PD-1/PD-L1 inhibitor therapy: transitioning from a second-line to a first-line therapy for non-small cell lung cancer

Recently, monoclonal antibodies targeting the programmed death 1 (PD-1)/PD ligand 1 (PD-L1) pathway have dramatically changed the treatment paradigm for non-small cell lung cancer (NSCLC). Several PD-1/PD-L1 inhibitors have been validated as second-line therapies for NSCLC, and are now being actively investigated as first-line therapies. In this paper, current data and future strategies for their use in first-line therapy are reviewed. There are five PD-1/PD-L1 inhibitors in development for NSCLC. Among them, three drugs (nivolumab, pembrolizumab, and atezolizumab) have been approved as second-line therapies for NSCLC in the United States. As a first-line therapy, pembrolizumab successfully showed superiority over platinum-based doublet chemotherapy in a strongly PD-L1-positive NSCLC group, while nivolumab failed to show efficacy as a first-line therapy. Currently, five PD-1/PD-L1 inhibitors are being tested as a first-line therapy for NSCLC in more than 10 phase III studies, with various study designs. Although it is not yet clear whether PD-1/PD-L1 inhibitors should be used as a monotherapy or in combination according to PD-L1 expression in first-line therapies, these promising drugs may play an important role in clinical practice as a first-line therapy for NSCLC in the near future

Comparison of Clinical Outcomes Following Gefitinib and Erlotinib Treatment in Non–Small-Cell Lung Cancer Patients Harboring an Epidermal Growth Factor Receptor Mutation in Either Exon 19 or 21

Background:Gefitinib and erlotinib, small-molecule kinase inhibitors that block epidermal growth factor receptor (EGFR) signaling, have demonstrated a dramatic response rate and prolonged progression-free survival (PFS) in patients harboring an activating EGFR mutation. We compared the clinical outcomes in gefitinib- and erlotinib-treated patients harboring EGFR mutations who had recurrent or metastatic non–small-cell lung cancer (NSCLC).Methods:A total of 375 patients with recurrent or metastatic stage IIIB/IV NSCLC, who had either exon 19 deletion or the L858R mutation in exon 21, and had received either gefitinib (n = 228) or erlotinib (n = 147), were included in the study. A matched-pair case-control study design was implemented in the analysis, where 121 pairs of gefitinib-treated and erlotinib-treated patients were matched according to sex, smoking history, Eastern Cooperative Oncology Group performance status, and types of EGFR mutation.Results:The median age of all patients was 58 years (range, 30–84), and more than half of patients had never been smokers (63.6%). Most patients had adenocarcinoma (98.3%) and good Eastern Cooperative Oncology Group performance status (0, 1) (90.9%). The median number of cycles of EGFR tyrosine kinase inhibitor (TKI) treatment was 12.7 in the gefitinib group and 10.8 in the erlotinib group. Of the 242 patients, 63 (26%) received EGFR TKI as first-line therapy. The overall response rates and disease control rates in the gefitinib- or erlotinib-treated groups were 76.9% versus 74.4% (p = 0.575) and 90.1% versus 86.8%, respectively (p = 0.305). There was no statistically significant difference with regard to PFS (median, 11.7 versus 9.6; p = 0.056) between the gefitinib- and erlotinib-treated groups. For patients receiving EGFR TKI as the first-line treatment, there was no significant difference between the two treatment groups in overall response rates (76.7% and 90.0%) (p = 0.431) and median PFS (11.7 versus 14.5 months) (p = 0.507).Conclusion:In NSCLC patients harboring EGFR mutation, treatment with gefitinib and erlotinib resulted in similar effectiveness

The Antioxidant Activity and Their Major Antioxidant Compounds from Acanthopanax senticosus and A. koreanum

