Prognostic effect of coexisting TP53 and ZFHX3 mutations in non-small cell lung cancer patients treated with immune checkpoint inhibitors.

In recent years, immune checkpoint inhibitor (ICI) therapy has revolutionized the treatment of patients with advanced-stage non-small cell lung cancer (NSCLC). The relationship between TP53 mutation and prognosis of non-small cell lung cancer (NSCLC) remains controversial. We aimed to identify advanced-stage NSCLC patients harboring TP53 mutation who would benefit from ICI treatment. Gene mutations and tumor mutational burden (TMB) data of NSCLC patients who received at least one dose of ICI therapy at the Memorial Sloan Kettering Cancer Center between 2013 and 2017 were extracted from the cBioPortal online platform. Gene clustering analyses were performed for patients with short and long overall survival (OS). The top ten significantly different mutated genes were identified. Furthermore, we analyzed the different OS of coexisting TP53 and other significantly different mutated genes to identify NSCLC patients with TP53 mutations who would benefit from immunotherapy. A total of 350 patients were enrolled in the study. Of these a total of 219 (62.6%) patients were found to harbor TP53 mutations, whereas 131 (37.4%) had wild-type TP53. There was no statistically significant difference in OS between TP53 mutated or wild-type NSCLC patients who underwent ICI treatment. However, coexisting TP53 and ZFHX3 mutations were independent prognostic factors. Higher somatic TMB (highest 20% in each histology) and combination of anti-CTLA-4 and anti-PD-1/PD-L1 therapy were also associated with longer OS in multivariate analysis. Coexisting TP53 and ZFHX3 mutations are independent prognostic factors for advanced-stage NSCLC patients undergoing ICI treatment. These findings could help identify patients harboring TP53 mutations that would benefit from ICI treatment.

Zhang L ，Zhang T ，Shang B ，Li Y ，Cao Z ，Wang H ... -  《-》

Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.

This study aimed to explore the novel biomarkers for immune checkpoint inhibitor (ICI) responses in non-small cell lung cancer (NSCLC) by integrating genomic profiling, tumor mutational burden (TMB), and expression of programmed death receptor 1 ligand (PD-L1). Tumor and blood samples from 637 Chinese patients with NSCLC were collected for targeted panel sequencing. Genomic alterations, including single nucleotide variations, insertions/deletions, copy number variations, and gene rearrangements, were assessed and TMB was computed. TMB-high (TMB-H) was defined as ≥10 mutations/Mb. PD-L1 positivity was defined as ≥1% tumor cells with membranous staining. Genomic data and ICI outcomes of 240 patients with NSCLC were derived from cBioPortal. EGFR-sensitizing mutations, ALK, RET, and ROS1 rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions, whereas KRAS, ALK, RET, and ROS1 substitutions/indels correlated with higher TMB and PD-L1+/TMB-H proportions than wild-type genotypes. Histone-lysine N-methyltransferase 2 (KMT2) family members (KMT2A, KMT2C, and KMT2D) were frequently mutated in NSCLC tumors, and these mutations were associated with higher TMB and PD-L1 expression, as well as higher PD-L1+/TMB-H proportions. Specifically, patients with KMT2C mutations had higher TMB and PD-L1+/TMB-H proportions than wild-type patients. The median progression-free survival (PFS) was 5.47 months (95% CI 2.5-NA) in patients with KMT2C mutations versus 3.17 months (95% CI 2.6-4.27) in wild-type patients (p = 0.058). Furthermore, in patients with NSCLC who underwent ICI treatment, patients with TP53/KMT2C co-mutations had significantly longer PFS and greater durable clinical benefit (HR: 0.48, 95% CI: 0.24-0.94, p = 0.033). TP53 mutation combined with KMT2C or KRAS mutation was a better biomarker with expanded population benefit from ICIs therapy and increased the predictive power (HR: 0.46, 95% CI: 0.26-0.81, p = 0.007). We found that tumors with different alterations in actionable target genes had variable expression of PD-L1 and TMB in NSCLC. TP53/KMT2C co-mutation might serve as a predictive biomarker for ICI responses in NSCLC. Cancer immunotherapies, especially immune checkpoint inhibitors (ICIs), have revolutionized the treatment of non-small cell lung cancer (NSCLC); however, only a proportion of patients derive durable responses to this treatment. Biomarkers with greater accuracy are highly needed. In total, 637 Chinese patients with NSCLC were analyzed using next-generation sequencing and IHC to characterize the unique features of genomic alterations and TMB and PD-L1 expression. Our study demonstrated that KMT2C/TP53 co-mutation might be an accurate, cost-effective, and reliable biomarker to predict responses to PD-1 blockade therapy in NSCLC patients and that adding KRAS to the biomarker combination creates a more robust parameter to identify the best responders to ICI therapy.

Shi Y ，Lei Y ，Liu L ，Zhang S ，Wang W ，Zhao J ，Zhao S ，Dong X ，Yao M ，Wang K ，Zhou Q ... -  《Cancer Medicine》

Association of TP53 mutations with response and longer survival under immune checkpoint inhibitors in advanced non-small-cell lung cancer.

