Impact of ramucirumab plus erlotinib on circulating cell-free DNA from patients with untreated metastatic non-small cell lung cancer with EGFR-activating mutations (RELAY phase 3 randomized study).

Background: An exploratory, proof-of-concept, liquid biopsy addendum to examine biomarkers within cell-free DNA (cfDNA) in the RELAY phase 3, randomized, double-blind, placebo-controlled study was conducted. RELAY showed improved progression-free survival (PFS) with ramucirumab (RAM), a human immunoglobulin G1 vascular endothelial growth factor receptor 2 antagonist, plus erlotinib (ERL), a tyrosine kinase inhibitor, compared with placebo (PL) plus ERL. Methods: Treatment-naïve patients with endothelial growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer were randomized (1:1) to RAM + ERL or PL + ERL. Plasma samples were collected at baseline, on treatment, and at 30-day post-study treatment discontinuation follow-up. Baseline and treatment-emergent gene alterations and EGFR-activating mutation allele counts were investigated by next-generation sequencing (NGS) and droplet digital polymerase chain reaction (ddPCR), respectively. cfDNA concentration and fragment size were evaluated by real-time polymerase chain reaction and the BioAnalyzer. Patients with a valid baseline plasma sample were included (70 RAM + ERL, 61 PL + ERL). Results: TP53 mutation was the most frequently co-occurring baseline gene alteration (43%). Post-study treatment discontinuation EGFR T790M mutation rates were 54.5% (6/11) and 41.2% (7/17) by ddPCR, and 22.2% (2/9) and 29.4% (5/17) by NGS, in the RAM + ERL and PL + ERL arms, respectively. EGFR-activating mutation allele count decreased at Cycle 4 in both treatment arms and was sustained at follow-up with RAM + ERL. PFS improved for patients with no detectable EGFR-activating mutation at Cycle 4 vs. those with detectable EGFR-activating mutation. Total cfDNA concentration increased from baseline at Cycle 4 and through to follow-up with RAM + ERL. cfDNA fragment size was similar between treatment arms at baseline [mean (standard deviation) base pairs: RAM + ERL, 173.4 (2.6); PL + ERL, 172.9 (3.2)] and was shorter at Cycle 4 with RAM + ERL vs. PL + ERL [169.5 (2.8) vs. 174.1 (3.3), respectively; P<0.0001]. Baseline vs. Cycle 4 paired analysis showed a decrease in cfDNA fragment size for 84% (48/57) and 23% (11/47) of patient samples in the RAM + ERL and PL + ERL arms, respectively. Conclusions: EGFR-activating mutation allele count was suppressed, total cfDNA concentration increased, and short fragment-sized cfDNA increased with RAM + ERL, suggesting the additional anti-tumor effect of RAM may contribute to the PFS benefit observed in RELAY with RAM + ERL vs. PL + ERL. Trial Registration: ClinicalTrials.gov; identifier: NCT02411448.

Patients' Preferences for Attributes of Molecular Targeting Therapies for Advanced Non-Small Cell Lung Cancer with EGFR Mutations in Japan-A Discrete-Choice Experiment.

AIM: This study aims to evaluate Japanese patients' preferences in first-line therapy choice for advanced non-small cell lung cancer(NSCLC)with epidermal growth factor receptor(EGFR)mutations. METHODS: A cross-sectional discrete-choice experiment was conducted on advanced NSCLC patients in Japan. Participants completed the online questionnaire that included different levels of 5 treatment attributes: time to disease progression, chance of rash, next therapy option, frequency of health care visits and administration route. The primary analysis estimated the relative attribute importance. The preferences of EGFR mutation-positive patients were compared with those of EGFR mutation-negative/unknown patients to observe whether preference differs by mutation status. RESULTS: A total of 158 participants completed the survey. The analysis on the overall study population revealed next therapy option(mean relative attribute importance[SD]: 39.30 [17.07])as the most important attribute, followed by time to disease progression(25.52[10.51]), chance of rash(21.58 [11.74]), with administration route(7.63[6.99])and frequency of health care visits(5.96[3.40])the least preferred. The results in the subgroups by EGFR mutation status were similar. CONCLUSION: Next therapy option is the major influencing factor for treatment choice of molecular targeting therapy among advanced NSCLC patients in Japan, emphasizing the importance of communicating the next treatment options to patients at the time of their first treatment.

