Editorial

Individualizing Therapy for Non–Small-Cell Lung Cancer: A Paradigm Shift from Empiric to Integrated Decision-Making

Data on the treatment of non–small cell lung cancer (NSCLC) in real-world clinical practice in Japan are limited. This large-scale, retrospective cohort study examined data on patients’ characteristics and systemic therapies for advanced or recurrent NSCLC in routine practice in Japan.

This study used an electronic health records–based database of health claims and Diagnosis Procedure Combination data from 215 consenting hospitals in Japan. Records from April 2008 to September 2015 were analyzed. Regimens were examined by histology, age, sex, and therapeutic line. Logistic regression analysis was performed to predict which clinical and demographic factors affected patients’ probability of receiving first- or second-line therapy or completing first-line platinum-based chemotherapy.

Among 16,413 patients, 67.9%, 39.2%, and 22.3% received first-, second-, and third-line systemic treatment, respectively. Treatment was more common in patients aged <75 versus ≥75 years (76.0% vs 51.6%), in female versus male patients (71.6% vs 65.4%), and in patients with nonsquamous versus squamous disease (75.6% vs 61.9%). More than 30 systemic regimens were administered. The most common first-line therapy was platinum-based chemotherapy (nonsquamous, 53.6%; squamous, 73.7%). Non–platinum-based chemotherapy use increased in the second-line setting, but platinum-based chemotherapy use remained high (nonsquamous, 33.9%; squamous, 38.6%). Tyrosine kinase inhibitors were used in 32.0% and 29.4% of patients with nonsquamous NSCLC in the first- and second-line settings, respectively. Switches from first- to second-line platinum-based chemotherapy and from first- to second-line tyrosine kinase inhibitors occurred. Forty-two percent of the patients died during hospitalization. In the logistic regression analysis, factors associated with a decreased likelihood of receiving first-line therapy were male sex, squamous histology, age >75 years, treatment at a general (vs cancer-specific) hospital, worse scores on certain activities of daily living, presence of chronic pulmonary disease, worse Hugh–Jones classification, and positive smoking status. The likelihood of completing first-line platinum-based chemotherapy was increased with greater body mass index, better activities of daily living scores, absence of chronic pulmonary disease, and better Hugh-Jones classification. The likelihood of continuing with second-line therapy was decreased with older age and recurrence of NSCLC.

Systemic treatment patterns for advanced or recurrent NSCLC in Japan were varied. Nearly 30% of all patients and approximately half of elderly patients did not receive systemic treatment. Treatment rates declined with subsequent therapeutic lines. Generally, guidelines were followed with first-line treatment administration, but not with second-line administration. These results underscore the need for better guideline adherence and more optimal treatment in and elderly patients and in those receiving later-line treatment in Japan.

Veliparib (V) potentiated therapeutic efficacy of cisplatin (C) and etoposide (E) in preclinical models of SCLC. We conducted this phase 1 study to establish the safety of the combination in human subjects.

The study employed the 3 + 3 dose escalation design to establish the safety and recommended phase 2 dose (RP2D) of V when combined with fixed doses of C (75 mg/m² on day 1) and E (100 mg/m² on days 1–3) in a 21-day cycle. The starting dose of V was 60 mg (bid days 1–7) with plan to escalate to 100 mg (days 1–7) or de-escalate to 40 mg (days 1–7) depending on the dose limiting toxicity (DLT) experience during cycle 1. Patients with treatment-naïve, extensive stage SCLC were included.

The study enrolled 9 patients: M/F (4/5); median age (60); White/African American (8/1). V was tolerated at the 60 mg (DLT in 0 of 3 patients) and 100 mg dose (DLT in 1 of 6 patients; grade 5 cardiac failure). Veliparib at 100 mg in combination with standard doses of C and E was established as the RP2D. Grades 3–5 adverse events irrespective of attribution during cycle 1 included: dehydration (1), diarrhea (1), fatigue (1), febrile neutropenia (1), heart failure (1), leukopenia (6), lymphopenia (1), nausea (2), neutropenia (8), respiratory failure (1), and thrombocytopenia (2). Investigator-assessed efficacy outcome in 7 evaluable patients were stable disease in 2/7 (28.6%), partial response in 4/7 (57.1%), and complete response in 1/7 (14.3%) patients.

