Professor Zhou Caicun: First-line treatment of immune combined chemotherapy brings long-term hope to NSCLC patients

2018 is the "first year" of first-line immune therapy for advanced non-small cell lung cancer (NSCLC), and four recognized landmark phase III clinical studies: KEYNOTE-189, KEYNOTE-407, KEYNOTE-042, and CheckMate-227 have successively announced the results of the study
。 Among them, KEYNOTE-189 and KEYNOTE-407 are global multicenter, randomized double-blind controlled phase III clinical studies of immune checkpoint inhibitors combined with platinum-containing chemotherapy that have reached the primary study endpoint.

During these four years, immunotherapy has rewritten the treatment guidelines for advanced squamous and non-squamous NSCLC, including in China and the United States, making immuno+chemotherapy the standard first-line treatment
for patients with advanced NSCLC.

FIVE-YEAR OS DATA FOR KEYNOTE-189 AND KEYNOTE-407, PRESENTED AT THE 2022 EUROPEAN SOCIETY OF MEDICAL ONCOLOGY (ESMO) ANNUAL MEETING ^[1,2], SHOWED THAT PEMBROLIZUMAB (K DRUG) COMBINED WITH PLATINUM-BASED CHEMOTHERAPY REGIMEN CONFINED BETTER LONG-TERM SURVIVAL THAN PLATINUM-BASED CHEMOTHERAPY, WITH A 5-YEAR OS OF 19.
4% AND 18.
4% FOR FIRST-LINE TREATMENT OF ADVANCED NON-SQUAMOUS NSCLC OR SQUAMOUS NSCLC, RESPECTIVELY, AND 11.
3% FOR CHEMOTHERAPY.
and 9.
7%.

The K-drug combination chemotherapy regimen became the world's first immuno-combination
chemotherapy first-line treatment of advanced NSCLC with 5-year OS rate data.

FIGURE 1 KEYNOTE-189 5 YEARS OS1

FIGURE 2 KEYNOTE-407 5 YEARS OS2

Also published are 5-year PFS (survival without disease progression) data
from the KEYNOTE-189 and KEYNOTE-407 studies.
At year 5, 7.
5% and 10.
8% of patients with non-squamous and squamous NSCLC still had no disease progression, respectively, compared with 0.
6% and 3.
5%
of the 5-year PFS rates in the control chemotherapy group.

FIGURE 3 KEYNOTE-189 5 PFS1

FIGURE 4 KEYNOTE-407 5 YEAR PFS2

At present, 4 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].

At present, only the 2-year OS rate (53.
4% vs 35.
0%) and 3-year OS rate (42.
8% vs 23.
7%) data of the first-line clinical study of carrelizumab combined with carboplatin and paclitaxel in the treatment of stage III.
b-IV.
squamous NSCLC (CameL-sq) were presented orally by Professor Zhou Caicun of Shanghai Pulmonary Hospital affiliated to Tongji University at the 2022 European Lung Cancer Congress (ELCC) ^[9].

Overlapping indications are a common situation faced by clinicians, and how to evaluate the efficacy of different PD-1 monoclonal antibody treatments has become a key to choosing a
treatment plan.

Is the 5-year OS rate of KEYNOTE-189 and KEYNOTE-407 meaningful to guide the current clinical practice of advanced NSCLC treatment in China? Is it necessary to follow KEYNOTE-189 and KEYNOTE-407 with the many PD-(L)1 combination chemotherapy regimens that are currently widely used in clinical practice to demonstrate long-term follow-up OS and PFS data to demonstrate long-term survival benefits?

CAN PATIENTS IN THE KEYNOTE-189 AND KEYNOTE-407 STUDIES WHO HAVE NO DISEASE PROGRESSION AT YEAR 5 AFTER TREATMENT WITH DRUG K-THERAPY CONSIDERED CLINICALLY CURED?

Recently, this platform invited Professor Zhou Caicun to answer
these questions.

Professor Zhou Caicun: In the era of chemotherapy and targeted therapy for advanced lung cancer, we all use OS as the main evaluation index
of anti-tumor drugs.

In the era of chemotherapy, the OS benefit of chemotherapy was limited, with a median OS extension of only two months
.
Later, the antiangiogenic drug bevacizumab combined with chemotherapy extended median OS by two months to six months
.
Although many targeted therapies prolong PFS compared with chemotherapy, the overall OS benefit is similar
to that of chemotherapy.

Therefore, in the era of chemotherapy and targeted therapy for advanced lung cancer, we can see changes in median OS, but we rarely see 3-year or 5-year survival data
.
However, the revolution brought about by immunotherapy has given us a glimpse of 5-year survival rates
for patients with advanced lung cancer.

The 5-year survival rate is a criterion for clinical cure of tumors, and the 5-year survival rate has improved, which also means that more tumor patients have been
cured clinically.
Therefore, in the era of immunotherapy, it is obviously not sufficient to evaluate the improvement of OS, and we need to evaluate the 3-year and 5-year survival rates
brought by PD-1 treatment.
That is to say, in the era of immunotherapy, whether a regimen can improve the 3-year and 5-year survival rates, and how many patients can be clinically cured, is a more important question
than how much the median OS is prolonged.

Currently, for immunotherapy, we need long-term follow-up to obtain data
on 4-year and 5-year survival.
Long-term survival should become a very important efficacy assessment index
for future clinical research.

Prof.
Caicun Zhou: The 5-year OS data results of KEYNOTE-024 show that the 5-year OS rate of 50% of the population with the first-line treatment of PD-L1 TPS ≥with K drug alone is 31.
9%, while the 5-year OS rate data of 29.
6% of the corresponding population in the KEYNOTE-189 study is similar in value, which tells us that for this group of people, the first-line treatment of K drug is sufficient without adding chemotherapy
.

However, in clinical practice, it is still necessary to analyze on a case-by-case basis
.
For example, if the patient has a large tumor burden or does not smoke, despite PD-L1 TPS ≥ 50%, I think it may be safer
to choose a treatment regimen with K drugs combined with chemotherapy.
Because of the high tumor burden and the need for rapid tumor shrinkage, the effect of K drug combined with chemotherapy will be faster; Patients who do not smoke tend to have a low tumor mutation burden (TMB) and may be less effective with immunomonotherapy, so choosing K drug plus chemotherapy may be more effective than K drug monotherapy
.

Another important significance for clinical practice is that although the 5-year OS rate of non-squamous NSCLC with low or negative expression of PD-L1 is lower than that of people with high expression of PD-L1, it is also significantly improved
compared with platinum-containing chemotherapy regimens.
This set of data means that the combination of K and chemotherapy regimens can also bring 5-year survival to a subset of this group of patients, supporting this regimen as standard first-line treatment
for patients with PD-L1-negative advanced NSCLC.