[Efficacy and Safety Analysis of Selpercatinib in Patients with RET Fusion-Positive Non-Small Cell Lung Cancer-Results from the Japanese Subset of a Global Phase 1/2 Study].

PURPOSE: Selpercatinib is a highly selective, potent, rearranged during transfection(RET)inhibitor. A global, multicenter, open-label, phase 1/2 study of selpercatinib(LIBRETTO-001, NCT03157128)has been ongoing since 2017. We evaluated the data of Japanese patients with RET fusion-positive non-small cell lung cancer(NSCLC)using 30 March 2020 cut-off data. METHODS: Phase 2 of LIBRETTO-001 started after confirming the safety of the recommended phase 2 dose(160 mg bid, orally, 28-day cycles)in Japanese. The primary endpoint was the independently assessed objective response rate(RECIST v1.1). RESULTS: Japanese NSCLC patients, including 44 patients in cohort 1 who had previously received platinum-based(or other)chemotherapy, programmed cell death-1/programmed death-ligand 1 immunotherapy, or both, and four previously untreated patients in cohort 2, were analyzed. The objective response rate was 55.3%(95% confidence interval: 38.3, 71.4; one confirmed complete response, 20 confirmed partial responses)in 38 evaluable patients in cohort 1 who could be followed for ≥2 post-baseline scans. The only evaluable patient in cohort 2 had no response. The most frequent treatment- emergent adverse events were increased alanine aminotransferase, increased aspartate aminotransferase, and diarrhea. CONCLUSIONS: Selpercatinib appeared to be effective in Japanese patients with RET fusion-positive NSCLC, and the safety profile was not substantially different from published results.

RELAY+: Exploratory Study of Ramucirumab Plus Gefitinib in Untreated Patients With EGFR-Mutated Metastatic NSCLC.

Introduction: Ramucirumab (RAM) plus erlotinib was found to have superior progression-free survival (PFS) versus placebo plus erlotinib in untreated EGFR-mutated metastatic NSCLC in the global phase 3 RELAY study. RELAY+ was an open-label, two-period, single-arm, exploratory study of RAM plus gefitinib (GEF; period 1) and RAM plus osimertinib (period 2) in East Asia (NCT02411448). Methods: Period 1 evaluated RAM (10 mg/kg) plus GEF (250 mg/d) in patients with untreated EGFR-mutated metastatic NSCLC. Period 2 evaluated RAM plus osimertinib (80 mg/d) in patients with disease progression who acquired T790M mutation in period 1. Exploratory end points included 1-year PFS rate (primary), other efficacy parameters, safety, and biomarker analyses of plasma (baseline, on-treatment, follow-up) using next-generation sequencing. Results: From December 2017 to August 2018, a total of 82 patients were enrolled and started treatment (period 1, RAM + GEF). The 1-year PFS rate was 62.9% (95% confidence interval: 50.3-73.1). Treatment-emergent adverse events of grade three or higher were reported with RAM plus GEF in 60 of 82 patients (73.2%; five patients [6.1%] grade four). There were two deaths owing to adverse events that occurred (acute cardiac failure, congestive cardiac failure). T790M rate at disease progression in plasma was 81.0% (13 of 16 patients). Conclusions: RELAY+ was found to have a favorable benefit-risk profile for RAM plus GEF in first-line treatment of East Asian patients with EGFR-mutated NSCLC.

[Differences between EGFR Exon 19 Deletion and Exon 21 L858R Point Mutation, Frequently Detected EGFR Mutations in Patients with Non-Small Cell Lung Cancer, from a Molecular Biology Viewpoint].

Epidermal growth factor receptor(EGFR)is a transmembrane receptor tyrosine kinase that plays an important role in regulating the growth and progression of cancer via signalling pathways. This review summarizes the differences in EGFR kinase structural changes, stability of active forms, and phosphorylation inhibitory effects of EGFR tyrosine kinase inhibitors between the exon 19 deletion mutation and the exon 21 L858R point mutation, which are frequently detected EGFR mutations in patients with non-small cell lung cancer.

