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K-Medicine's "Pride and Hao"

 Last Update: 2022-10-25
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Regardless of success or failure and cost, it attracts the pride and pride of countless heroes

Entering the golden autumn October, China's advanced liver cancer immunotherapy has reaped major benefits
.
PD-1 monoclonal antibody pembrolizumab (commonly known as "K drug") is approved
in China for the treatment of advanced primary hepatocellular carcinoma (HCC) treated with previous sorafenib or oxaliplatin chemotherapy.
This is the 9th indication approved by K drug in China, and also brings the number of approved gastrointestinal tumor indications to 4, covering advanced esophageal cancer, advanced liver cancer and colorectal cancer
with microsatellite instability or DNA mismatch repair defects (MSI-H/dMMR).

The phase III clinical study KEYNOTE-394, on which the new indication for liver cancer is approved, is the world's first phase III clinical trial
of PD-1 inhibitor monotherapy for advanced liver cancer with positive results.
THE EFFICACY AND SURVIVAL BENEFITS OF SECOND-LINE TREATMENT OF ADVANCED HCC WERE FINALLY VERIFIED IN KEYNOTE-394, WHICH ALSO ENDED MANY PREVIOUS CONTROVERSIES ABOUT K-DRUG MONOTHERAPY FOR ADVANCED HCC AND PUT AN END
TO ANY DOUBTS.

The journey of K drug to explore immunotherapy for digestive tract tumors has not been smooth
.
Although K drug was conditionally accelerated approved by the US FDA for the treatment of advanced gastric cancer and advanced HCC in the second line and as early as 2018, respectively, the phase III confirmatory clinical studies KEYNOTE-062 and KEYNOTE-240 announced at the American Congress of Clinical Oncology (ASCO) in 2019 encountered "Waterloo" [1,2] due to study design and other reasons, and were "missed" by formal approval ”
。

In the real sense, K drug won the "first battle" in the field of digestive tract tumor treatment is actually the single-drug second-line treatment of advanced esophageal cancer, relying on the phase III clinical study KEYNOTE-181
.

In July 2019, based on the results of the phase III clinical study KEYNOTE-181, drug K was approved in the United States for the single-agent second-line treatment of PD-L1 expression positive (CPS≥10, based on an FDA-approved detection reagent) for relapsed locally advanced or metastatic esophageal cancer squamous cell carcinoma
.
Almost a year later, (June 2020), the indication was approved in China, sounding the "charge"
of K drug to enter the treatment of digestive tract tumors.

The journey of K drug exploration of gastrointestinal tumor immunotherapy has ups and downs, reverberating and endlessly aftertaste, highlighting the "personality"
of K drug.
To get a glimpse of the personality of K drugs, several milestone studies in the field of esophageal cancer treatment are undoubtedly the best starting point
.

Take the KEYNOTE-590 as a starting point

In the golden autumn of 2021 (September), based on the results of the milestone phase III clinical study KEYNOTE-590, China's National Medical Products Administration (NMPA) approved the first-line treatment of K-drug combined with chemotherapy (cisplatin and 5-fluorouracil) for the first-line treatment of locally advanced unresectable or metastatic esophageal or gastroesophageal junction cancer, so immunotherapy was advanced from the second line to the first line of advanced esophageal cancer for the first time
.

Professor Li Yin, Department of Esophageal Surgery, Cancer Hospital, Chinese Academy of Medical Sciences, and Professor Huang Jing, Department of Medical Oncology, Cancer Hospital of Chinese Academy of Medical Sciences, said:

“
KEYNOTE-590 is a groundbreaking research on first-line immunotherapy for advanced esophageal cancer, which is a
milestone for comprehensively promoting the development of esophageal cancer immunotherapy in China.

