Comparison of immune checkpoint inhibitor plus chemotherapy or ipilimumab plus nivolumab-based therapy for NSCLC patients with PD-L1 TPS (1-49 %): TOPGAN2023-01.
Immune checkpoint inhibitors (ICIs) plus chemotherapy is now a standard treatment for non-small cell lung cancer (NSCLC). Whether ICI plus chemotherapy (ICI-chemo) or ipilimumab plus nivolumab (I-N)-based therapy is superior for patients with NSCLC with a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) of 1-49 % has not been evaluated.
This multicenter retrospective study included NSCLC patients with a TPS score of 1-49 %, who began first-line chemotherapy. Propensity score matching analysis was used to adjust for various confounders and evaluate treatment efficacy.
A total of 401 patients were enrolled, of whom 308 received ICI-chemo and 93 received I-N-based therapy. The median OS was 21.0 months in the ICI-chemo group and 20.0 months in the I-N-based therapy group. After propensity score matching, there was no difference in OS or PFS between the ICI-chemo group and the I-N-based therapy group (OS: hazard ratios (HR), 0.83; 95 % confidence interval [CI], 0.54-1.26, PFS: HR, 0.72; 95 % CI, 0.52-1.00). Among PD-L1 TPS 25-49 %, there was a tendency for OS to be favorable for the ICI-chemo group (OS: HR, 0.30; 95 % CI, 0.09-0.85). Treatment discontinuation occurred for 26.2 % of the patients in the ICI-chemo group and 41.9 % in the I-N-based therapy group.
Among PD-L1 TPS 1-49 %, there was no significant difference in survival outcomes between the ICI-chemo group and the I-N-based therapy group. Based on the results of a subgroup analysis, ICI-chemo may be superior for treating NSCLC with a TPS of 25-49 %.
Tanaka H
，Makiguchi T
，Tozuka T
，Kawashima Y
，Oba T
，Tsugitomi R
，Koyama J
，Tambo Y
，Ogusu S
，Saiki M
，Gyotoku H
，Hasegawa T
，Miyauchi E
，Sonoda T
，Saito R
，Nakatomi K
，Sakatani T
，Kudo K
，Tsuchiya-Kawano Y
，Nishio M
... -
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Comparison of efficacy and safety of PD-1/PD-L1 combination therapy in first-line treatment of advanced NSCLC: an updated systematic review and network meta-analysis.
The use of immune checkpoint inhibitors has led to an increase in randomized controlled trials exploring various first-line combination treatment regimens. With the introduction of new PD-1/PD-L1 inhibitors, there are now more clinical options available. For the first time, the AK105 monoclonal antibody Penpulimab, developed in China, was included. The AK105-302 Phase III trial studied the efficacy and safety of Penpulimab combined with chemotherapy in patients with advanced or metastatic squamous NSCLC. To determine the optimal treatment options, we conducted an updated network meta-analysis to compare the effectiveness and safety of these regimens.
The system retrieves data from Chinese and English electronic databases, Clinical Trials, and the gov Clinical Trial Registration website up to September 6, 2023. The study indirectly compared the efficacy and safety of PD-1/PD-L1 combination regimens, including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), all-grade adverse events, and above-grade III adverse events. Subgroup analyses were conducted based on programmed death ligand 1 (PD-L1) level, histological type, ECOG score, sex, and smoking history.
Nineteen RCTS were included, with a total of ten thousand eight hundred patients. Penpulimab plus chemotherapy (Pen + CT) provided the best OS (HR = 0.55, 95% CI 0.38-0.81) for PD-L1 patients with non-selective advanced NSCLC. Except Nivolumab plus Ipilimumab (Niv + Ipi), other PD-1/PD-L1 combination therapies significantly extended PFS compared with CT, and Nivolumab plus Bevacizumab combined with chemotherapy (Niv + Bev + CT) (HR = 0.43, 95% CI 0.26-0.74) provided the best PFS benefit and was comparable to Pen + CT (HR = 1.0) for PFS prolongation. For ORR, except Niv + Ipi, all the other regimens significantly improved ORR compared with CT. In terms of safety, except Tor + CT, the incidence of any-grade AEs or grade ≥ 3 adverse events may be higher than those of chemotherapy. The subgroup analysis revealed that for patients with PD-L1 levels below 1%, treatment with Tor + CT resulted in the best progression-free survival (HR = 0.47, 95% CI 0.25-0.86). For patients with PD-L1 levels of 1% or higher, Sintilimab plus chemotherapy (Sin + CT) (HR = 0.56, 95% CI 0.31-0.99) and Camrelizumab plus chemotherapy (Cam + CT) (HR = 0.43, 95% CI 0.28-0.64) were associated with the best overall survival and progression-free survival, respectively. For patients with SqNSCLC, combined immunotherapy may provide greater survival benefits. For patients with Non-sqNSCLC, Niv + Bev + CT and Tor + CT were associated with optimal PFS and OS, respectively. Cam + CT provided the best PFS in male patients with a history of smoking and an ECOG score of 0. In both female and non-smoking patient subgroups, Pem + CT was associated with the best PFS and OS benefits.
