Keytruda leads the "leader gene" in the treatment of gastrointestinal tumors

Recently, the PD-1 immune checkpoint inhibitor pembrolizumab (Drug K) was approved as a single-agent first-line treatment for metastatic colorectal patients with hypermicrosatellite instability (MSI-H) or mismatch repair defects (dMMR) in China Cancer, the K drug has been approved for 7 indications in China, and it still ranks first among the 8 PD-(L)1 immune checkpoint inhibitors that have been approved for marketing

Drug K is currently the PD-(L)1 monoclonal antibody with the largest number of approved first-line treatment indications (5), and is far ahead of the 8 domestically approved PD-(L)1 monoclonal antibodies

The approval of drug K for the first-line treatment of colorectal cancer is its second indication for the treatment of gastrointestinal tumors in China, and it is also the first indication for the first-line treatment of gastrointestinal tumors, which has sounded the entry of K drugs into gastrointestinal tumors in China.

In the global and China's advanced non-small cell lung cancer (NSCLC) first-line treatment market, K drug is the absolute market leader.

And with the conclusion of this year’s ASCO conference, the hegemony of K drug in the field of gastrointestinal tumors is also "unknown": KEYNOTE-177 for colorectal cancer, KEYNOTE-590 for esophageal cancer, KEYNOTE-811 for gastric cancer, And KEYNOTE-240 for liver cancer; these are the first releases or updated data, allowing K drug to complete the first-line treatment grand slam for gastrointestinal tumors and once again lead the industry

The legend will continue KEYNOTE-177

At the ASCO conference in 2020, the results of the first interim analysis of KEYNOTE-177 were selected and published as one of the five most important studies [1]

Soon afterwards, based on the KEYNOTE-177 study, drug regulatory agencies in the United States and the European Union approved K-drug monotherapy for the first-line treatment of unresectable or metastatic MSI-H/dMMR colorectal cancer indications, NCCN (United States National Comprehensive Cancer Network) The released 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 also specifically list MSI -H/dMMR metastatic colorectal cancer, and give K drug single-agent first-line treatment plan (the only plan) I grade expert recommendation (evidence level 1A)

There is no doubt that in the field of treatment of metastatic colorectal cancer with MSI-H/dMMR, KEYNOTE-177, a landmark study, has achieved K drug, making it the recognized absolute "leader" in this treatment market

However, KEYNOTE-177 has not ended its journey to lead the treatment.

At this year’s ASCO conference, the results of KEYNOTE-177’s 44-month follow-up of OS were released [2], and the results showed that the median OS of the K drug group had a significant improvement trend, and the median OS of the K drug group had not yet reached the control group.

KEYNOTE-177 Kaplan-Meier OS curve graph[2]

At 36 months, 61% of patients in the K drug group (50% in the control group) are still alive, and the probability of this part of patients living past five years is very high

Will KEYNOTE-177 release 4-year or even 5-year OS follow-up data results in ASCO or ESMO in 2022? This should be a necessity, because this is the fundamental reason why K medicine can lead, and it is also the root of the hardest lasting data

OS is the gold standard among all the indicators used to evaluate the clinical research of a new oncology drug.

While other competing PD-1 products of the same kind are still trying to rise from PFS to OS as the primary end point of its phase III clinical study, Drug K seems to have taken research and improvement of patient long-term survival rate and even clinical cure as its motto and goal.

No study can better explain the non-cost of K drug than the 36-month survival rate released by ASCO this year KEYNOTE-240

Regardless of cost, pursue long-term survival KEYNOTE-240

KEYNOTE-240 is a global multicenter, randomized, double-blind, phase III clinical study of K-drug second-line treatment of unresectable advanced hepatocellular carcinoma with disease progression after Sorafenib treatment

In 2019, ASCO, KEYNOTE-240 announced for the first time the final OS data analysis results of the K drug treatment group with a median follow-up of 13.
8 months.
Compared with the best maintenance treatment, K drug treatment 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) [3]
.
The research results were published in the Journal of Clinical Oncology in 2019 [4]
.

KEYNOTE-240: K drug second-line treatment of OS and PFS in unresectable liver cancer[4]

Although KEYNOTE-240 shows the trend of OS benefit brought by K drug second-line treatment, due to statistical design reasons, the dual end points of OS and PFS failed to reach the preset statistically significant p value, so KEYNOTE-240 was once The industry sighed with regret
.

However, KEYNOTE-240 did not "stop"
.

This year’s ASCO conference announced the data analysis results of an additional 18 months follow-up (median follow-up 40 months) after the final data analysis of KEYNOTE-240 [5], showing that the median OS of the K drug group was 13.
9 (11.
6-16.
0) months In the control group for 10.
6 months (8.
3-13.
5) months, the risk of death was reduced by 23% (HR = 0.
77, 95% CI: 0.
62-0.
96, p=0.
0112); the 36-month OS rate was 28.
8% (control group 17.
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, 95% CI: 0.
56-0.
89, p=0.
0011)
.

KEYNOTE-240 OS and PFS for long-term follow-up

KEYNOTE-240 is a large phase III clinical study covering 119 centers in 27 countries around the world
.
After the final OS results are announced, it will take courage and capital investment to continue to follow patients in these countries and centers, but K drug seems to be worth it, because for doctors and patients, the difference in the 3-year overall survival rate is in clinical decision-making.
The above still has a pivotal significance
.