”

In the short period of one year since the approval of KEYNOTE-590, the first-line immune therapy for advanced esophageal cancer in China has "fully exploded", and a total of 4 PD-1 monoclonal antibodies including carrelizumab, sindilimab and trepilimab have been approved for the first-line treatment of unresectable locally advanced or metastatic esophageal squamous cell carcinoma, including carrelizumab
, sindilimab and trepilimab.
Multiple PD-1 monoclonal antibody combined chemotherapy regimens have been recommended by the Chinese Clinical Oncology (CSCO) Esophageal Cancer Diagnosis and Treatment Guidelines (2022) for Grade I or II, and immunization combined with cisplatin-based chemotherapy has become a new standard
for first-line treatment of advanced esophageal cancer in clinical practice.

CSCO Guidelines for the Diagnosis and Treatment of Esophageal Cancer (2022): Recommendations for treatment options for metastatic esophageal cancer

"Overnight", Chinese doctors who have become the world's most first-line immune treatment options for advanced esophageal cancer suddenly find themselves trapped by "happiness troubles
".
With the opening and advancement of medical insurance negotiations in 2022, a number of domestic PD-1 monoclonal antibody combined chemotherapy regimens will also enter the medical insurance reimbursement directory with a high probability, thereby greatly improving patient accessibility, strengthening the popularity of clinical application, and consolidating the first-line standard status
of the treatment program.

In the context of PD-1 combined chemotherapy regimen sweeping the first-line treatment of advanced esophageal cancer, the concept of precision immunotherapy for esophageal cancer seems to be less mainstream
than precision immunotherapy for advanced non-small cell lung cancer (NSCLC) and MSI-H/dMMR-based precision immunotherapy for colorectal cancer.
In clinical practice, the use of immunotherapy in combination with chemotherapy in all advanced esophageal cancer populations seems to be the rule, although the KEYNOTE-590 study showed a more significant benefit of PFS and OS in PD-L1 CPS≥10 populations [3].

SPEAKING OF WHICH, I HAVE TO GIVE A THUMBS UP
TO THE KEYNOTE-590 STUDY.

KEYNOTE-590 is not only the first phase III clinical study of immune combined chemotherapy for the first-line treatment of advanced esophageal cancer with positive results of "eating crabs", but also the only clinical study
of stage III esophageal cancer that has obtained positive results for adenocarcinoma of esophageal cancer, squamous cell carcinoma and gastroesophageal cancer.

The design of the KEYNOTE-590 study is bold, scientific, and shows a domineering arrogance, but more importantly, the KEYNOTE-590 study has a pure original intention to pursue high-level evidence-based medical evidence, the pride of ignoring the results of yin and yang, and the arrogance born only to serve clinical practice
.

KEYNOTE-590'S PRIDE

KEYNOTE-590 established seven primary study endpoints for esophageal squamous cell carcinoma (ESCC), ESCC with a PD-L1 composite positive score (CPS) of ≥10, and the overall population, as well as all populations, including OS for these four groups, and the overall population of ESCC, PD-L1 CPS≥10, and PFS
for the entire population.
Secondary endpoints include ORR, duration to remission (DOR), and safety and tolerability [3].

When a clinical study has up to seven hypotheses, this requires a fine and reasonable allocation of α values between the two primary endpoints of OS and PFS, so as to ensure that the overall α value of the study is controlled within
0.
025 on one side of the study.
In the KEYNOTE-590 study, the α value of PFS was 0.
002 and the α value of OS was 0.
023 [3].

Statistical analysis of KEYNOTE-590: distribution of α values [3].

AT THE SAME TIME, KEYNOTE-590 FURTHER LAYERED
SEVEN RESEARCH HYPOTHESES.

The top layer of PFS is the ESCC population with a α value of 0.
002, and the top layer of OS is the ESCC population with PD-L1 CPS≥10 and ESCC population, with α values of 0.
012 and 0.
011
, respectively.
Only when the top-level hypotheses are statistically valid, i.
e.
the study endpoint is reached, can the second-level analysis
begin.
This means that if the ESCC PFS fails to meet a statistically significant target, PFS results for the PD-L1 CPS≥10 population (level 2) or the overall population (level 3) will not be successful
, regardless of the p-value.