For patients with advanced non-selective PD-L1 NSCLC, two effective regimens are Pen + CT and Niv + Bev + CT, which rank first in OS and PFS among all patients. Cam + CT and Tor + CT have advantages for OS in patients with SqNSCLC and Non-sqNSCLC, respectively. Niv + Ipi + CT provided the best OS benefit for patients with an ECOG score of 0, while Pem + CT may be the most effective treatment for patients with an ECOG score of 1. Pem + CT has a better effect on female patients and non-smokers. Sin + CT was found to be the most effective treatment for male patients and the smoking subgroup, while Cam + CT was found to be the most effective for PFS. In addition, Tor + CT was associated with the best PFS for patients with negative PD-L1 expression. Pem + CT was found to significantly improve both PFS and OS compared to CT alone. For patients with positive PD-L1 expression, Sin + CT and Cam + CT were found to be optimal for OS and PFS, respectively. It is important to note that, with the exception of Tor + CT, the toxicity of the other combinations was higher than that of CT alone.
Yang Y
，Chen W
，Dong L
，Duan L
，Gao P
... -
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Depth of response and treatment outcomes of immune checkpoint inhibitor-based therapy in patients with advanced non-small cell lung cancer and high PD-L1 expression: An exploratory analysis of retrospective multicenter cohort.
The association between depth of response (DpR) and treatment outcomes has been documented across various types of cancer. Immune checkpoint inhibitor (ICI)-based treatment is globally used as first-line treatment for non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥ 50%. However, in this population, the significance of DpR is not elucidated. Patients with advanced NSCLC and PD-L1 expression ≥ 50% who received ICI-monotherapy or ICI plus chemotherapy were retrospectively enrolled into this study. Treatment responses were grouped into DpR 'quartiles' by percentage of maximal tumor reduction (Q1 = 1-25%, Q2 = 26-50%, Q3 = 51-75%, and Q4 = ≥ 76%), and no tumor reduction (NTR). The association between DpR and survival rates were determined using hazard ratios (HR) generated by the Cox proportional hazards model. The Kaplan-Meier method was used to determine survival outcomes. A total of 349 patients were included, of which 214 and 135 patients received pembrolizumab monotherapy and ICI plus chemotherapy, respectively, as first-line treatments. The majority of the patients were male. All DpR quartiles, especially Q4, showed an association with progression-free survival (PFS)/overall survival (OS). In the Q4 cohort, patients who received pembrolizumab had a longer PFS than those who received ICI plus chemotherapy. High DpR was associated with longer PFS and OS, with a more pronounced effect observed with pembrolizumab monotherapy than with ICI plus chemotherapy.
Tachibana Y
，Morimoto K
，Yamada T
，Kawachi H
，Tamiya M
，Negi Y
，Goto Y
，Nakao A
，Shiotsu S
，Tanimura K
，Takeda T
，Okada A
，Harada T
，Date K
，Chihara Y
，Hasegawa I
，Tamiya N
，Katayama Y
，Nishioka N
，Iwasaku M
，Tokuda S
，Kijima T
，Takayama K
... -
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Biomarkers of success of anti-PD-(L)1 immunotherapy for non-small cell lung cancer derived from RNA- and whole-exome sequencing: results of a prospective observational study on a cohort of 85 patients.
Immune checkpoint inhibitors (ICIs) treatment have shown high efficacy for about 15 cancer types. However, this therapy is only effective in 20-30% of cancer patients. Thus, the precise biomarkers of ICI response are an urgent need.
We conducted a prospective observational study of the prognostic potential ofseveral existing and putative biomarkers of response to immunotherapy in acohort of 85 patients with lung cancer (LC) receiving PD-1 or PD-L1 targeted ICIs. Tumor biosamples were obtained prior to ICI treatment and profiled by whole exome and RNA sequencing. The entire 403 putative biomarkers were screened, including tumor mutation burden (TMB) and number of cancer neoantigens, 131 specific HLA alleles, homozygous state of 11 HLA alleles and their superfamilies; four gene mutation biomarkers, expression of 45 immune checkpoint genes and closely related genes, and three previously published diagnostic gene signatures; for the first time, activation levels of 188 molecular pathways containing immune checkpoint genes and activation levels of 19 pathways algorithmically generated using a human interactome model centered around immune checkpoint genes. Treatment outcomes and/or progression-free survival (PFS) times were available for 61 of 85 patients with LC, including 24 patients with adenocarcinoma and 27 patients with squamous cell LC, whose samples were further analyzed. For the rest 24 patients, both treatment outcomes and PFS data could not be collected. Of these, 54 patients were treated with PD1-specific and 7 patients with PD-L1-specific ICIs. We evaluated the potential of biomarkers based on PFS and RECIST treatment response data.
In our sample, 45 biomarkers were statistically significantly associated with PFS and 44 with response to treatment, of which eight were shared. Five of these (CD3G and NCAM1 gene expression levels, and levels of activation of Adrenergic signaling in cardiomyocytes, Growth hormone signaling, and Endothelin molecular pathways) were used in our signature that showed an AUC of 0.73 and HR of 0.27 (p=0.00034) on the experimental dataset. This signature was also reliable (AUC 0.76, 0.87) for the independent publicly available LC datasets GSE207422, GSE126044 annotated with ICI response data and demonstrated same survival trends on independent dataset GSE135222 annotated with PFS data. In both experimental and one independent datasets annotated with samples' histotypes, the signature worked better for lung adenocarcinoma than for squamous cell LC.
The high reliability of our signature to predict response and PFS after ICI treatment was demonstrated using experimental and 3 independent datasets. Additionally, annotated molecular profiles obtained in this study were made publicly accessible.
Poddubskaya E
，Suntsova M
，Lyadova M
，Luppov D
，Guryanova A
，Lyadov V
，Garazha A
，Sorokin M
，Semenova A
，Shatalov V
，Biakhova M
，Simonov A
，Moisseev A
，Buzdin A
... -
《Frontiers in Immunology》
ResearchGate
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钛学术
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