Professor Hu Jie: Treatment of advanced NSCLC - PD-(L)1 is the cornerstone K drug is the best choice

KEYNOTE-407 is the world's first published Phase III clinical study of PD-1 immune checkpoint inhibitor combined with platinum-based chemotherapy in the first-line treatment of metastatic squamous non-small cell lung cancer (sq-NSCLC)
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The results of the KEYNOTE-407 interim analysis, first published at the American Congress of Clinical Oncology in 2018, showed that pembrolizumab (commonly known as K drug) combined with chemotherapy (carboplatin and paclitaxel) in the first-line treatment of metastatic sq-NSCLC compared with platinum-containing chemotherapy , resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS), regardless of PD-1 expression levels
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In November 2019, with the results of the Phase III clinical trial KEYNOTE-407, Drug K was officially approved for this treatment indication in China
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Prior to this (March 2019), Drug K has been approved in China for the first-line treatment of metastatic non-squamous NSCLC (nsq-NSCLC) in combination with platinum-containing chemotherapy
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The approval of these two indications ushered in the era of immunotherapy for advanced NSCLC with PD-1 as the cornerstone
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Within two years after the approval of this indication, the long-term follow-up data of KEYNOTE-407, KEYNOTE-189 and Phase II clinical trial KEYNOTE-021g have been released one after another.
K drug combined with chemotherapy as first-line treatment can be used for advanced NSCLC patients in China.
Bring lasting survival benefits
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➤ At the 2021 World Conference on Lung Cancer (WCLC), Professor Cheng Ying of Jilin Cancer Hospital, as the lead PI of the KEYNOTE-407 China extension study, reported the final analysis results of the study: Among the 125 patients enrolled, drug K The combination therapy group showed a sustained OS benefit, with a 2-year OS rate of 56.
9% (31.
7% in the control group) and a 56% reduction in the risk of death
.

➤ At the European Society of Medical Oncology Immuno-Oncology (ESMO-IO) Congress in December 2021, a pooled analysis of the KEYNOTE-407, KEYNOTE-189 and KEYNOTE-021G studies was announced.
The 3-year OS rate for PD-L1-negative NSCLC was 33% (19% in the chemotherapy control group), the median OS was 21.
3 months (12.
6 months in the control group), and the risk of death was reduced by 45%
.