In May of this year, the oncology expert advisory committee organized by the U.
S.
FDA unanimously supported the FDA's decision to accelerate the approval of drug K for the second-line treatment of advanced unresectable hepatocellular carcinoma in 2018
.

Dare to be the first to eat crab KEYNOTE-590

If the Phase III clinical studies of KEYNOTE-177 and KEYNOTE-240, the two single-drug treatments, highlight the persistence of K drugs in the pursuit of long-term survival or clinical cure, then KEYNOTE-811 and KEYNOTE-590 show that K drugs dare to be the first The courage of a PD-1 who eats crabs
.

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[6].
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 combined with chemotherapy as first-line treatment brings significant OS benefits to the whole population[6]

This year ASCO released KEYNOTE-590 Chinese subgroup data analysis results [7], the results show that in 107 cases of Chinese esophageal cancer (esophageal squamous cell carcinoma accounted for 98.
1%), compared with the control group, K drug combined with platinum First-line chemotherapy can reduce the risk of death by 49% (HR=0.
51; 95% CI: 0.
32-0.
81)
.

KEYNOTE-590 Chinese population Kaplan-Meier OS[7]

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); drug K is still the only PD-1 immune checkpoint inhibitor approved for first-line treatment of advanced esophageal cancer in the world
.

The application for the indication for the first-line treatment of esophageal cancer with K-drug combined with chemotherapy in China was submitted at the end of last year; based on the data of the KEYNOTE-590 Chinese subgroup released by ASCO this time, the indication is also expected to be approved in China this year.
After K drug won the single-agent first-line treatment indication for MSI-H/dMMR metastatic colorectal cancer, it became the second "bridgehead" for K drug to fully occupy the gastrointestinal tumor treatment field in China in 2021
.

KEYNOTE-811 Surprising 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 for the first-line treatment of patients with HER2-positive locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma The approval of the indication is based on the interim analysis results of a global multi-center, randomized controlled, double-blind phase III clinical study KEYNOTE-811
.

ASCO announced the results of the study for the first time this year [8], including the objective response rate (ORR) and duration of response (DOR) analysis for the first batch of 264 patients enrolled in the group, as well as 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 patients in the treatment group achieved The imaging 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 was similar to that of the control group (57.
1% vs 57.
4%), the mortality rate was 3.
2% vs 4.
6%, and the treatment discontinuation was 24.
4% vs 25.
9%5
.

Drug K is the world's first and currently 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
.

Can scientific leadership be transformed into market leadership?

There is no doubt that China, which has 8 approved PD-(L)1 monoclonal antibodies, is the most competitive market for tumor immunotherapy, and it is also the most special market
.
At present, even in the next 5 years, K drug is a global leader in immunotherapy research and development, as well as the most commercially successful tumor immunotherapy drug, and a market leader
.
As of the first quarter of 2021, Drug K has been approved for 29 indications in the United States, and its global sales are far ahead of the second-ranked nivolumab
.

Moreover, the estimated approved indications of K drug will reach at least 50 and 90 in 2025 and 2028, respectively [9]
.

But in China, in the face of the blowout of domestically produced PD-1, there are currently 7 treatment indications and 5 first-line treatment indications.
Will the K drug, which will have the second first-line treatment indication for gastrointestinal tumors, continue to lead? Can scientific leadership be transformed into market leadership?

Undoubtedly, K drug leads China's tumor immunotherapy market and will face immeasurable challenges!

But it is also unquestionable that there is enough evidence that K drug, which is called PD-1, which allows patients to "live long", is the hardest indicator of long-term survival for patients, which is currently not available in China.
PD-1 can stand up to it; and its fear of failure and the courage to be the first PD-1 to eat crabs will also help it to stay at the forefront forever, only to be imitated, not to be surpassed
.

These two unique "leader genes" will help K drug have its own place among doctors and patients, and it is difficult to be replaced, whether it is in the Chinese or American market, and whether it is in the treatment of gastrointestinal tumors or other malignant tumors.
Market
.

Note: The original text has been deleted

Reference

[1] Thierry Andre, First-line therapy of pembrolizumab versus standard of 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 microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC).
2021 ASCO Abstract 3500

[3] Richard Finn et al.
, Results of KEYNOTE-240: Phase 3 Study of Pembrolizumab vs Best Supportive Care for Second-Line Therapy in Advanced Heptocellular Carcinoma, 2019 ASCO, Abstract 4004, Oral Abstract Session

[4] 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.

[5] Richard S.
Finn et al.
, Pembrolizumab (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

[6] Ken Kato et al.
, Pembrolizumab Plus Chemotherapy Versus Chemotherapy as First-Line Therapy in Patients with Advanced Esophageal Cancer: The Phase 3 KEYNOTE-590 Study, ESMO 2020, LBA 8

[7] Zhigang Li et al.
, First-line pembrolizumab plus chemotherapy versus chemotherapy in patients with advanced esophageal cancer: Chinesesubgroup analysis of KEYNOTE-590.
2021 ASCO Abstract 4049

[8] Yelena Y.
Janjigian, et al.
, Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ)cancer: Initial findings of the global phase 3 KEYNOTE-811 study.
2021 ASCOAbstract 4013

[9] Merck Oncology Investor Event, 2021 ASCO,