Similarly, ESCC and/or ESCC studies of PD-L1 CPS≥10 in Tier 1 that did not meet statistically significant endpoints negatively affected the overall population and the overall study population
of PD-L1 CPS≥10 at Tier 2 and Tier 3, respectively.

This design is very bold, not only reflecting the great confidence of the study designers in the efficacy of the first-line treatment of K drug combined with chemotherapy, but also showing the pride of K drug as a leader and leader in immunotherapy research, so it does not count success or failure
.

"Howe" of the KEYNOTE-590

The KEYNOTE-590 and K monotherapy studies in patients with locally advanced or metastatic esophageal cancer who have failed prior first-line systemic therapy have both OS in PD-L1 CPS≥10 populations as one of the primary endpoints [4].

Although the number of phase III clinical studies of PD-1 in the treatment of esophageal cancer is constantly "expanding", K drug is still the only PD-1 monoclonal antibody
that takes the OS of PD-L1 CPS≥10 population as the main research endpoint from second-line treatment to first-line treatment.

Primary endpoints designed in different PD-1 phase III clinical studies for the treatment of esophageal cancer [3-11].

The KEYNOTE-181 study has demonstrated significant OS benefits from the single-agent second-line treatment of PD-L1 CPS≥10 esophageal squaf carcinoma in people with K drug combination with chemotherapy, so it is also likely to have positive results
in the treatment of this group of people with K drug combined with chemotherapy in the earlier stages of the disease.
In this context, it seems that it does not make much sense to devote research
energy and financial resources to this group of people.
Therefore, it is not surprising why ESCORT-1st, JUPITER-06, and CheckMate-648 do not establish primary study endpoints for treating select populations [9-11].

BUT WHY DID THE KEYNOTE-590 DO THIS? The results of the KEYNOTE-590 study show the mystery
.

KEYNOTE-590 enrolled a total of 749 patients with unresectable locally advanced or metastatic esophageal cancer who had not received medical treatment, more than 50% (51.
1%) of patients with PD-L1 CPS≥10, and more than 70% (73.
2%) of patients with esophageal squaleiform cell carcinoma
.

KEYNOTE-590：

Overall population, ESCC, ITT of PD-L1 CPS≥10, and OS of ESCC population[1].

OS DATA ANALYSIS RESULTS OF KEYNOTE-590:

In the ITT population, the K drug plus chemotherapy group reduced the risk of death by 27%; In the population with PD-L1 CPS≥10, the K drug combined with chemotherapy group reduced the death stroke by 38%;
In the ESCC population, the risk of death was reduced by 28% in the K plus chemotherapy group and 43%
in the ESCC group with PD-L1 CPS≥10.

OS data analysis of KEYNOTE-590 subgroup in China highlights the advantages of PD-L1 CPS≥10 population: the K drug combined with chemotherapy group reduces the risk of death in ITT people with PD-L1 CPS≥10 by 67% [12].

It is clear that the PD-L1 CPS≥10 population benefits more from the K combination chemotherapy regimen, and KEYNOTE-590 thus validates that PD-L1 CPS≥10 can be used as a predictor of the efficacy of the K drug combination chemotherapy regimen
.

Professor Li Yin pointed out that there are not many explorations on the efficacy and safety prediction of immunotherapy for esophageal cancer and esophageal and gastric junction cancer, but they are still inconclusive, and the pembrolizumab combined chemotherapy shown in the KEYNOTE-590 research institute not only shows that it can reduce the risk of death in the overall population of advanced esophageal cancer, but also reduces the risk of death of PD-L-1 CPS≥10 Chinese patients, which is still very meaningful for clinical practice
。

Professor Huang Jing believes that one of the biggest challenges in tumor immunotherapy is how to screen out the people who benefit from immunotherapy, especially in the field of digestive tract tumor treatment with relatively high heterogeneity.

But from a business perspective, select treatment populations are a double-edged sword, as it may lead to better efficacy data, but at the same time it narrows down the target population
.
But for clinical practice, this exploration is of great significance, especially for the treatment of
digestive tract tumors.