Ramucirumab Plus Erlotinib Versus Placebo Plus Erlotinib in Patients With Untreated Metastatic EGFR-Mutated NSCLC: RELAY Japanese Subset.

INTRODUCTION: The phase 3 RELAY global study (NCT02411448) revealed significant improvement in progression-free survival (PFS) with ramucirumab plus erlotinib (RAM + ERL) compared with placebo plus ERL (PL + ERL) in untreated EGFR-mutated metastatic NSCLC (hazard ratio [HR] = 0.59 [95% confidence interval (CI): 0.46-0.76, p < 0.0001]). This prespecified analysis evaluates efficacy, safety, and postprogression EGFR T790M rates of RELAY patients enrolled in Japan. METHODS: Patients were randomized (1:1) to oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL every 2 weeks. End points included PFS (primary), safety (secondary), and biomarker analyses (exploratory). Plasma samples collected at baseline and poststudy treatment discontinuation were evaluated for EGFR T790M mutations by next-generation sequencing. RESULTS: The Japanese subset included 211 of 449 (47.0%) RELAY patients (RAM + ERL, n = 106; PL + ERL, n = 105). Median PFS was 19.4 versus 11.2 months for RAM + ERL versus PL + ERL treatment (HR = 0.610 [0.431-0.864]) in the Japanese intent-to-treat population, 16.6 versus 12.5 months (HR = 0.701 [0.424-1.159]) in the EGFR exon 19 deletion subgroup, and 19.4 versus 10.9 months (HR = 0.514 [0.317-0.835]) in the EGFR exon 21 L858R subgroup, respectively. Adverse events of grade 3 or above with RAM + ERL included hypertension (24.8%, all grade 3) and dermatitis acneiform (23.8%). Postprogression treatment-emergent T790M rates were similar between arms (RAM + ERL: 47%, 9 of 19 patients; PL + ERL: 50%, 20 of 40 patients). CONCLUSIONS: Clinically meaningful efficacy was observed with RAM + ERL versus PL + ERL in the RELAY Japanese subset, with no new safety concerns. Postprogression T790M rates were similar across treatment arms, indicating the addition of RAM did not affect the ERL-associated EGFR T790M rates at disease progression.

[Exon 19 Deletion and Exon 21 L858R Point Mutation in EGFR Mutation‒Positive Non‒Small Cell Lung Cancer].

Epidermal growth factor receptor(EGFR)is a transmembrane receptor tyrosine kinase the signaling of which is important for growth and progression of cancer. An exon 19 deletion mutation and an exon 21 L858R point mutation are frequently detected as EGFR mutations in patients with non‒small cell lung cancer. This review summarizes the differences in epidemiological, nonclinical, and clinical characteristics between the exon 19 deletion mutation and the exon 21 L858R point mutation.

Abemaciclib in combination with endocrine therapy for East Asian patients with HR+, HER2- advanced breast cancer: MONARCH 2 & 3 trials.

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double-blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression-free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P < .001; median: 21.2 vs 11.6 months) and MONARCH 3 (HR, 0.326; 95% CI, 0.200 to 0.531, P < .001; median: not reached vs 12.82 months). Diarrhea (MONARCH 2: 90%; MONARCH 3: 88%) and neutropenia (MONARCH 2: 68%; MONARCH 3: 58%) were the most frequent adverse events observed in the East Asian populations. Abemaciclib exposures and PK were similar in East Asians and the non-East Asian populations of both trials. Abemaciclib in combination with ET in the East Asian populations of MONARCH 2 and MONARCH 3 provided consistent results with the ITT populations, demonstrating improvements in efficacy with generally tolerable safety profiles for patients with HR+, HER2- advanced breast cancer.

Ramucirumab or placebo plus erlotinib in EGFR-mutated, metastatic non-small-cell lung cancer: East Asian subset of RELAY.

