This article summarizes the current status of first-line immunotherapy for non-small cell lung cancer

preface

Immune checkpoint inhibitors (ICIs)-based therapies 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 reviews the current status
of immunotherapy for advanced NSCLC.

First-line immunomonotherapy

1

• 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 longer
  than platinum-based chemotherapy PFS and OS in patients with advanced NSCLC with PD-L1 expression ≥ 50%.
  

2

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

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

First-line immunization combined

1

• THE KEYNOTE 189 STUDY SHOWED THAT PEMBROLIZUMAB COMBINED WITH PEMETREXED AND PLATINUM HAD SIGNIFICANT BENEFITS OVER CHEMOTHERAPY ALONE IN THE FIRST-LINE TREATMENT OF NON-SQUAMOUS PATIENTS WITH METASTATIC NSCLC WITHOUT EGFR OR ALK GENE MUTATIONS, AND THE GREATEST
  BENEFIT WAS GREATEST IN PATIENTS WITH PD-L1 ≥ 50%.
  

  
  

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

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

  
  

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

• In addition, based on the CAMEL study, ORIENT-11 study and RATIONALE 304 study, China's self-developed PD-1 monoclonal antibody carrelizumab/sindilimab/tirelizumab 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

• The KEYNOTE-407 study showed that pembrolizumab plus chemotherapy for 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 all PD-L1 levels, with the greatest reduction in the
  risk of death in patients with PD-L1 ≥ 50%.
  

  
  

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

• Based on the CameL-sq/RATIONALE 307 study, the NMPA approved the PD-1 inhibitor carrelizumab/tirelizumab 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 drugs 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 that penpulimab in combination with paclitaxel and carboplatin be used as the first-line treatment for locally advanced or metastatic squamous NSCLC that cannot be resected, which is currently pending
  NMPA approval.
  Based on the CHOICE-01 study, NMPA has accepted a new indication for the first-line treatment of trepilimab in combination with pemetrexed/paclitaxel and carboplatin for the first-line treatment of EGFR/ALK-negative metastatic nonsquamous/squamous NSCLC
  .
  

3

• The CheckMate 9LA study showed that dual immunity (nivolumab + ipilimumab) combined with two-cycle chemotherapy significantly prolonged OS compared with standard chemotherapy alone in patients with EGFR/ALK-negative advanced NSCLC, regardless of the patient's PD-L1 expression level and tumor histology type, and has shown a sustained trend of survival benefit in the early stage
  .
  

  
  

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

PD-L1 expression ≥ treatment in 50% of patients

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

• A pooled analysis at the 2022 ASCO meeting included data from 12 randomized controlled trials comparing the efficacy
  of anti-PD-(L)1 chemotherapy ± first-line treatment in 50% of patients with advanced NSCLC in PD-L1≥ 。 Results showed that the median OS in the combination group (N=455) and monotherapy group (N=1,298) was 25.
  0 months and 20.
  9 months, and the median PFS was 9.
  6 months and 7.
  1 months, respectively.
  ORR was higher in the combination therapy group than in the monotherapy group (61% versus 43%), but for patients ≥ 75 years of age, immunocombination therapy did not improve
  compared with monotherapy.
  In addition, for patients with NSCLC with PD-L1 expression of 1 to 49%, higher mortality
  was observed in the first year of 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 first-line treatment of EGFR/ALK-negative and nonoperable resectable locally advanced or metastatic NSCLC with PD-L1 ≥1%.
  。 The results of the study showed that dual immune combination therapy significantly prolonged PFS in patients compared with single therapy (5.
  6 months 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 benefit of dual immune combination therapy was mainly in 50% of patients with PD-L1≥ (PFS: 16.
  6 months 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 benefited from dual immune combination therapy was not obvious
  .
  

PD-L1 expression < treatment in 1% of patients

• The 4-year follow-up of the KEYNOTE-189 study showed that pembrolizumab in combination with chemotherapy confers a survival benefit
  regardless of PD-L1 expression level.
  Among them, the 3-year OS rates in the combination treatment group compared with the chemotherapy group were 23.
  3% and 5.
  3% in PD-L1<1% of patients, respectively; The risk of death and 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 combination chemotherapy was also superior to chemotherapy alone, with an OS of 15.
  9 months and an ORR of 44%<b10> in the control group and 10.
  5 months in the control group.
  

• The results of IMpower150 studies showed that for 1% of patients with PD-L1<1 the first-line treatment of non-squamous NSCLC patients with the combination regimen of atezolizumab + bevacizumab + paclitaxel/carboplatin IV was improved (16.
  9 months vs 14.
  1 months, HR 0.
  90).
  
  However, the three-drug combination regimen of atezolizumab + carboplatin + paclitaxel compared with bevacizumab + carboplatin + paclitaxel showed no significant difference
  in OS results in PD-L1-negative people.
  

• The 5-year survival results of the CheckMate 227 study showed a long-term and durable benefit
  of nivolumab plus ipilimumab compared with 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.
  

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

In summary, immunocombination therapy is the first-line standard of care for NSCLC, regardless of
PD-L1 expression.
Anti-CTLA-4 monoclonal antibody is an important exploration direction in the future in PD-L1<1% of the population, 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].
China 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.