The antioxidant activity and chlorogenic acid and caffeic acid contents were investigated from different parts of Acanthopanax senticosus and A. koreanum. Antioxidant activity was assessed by various in vitro assays such as DPPH, ABTS, FRAP, reducing power assays and ORAC, and the chlorogenic acid and caffeic acid were validated by HPLC chromatography. Among the various extracts, the fruit extracts of A. senticosus and A. koreanum exhibited strongest antioxidant activities including ABTS, FRAP, reducing power and ORAC, however, strongest DPPH radical scavenging activity was observed from the leaf extract of A. senticosus. In addition, the antioxidant activities of various extracts were correlated with total phenolic and proanthocyanidin contents. The major phenolic contents from various parts of these plants observed that leaf extract of A. senticosus expressed higher levels of chlorogenic acid (14.86 mg/dry weigh g) and caffeic acid (3.09 mg/dry weigh g) than other parts. Therefore, these results suggest that the leaf of A. senticosus may be an excellent natural source for functional foods and pharmaceutical agents, and the validated method was useful for the quality control of A. senticosus

Who Are Less Likely to Receive Subsequent Chemotherapy Beyond First-Line Therapy for Advanced Non-small Cell Lung Cancer?: Implications for Selection of Patients for Maintenance Therapy

BackgroundProspective studies have implied that maintenance therapy for non-small cell lung cancer (NSCLC) has its effect by giving active drugs earlier to patients who otherwise die without receiving second-line therapy. The purpose of this study was to select patients with NSCLC who could most benefit from maintenance therapy, by evaluating which patients would be less likely to receive second-line therapy.MethodsClinicopathologic data of patients with advanced NSCLC who received four cycles of first-line chemotherapy followed by time-off therapy and eventual disease progression or death were reviewed retrospectively. Patients were grouped into ones with first-line therapy only or ones with more than first-line therapy. Clinical characteristics between the two groups were compared.ResultsA total of 271 patients were eligible for analysis, and 39 patients (14.4%) received only first-line therapy. Patients significantly more likely to receive only first-line therapy had performance status of two or three after first-line therapy, large volume of initial target lesions (sum of long diameters ≥70 mm), or smaller decrease in target lesions (decrease <20%) after first-line therapy. Median overall survival of the 143 patients (52.8%) with at least one of these characteristics (16.3 months) was significantly shorter than that of patients without any of these characteristics (23.5 months, p = 0.007).ConclusionMaintenance therapy may be of greater benefit to patients with NSCLC who have clinical characteristics including poor performance status after first-line therapy, large initial target lesions, or smaller decrease in target lesions after first-line therapy

DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load

Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy

A randomized, phase II study of gefitinib alone versus nimotuzumab plus gefitinib after platinum-based chemotherapy in advanced non-small cell lung cancer (KCSG LU12-01)

We aimed to evaluate the efficacy of dual inhibition of epidermal growth factor receptor (EGFR) with nimotuzumab (EGFR monoclonal antibody) plus gefitinib (EGFR-tyrosine kinase inhibitor) in advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy. An open label, randomized, phase II trial was conducted at 6 centers; 160 patients were randomized (1:1) to either gefitinib alone or nimotuzumab (200 mg, i. v. weekly) plus gefitinib (250 mg p. o. daily) until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) at 3 months. Of the total 160 enrolled patients, 155 (77: gefitinib, 78: nimotuzumab plus gefitinib) received at least one dose and could be evaluated for efficacy and toxicity. The majority had adenocarcinoma (65.2%) and ECOG performance status of 0 to 1 (83.5%). The median follow-up was 22.1 months, and the PFS rate at 3 months was 48.1% in gefitinib and 37.2% in nimotuzumab plus gefitinib (P = not significant, NS). The median PFS and OS were 2.8 and 13.2 months in gefitinib and 2.0 and 14.0 months in nimotuzumab plus gefitinib. Combined treatment was not associated with superior PFS to gefitinib alone in patients with EGFR mutation (13.5 vs. 10.2 months in gefitinib alone, P=NS) or those with wild-type EGFR (0.9 vs. 2.0 months in gefitinib alone, P=NS). Combined treatment did not increase EGFR inhibition-related adverse events with manageable toxicities. The dual inhibition of EGFR with nimotuzumab plus gefitinib was not associated with better outcomes than gefitinib alone as a second-line treatment of advanced NSCLC (NCT01498562).