In the global phase III RELAY study, ramucirumab plus erlotinib (RAM + ERL) demonstrated superior progression-free survival (PFS) to placebo plus erlotinib (PL + ERL) in untreated patients with epidermal growth factor receptor (EGFR) mutation-positive metastatic non-small-cell lung cancer (NSCLC) (hazard ratio (HR) [95% CI]: 0.59 [0.46-0.76]). This prespecified analysis assessed RAM + ERL efficacy and safety in the RELAY subset enrolled in East Asia (Japan, Taiwan, South Korea, Hong Kong). Randomized (1:1) patients received oral ERL (150 mg/d) plus intravenous RAM (10 mg/kg) or PL Q2W. Primary endpoint was PFS (investigator-assessed). Key secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), and safety. Exploratory endpoints included biomarker analyses and time to second progression (PFS2). Median PFS was 19.4 vs 12.5 mo for RAM + ERL (n = 166) vs PL + ERL (n = 170) (HR: 0.636 [0.485-0.833]; P = .0009). The 1-y PFS rate was 72.4% vs 52.2%, respectively. PFS benefit was consistent in most subgroups, including by EGFR mutation (Ex19del, Ex21.L858R). ORR and DCR were similar in both arms, but median DoR was longer with RAM + ERL. OS and PFS2 were immature at data cut-off (censoring rates, 81.2%-84.3% and 64.1%-70.5%, respectively). Grade ≥ 3 treatment-emergent adverse events were more frequent with RAM + ERL (70.7%) than PL + ERL (49.4%). Adverse events leading to treatment discontinuation were similar in both arms (RAM + ERL, 13.3%; PL + ERL, 12.9%), as were post-progression EGFR T790M mutation rates (43%; 50%). With superior PFS over PL + ERL and safety consistent with the overall RELAY population, RAM + ERL is a viable treatment option for EGFR-mutated metastatic NSCLC in East Asia.

A Randomized Phase 2 Study of Gefitinib With or Without Pemetrexed as First-line Treatment in Nonsquamous NSCLC With EGFR Mutation: Final Overall Survival and Biomarker Analysis.

INTRODUCTION: Clinical studies have shown that a combination of a tyrosine kinase inhibitor (TKI) and pemetrexed overcame acquired resistance to epidermal growth factor receptor (EGFR) TKI in NSCLC. Previously, pemetrexed+gefintib (P+G) had improved progression-free survival (PFS) compared with gefitinib. We present OS, updated PFS, biomarker analysis, and safety of P+G versus gefitinib. METHODS: This was a phase 2, multicenter, randomized study conducted in East Asian patients with advanced nonsquamous NSCLC with EGFR mutations. Patients were randomized (2:1) to receive P+G (500 mg/m2 intravenously 3-weekly + 250 mg/day orally) or gefitinib. RESULTS: In total, 191 patients (P+G, n=126; gefitinib, n=65) comprised the intent-to-treat and safety populations. Median OS was 43.4 months in P+G versus 36.8 months in gefitinib arm; adjusted HR 0.77 (95% CI, 0.5-1.2); one-sided P=0.105. Median PFS was significantly longer in the P+G (16.2 months) versus gefitinib arm (11.1 months); adjusted HR 0.67 (95% CI, 0.5-0.9); one-sided P=0.009. In the P+G and gefitinib arms, median PFS was 22.6 and 11.0 months, respectively, in patients with low thymidylate synthase (TS) expression, and 12.6 and 9.9 months, respectively, in patients with high TS expression. Common second-line post-discontinuation systemic therapies were EGFR-TKIs and chemotherapy. Most patients experienced at least one adverse event. CONCLUSIONS: Addition of pemetrexed to EGFR TKI gefitinib resulted in significantly improved PFS and numerically longer OS compared with gefitinib in treatment-naïve patients with EGFR-mutated advanced nonsquamous NSCLC. Low TS expression appeared to be a good predictor for treatment outcomes.

Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC. METHODS: This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up. FINDINGS: Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8-27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months [95% CI 15·4-21·6]) than in the placebo plus erlotinib group (12·4 months [11·0-13·5]), with a stratified hazard ratio of 0·59 (95% CI 0·46-0·76; p<0·0001). Grade 3-4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3-4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 [24%]; grade 3 only) and dermatitis acneiform (33 [15%]), and in the placebo plus erlotinib group were dermatitis acneiform (20 [9%]) and increased alanine aminotransferase (17 [8%]). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven [3%]) and cellulitis and pneumothorax (four [2%], each); the most common in the placebo plus erlotinib group were pyrexia (four [2%]) and pneumothorax (three [1%]). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group. INTERPRETATION: Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC. FUNDING: Eli Lilly.