Professor Huang Jing pointed out that digestive tract tumors may affect patients' eating, swallowing, and nutrient absorption, so patients' nutrient intake and absorption are generally poor, and their overall physical condition is biased
.
Therefore, precise individualized treatment is particularly important
for digestive tract tumors.

But who benefits more from immunotherapy? The results of KEYNOTE-590 suggest that people with positive expression of PD-L1 CPS are the most likely to benefit from survival from immunotherapy, providing clinicians with a basis for precise treatment of esophageal cancer, ultimately improving the efficacy and quality of patients, and improving the survival of
esophageal patients.

From another perspective, KEYNOTE-590's exploration of selected populations for immune combination chemotherapy therapy increases the flexibility of doctors in clinical practice, that is, doctors can accurately treat patients according to their conditions, in exchange for the maximum and highest quality survival benefits
of patients at the smallest cost.
This is extremely important
in clinical practice.

Regardless of cost, everything serves clinical practice, this is the pride of KEYNOTE-590
.

The "proud pride" of K medicine

The "Proud and Hao" of K drug is not limited to KEYNOTE-590, it runs through the research of K drug, and is particularly prominent
in the exploration of its gastrointestinal tumor immunotherapy.

The results of the KEYNOTE-177 study, first released at the 2020 American Society of Clinical Oncology (ASCO) Congress, showed that K drug monotherapy first-line treatment of MSI-H/dMMR metastatic colorectal cancer (mCRC) pressed 6 chemotherapy +/- targeted regimens (mFOLFOX, mFOLFOX 6+ bevacizumab, mFOLFOX6 + cetuximab, FOLFIRI, FOLFIRI + bevacizumab, FOLFIRI + cetuximab) , significantly improved progression-free survival (PFS) with a median PFS of 16.
5 months, double that of the control group (8.
2 months) [13].

IN 2020, ASCO FIRST ANNOUNCED THE PFS FOR KEYNOTE-177 [11].

In June 2021, K drug was approved as a single-agent first-line treatment of MSI-H/dMMR metastatic colorectal cancer in China, changing the clinical practice
of treating this part of the mCRC population.

Only about 10% to 15% of patients with CRC present with MSI-H/dMMR, and this proportion decreases
with progression of stage.
The exploration of K drug for the treatment of MSI-H/dMMR advanced colorectal cancer highlights its leading position as a leader in precision immunotherapy, and more importantly, KEYNOTE-177 has changed the treatment mode of mCRC disease and promoted K drug to replace traditional chemotherapy + targeted therapy
in the first-line treatment of mCRC.

The CSCO Guidelines for the Diagnosis and Treatment of Colorectal Cancer (2021) for the first time separately listed MSI-H/dMMR initial unresectable metastatic colorectal cancer, and for the first time divided mCRC into two types of diseases
: MSI-H/dMMR and MSS or MSI-L/PMMR.

If KEYNOTE-177 challenges traditional chemotherapy combined with cetuximab or bevacizumab in the treatment of microsatellite instability (MSI-H)/mismatch repair defect (dMMR) in the treatment of microsatellite instability (MSI-H)/mismatch repair defect (dMMR) in the population with metastatic colorectal cancer with the power of K drug monotherapy, it is reminiscent of the statistical protocol of the KEYNOTE-590 study and the unremitting pursuit of precision immunotherapy The LEAP-002, which released the final analysis results at ESMO this year, once again vividly demonstrated the "arrogance"
of K medicine regardless of success or failure, regardless of gain and loss.

LEAP-002 is a randomized, double-blind, multicenter phase III clinical trial exploring the efficacy and safety of K-drug + lenvatinib (commonly known as "cola" combination) compared with lenvatinib in advanced first-line HCC, selecting OS and PFS as the dual endpoints of the study [14].

LEAP-002 study design[14].

