In an interim analysis of a trial involving 296 patients with
ALK
-positive non–small-cell lung cancer, lorlatinib, an anaplastic lymphoma kinase inhibitor, was superior to crizotinib in response (in ...76% vs. 58%), 12-month progression-free survival (78% vs. 39%), and intracranial disease response (82% vs. 23%). Altered lipid levels were the major toxic effect associated with lorlatinib.
Although the progression-free survival and overall survival in patients with non-small-cell lung cancer (NSCLC) have improved in recent years with the clinical introduction of immune checkpoint ...inhibitors, the long-term survival rates are still low. One possible reason for this is that the inflammatory cytokine interleukin-1β (IL-1β) may suppress anti-tumor immune responses by enhancing tumor-associated inflammation in the tumor microenvironment (TME). Canakinumab, a human monoclonal antibody that targets IL-1β, was shown to significantly lower the incidence and mortality rate of lung cancer in the CANTOS trial. It has been suggested that canakinumab may enhance the anti-tumor immune response and suppress tumor growth by inhibiting IL-1β activity. We herein report the association between tumor and inflammation and the role of IL-1β in the TME. We also provide an overview of ongoing clinical research of canakinumab as a promising future treatment option for NSCLC.
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations (Exon20ins) account for 4-12% of all EGFR mutations in non-small cell lung cancer (NSCLC) patients. Data on the differences in ...clinical characteristics between patients with Exon20ins and major mutations (M-mut) such as exon 19 deletion and L858R are limited. We retrospectively reviewed advanced NSCLC patients with EGFR mutations, who were treated with systemic therapy between January 2011 and December 2019. We identified 23 patients with Exon20ins and 534 patients with M-mut. In Exon20ins patients, the median age was 60 (range 27-88) years, and females and never-smokers were predominant. Clinical characteristics were similar in the two groups. In Exon20ins patients, 17 patients received platinum doublet as first-line therapy, and the overall response rate (ORR) and median progression-free survival (mPFS) were 11.8% and 8.9 months. Additionally, seven patients received conventional EGFR-tyrosine kinase inhibitors (TKIs), and eight patients anti-PD-1 antibodies in any-line therapy. ORR and mPFS of EGFR-TKIs and anti-PD-1 antibodies were 0%, 2.2 months and 25%, 3.1 months, respectively. Overall survival was significantly shorter in Exon20ins patients than in M-mut patients (29.3 vs. 43.4 months, p = 0.04). The clinical outcomes in Exon20ins patients were not satisfactory compared to M-mut patients.
According to rapid development of chemotherapy in advanced non-small cell lung cancer (NSCLC), the Japan Lung Cancer Society has been updated its own guideline annually since 2010. In this latest ...version, all of the procedure was carried out in accordance with grading of recommendations assessment, development and evaluation (GRADE) system. It includes comprehensive literature search, systematic review, and determination of the recommendation by multidisciplinary expert panel which consisted of medical doctors, pharmacists, nurses, statisticians, and patients from patient advocacy group. Recently, we have had various types of chemotherapeutic drugs like kinase inhibitors or immune-checkpoint inhibitors. Thus, the guideline proposes to categorize patients into three entities: (1) driver oncogene-positive, (2) PD-L1 ≥ 50%, and (3) others. Based on this subgroup, 31 clinical questions were described. We believe that this attempt enables clinicians to choose appropriate treatment easier. Here, we report an English version of the Japan Lung Cancer Society Guidelines 2018 for NSCLC, stages IV.
ALK, ROS1, and RET kinase fusions are important predictive biomarkers of tyrosine kinase inhibitors (TKIs) in non‐small‐cell lung cancer (NSCLC). Analysis of cell‐free DNA (cfDNA) provides a ...noninvasive method to identify gene changes in tumor cells. The present study sought to use cfRNA and cfDNA for identifying fusion genes. A reliable protocol was established to detect fusion genes using cfRNA and assessed the analytical validity and clinical usefulness in 30 samples from 20 cases of fusion‐positive NSCLC. The results of cfRNA‐based assays were compared with tissue biopsy and cfDNA‐based liquid biopsy (Guardant360 plasma next‐generation sequencing NGS assay). The overall sensitivity of the cfRNA‐based assay was 26.7% (8/30) and that of cfDNA‐based assay was 16.7% (3/18). When analysis was limited to the samples collected at chemo‐naïve or progressive disease status and available for both assays, the sensitivity of the cfRNA‐based assay was 77.8% (7/9) and that of cfDNA‐based assay was 33.3% (3/9). Fusion gene identification in cfRNA was correlated with treatment response. These results suggest that the proposed cfRNA assay is a useful diagnostic test for patients with insufficient tissues to facilitate effective administration of first‐line treatment and is a useful tool to monitor the progression of NSCLC for consideration of second‐line treatments.
cfRNA‐ and cfDNA‐based assays are evaluated in 20 cases of fusion‐positive NSCLC. cfRNA assay was superior to cfDNA assay for the detection of gene fusions. The results of the cfRNA assay were consistent with the therapeutic effect.
