Pembrolizumab has another 5 years of survival data, defining the OS "ceiling" and pointing to the benefit of the whole population

The 2022 European Society of Medical Oncology (ESMO) Annual Meeting, which concluded on September 13, announced the five-year OS follow-up data of KEYNOTE-189 and KEYNOTE-407, a global multicenter phase III clinical study KEYNOTE-189 and KEYNOTE-407, a number of PD-1 immune checkpoint inhibitors pembrolizumab (commonly known as "K drug"), in the first-line treatment of metastatic non-squamous and squamous non-small cell lung cancer (NSCLC) ^[1,2].
The results showed that K drug combined with platinum-based chemotherapy regimen could bring better long-term survival than platinum-based chemotherapy, with five-year OS rates of 18.
4% and 19.
4% for first-line treatment of advanced squamous NSCLC or non-squamous NSCLC, respectively, compared with 9.
7% and 11.
3%
for chemotherapy, respectively.

KEYNOTE-189 5 OS¹

KEYNOTE-407 5 YEARS^{OS 2}

KEYNOTE-189 and KEYNOTE-407, WHICH FIRST PUBLISHED THEIR FINDINGS IN 2018, ARE THE FIRST GLOBAL MULTICENTER, RANDOMIZED, DOUBLE-BLIND PHASE III CLINICAL STUDIES
OF IMMUNE CHECKPOINT INHIBITORS COMBINED WITH PLATINUM-BASED CHEMOTHERAPY TO MEET THE PRIMARY STUDY ENDPOINT.
During these four years, the findings have rewritten treatment guidelines for advanced squamous and non-squamous NSCLC worldwide, including in China and the United States, as the standard first-line treatment
for platinum-based chemotherapy.

Defining the "ceiling" of the OS

At present, a number of domestic original PD-1 monoclonal antibodies have been approved for the first-line treatment of locally advanced or metastatic NSCLC
in combination with chemotherapy.
These phase III clinical studies of PD-1 monoclonal antibodies, whether in squamous or non-squamous NSCLC, had the primary endpoint PFS, not OS, and included varying proportions of patients with stages IIIB and IIIC ^[3-8].

THE PFS HR AND OS HR VALUES OF THESE STUDIES WERE SIMILAR TO THOSE OF THE KEYNOTE-189 AND KEYNOTE-407 STUDIES OF DRUG K, BUT HAVE NOT BEEN SURPASSED ^[9,10].

Data from phase III studies of PD-1 combined chemotherapy first-line regimens approved for the treatment of NSCLC in China

However, the five-year survival data for KEYNOTE-189 and KEYNOTE-407 clearly set a new "ceiling" for immunotherapy for advanced metastatic NSCLC, defining a new "starting line"
for the efficacy of other PD-1 competitions.

In this regard, the medical community specially invited Professor Cheng Ying of Jilin Provincial Cancer Hospital to share this wonderfully:

In this context, is the five-year OS follow-up data just the "icing on the cake", or a "must-have" for all immunotherapy research?

In the context of the long-term benefits of immunotherapy for lung cancer patients, five-year OS follow-up data is undoubtedly a "must"
for immunotherapy research.
Due to the "tailing effect" of immunotherapy, the longer the follow-up time, the more prominent
the survival advantage.
Median OS can only reflect the difference between the two survival curves at 50% survival rate, but after the data mature to a certain extent, the median OS usually does not change with the extension of follow-up time, so simply comparing the two groups of median OS has limited
differences in assessing the long-term survival benefit of immunotherapy.
In this case, evaluating the 3-year and 5-year OS rates can visualize patient information
on long-term survival of immunotherapy.
From the 5-year follow-up data of the KEYNOTE189/407 study, the five-year OS rates for the first-line treatment of advanced squamous and non-squamous NSCLC were 18.
4% and 19.
4%, respectively, and 9.
7% and 11.
3% in the chemotherapy group, respectively, and we saw that the 5-year OS rate in the chemotherapy group was also higher than the historical data, possibly because 41.
3% of patients in the chemotherapy group of the KEYNOTE-189 study had subsequent immunotherapy (including 32.
5% crossover to the PEMBRO group).
49.
1% of patients in the chemotherapy group of the KEYNOTE-407 study were subsequently treated with immunotherapy (including 40.
1% crossover to the pegmbro group), resulting in a higher 5-year OS rate
in the chemotherapy group.
Against this background, we still saw an 8.
7% and 8.
1% improvement in the 5-year OS rate in the immunotherapy group compared with the chemotherapy group, respectively, and these long-term benefit patient information was not reflected in the median OS
.
In the future, as more and more studies report long-term follow-up data, the 5-year OS rate will become an important research index
to evaluate the efficacy of immunotherapy.

For the clinical practice of PD-(L)1 combined with chemotherapy first-line treatment of advanced NSCLC in China, are the results of 5-year OS follow-up data of guiding significance for protocol selection? Does it make sense to communicate with patients about the long-term OS rate of a treatment plan?

Based on the important role of 5-year OS rate in lung cancer immunotherapy, it will also have an impact on
the choice of clinical treatment plan.
Pembrolizumab combination chemotherapy was the first to change the clinical practice of advanced NSCLC immunocombination therapy and has been the preferred regimen
recommended by guidelines for many years.
In the past two years, a number of domestic PD-1/L1 inhibitors have been successfully and approved for marketing, adding more alternative treatment options for clinical trials, but the main endpoint of these studies is PFS, and there is no OS data report
for long-term follow-up.
The 5-year OS data of KEYNOTE189/407 is the clinical study data of immunological combination chemotherapy with the longest follow-up time so far, and the results further strengthen and support pembrolizumab combination chemotherapy as the preferred regimen
for advanced NSCLC first-line therapy.