This is the only evidence that immune checkpoint inhibitors can bring long-term survival to this part of the advanced NSCLC population
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The two indications of K drug combined with platinum-containing chemotherapy for the first-line treatment of advanced NSCLC have been approved for clinical application in China for more than two years.
What is the application in the real world? Has immunotherapy combined with chemotherapy become the gold standard for first-line treatment of advanced NSCLC? Which regimens should be the preferred first-line therapy? Recently, during the 2022 Damo Infinite Tumor Summit Forum, this platform interviewed Professor Hu Jie from the Department of Respiratory Medicine, Zhongshan Hospital Affiliated to Fudan University, and discussed these issues with her
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Q: You have participated in a number of K drug clinical studies in China
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Please share a case that impressed you the most
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First of all, Professor Hu Jie is very grateful to many experts in the field of lung cancer treatment in China for leading us to carry out clinical research on immune checkpoint inhibitor drugs, and to come up with the data of our Chinese population cohort
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 I have the honor to participate in a number of clinical studies of K drug registered in China for the treatment of advanced NSCLC, including the KEYNOTE-407 China expansion cohort clinical study led by Professor Cheng Ying as the Leading PI
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My center has enrolled more than a dozen patients with advanced NSCLC with negative PD-L1 expression, and several of these patients are currently under long-term follow-up
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 I was more impressed with one of the patients
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This patient was stage T3N3M1 left lower lung squamous cell carcinoma with adrenal metastases
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The patient's family financial conditions were very poor, so he participated in the KEYNOTE-407 clinical study and was randomly assigned to the first-line treatment cohort of K drug combined with chemotherapy
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The patient finally showed a very good effect, and after two cycles, the tumor shrank
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After the patient completed four cycles of immunotherapy plus chemotherapy and then received K-drug monotherapy for 35 cycles, the tumor maintained a sustained radiographic response
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In the KEYNOTE-407 study, after two years of treatment with the K drug, patients were able to stop the drug
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 This patient had been enrolled for nearly four years from the time of the last follow-up to the last follow-up, and two of them had basically not received any drug treatment
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Subsequent follow-up examination results showed that the tumor was in a state of continuous shrinkage, which we called maintaining a partial response (PR)
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The patient currently maintains a very good living condition and can live a normal life, which is almost equivalent to no symptoms
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Q: The results of the pooled analysis show that the three-year OS rate of the PD-L1 negative population can reach 33%.
What guidance does this result have for clinical practice? Professor Hu Jie's three-year OS rate of 33% is a huge breakthrough
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The historical survival data of patients with advanced NSCLC in the past have never achieved such a good OS, which means that even for advanced lung cancer, after receiving the first-line treatment of K drug combined with chemotherapy, 1/3 of the patients can still survive for more than three years
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In the chemotherapy era, median OS was less than one year
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Therefore, K drug does bring long-term survival benefits to patients, which is beyond doubt
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Q: Is the immunocombination chemotherapy regimen the first-line treatment regimen currently used in clinical practice for advanced non-small cell lung cancer in China? Professor Hu Jie's Chinese CSCO non-small cell lung cancer guidelines will also be updated in 2021
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The guidelines recommend K-drug single-agent first-line therapy for patients with PD-L1-positive advanced NSCLC, and K-drug combined with chemotherapy for first-line treatment of all advanced NSCLC patients, regardless of PD-L1 expression
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Drug K has multiple indications approved for first-line treatment of advanced NSCLC in China, so there is no doubt that drug K is the mainstay of first-line treatment for advanced NSCLC at present
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 Of course, we also have domestic PD-(L)1 inhibitors approved for first-line treatment of advanced NSCLC, so Chinese doctors and patients are more fortunate than Western populations because they have more choices
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However, the currently approved indications for domestic PD-1 inhibitors are all combination chemotherapy regimens, and they are only based on registered clinical studies in China
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Q: There are several PD-(L)1 combination chemotherapy regimens approved for first-line treatment of advanced NSCLC in China
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how to choose? Professor Hu Jie should say that to a certain extent, the combination therapy based on K drug can beat any PD-(L)1
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Because, the results of multiple global multi-center, randomized controlled phase III registration clinical studies in different NSCLC populations have confirmed that K drug treatment of advanced NSCLC can bring long-term OS benefits superior to platinum-containing chemotherapy regimens
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At present, for the first-line treatment of advanced NSCLC with PD-(L)1 combined with chemotherapy, only K drugs are supported by such high-level evidence-based medical evidence
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 In the advanced NSCLC population with positive tumor PD-L1 TPS expression, likewise, high-level evidence-based medical evidence has demonstrated that K-drug monotherapy is superior to chemotherapy
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And in 2021, the 3-year and 5-year OS rate data of its monotherapy is also exciting, allowing us to see that some patients with advanced NSCLC without EGFR/ALK driver gene mutation are expected to achieve long-term survival and even clinical cure
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In the past three years, the two clinical studies, KEYNOTE-189 and KEYNOTE-407, have also continuously updated OS follow-up data, and both have shown long-term OS benefits
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Therefore, there is no doubt that at present, immunotherapy is the mainstay of clinical first-line treatment of advanced NSCLC, and K-drug-based regimens are undoubtedly the preferred clinical regimens, and other PD-(L)1 regimens are only optional regimens
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As for whether to choose the K drug alone or the K drug combined with chemotherapy, this needs to be selected according to the expression status of PD-L1 in the patient's tumor tissue
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Q: Domestic PD-(L)1 clinical studies all use PFS rather than OS as the treatment endpoint
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How do you view the significance of PFS and OS as study endpoints? Prof.
Hu Jie's OS is a very objective research endpoint, and it is also the hardest and most powerful indicator to verify the efficacy of a drug
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If a positive OS result is obtained, it means that the efficacy of such a drug is definite, unquestionable, and very powerful
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 For studies with PFS as the endpoint, relatively speaking, the sample size of the study can be smaller, and the time required for the study to be carried out will be shorter
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PFS more reflects the situation of short-term survival benefit, in some cases it can be converted into OS, so it is used as a surrogate verification indicator of OS
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However, when judging PFS, it may be affected by different factors, and there is a certain judgment offset
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 If a clinical study adopts the dual endpoints of PFS and OS, the rigor of the study design and the certainty of the data are beyond doubt, providing a higher-level reference for clinical drug selection
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 Both KEYNOTE-189 and KEYNOTE-407 have dual endpoints of PFS and OS, so the data from these two studies can provide us with more reliable evidence of OS benefit
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Q: In clinical practice, how do doctors help patients choose different treatment options? Dr.
Hu Jie should first understand the patient's understanding of the disease, future life needs and planning, and outlook on life; he also needs to have a comprehensive understanding of the patient's entire family's economic status
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Only on this basis can the most suitable treatment plan be recommended for the patient
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At the same time, this treatment plan should not only take into account the efficacy, but also the safety, as well as the social and economic pressure that the patient can bear
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Now immune checkpoint inhibitor treatment is not so expensive.
In addition to medical insurance coverage, there are various charitable drug donation policies, and there are other insurance mechanisms in various places.
For example, Shanghai patients can also choose Shanghai Huibao
.

These all greatly reduce the financial pressure for patients
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Q: In the future, will more advanced NSCLC patients live beyond five years and even achieve clinical cure? Professor Hu Jie I believe this is inevitable
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As our understanding of immunotherapy deepens, and the selection of populations becomes more precise, as well as the individualization and precision of treatment, I believe that more patients will benefit from immunotherapy for long-term survival
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Expert Profile Professor Hu Jie, Department of Respiratory and Critical Care Medicine, Zhongshan Hospital Affiliated to Fudan University, Deputy Director, Cell and Molecular Biology Laboratory, Shanghai Institute of Respiratory Diseases, Senior Member of ACCP, American College of Chest Physicians (FCCP) ) Member of the Lung Cancer Professional Committee Member of the Chinese Medical Doctor Association Respiratory Physician Branch (CACP) Member of the Lung Cancer Professional Committee, Secretary of the China Lung Cancer Prevention and Control Alliance Vice Chairman of the Immunotherapy Committee Member of the Chinese Society of Clinical Oncology (CSCO) Member of the Immunotherapy Expert Committee Member of the China Anti-Cancer Association Chemotherapy Professional Committee Member of the Standing Committee of the Professional Committee of Tumor Respiratory Endoscopy of the Shanghai Anti-Cancer Association Member of the Standing Committee of the Professional Committee of Molecular Targeting and Immunotherapy of Lung Cancer of the Shanghai Anti-Cancer Association Member of the Standing Committee of the Professional Committee of Brain Metastasis of the Shanghai Anti-Cancer Association Member of the lung cancer group of Shanghai Medical Association Respiratory Medicine Branch