[Pharmacological Effects of CDK4 & 6 Selective Inhibitor Abemaciclib in Hormone Receptor-Positive Breast Cancer].

Abemaciclib, a selective cyclin dependent kinases 4 and 6(CDK4 & 6)inhibitor, is under development for the treatment of hormone receptor(HR)-positive, HER2-negative breast cancer. CDK4 & 6 inhibitors attenuate Rb phosphorylation resulting in a G1 arrest and tumor growth inhibition. Abemaciclib potently inhibits both CDK4 and CDK6, with 14-fold higher potency for CDK4-cyclin D1 complexes than CDK6-cyclin D3 in enzymatic assays. Low frequency of severe neutropenia requiring drug holiday in clinical trials of abemaciclib in breast cancer patients enables continuous daily dosing. Abemaciclib's preclinical difference in selectivity for CDK4 vs CDK6 could help explain its safety profile and ability to be dosed on a continuous schedule. Continuous inhibition of CDK4 & 6 by abemaciclib results in irreversible growth inhibition through induction of senescence and apoptosis in breast cancer cell lines. Abemaciclib shows its growth inhibitory effect particularly in estrogen receptor(ER)- positive breast cancer, and sensitivity to abemaciclib is associated with high ER levels and Rb positivity. In animals bearing ERpositive breast cancer, significant tumor growth inhibition was shown by single-agent and combination with anti-estrogen agents. Abemaciclib penetrates the blood-brain barrier and showed antitumor activity in glioma models. As described above, there are some characteristics demonstrate differences of abemaciclib and other CDK4 & 6 inhibitors. In clinical studies, abemaciclib has demonstrated efficacy and generally tolerable safety profile in HR-positive, HER2-negative breast cancer patients.

Patients' preferences for postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer treatments in Japan.

BACKGROUND: This study aimed to identify factors affecting patients' preferences for postmenopausal hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer treatments, their relative importance, and impact of sociodemographic/clinical characteristics. METHODS: Japanese postmenopausal patients with HR+ breast cancer chose between 2 hypothetical treatments for HR+/HER2- advanced breast cancer using an online discrete choice experiment, defined by different levels of 5 attributes: progression-free survival (PFS), incidence of diarrhea (IOD), frequency of loose stools of grade 1-3 severity (FOS), duration of diarrhea (DOD), and route/frequency of administration (RFA). Conditional logit modeling identified relative preferences for each attribute. Subgroup analyses, based on sociodemographic characteristics (age, employment status, age of youngest child, marital status) and clinical characteristics (relapse/metastasis, hormone sensitivity), identified factors affecting preferences. RESULTS: Of 896 participants screened, 258 eligible participants were included in analyses. Patient preferences, when the potential frequency of diarrhea was grade 2, were (strongest to weakest): PFS, DOD, FOS, IOD, RFA; however, when the potential frequency of diarrhea was grade 3, FOS became most important. Sociodemographic/clinical characteristics tended to affect preferences. CONCLUSIONS: Japanese postmenopausal patients with HR+ breast cancer preferred treatments that extend PFS despite potential grade 2 diarrhea. However, when diarrhea severity increased to grade 3, patients were more willing to sacrifice PFS to avoid more frequent diarrhea. Prevention or limitation of diarrhea to grade ≤ 2 is important for maintaining patients' motivation for treatment that can extend PFS. Additionally, patient characteristics (age, family context, therapeutic experience) should be considered during treatment choice.

Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line treatment for stage IV squamous non-small cell lung cancer: A phase 1b and randomized, open-label, multicenter, phase 2 trial in Japan.