Tumor mutational burden (TMB) correlates with response to immune checkpoint inhibitors (ICI) in advanced non-small-cell lung cancer (aNSCLC). We hypothesized that TP53 mutations could reflect TMB and be associated with ICI benefit. TP53 mutations were assessed by next-generation sequencing in aNSCLC patients treated with programmed death-1 (PD-1) blockers. Clinical data, tumor programmed death ligand-1 (PD-L1) expression, and KRAS mutational status were collected. The primary endpoint was overall survival (OS). In total, 72 patients (median [interquartile range] age: 61 [33-83] years) were included; 52 (72%) were male; 39 (54%) had performance status 0-1; 53 (74%) had adenocarcinoma; 20 (28%) received first-line ICI, 52 (72%) second line or more. In 65 patients with available data, 36 (55%) expressed PD-L1 in ≥50% of tumor cells, 20 (31%) in 1-49% of cells, and nine (14%) were PD-L1-negative. Non-synonymous TP53 mutations were observed in 41 (57%) and 25 (35%) harbored KRAS-mutated tumors. After a median follow-up of 15.2 months (95% confidence interval [CI] 10.3-17.4 m), the median OS in the TP53-mutated group was 18.1 months (95% CI 6.6-not reached), vs. 8.1 months (95% CI 2.2-14.5, hazard ratio [HR] = 0.48; 95% CI 0.25-0.95, p = 0.04) in the TP53-wild-type group. Median progression-free survival was significantly longer in TP53-mutated patients (4.5 months, 95% CI 2.8-18.1 versus 1.4, 95% CI 1.1-3.5; p = 0.03), although TP53 mutation status failed to significantly influence PFS in the multivariate analysis (p = 0.32). Objective response rate (ORR) was higher in patients with TP53 mutation (51.2% vs. 20.7%; p = 0.01). In multivariate analysis, TP53 mutations independently associated with longer OS (HR = 0.35, 95% CI 0.16-0.77, p = 0.009). TP53-mutated status correlated with immunotherapy OS benefit in aNSCLC.

Assoun S ，Theou-Anton N ，Nguenang M ，Cazes A ，Danel C ，Abbar B ，Pluvy J ，Gounant V ，Khalil A ，Namour C ，Brosseau S ，Zalcman G ... -  《-》

ZFHX3 mutation as a protective biomarker for immune checkpoint blockade in non-small cell lung cancer.

Zhang J ，Zhou N ，Lin A ，Luo P ，Chen X ，Deng H ，Kang S ，Guo L ，Zhu W ，Zhang J ... -  《-》

Comparison of Efficacy and Safety of Single and Double Immune Checkpoint Inhibitor-Based First-Line Treatments for Advanced Driver-Gene Wild-Type Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have improved survival for advanced wild-type non-small cell lung cancer (NSCLC) significantly, but few studies compared single ICI (SICI)-based treatments and double ICIs (DICI)-based treatments. We summarized the general efficacy of ICI-related treatments, compared the efficacy and safety of SICI-based [programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors ± chemotherapy (CT)] and DICI-based (PD-1/PD-L1 inhibitors+CTLA-4 inhibitors ± chemotherapy) treatments vs. CT in the first-line treatment. We included phase II/III randomized controlled trials (RCTs), including patients with histologically confirmed stage IIIB-IV driver-gene wild-type NSCLC who received first-line ICI-related therapy in at least one arm. PubMed, Embase, and Cochrane Library were searched from January 1, 2005, to December 31, 2020. This network meta-analysis was performed in a Bayesian framework using GEMTC and JAGS package in R.3.6.1. The research was registered with PROSPERO (CRD42020184534). Twenty RCTs were involved, including 13,032 patients and 17 treatment regimens. The results showed that ICI-based therapies could provide a pooled median overall survival (mOS) (POS) of 15.79 (95% CI: 14.85-16.73) months, and there were no significant differences in OS, progression-free survival (PFS), objective response rate (ORR), and grade 3 or higher adverse events (≥3AEs) between DICI-based treatments (POS: 14.81, 12.11-17.52 months) and SICI-based treatments (POS: 16.17, 14.59-17.74 months) in overall patients. However, DICI-based treatments had significantly prolonged the OS over SICI-based treatments in squamous and PD-L1 <1% subgroups. The ranking of OS benefit by Bayesian surface under the cumulative ranking curve (SUCRA) spectrum showed that DICI+chemotherapy ranked first for overall population and subgroups including squamous, non-squamous, any level of PD-L1 expression, smoking, male, Eastern Cooperative Oncology Group performance status (ECOG PS) = 0/1, age < 65/≥65 while SICI+CT for low tumor mutation burden (TMB), non-smoking, and female subgroups, and DICI for high TMB subgroups. In the first-line therapy for advanced wild-type NSCLC, both SICI- and DICI-based treatments could bring significant overall advantages over chemotherapy, with comparable outcomes of efficacy and ≥3AEs. DICI-based treatments were more effective than SICI-based treatments in squamous and PD-L1 <1% subgroups. For most populations, DICI+chemotherapy could be the best choice with a survival benefit, while SICI+chemotherapy has established its position actually. [PROSPERO], identifier [CRD42020184534].

Xu Q ，Zhang X ，Huang M ，Dai X ，Gao J ，Li S ，Sheng L ，Huang K ，Wang J ，Liu L ... -  《Frontiers in Immunology》