For patients with advanced lung cancer, how to live longer is a common concern of
doctors and patients.
From the patient's point of view, the 5-year OS follow-up data determines the probability
of long-term survival of the patient.
The 5-year OS rate is usually used clinically to evaluate the prognosis of malignant tumors, and the possibility of recurrence or metastasis is low after 5 years, and the 5-year OS rate is an indicator
that reflects the degree of "cure" of the disease 。 The release of 5-year OS data of pembrolizumab combined with chemotherapy provides clinicians with more confident and reliable answers, when faced with an advanced lung squamous cell carcinoma or non-squamous NSCLC patient, regardless of their PD-L1 expression status, immune combination chemotherapy regimen can bring long-term survival, close to 20% of patients can be clinically "cured", which is very encouraging data, 5-year OS follow-up data can not only bring reference for clinical practice, but also enhance the confidence and hope of long-term survival for patients
。

Long-term survival is no longer a benefit for specific populations alone

AT THE WORLD CONGRESS ON LUNG CANCER (WLC) IN SEPTEMBER 2021, YOU REPORTED THE FINAL OS ANALYSIS RESULTS
OF THE KEYNOTE-407 EXTENDED STUDY IN CHINA AT 28.
1 MONTHS OF MEDIAN FOLLOW-UP IN THE KEYNOTE-407 CHINA EXTENDED STUDY.
At ESMO IO 2021, you also reported a summary of data on pembrolizumab combined with chemotherapy for PD-L1-negative advanced NSCLC in Asia (KEYNOTE-021G, 189 and 407 studies pooled analysis, 3-year OS rate of 33%, median OS over 20 months).

PD-(L)1 immunotherapy also brings survival benefits to the whole population, especially negative people, what is the guiding significance for clinical practice? Should there be more long-term follow-up data for PD-(L)1 treated Chinese?

From the perspective of the mechanism of action of immunotherapy, PD-L1-positive people can benefit more from
immunotherapy.
KEYNOTE-001, a phase I study, was the first to find that pembrolizumab had good efficacy in PD-L1-positive people, especially in people with high PD-L1 expression
.
TWO phase III studies, KEYNOTE-024 and KEYNOTE-042, confirmed a 5-year OS rate of 31.
9% and 16.
6% in PD-L1≥50% and PD-L1≥1% of the population, respectively, and pembrolizumab confers long-term survival benefits
in PD-L1-positive people.

For PD-L1 negative people, whether immunotherapy can bring long-term survival is still unclear, due to the complexity of immune microenvironment, a variety of factors affect the efficacy of immunotherapy, in addition to PD-L1 expression, TMB, MSI, intestinal microenvironment, etc.
are also important factors
affecting immunotherapy.
Therefore, even people with negative PD-L1 expression may benefit from
immunotherapy.
At the 2021 ESMO IO Conference, we also reported that the 3-year OS rate of PD-L1-negative patients in East Asian populations reached 33% in three studies of KEYNOTE-021G/189/407, which provided reliable evidence support
for the clinical practice of immunotherapy in PD-L1-negative populations.
This year, the KEYNOTE-189/407 study published 5-year OS data showing long-term survival benefits
in all populations regardless of PD-L1 expression status.
In the PD-L1-negative subgroup, the 5-year OS rates of non-squamous cell carcinoma and squamous cell carcinoma patients were 9.
6% and 10.
7%, respectively, and the results further support the use of immune combination chemotherapy strategies
in PD-L1-negative populations.

THE KEYNOTE189/407 GLOBAL Cohort Chinese HAS A LIMITED SAMPLE SIZE, WITH ONLY 4 U(1%) CASES IN THE IMMUNOTHERAPY GROUP OF THE KEYNOTE-189 STUDY AND 54 (19.
4%) IN THE EAST ASIAN POPULATION OF THE KEYNOTE-407 STUDY, and we expect to see more long-term follow-up data
for Chinese groups 。 In the Chinese cohort of KEYNOTE-407 study, we see that Chinese groups have a better OS benefit trend, at present, a number of domestic PD-1/PD-L1 inhibitors combined with chemotherapy phase III studies have been successful and approved for marketing, but the long-term follow-up data of Chinese groups is not sufficient, and the extension of follow-up time will provide us with more Chinese groups of 5-year OS data
。 With the wide application of immunotherapy in clinical practice, more real-world data will be presented in the future, making the long-term follow-up data of Chinese patients receiving immunotherapy more complete, providing a more solid evidence base, and providing more treatment strategy choices and decision-making basis
for the long-term survival of Chinese patients.

Challenging the "ceiling" to help achieve the 2030 target

DRUG K IS CURRENTLY THE ONLY PD-(L)1 THAT PROVES THAT ITS COMBINATION WITH PLATINUM-CONTAINING CHEMOTHERAPY FIRST-LINE TREATMENT OF ADVANCED NSCLC CAN BRING ABOUT FIVE-YEAR LONG SURVIVAL, AND THIS DATA IS BOUND TO BE "INCLUDED" BY THE NCCN NSCLC GUIDELINES OF THE 2022 V5 EDITION, AND TOGETHER WITH THE FIVE-YEAR OS DATA OF KEYNOTE-001, KEYNOTE-024 AND KEYNOTE-010, CONTINUE TO LOCK K DRUGS IN "PRIORITY RECOMMENDATION"
.

Because KEYNOTE-189 and KEYNOTE-407 allow Chinese advanced lung cancer patients to see longer survival time and greater hope for cure, helping China achieve the 2030 goal
of improving the five-year survival rate of malignant tumors.