YAP1, the main Hippo pathway effector, is a potent oncogene and is overexpressed in non‐small‐cell lung cancer (NSCLC); however, the YAP1 expression pattern in small‐cell lung cancer (SCLC) has not ...yet been elucidated in detail. We report that the loss of YAP1 is a special feature of high‐grade neuroendocrine lung tumors. A hierarchical cluster analysis of 15 high‐grade neuroendocrine tumor cell lines containing 14 SCLC cell lines that depended on the genes of Hippo pathway molecules and neuroendocrine markers clearly classified these lines into two groups: the YAP1‐negative and neuroendocrine marker‐positive group (n = 11), and the YAP1‐positive and neuroendocrine marker‐negative group (n = 4). Among the 41 NSCLC cell lines examined, the loss of YAP1 was only observed in one cell line showing the strong expression of neuroendocrine markers. Immunostaining for YAP1, using the sections of 189 NSCLC, 41 SCLC, and 30 large cell neuroendocrine carcinoma (LCNEC) cases, revealed that the loss of YAP1 was common in SCLC (40/41, 98%) and LCNEC (18/30, 60%), but was rare in NSCLC (6/189, 3%). Among the SCLC and LCNEC cases tested, the loss of YAP1 correlated with the expression of neuroendocrine markers, and a survival analysis revealed that YAP1‐negative cases were more chemosensitive than YAP1‐positive cases. Chemosensitivity test for cisplatin using YAP1‐positive/YAP1‐negative SCLC cell lines also showed compatible results. YAP1‐sh‐mediated knockdown induced the neuroendocrine marker RAB3a, which suggested the possible involvement of YAP1 in the regulation of neuroendocrine differentiation. Thus, we showed that the loss of YAP1 has potential as a clinical marker for predicting neuroendocrine features and chemosensitivity.
YAP1 is possibly involved in the regulation of neuroendocrine differentiation of lung tumors. Loss of YAP1 correlated with strong expression of neuroendocrine markers. Loss of YAP1 is a predictor of chemothensitivity in high‐grade neuroendocrine tumors.
•Nivolumab systemically activates the lymphocytes in NSCLC patients.•Increase in Lymphocyte-to-monocyte ratio after nivolumab is related to prolonged PFS.•Increase in Lymphocyte-to-monocyte ratio ...after docetaxel is not associated with PFS.
Nivolumab, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody, has been shown to yield a durable response and significant prolongation of the survival in some patients with non-small-cell lung cancer (NSCLC). However, identification of patients who are likely to respond to nivolumab remains difficult at present.
We conducted a retrospective analysis of the clinical data of 87 consecutive patients with advanced NSCLC seen in clinical practice who received nivolumab monotherapy at the National Cancer Center Hospital in Japan between January 2016 and July 2016 (discovery cohort). In addition, we also collected the clinical data of 75 patients who were administered nivolumab monotherapy between August 2016 and March 2017 (validation cohort). For this study, we focused on the changes in the lymphocyte-to-monocyte ratio (LMR) observed after nivolumab monotherapy.
In the discovery cohort, increase (≥10%) of the LMR at 4 weeks after the start of nivolumab monotherapy relative to the pretreatment LMR was positively correlated with an objective response (objective response rate (ORR); 39.4% vs 11.8%, p = 0.0065). When this cutoff value of ≥10% was used, increase of the LMR was significantly associated with a prolonged progression-free survival (PFS) (median PFS mPFS; 7.3 months vs 2.5 months, p = 0.0049) and overall survival (OS) (median survival time; 15.6 months vs 8.9 months, p = 0.014). In the validation cohort also, increase of the LMR was significantly associated with higher ORR (50.0% vs 20.0%, p = 0.015) and prolonged PFS (mPFS; not reached vs 3.1 months, p = 0.0092). On the other hand, no such correlation was observed among patients treated with docetaxel.
A rapid increase of the LMR was significantly associated with the effects of nivolumab monotherapy in our study cohort. Therefore, early change of the LMR may be used as a novel effective surrogate marker to decide on continuation of anti-PD-1 therapy.
Programmed death-ligand 1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti–programmed cell death protein-1 (PD-1)/PD-L1 therapy in patients with advanced ...NSCLC. Immune-related tumor microenvironment (TME) is classified into four different types based on the tumor-infiltrating lymphocyte (TIL) status and PD-L1 expression.