The results showed that the "cola" treatment group failed to meet the preset statistically significant research indicators
in both OS and PFS.
The median overall survival of the "cola" combination was as high as 21.
2 months (vs lenvatinib 19.
0 months), HR=0.
84, p=0.
0227, and did not meet the statistical endpoint [14].

The negative result of LEAP-002 was surprising, but the most surprising was that the control group had an OS of 19.
0 months, far exceeding the 13.
6 months in the phase III clinical study (REFLECT) of lenvatinib versus sorafenib [15].

SHR-1210-III-310, which also announced results this year, is also an international multicenter phase III study of immunological combined with targeted control targeted drugs for the first-line treatment of unresectable or metastatic HCC, which explored the safety and efficacy of carrelizumab combined with apatinib combination (commonly known as "double AI" combination in China) compared with sorafenib, and the primary endpoints were PFS and OS evaluated by IRC, both of which achieved statistical significance [16].

。

This is not only reminiscent of whether the "cola" combination control sorafenib could also obtain positive results
for PFS and OS if a sorafenib control group was added to the design of the LEAP-002 study.

The researchers of LEAP-002 obviously wouldn't have failed to take this into account, but why not?

Before lenvatinib was first approved for the first-line treatment of unresectable HCC in 2017, sorafenib was the only approved HCC-targeted drug, so it was able to dominate the systemic drug treatment of advanced HCC for nearly 10 years, although its clinical efficacy was not satisfactory
.

With the entry into clinical practice of lenvatinib, which is superior to sorafenib in ORR, PFS and other indicators, sorafenib has faded rapidly; According to Professor Chen Minshan, director of the Institute of Liver Cancer of Sun Yat-sen University, in his clinical practice, only 10% of HCC patients may still be treated
with sorafenib.

Therefore, even if a "soft persimmon" may be compared to obtain a positive PFS and OS result, it is a far from a
far choice for K drugs that regard the highest therapeutic value and clinical significance as the sole goal, regardless of success or failure.

Does the "failed" study of LEAP-002 have guiding value for HCC clinical practice? Professor Chen Minshan's answer is yes
.
He believes that firstly, the 19.
0-month OS data of the control group in LEAP-002 verified the efficacy of first-line treatment of lenvatinib, and the 40.
8% ORR (mRECIST) of the "cola" combination also supported the clinical practice
of this regimen for the conversion therapy of unresectable HCC.

LEAP-002：ORR、DCR&DoR（RECIST 1.
1&mRECIST）[14]

Can the "cola" combination be approved for first-line treatment of advanced HCC?
However, whether the "cola" combination has the potential to continue to be used with HCC treatment, the answer to the domestic liver cancer treatment community is more likely to be yes
.

With the approval of the indications for the second-line treatment of HCC with K drugs, its clinical practice for HCC treatment is bound to become more common, and the richer the doctors' experience, the application value of "cola" combination in the comprehensive treatment of intermediate and advanced HCC will continue to be verified
in the real world.

But for the "universe" of tumor immunotherapy that has broken out in China, a more meaningful question may be this:

The pride of following science regardless of success or failure, and the pride of creating value for life regardless of cost, which is displayed in the immunotherapy research of digestive tract tumor immunotherapy of KEYNOTE-590, KEYNOTE-177 and LEAP-002, is meaningful for exploring the true value of immunotherapy, and whether it is worthy of serious reference and learning
from various PD-1 clinical studies in the domestic blowout outbreak.

Expert Profile
Professor Huang Jing

Deputy Director of the Department of Internal Medicine, Cancer Hospital, Chinese Academy of Medical Sciences
Doctor of Medicine, Chief Physician, Professor, NCI Postdoctoral Fellow, Doctoral Supervisor