OBJECTIVES: This open-label, multicenter, phase 1b/2 study assessed necitumumab plus gemcitabine and cisplatin (GC + N) in patients with previously untreated squamous non-small cell lung cancer in Japan. MATERIALS AND METHODS: The phase 1b part determined the gemcitabine dose for the phase 2 part, in which patients were randomized 1:1 to GC + N or gemcitabine and cisplatin (GC) (gemcitabine 1250 mg/m2 on days 1 and 8; cisplatin 75 mg/m2 on day 1 of maximum four 3-week cycles; nectimumab 800 mg on days 1 and 8 of a 3-week cycle continued until progressive disease or unacceptable toxicity). The primary endpoint of the phase 2 part was overall survival. RESULTS: In the phase 2 part, 181 patients received GC + N (N = 90) or GC (N = 91). Overall survival was significantly improved with GC + N versus GC (median, 14.9 months vs 10.8 months; hazard ratio [HR] = 0.66, 95% CI: 0.47 - 0.93, p = 0.0161). Improvements were also observed in progression-free survival (median, 4.2 months vs 4.0 months; HR = 0.56; p = 0.0004) and objective response rate (51% vs 21%; p < 0.0001). Survival was also significantly prolonged with GC + N versus GC for patients with epidermal growth factor receptor-positive tumors. Grade ≥3 treatment-emergent adverse events at ≥5% higher incidence with GC + N than GC were neutrophil count decreased (42% vs 35%), febrile neutropenia (12% vs 3%), decreased appetite (11% vs 4%), and dermatitis acneiform (6% vs 0%). CONCLUSION: GC + N is well tolerated and has significant and clinically meaningful treatment benefit in the first-line treatment of patients with squamous non-small cell lung cancer in Japan. Clinicaltrials.gov identifier: NCT01763788.

Pemetrexed and carboplatin combination therapy followed by pemetrexed maintenance in Japanese patients with non-squamous non-small cell lung cancer: A subgroup analysis of elderly patients.

BACKGROUND: The combination of pemetrexed and carboplatin is commonly used for the treatment of advanced non-squamous non-small cell lung cancer (NSCLC), mainly because it is comparatively effective and less toxic than other platinum-doublet therapies. Using the JMII (JACAL) study, we report the efficacy and safety of this treatment followed by pemetrexed maintenance in the elderly population (≥70 years of age). METHODS: The JMII study was a multicenter, post-marketing study that assessed the efficacy and safety of carboplatin (AUC6) and pemetrexed (500 mg/m2, given on Day 1 of a 21-day cycle, 4 cycles) followed by pemetrexed (500 mg/m2) maintenance in advanced non-squamous NSCLC patients (n = 109). Retrospective subgroup analyses were performed in elderly patients aged ≥70. RESULTS: The study includes younger (<70 years, n = 84) and elderly (≥70 years, n = 25) patients who received induction therapy. Median progression-free survival and overall survival from the start of the induction phase were 5.2 (95% CI: 3.5, 8.2) and 16.8 (95% CI: 10.3, NC) months for the elderly patients compared with 5.8 (95% CI: 4.3, 7.4) and 20.5 (95% CI: 16.7, NC) months for the younger patients, respectively. Grade 3/4 hematologic toxicities were more frequent in the elderly patients. Non-hematologic toxicities in the elderly patients were comparable to those in younger patients. Dose reduction was more common in the elderly (44% vs 23%), due to hematologic toxicities. CONCLUSIONS: There was no difference in efficacy (evaluated by progression-free survival) between elderly and younger patients. Although grade 3/4 hematologic toxicities were frequently observed in the elderly patients, they were easily managed with dose adjustment.

[Pemetrexed for Treatment of Nonsquamous Non-Small-Cell Lung Cancer].

Pemetrexed(Alimta®)is a multi-targeted antifolate that shows antitumor effects by inhibiting enzymes in the folate metabolic pathway essential for cell replication. Pemetrexed is a standard treatment for Japanese patients with nonsquamous, non-small-cell lung cancer. In this review, we summarize the evidence of clinical studies for the efficacy and safety of pemetrexed in the treatment of nonsquamous non-small-cell lung cancer as first-line chemotherapy and continuation maintenance therapy. In addition, we describe future prospects for pemetrexed in combination with a recent approved PD-1 path- way inhibitor.

A phase 1 study of ramucirumab in Japanese patients with advanced solid tumors.

