This article reviews the current status of first-line immunotherapy for NSCLC

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Immune checkpoint inhibitors (ICIs) targeting programmed death [protein]-1 (PD-1) or programmed death [protein] ligand-1 (PD-L1) have become one of
the standard treatments for advanced non-small cell lung cancer (NSCLC).
Although PD-L1 expression is not a perfect biomarker, it is currently a key factor
in determining the choice of first-line immunotherapy for NSCLC.
This article summarizes the current status
of immunotherapy for advanced NSCLC.

First-line immunization monotherapy

1.
PD-1 inhibitors

The KEYNOTE-024 study showed that in patients with advanced NSCLC with PD-L1 expression ≥ 50% and ALK or EGFR negative, the PD-1 inhibitor pembrolizumab had significantly longer progression-free survival (PFS) and overall survival (OS) and fewer
adverse events (AEs) compared with platinum-based chemotherapy.

The EMPOWER-Lung 1 study also showed that the PD-1 inhibitor cemiplimab was significantly prolonged
compared with platinum-based chemotherapy PFS and OS in patients with advanced NSCLC with PD-L1 expression of ≥ 50%.

2.
PD-L1 inhibitors

The phase II BILCH study demonstrated that the PD-L1 inhibitor atezolizumab was effective and well tolerated in PD-L1 single-agent first-line treatment with PD-L1 selected advanced NSCLC, with a median OS of 23.
5 months [26.
9 months in the TC3 subgroup (PD-L1≥50%) or IC3 subgroup (PD-L1≥10%)), outperforming OS data
from previous first-line chemotherapy.

The IMpower 110 study showed a significant prolongation
of atezolizumab versus platinum-based chemotherapy OS in patients with NSCLC with high PD-L1 expression, regardless of histologic type.

First-line immunization combination

1.
Non-squamous NSCLC

The KEYNOTE 189 study showed significant benefit from pembrolizumab in combination with pemetrexed and platinum compared with chemotherapy alone in patients with metastatic NSCLC who are non-squamous and do not have EGFR or ALK gene mutations, with the greatest
benefit in patients with PD-L1 expression ≥ 50%.

The IMpower132 study showed that atezolizumab combined with pemetrexed and platinum-based first-line treatment with non-squamous NSCLC significantly prolonged PFS by 2.
5 months compared with chemotherapy alone, and the combination group had a clinical benefit
on OS for nearly 4 months.

The IMpower150 study showed significant improvements
in PFS and OS in patients with non-squamous metastatic NSCLC in combination with atezolizumab and bevacizumab in the treatment of patients with non-squamous metastatic NSCLC, regardless of PD-L1 expression and EGFR/ALK gene mutation status.

The IMpower130 study showed that atezolizumab plus chemotherapy significantly prolonged PFS and OS
in patients with non-squamous NSCLC compared with chemotherapy alone.
The higher the PD-L1 expression, the better
the PFS.

In addition, based on CAMEL research, ORIENT-11 research and RATIONALE 304 research, China's self-developed PD-1 monoclonal antibody carrelizumab/sindilimab/tislelizumab combined with pemetrexed and carboplatin have been approved by the National Medical Products Administration (NMPA) for the first-line treatment of EGFR/ALK-negative advanced non-squamous cell carcinoma NSCLC
。

2.
Squamous NSCLC

The KEYNOTE-407 study showed that pembrolizumab plus chemotherapy in the first-line treatment of metastatic squamous NSCLC significantly prolonged OS and PFS
compared with placebo plus chemotherapy (carboplatin + paclitaxel or albumin paclitaxel).
Benefits were observed in people with all PD-L1 levels, with the greatest
reduction in risk of death in 50% of patients with PD-L1 ≥.

The IMpower131 study showed that the PFS of patients with advanced squamous NSCLC in the first-line treatment of atezolizumab combined with chemotherapy was significantly higher than that in the control group, but there was no significant difference
between the two groups of OS.
The higher the PD-L1 expression, the greater the benefit for the patient
.

Based on the CameL-sq/RATIONALE 307 study, the NMPA approved the PD-1 inhibitor carrelizumab/tislelizumab in combination with paclitaxel and carboplatin for the first-line treatment
of EGFR/ALK-negative unresectable locally advanced or metastatic squamous NSCLC.
Based on the ORIENT-12 study, the NMPA approved sindilimab in combination with gemcitabine and platinum for the first-line treatment
of EGFR/ALK-negative unresectable locally advanced or metastatic squamous NSCLC.

In addition, based on the AK105-302 study, CSCO guidelines also recommend péamplimab in combination with paclitaxel and carboplatin for first-line treatment of unresectable locally advanced or metastatic squamous NSCLC, an indication currently pending NMPA approval
.
Based on the CHOICE-01 study, NMPA has accepted a new indication for teripulimab in combination with pemetrexed/paclitaxel and carboplatin for the first-line treatment of EGFR/ALK-negative metastatic non-squamous NSCLC
.