A Case of Infantile Alexander Disease Accompanied by Infantile Spasms Diagnosed by DNA Analysis

Alexander disease (AD) is a rare leukodystrophy of the central nervous system of unknown etiology. AD is characterized by progressive failure of central myelination and the accumulation of Rosenthal fibers in astrocytes, and is inevitably lethal in nature. Symptomatically, AD is associated with leukoencephalopathy with macrocephaly, seizures, and psychomotor retardation in infants, and usually leads to death within the first decade. Its characteristic magnetic resonance imaging (MRI) findings have been described as demyelination predominantly in the frontal lobe. Moreover, dominant mutations in the GFAP gene, coding for glial fibrillary acidic protein (GFAP), a principal astrocytic intermediate filament protein, have been shown to lead to AD. The disease can now be detected by genetic diagnosis. We report the Korean case of an 8-month-old male patient with AD. He was clinically characterized due to the presence of psychomotor retardation, megalencephaly, spasticity, and recurrent seizures including infantile spasms which is a remarkable presentation. Demyelination in the frontal lobe and in a portion of the temporal lobe was demonstrated by brain MRI. Moreover, DNA analysis of peripheral blood showed the presence of a R239L mutation in the GFAP gene, involving the replacement of guanine with thymine

Genetic Alterations in Primary Gastric Carcinomas Correlated with Clinicopathological Variables by Array Comparative Genomic Hybridization

Genetic alterations have been recognized as an important event in the carcinogenesis of gastric cancer (GC). We conducted high resolution bacterial artificial chromosome array-comparative genomic hybridization, to elucidate in more detail the genomic alterations, and to establish a pattern of DNA copy number changes with distinct clinical variables in GC. Our results showed some correlations between novel amplified or deleted regions and clinical status. Copy-number gains were frequently detected at 1p, 5p, 7q, 8q, 11p, 16p, 20p and 20q, and losses at 1p, 2q, 4q, 5q, 7q, 9p, 14q, and 18q. Losses at 4q23, 9p23, 14q31.1, or 18q21.1 as well as a gain at 20q12 were correlated with tumor-node-metastasis tumor stage. Losses at 9p23 or 14q31.1 were associated with lymph node status. Metastasis was determined to be related to losses at 4q23 or 4q28.2, as well as losses at 4q15.2, 4q21.21, 4q 28.2, or 14q31.1, with differentiation. One of the notable aspects of this study was that the losses at 4q or 14q could be employed in the evaluation of the metastatic status of GC. Our results should provide a potential resource for the molecular cytogenetic events in GC, and should also provide clues in the hunt for genes associated with GC

Angiogenesis inhibitor therapies for advanced renal cell carcinoma: Toxicity and treatment patterns in clinical practice from a global medical chart review

The aim of this study was to assess the treatment patterns and safety of sunitinib, sorafenib and bevacizumab in real-world clinical settings in US, Europe and Asia. Medical records were abstracted at 18 community oncology clinics in the US and at 21 tertiary oncology centers in US, Europe and Asia for 883 patients ≥18 years who had histologically/cytologically confirmed diagnosis of advanced RCC and received sunitinib (n=631), sorafenib (n=207) or bevacizumab (n=45) as first‑line treatment. No prior treatment was permitted. Data were collected on all adverse events (AEs) and treatment modifications, including discontinuation, interruption and dose reduction. Treatment duration was estimated using Kaplan-Meier analysis. Demographics were similar across treatment groups and regions. Median treatment duration ranged from 6.1 to 10.7 months, 5.1 to 8.5 months and 7.5 to 9.8 months for sunitinib, sorafenib and bevacizumab patients, respectively. Grade 3/4 AEs were experienced by 26.0, 28.0 and 15.6% of sunitinib, sorafenib and bevacizumab patients, respectively. Treatment discontinuations occurred in 62.4 (Asia) to 63.1% (US) sunitinib, 68.8 (Asia) to 90.0% (Europe) sorafenib, and 66.7 (Asia) to 81.8% (US) bevacizumab patients. Globally, treatment modifications due to AEs occurred in 55.1, 54.2 and 50.0% sunitinib, sorafenib and bevacizumab patients, respectively. This study in a large, global cohort of advanced RCC patients found that angiogenesis inhibitors are associated with high rates of AEs and treatment modifications. Findings suggest an unmet need for more tolerable agents for RCC treatment