherapy +/- targeted treatment options (mFOLFOX, mFOLFOX 6+beva, mFOLFOX6+ cetuximab) Anti-FOLFIRI, FOLFIRI+Cetuximab), significantly improved progression-free survival (PFS), doubled the median PFS, and the 2-year duration of remission (DOR) rate was 83% [1]
.

 Because of KEYNOTE-177, the drug regulatory agencies in the United States and the European Union have given the K-drug single-agent first-line treatment of unresectable or metastatic MSI-H/dMMR colorectal cancer indications "green light", the United States NCCN (National Comprehensive Cancer Network ) Colon cancer diagnosis and treatment guidelines (2021 V2 version) and rectal cancer diagnosis and treatment guidelines (2021 V1 version) also give priority to the treatment plan; the newly released Chinese Society of Clinical Oncology (CSCO) colorectal cancer diagnosis and treatment guidelines give this treatment Plan I level expert recommendation (evidence level 1A)
.

According to the official website of the State Drug Administration of China, the indication has completed its technical review on June 7 and entered the administrative approval process.
It is expected to be approved in the near future, thereby changing domestic clinical practice
.

 The overall survival (OS) results of the 44-month follow-up of KEYNOTE-177 were released at this year’s ASCO conference [2].
The results showed that the median OS of the K drug group had a significant improvement trend, but because 60% of the patients in the control group were in the disease After progression, cross-receiving immunotherapy, the OS advantage did not reach statistical significance [The median OS in the K drug group has not yet reached, and the median OS in the control group is 36.
7 months, and the risk of death is reduced by 26% (HR 0.
74; 95%CI 0.
53- 1.
03; p=0.
0359)]
.

The median OS of 36.
7 months in the control group was “super performance”, and the median OS of chemotherapy (+/- targeted therapy) regimens was generally around 26 months
.

The DOR of the K drug group did not reach (2.
3+ to 53.
5+), and the control group was 10.
6 months (2.
8 to 48.
3+) [2]
.

KEYNOTE-177 Kaplan-Meier OS curve[2] At 36 months, 61% of patients in the K drug group (50% of the control group) were still alive, and at a follow-up of 44.
5 (36.
0-60.
3) months, the K drug The median OS of the group has not yet reached, and it is expected that the results of the follow-up analysis of OS in the study for a median follow-up of 5 years
.

 From 2018 to 2019, the KEYNOTE research series has braved the wind and waves in the treatment of advanced NSCLC; however, although KEYNOTE-177 is a latecomer, as a "weapon" for drug K to enter gastrointestinal tumors, it has shown its "sharp" in this year's ASCO; in ASCO in 2022, expect KEYNOTE-177 to reignite ASCO as the most important research based on the results of 5-year OS follow-up! The data is hard to open the way-KEYNOTE-590 to enter the esophageal cancer If KEYNOTE-177 sounded the "charge" of K drug to enter the treatment of gastrointestinal tumors, then KEYNOTE-590 is the "pioneer" of K drug
.

KEYNOTE-590 is a global multi-center, randomized, double-blind, controlled phase III clinical study of K drug combined with chemotherapy for the first-line treatment of unresectable locally advanced or metastatic esophageal cancer
.

 The 2020 ESMO conference announced the interim analysis results of KEYNOTE-590 with a median follow-up of 10.
8 months in the form of LBA[3].
The results showed that K drug combined with chemotherapy (cisplatin and fluorouracil) was the first-line treatment for unresectable locally advanced or metastatic esophageal cancer.
All established primary and secondary endpoints have been reached: the K-drug plus chemotherapy first-line treatment plan showed statistically significant improvements in OS, PFS, and tumor objective response rate (ORR) compared to platinum-containing chemotherapy
.

KEYNOTE-590: K-drug plus chemotherapy first-line treatment brings significant OS benefits to the entire population [3] This year ASCO released the results of KEYNOTE-590 Chinese subgroup population data analysis [4], the results show that there are 107 cases of esophageal cancer in China Among the population (98.
1% of esophageal squamous cell carcinoma), the K drug combined with platinum-containing chemotherapy first-line treatment can reduce the risk of death by 49% (HR, 0.
51; 95% CI 0.
32-0.
81) compared to the control group
.

KEYNOTE-590 Chinese population Kaplan-Meier OS[4] It is worth noting that compared with the overall population, the physical condition of the Chinese subgroup of KEYNOTE-590 is worse.
Patients with an ECOG PS score of 1 accounted for 81.
1%.
The proportion of the overall population (59.
8%) is 21.
3% higher
.