3.
Non-squamous & squamous NSCLC

The CheckMate 9LA study showed that dual immunity (nivolumab + ipilimumab) combined with two cycles of chemotherapy compared with standard chemotherapy alone in the first-line treatment of EGFR/ALK-negative patients with advanced NSCLC significantly prolonged, regardless of PD-L1 expression level and tumor histological type, and has shown a trend of sustained survival benefit in the early stages
.

In addition, based on the GEMSTONE-302 study, the NMPA approved the PD-L1 inhibitor sugemalimab in combination with pemetrexed/paclitaxel and carboplatin for the first-line treatment
of EGFR/ALK-negative metastatic non-squamous NSCLC.

PD-L1 expression ≥ treatment in 50% of patients

For PD-L1≥ 50% of NSCLC patients, from the current evidence-based medical evidence, it is the population
most likely to benefit from immunotherapy.
So in clinical practice, should these patients choose immune monotherapy or combination therapy?

A pooled analysis at the 2022 ASCO meeting included data from 12 randomized controlled trials comparing anti-PD-(L)1 regimens ± chemotherapy for first-line treatment
of PD-L1≥50% of patients with advanced NSCLC 。 The median OS of the combination group (N=455) and the monotherapy group (N=1,298) was 25.
0 months and 20.
9 months, respectively, and the median PFS was 9.
6 months and 7.
1 months, respectively.
ORR was higher in the combination group than in the monotherapy group (61% versus 43%), but there was no improvement
in immunotherapy compared with monotherapy in patients aged ≥ 75 years.
In addition, for patients with NSCLC with PD-L1 expression of 1-49%, higher mortality
was observed in the first year with immunomonotherapy.

The CITYSCAPE study is a prospective, randomized, double-blind, placebo-controlled phase II clinical study comparing the efficacy and safety
of TIGIT monoclonal antibody tiragolumab with or without atezolizumab for the first-line treatment of EGFR/ALK-negative PD-L1≥1% unresectable locally advanced or metastatic NSCLC 。 The results showed that dual immunotherapy significantly prolongs PFS (5.
6 versus 3.
9 months; HR = 0.
62, 95% CI: 0.
42 ~ 0.
91) and OS (23.
2 months vs 14.
5 months; HR=0.
69，95% CI：0.
44 ~ 1.
07）
。 Exploratory analysis found that the population benefiting from dual immunotherapy was mainly 50% of patients with PD-L1 ≥ (PFS: 16.
6 versus 4.
1 months; HR=0.
29,95% CI:0.
15 ~ 0.
53;OS:NR vs 12.
8 months; HR = 0.
23, 95% CI: 0.
10 ~ 0.
53), while PD-L1 1% ~ 49% of patients did not benefit significantly from dual immune combination therapy
.

PD-L1 expression < treatment in 1% of patients

The results of the 4-year follow-up of the KEYNOTE-189 study showed that pembrolizumab combined with chemotherapy confered a survival benefit
regardless of PD-L1 expression level.
Among them, the 3-year OS rates of PD-L1<1% patients in the combination therapy group and the chemotherapy group were 23.
3% and 5.
3%, respectively.
The risk of death was reduced by 48% and the risk of disease progression or death was reduced by 32%
in the combination treatment group.

IMpower 132 study OS results showed that for PD-L1<1% of patients, atezolizumab combined with chemotherapy was also superior to chemotherapy alone, with OS of 15.
9 months and ORR of 44% in the combination group, 10.
5 months in the control group, and an ORR of 44%.
<b10>

The results of the IMpower150 study showed that for PD-L1<1%, the first-line combination of atezolizumab + bevacizumab + paclitaxel/carboplatin improved OS in patients with nonsquamous NSCLC (16.
9 versus 14.
1 months, HR 0.
90).

However, the three-drug combination regimen of atezolizumab + carboplatin + paclitaxel did not show a significant difference
in OS results compared with bevacizumab + carboplatin + paclitaxel in PD-L1-negative people.

The CheckMate 227 study showed 5-year survival outcomes showing long-term lasting benefit
of nivolumab plus ipilimumab versus chemotherapy.
The 5-year OS rate was 24% vs.
14% in the PD-L1≥1% population and 19% vs.
7% in the PD-L1<1<b11>% population, respectively.

Update data from the 3-year results of the CheckMate 9LA study showed that nivolumab plus ipilimumab and 2 cycles of chemotherapy continued to improve overall survival in first-line NSCLC patients: median OS 17.
7 vs 9.
8 (PD-L1<1%), reducing the risk of death by 33%; The median OS was 15.
8 versus 10.
9 (PD-L1≥1%), reducing the risk of death by 26%.
<b10>

In summary, combination immunotherapy is the first-line standard of care for NSCLC, regardless of
PD-L1 expression.
Anti-CTLA-4 monoclonal antibody is an important direction for exploration in the PD-L1<1% population in the future, and it is still necessary to continue to find more effective combination therapy strategies
.

References:

1.
SU Chunxia,ZHOU Caicun.
Current status and future direction of immunotherapy for advanced non-small cell lung cancer[J].
Chinese Journal of Oncology, 2022, 32 (6): 478-486.

2.
 First-Line Choice in PD-L1 Negative Patients.
2022WCLC.

3.
 First-Line Choice in PD-L1 Positive Patients.
2022WCLC.