We retrospectively reviewed patients with advanced NSCLC treated with anti–PD-1/PD-L1 therapy between 2015 and 2019. We investigated the association between the efficacy of anti–PD-1/PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, the density of CD8-positive TILs assessed by immunohistochemistry, and mutational profiles by next-generation sequencing.
Overall, 228 patients were included in the analysis. The patients were classified into the following four groups: type I: PD-L1High (tumor proportion score ≥ 50%)/TILHigh (≥85/mm2; n = 73); type II: PD-L1Low (tumor proportion score < 50%)/TILLow (<85/mm2; n = 70); type III: PD-L1High/TILLow (n = 37); and type IV: PD-L1Low/TILHigh (n = 48). The objective response rate (ORR) and progression-free survival (PFS) of anti–PD-1/PD-L1 therapy clearly differed according to the different TME types (ORR and PFS; type I: 64%, 14.5 mo; type II: 12%, 2.1 mo; type III: 24%, 3.6 mo; type IV; 41%, 10.8 mo). In patients with PD-L1High tumors, type I tumors had significantly better ORR and PFS than type III tumors (ORR: p < 0.001 and PFS: p < 0.001). The presence of TP53 and KRAS mutation was related to the density of CD8-positive TILs and PD-L1 expression, respectively.
Differential types of TME, including PD-L1 expression and TIL status, could accurately predict the efficacy of anti–PD-1/PD-L1 therapy.
Thymic squamous cell carcinoma (TSC) presents distinct immunohistochemical features with its expression of CD5 and CD117, both of which are rarely expressed in squamous cell carcinoma in other ...organs. We found insulinoma-associated-1 (INSM1) expression in some TSCs; thus, a series of thymic tumors were examined retrospectively. Using surgically resected thymic tumors (TSC,
n
= 35; thymic atypical carcinoid TAC,
n
= 4; and thymoma,
n
= 112) and non-neoplastic thymic tissue (
n
= 26), we evaluated immunohistochemically the expressions of INSM1, ASCL1, SOX2, NE markers (synaptophysin, chromogranin A, and CD56), and conventional TSC markers (CD5 and CD117). INSM1 was expressed in 22 TSCs (63%), whereas the positive frequencies of synaptophysin, chromogranin A, and CD56 were limited to 13, 10, and 1 cases, respectively. The discordance was highly contrasted with concordantly positive TACs. INSM1 and NE makers were rarely expressed in thymomas. INSM1 expression in TSCs was also associated with CD5 expression, which was significantly less frequent in INSM1-negative TSCs. INSM1, ASCL1, and SOX2 expressions were correlated with one another, but none of the single transcription factors or their combinations is associated with NE expression. The non-neoplastic medullary thymic epithelium was dispersedly positive for INSM1, particularly around Hassall’s corpuscles. Despite positive INSM1, a significant decrease in the frequency of NE maker expression may present as a diagnostic pitfall in TSCs. Furthermore, the discordance, which was inherent in the non-neoplastic thymic epithelium, might be a characteristic feature in TSCs.
The safety of anti-programmed cell death 1 (PD-1) antibody for patients with preexisting interstitial lung disease (ILD) remains unknown. The aim of this study was to evaluate the dependence of ...preexisting ILD on anti-PD-1 antibody-induced pneumonitis in non-small cell lung cancer (NSCLC) patients. We retrospectively reviewed the association of preexisting ILD with the incidence, radiographic pattern, and outcome of pneumonitis in NSCLC patients receiving anti-PD-1 antibody. A total of 331 patients were included in this study. Of these patients, 17 had preexisting ILD. The incidence of pneumonitis was higher among the patients with preexisting ILD than among those without preexisting ILD (29% vs. 10%,
P
= 0.027). The distributions of the CT appearances at the onset of anti-PD-1 antibody-induced pneumonitis were as follows: for the patients with preexisting ILD, two patients (40%) had diffuse alveolar damage (DAD), one patient each with organizing pneumonia-like (OP), hypersensitivity pneumonitis (HP), and other patterns (20% each); for the patients without preexisting ILD, 19 patients (61%) had OP, 8 (26%) had HP, 3 (10%) had DAD, and 1 (3.2%) had other patterns. The median onset time from the initiation of anti-PD-1 antibody treatment until the development of pneumonitis was 1.3 months (range 0.3–2.1 months) for the patients with preexisting ILD and 2.3 months (range 0.2–14.6 months) for the patients without preexisting ILD. Careful attention to the development of pneumonitis is needed, especially within the first 3 months after the start of anti-PD-1 antibody treatment, when using anti-PD-1 antibody to treat patients with preexisting ILD.
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