KEYNOTE-590 was enrolled in the baseline characteristics of the Chinese population [5] However, even so, K drug combined with chemotherapy in the first-line treatment of Chinese patients with advanced esophageal cancer still seems to have a better survival benefit trend.
Compared with the overall population data of the treatment study, death The risk reduction is even more significant (49% vs 27%)
.

 In this ASCO, there are also multiple studies of PD-1 combined with chemotherapy in the first-line treatment of advanced esophageal cancer.
However, drug K has won the weather vane of global drug regulatory agencies with the help of KEYNOTE-590.
The US Food and Drug Administration (FDA) favored it.
In March this year, combined chemotherapy was approved in the United States for the first-line treatment of the entire population of advanced esophageal cancer (regardless of PD-L1 level); currently K drug is still the only PD-1 immune checkpoint inhibitor approved for the first-line treatment of advanced esophageal cancer in the world
.

The marketing application of this therapeutic indication in China has been submitted to the National Medical Products Administration (NMPA) in December 2020; based on the data of the KEYNOTE-590 Chinese subgroup published by ASCO, this indication is expected to be available in China this year.
Approved, after K medicine won the indication for the first-line treatment of MSI-H/dMMR metastatic colorectal cancer, it will become the second "bridgehead" for K medicine to fully occupy the gastrointestinal tumor treatment field in China in 2021
.

 The first-line "dark horse" Liu Yinhuaming-KEYNOTE-811 that attacks gastric cancer.
On May 5 this year, the US FDA accelerated the approval of drug K in combination with trastuzumab and fluoropyrimidine/platinum-based chemotherapy to treat HER2-positive locally advanced unresectable Or patients with metastatic gastric or gastroesophageal junction adenocarcinoma; the indication approval is based on the interim analysis results of a global multicenter, randomized controlled, double-blind phase III clinical study KEYNOTE-811
.

This year ASCO announced the results of the study for the first time [5], including the objective response rate (ORR) and duration of response (DOR) analysis for the first batch of 264 patients enrolled, and the acceptance of all enrolled before June 17, 2020 Safety analysis of treated patients
.

The ORR of the K drug treatment group reached 74.
4% (66.
2-81.
6), and the control group 51.
9% (43.
0-60.
7); an increase of 22.
7% (95% CI 11.
2-33.
7, p=0.
00006); 11.
3% of the treatment group received images The complete remission (CR) was 3.
1% in the control group
.

KEYNOTE-811 related efficacy and safety data [5] The incidence of grade 3-5 adverse reactions in the K drug group is similar to that of the control group (57.
1% vs 57.
4%), the mortality rate is 3.
2% vs 4.
6%, and the treatment discontinuation 24.
4% vs 25.
9 %[5]
.

 Drug K is the world's first and currently the only PD-1 approved for the first-line treatment of HER2-positive advanced gastric cancer.
The approval of this indication will inevitably rewrite the gastric cancer treatment guidelines in various countries and change the current clinical practice of treating this part of patients
.

 It is worth mentioning that KEYNOTE-811 is not the first study that KEYNOTE has rewritten guidelines and changed clinical practice in the field of gastric cancer treatment
.

 In 2019, ASCO, the world's first PD-1 immune checkpoint inhibitor for the first-line treatment of advanced gastric cancer, the global multicenter, randomized controlled phase III clinical study KEYNOTE-062 announced the results in the form of LBA[6], showing that K drug single-agent first-line treatment of HER2 Negative, patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS ≥ 1 are not inferior to chemotherapy, reaching the first OS study endpoint; and in PD-L1 CPS Among the population ≥10, the K drug single-agent group showed a clinically significant OS advantage compared to the control group.
The median OS reached 17.
4 months (the control group 10.
8 months), and the risk of death was reduced by 41%
.

The final analysis result of KEYNOTE-062 will also be published in JAMA Oncology [7] in full in 2020
.

 KEYNOTE-062: K drug treatment of OS in the population with PD-L1 CPS ≥1 and PD-L1 CPS ≥10 [6] The results of the Asian population subgroup data analysis of the KEYNOTE-062 study published by ASCO in 2020 show that [8], K drug treatment The advantages of OS are more obvious.
The risk of death for people with PD-L1 CPS≥1 and PD-L1 CPS≥10 is reduced by 46% and 57%, respectively
.

KEYNOTE-062 Asian population subgroup data: K drug treatment of PD-L1 CPS ≥1 (A) and PD-L1 CPS ≥10 (B) population OS[8] Based on the results of the KEYNOTE-062 study Asian population data, clinical tumors in China The CSCO guidelines recommend K-drug monotherapy for first-line treatment of unresectable locally advanced or metastatic gastric cancer with HER2 negative and PD-L1 CPS ≥ 1
.