This study demonstrated the safety of combining veliparib with cisplatin and etoposide in previously untreated SCLC patients.

The role of KRAS mutations in molecular targeted therapy by epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non–small cell lung cancer (NSCLC) has not been fully understood. The present investigation is aimed at an elucidation of the role of specific KRAS mutation types in predicting outcomes of patients with advanced NSCLC receiving EGFR-TKI therapy. Initially, 448 NSCLC patients were tested for the presence of KRAS mutations, to obtain frequencies of specific KRAS mutation types. Subsequently, the clinical outcome of treatment was evaluated in a subgroup of 38 KRAS-positive patients receiving EGFR-TKI therapy. KRAS mutations were detected in 69 of 448 patients (15.4%), mostly in smokers (17.86% vs. 5.8%, P = 0.0048), and appeared more frequently in adenocarcinomas than in squamous cell NSCLC or NSCLC that is not otherwise specified (21% vs. 6.99% vs. 4.4%, P = 0.0004). The most frequent type of KRAS mutation was G12C. The progression-free survival (PFS) was doubled in a group of non-G12C patients compared with that of the G12C group (9.0 wk vs. 4.3 wk, P = 0.009). The overall survival (OS) was not significantly different between non-G12C and G12C groups (12.1 wk vs. 9.3 wk, P = 0.068). The G12C KRAS mutation is a strong negative predictor for EGFR-TKI treatment, whereas other KRAS mutation types have not negatively predicted treatment efficacy compared with that for the wild-type KRAS genotype.

We aimed to explore the prognostic impact of the hypoxia induced factors (HIFαs) 1–2 and the metabolic HIF-regulated glucose transporter GLUT1, lactate dehydrogenase 5 (LDH5) and carbonic anhydrase IX (CAIX) in non-small cell lung cancer (NSCLC).

Tumor and stroma tissue samples from 335 unselected patients with stage I–IIIA NSCLC were obtained and tissue microarrays constructed. Immunohistochemistry was used to evaluate expression.

For squamous cell carcinoma patients, high tumor cell expression of HIF1α and low stromal cell expression of HIF1α and HIF2α correlated significantly with a poor disease-specific survival (DSS) in both univariate (tumor HIF1α, P = 0.001; stromal HIF1α, P = 0.009; stromal HIF2α, P = 0.005) and multivariate analyses (tumor HIF1α, HR = 3.3, P = 0.001; stromal HIF1α, HR = 2.1, P = 0.008; stromal HIF2α, HR 2.3, P = 0.005). Among adenocarcinoma patients high tumor expression of GLUT1 and low stromal expression of LDH5 correlated significantly with a poor DSS in both univariate (GLUT1, P = 0.01; LDH5, P = 0.03) and multivariate analyses (GLUT1, HR = 1.9, P = 0.046; LDH5, HR = 2.3, P = 0.03).

These markers show highly diverging prognostic impacts between histological subgroups and between tumor and stromal compartments in NSCLC.

Activating somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have recently been characterized in a subset of patients with advanced non-small cell lung cancer (NSCLC). Patients harboring these mutations in their tumors show excellent response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The EGFR-TKI gefitinib has been approved in Europe for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of the EGFR TK. Because EGFR mutation testing is not yet well established across Europe, biomarker-directed therapy only slowly emerges for the subset of NSCLC patients most likely to benefit: those with EGFR mutations.

The “EGFR testing in NSCLC: from biology to clinical practice” International Association for the Study of Lung Cancer-European Thoracic Oncology Platform multidisciplinary workshop aimed at facilitating the implementation of EGFR mutation testing. Recommendations for high-quality EGFR mutation testing were formulated based on the opinion of the workshop expert group.

Co-operation and communication flow between the various disciplines was considered to be of most importance. Participants agreed that the decision to request EGFR mutation testing should be made by the treating physician, and results should be available within 7 working days. There was agreement on the importance of appropriate sampling techniques and the necessity for the standardization of tumor specimen handling including fixation. Although there was no consensus on which laboratory test should be preferred for clinical decision making, all stressed the importance of standardization and validation of these tests.

The recommendations of the workshop will help implement EGFR mutation testing in Europe and, thereby, optimize the use of EGFR-TKIs in clinical practice.