OBJECTIVE: Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. The aim of this phase 1 study was to evaluate the safety and tolerability of ramucirumab monotherapy in Japanese patients with advanced solid tumors. METHODS: Patients with solid tumors who had not responded to standard therapy or for whom no standard therapy was available received escalating doses of ramucirumab, administered once every 2 (Q2W) or 3 (Q3W) weeks. The primary objective was to establish the safety and pharmacokinetic profiles of ramucirumab. Secondary and exploratory objectives included assessment of immunogenicity and antitumor activity. ClinicalTrials.gov: NCT01005355. RESULTS: Fifteen patients were treated with ramucirumab at a dose of 6 mg/kg Q2W (N = 3), 8 mg/kg Q2W (N = 6) or 10 mg/kg Q3W (N = 6). There were no dose-limiting toxicities and the maximum tolerated dose was not reached. The most common ramucirumab-related adverse events were headache, pyrexia, hypertension and increased aspartate aminotransferase. Following single-dose administration of ramucirumab, there appeared to be a dose-proportional increase in maximum observed drug concentration but not in area under the curve. Treatment-emergent anti-ramucirumab antibodies were not detected in any patient. CONCLUSIONS: Ramucirumab monotherapy was well tolerated and feasible at the doses and schedules used in this study population of Japanese patients with advanced solid tumors.

Pemetrexed-related interstitial lung disease reported from post marketing surveillance (malignant pleural mesothelioma/non-small cell lung cancer).

BACKGROUND: Interstitial lung disease (ILD) is important drug related toxicity because it commonly forced to discontinue the treatment. METHODS: To characterize the prevalence and patterns of pemetrexed induced ILD, an independent ILD advisory board composed of external experts performed reassessment of ILD in two post marketing surveillance (PMS) studies for malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). RESULTS: ILD incidences were originally 1.6% and 2.6% in 903 MPM and 683 NSCLC patients in safety analyses, respectively. Based on the reassessment by the board, the incidence was 1.1% MPM and 1.8% NSCLC. Common possible risk factors of ILD in MPM and NSCLC patients were male gender, 60 years or older age, and pre-existing ILD. Asbestosis in MPM, and smoking history in NSCLC are also considered as risk, respectively. In terms of computed tomography (CT) pattern, 7 of 10 cases in MPM patients had acute interstitial pneumonia pattern, which four were fatal. Eight of the 12 NSCLC patients had diffuse grand glass opacity, which all had recovered. Onset of ILD in MPM varied between the first and the fifth courses of pemetrexed treatment, and the latest onset was 48 days after the last administration. For NSCLC, it was between the second and the ninth course, 7 and 56 days after the last administration. CONCLUSIONS: The risk of pemetrexed-related ILD is similar level as other anti-cancer drugs under clinical settings. Careful observations continuously during and at least for 2 months after the last administration of pemetrexed are advised.

Phase I study of the second-generation, recombinant, human EGFR antibody necitumumab in Japanese patients with advanced solid tumors.

PURPOSE: To establish the safety and pharmacokinetic profile of necitumumab in Japanese patients with advanced solid tumors not responsive to standard therapy or for which no standard therapy was available. METHODS: In this phase I study, patients aged ≥20 years with advanced solid tumors, and an Eastern Cooperative Oncology Group performance statuses of 0-1 were enrolled in a 3 + 3 design, with dose-escalation based on dose-limiting toxicity (DLT). Planned dose levels were: cohort 1: 600 mg IV, days 1 and 8, every 3 weeks; cohort 2: 800 mg IV, day 1, every 2 weeks; and cohort 3: 800 mg IV, days 1 and 8, every 3 weeks. After the first 6-week cycle, patients with an objective response or stable disease could continue to receive necitumumab (same dose and schedule) until disease progression or other withdrawal criteria were met. Safety, antitumor activity, and pharmacokinetics were assessed. RESULTS: Fourteen of 15 enrolled patients received all scheduled infusions in cycle 1 (median cycles: N = 2, range 1-4). No DLTs were observed. The most common treatment-emergent adverse events were headache (73 %), dry skin (67 %), pruritus (60 %), and rash (53 %), mostly grade 1/2. All patients achieved serum trough concentrations >40 µg/mL, a level associated with antitumor activity in preclinical models. No patients had an objective response; stable disease was seen in 67 % of patients. CONCLUSIONS: Necitumumab can be safety administered to Japanese patients at dose levels established in Western patients: 800 mg every 2 weeks, or on days 1 and 8 of a 3-week cycle.