 Although drug K has been approved as a first-line treatment indication for advanced gastric cancer in the United States with KEYNOTE-811, in China, the advancement of drug K into the first-line treatment of advanced gastric cancer needs to rely on two phase III clinical studies: drug K combined with chemotherapy (5- FU or oxaliplatin combined with capecitabine) for the first-line treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma (KEYNOTE-859 Chinese extended population) [9], and K-drug single-agent second-line chemotherapy (platinum-containing chemotherapy +5 -FU) advanced Asian gastric cancer or gastroesophageal junction adenocarcinoma after progression (KEYNOTE-063) [8]
.

The KEYNOTE-063 research involving 25 Chinese centers will be initially completed in June this year, and we look forward to the first results release this year
.

Persevering in the dark night, "liver cancer" KEYNOTE-240 KEYNOTE-240 announced this year’s ASCO conference announced the K drug second-line treatment of unresectable advanced hepatocellular carcinoma treated with sorafenib, a phase III clinical study of KEYNOTE-240 with a median follow-up of 40 months Data analysis results [10] showed that the median OS of the K drug group was 13.
9 (11.
6 -16.
0) months, and the control group was 10.
6 (8.
3-13.
5) months, and the risk of death was reduced by 23% [HR 0.
77 (0.
62-0.
96), p=0.
0112]; OS rates at 24 months and 36 months were 28.
8% (control group 17.
7%) and 20.
4% (control group 11.
7%)
.

The K drug group also showed long-term PFS benefits, with a 30% reduction in the risk of disease progression or death [HR 0.
77 (0.
56-0.
89), p=0.
0011]
.

KEYNOTE-240 long-term follow-up OS and PFS In 2019 ASCO, KEYNOTE-240 first announced the data analysis results of a median follow-up of 13.
8 months.
Compared with the best maintenance treatment, pembrolizumab prolonged the OS by 3 months (13.
9 months vs 10.
6 months, HR 0.
781; p=0.
0238), PFS also improved (HR, 0.
718; p=0.
0022) [11]
.

The research results were published in the Journal of Clinical Oncology in 2019 [12]
.

KEYNOTE-240: K drug second-line treatment of OS and PFS of unresectable liver cancer[12] Moreover, K drug second-line treatment of OS and PFS in Asian subgroups with high HBV infection rate has more significant benefits, death risk and no disease progression or death The risk is reduced by 45% and 52%, respectively [13]
.

KEYNOTE-240 Asian subgroup population data: K drug second-line treatment of OS and PFS in unresectable liver cancer [13] In May this year, the oncologist advisory committee organized by the FDA unanimously supported the FDA to maintain the accelerated approval of K drug single-agent second-line treatment in 2018 Decision of indications for advanced unresectable hepatocellular carcinoma
.

 In addition to the results of the KEYNOTE-240 study, another important factor influencing this decision is the phase III clinical study KEYNOTE-394, which is only for Asian populations (Mainland China, Hong Kong, Taiwan, South Korea, and Malaysia).
It is expected that KEYNOTE-394 will be launched in June this year.
Completed [9], the research results are expected to be released this year
.

Another phase III clinical study on which drug K is leading the treatment of liver cancer in China is LEAP-002
.

 In 2018, the ASCO conference announced for the first time the results of the Phase Ib study KEYNOTE-524 of the K drug combined with the multi-target multi-kinase inhibitor lenvatinib (commonly known as the "cola combination") for the first-line treatment of unresectable hepatocellular carcinoma, demonstrating PD -1 The potential of the "strong combination" of small molecule targeting multi-target drugs [14]
.

The updated research results released by the ASCO conference in 2020 show that the objective efficiency of the "Cola" combination evaluated according to the mRECIST standard reached 46%, and the median overall survival reached 22.
0 months [15]
.

KEYNOTE-524: ASCO released updated data in 2020, ORR 46% (mRECISTper IIR), DCR 88% (mRECIST perIIR) [14]KEYNOTE-524: ASCO released follow-up updated data in 2020, mOS 22.
0 months [14] LEAP- 002 is a global multicenter (172), randomized, double-blind, controlled phase III clinical study comparing the efficacy and safety of the "cola" combination and lenvatinib in the first-line treatment of advanced hepatocellular carcinoma; the study started at the end of 2018 , 750 patients are planned to be enrolled [9]
.

 Whether LEAP-002 can receive the KEYNOTE-524 torch, rewrite the first-line treatment plan for liver cancer, and change clinical practice, it is expected to be revealed in 2021
.