Director of the Chinese Society of Clinical Oncology (CSCO).
Vice Chairman and Secretary General of CSCO Esophageal Cancer Expert Committee
Vice Chairman of the Colorectal Cancer Committee of Beijing Oncology Society
Vice Chairman of the Cancer Rehabilitation Branch of the Chinese Gerontology and Geriatrics Association
Vice Chairman of CSCO Expert Committee on Oncology Cardiology
Member of the Standing Committee of Esophageal Cancer Professional Committee of Chinese Anti-Cancer Association
Member of the Standing Committee of the Colorectal Cancer Professional Committee of the Chinese Medical Doctor Association
Vice Chairman of the Internal Medicine Treatment Committee of the Colorectal Oncology Professional Committee of the Chinese Medical Doctor Association
Deputy head of the gastric cancer group of the Cancer Prevention and Treatment Expert Committee of the Cross-Strait Medical and Health Exchange Association
Director of Beijing Heesco Clinical Oncology Research Foundation

Expert profile
Li Yin

Director of the Esophageal Ward of the Department of Thoracic Surgery, Cancer Hospital of the Chinese Academy of Medical Sciences
Doctoral supervisor, professor, chief physician
Experts who enjoy special government allowances from the State Council
Academician of the Royal College of Surgeons of the United Kingdom, chief expert of the National Advanced Training Program in Minimally Invasive Surgery for Esophageal Cancer
Group leader of esophageal diseases, Thoracic and Cardiovascular Surgery Branch of Chinese Medical Association
Chairman of the Expert Committee of Esophageal Surgery of the Thoracic Surgery Branch of the Chinese Medical Doctor Association
Chairman-elect of CSCO Esophageal Cancer Committee
Vice Chairman of the Esophageal Cancer Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Expert Committee on Accelerated Rehabilitation of the Thoracic Surgeons Branch of the Chinese Medical Doctor Association
Vice Chairman of the Thoracic Surgery Branch of China Association for the Promotion of International Exchanges in Healthcare
Group leader of esophageal cancer group of Thoracic Surgery Branch of China Association for the Promotion of International Exchanges in Healthcare
Training experts of the Greater China Thoracoscopy Development and Promotion Committee
Standing member of the Thoracic Surgery Branch of the National Endoscopy and Minimally Invasive Professional Technology Evaluation Committee
Thoracic surgeons of the Ministry of Health regularly evaluate the members of the editorial board
Member of the International Association for the Study of Lung Cancer (IASLC), Member of the International Thymoma Collaboration Group (ITMIG), Member of the European Association of Thoracic Surgeons (ESTS), Member of the International Association of Esophageal Diseases
Editor-in-Chief of Annals of Esophagus, Standing Editorial Board Member of Chinese Journal of Lung Cancer, Editorial Board Member of Journal of Hepatology and Gastroenterology, Editorial Board Member of THORACIC CANCER, and Editorial Board Member of INNOVATION Chinese Edition
He specializes in minimally invasive surgical treatment and comprehensive treatment
of esophageal cancer, cardia cancer and mediastinal tumors.
The first "tube-free and ban-free" minimally invasive accelerated rehabilitation surgical model for esophageal cancer, which is internationally leading
.

References:

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Tabernero et al.
,Pembrolizumab With or Without Chemotherapy Versus Chemotherapy in Advanced G/GEJ Adenocarcinoma:The Phase 3,KEYNOTE-062 Study,2019 ASCO LBA4007 [2] 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[3]Sun JM et al.
,Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer(KEYNOTE-590):a randomised ,placebo-controlled,phase 3 study,Lancet,2021 Aug 28; 398(10302):759-771.
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[7]Lin Shen,Ken Kato,Sung-Bae Kim,et al.
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(ORIENT-15) [9]Luo HY et al.
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[10]Yuichiro Doki et al.
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[11]Wang Z-X et al.
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[12]Li Z et al.
,First-Line Pembrolizumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Esophageal Cancer:China Subgroup Analysis of KEYNOTE-590,ASCO 2021 Abstract #4049[13]Thierry André.
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[14]Finn R et al.
,Primary Results From the Phase 3 LEAP-002 Study:Lenvatinib Plus Pembrolizumab Versus Lenvatinib as First-line Therapy for Advanced Hepatocellular Carcinoma; 2022 ESMO,LBA 34[15]Kudo M et al.
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