Reference: [1] Thierry Andre, First-line therapy of pembrolizumab versus standardof care (SOC) in microsatellite instability-high/mismatch repairdeficient metastatic colorectal cancer: The phase III, KEYNOTE-177 study.
ASCO 2020, LBA4[2] Thierry Andre et al.
, Final overall survival for the phase IIIKN177 study: Pembrolizumab versus chemotherapy in microsatelliteinstability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).
2021 ASCO Abstract 3500[3] Ken Kato et al .
, Pembrolizumab Plus Chemotherapy VersusChemotherapy as First-Line Therapy in Patients with Advanced Esophageal Cancer:The Phase 3 KEYNOTE-590 Study, ESMO 2020, LBA 8[4] Zhigang Li et al.
, First-line pembrolizumab plus chemotherapyversus chemotherapy in patients with advanced esophageal cancer: Chinesesubgroup analysis of KEYNOTE-590.
2021 ASCO Abstract 4049[5] Yelena Y.
Janjigian, et al.
, Pembrolizumab plus trastuzumab andchemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: Initial findings of the global phase 3 KEYNOTE-811 study.
2021 ASCO Abstract 4013 [6] J.
Tabernero et al.
, Pembrolizumab With or Without ChemotherapyVersus Chemotherapy in Advanced G/GEJ Adenocarcinoma: The Phase 3, KEYNOTE-062Study, 2019 ASCO LBA4007[7] Kohei Shitara et al.
, Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer The KEYNOTE-062Phase 3 Randomized Clinical Trial, JAMAOncol.
doi:10.
1001/jamaoncol.
2020.
3370 Published online September 3, 2020.
[8] H.
Satake et al.
,Pembrolizumab Versus Standard-of-CareChemotherapy in Patients With Advanced Gastric or Gastroesophageal JunctionAdenocarcinoma: Asian Subgroup Analysis of KEYNOTE-062, 2020 ASCO PosterDiscussion, Abstract 4523[9] Richard S.
Finn et al.
, Pembrolumab (Pembro) versus placebo (pbo) in patients (pts) with advanced hepatocellular carcinoma (aHCC) previously treated with sorafenib: Updated data from the randomized,phase 3 KEYNOTE-240 study.
2021 ASCO Abstract 4072[11] Richard Finn et al.
, Results of KEYNOTE-240: Phase 3 Study of Pembrolizumab vs Best Supportive Care for Second-Line Therapy in AdvancedHeptocellular Carcinoma, 2019 ASCO, Abstract 4004, Oral Abstract Session[12] Finn RS, Ryoo BY, Merle P, et al.
Pembrolizumab as second-linetherapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: arandomized,double-blind, phase III trial.
J Clin Oncol 2020; 38:193-202.
[13] Kudo M et al.
, Pembrolizumab as Second-Line Therapy for AdvancedHepatocellular Carcinoma: A Subgroup Analysis of Asian Patients in the Phase 3KEYNOTE-240 Trial.
Liver Cancer.
Published online: April 27, 2021, DOI:10.
1159/000515553[14]Ikeda M, Sung MW, Kudo M, et al.
A phase 1b trial of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma.
JCO.
2018;36:4076.
doi:10.
1200/JCO.
2018.
36.
15_suppl.
4076[15] Andrew X.
Zhu et al.
A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC).
2020 ASCO.
Abstract 4519*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platformA Subgroup Analysis of Asian Patients in the Phase 3KEYNOTE-240 Trial.
Liver Cancer.
Published online: April 27, 2021, DOI:10.
1159/000515553[14]Ikeda M, Sung MW, Kudo M, et al.
A phase 1b trial of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma.
JCO.
2018;36:4076.
doi:10.
1200/JCO.
2018.
36.
15_suppl.
4076[15] Andrew X.
Zhu et al.
A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC).
2020 ASCO.
Abstract 4519*This article is only used to provide scientific information to medical professionals and does not represent the views of this platformA Subgroup Analysis of Asian Patients in the Phase 3KEYNOTE-240 Trial.
Liver Cancer.
Published online: April 27, 2021, DOI:10.
1159/000515553[14]Ikeda M, Sung MW, Kudo M, et al.
A phase 1b trial of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma.
JCO.
2018;36:4076.
doi:10.
1200/JCO.
2018.
36.
15_suppl.
4076[15] Andrew X.
Zhu et al.
A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC).
2020 ASCO.
Abstract 4519*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform1200/JCO.
2018.
36.
15_suppl.
4076[15] Andrew X.
Zhu et al.
A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC).
2020 ASCO.
Abstract 4519*This article is only Used to provide scientific information to medical professionals and does not represent the views of this platform1200/JCO.
2018.
36.
15_suppl.
4076[15] Andrew X.
Zhu et al.
A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC).
2020 ASCO.
Abstract 4519*This article is only Used to provide scientific information to medical professionals and does not represent the views of this platform