Background

Vitamin B12 & folic acid supplementation (B12-FAS) reduces the incidence & severity of toxicity in pemetrexed based chemotherapy. It is recommended to initiate B12-FAS, 5-7 days before the 1st cycle. Observational & prospective single arm studies have not shown any increase in toxicity when pemetrexed was started earlier than recommended duration of B12-FAS.

Methods

This is a secondary analysis of PEMVITASTART – an open label randomized trial that assessed differences in hematological toxicity between patients initiated on pemetrexed-platinum chemotherapy following 5-7 days of B12-FAS (Delayed arm; DA) versus those receiving B12-FAS simultaneously (≤24 hours) with chemotherapy initiation (Immediate arm; IA). Eligible patients had locally advanced/metastatic non-squamous NSCLC & ECOG PS0-2. Block randomization was 1:1 into DA & IA. All enrolled patients received 3 weekly pemetrexed-platinum doublet [500mg/m² AND cisplatin (65mg/m²) OR carboplatin AUC 5.0mg/ml/min) each on D1] for a maximum of 6 cycles. Supplementation was 1000 µgm FA PO daily & 3 weekly 1000 µgm im vitamin B12. Herein, we present the non-hematological toxicity profile of PEMVITASTART.

Results

Of the 161 patients recruited (81 IA, 80 DA), 150 (77 IA, 73 DA) received ≥ 1 cycle & were included in modified ITT analysis. Baseline parameters were matched except for more females in DA (IA = 10.4%, DA = 23.3%, p = 0.03). The overall incidence of severe (≥grade 3) non hematological adverse events (AEs) was 25.3% (n = 38). The incidence of any grade & severe non hematological AEs was equal in both arms [any grade: IA 79.3% (n = 61), DA 78.1% (n = 57) p value=0.87; grade 3/4: IA 23.3% (n = 18), DA 27.4% (n = 20) p value=0.57], Table.Table: 417O

Non hematological AEs in PEMVITASTART

Conclusions

Secondary analysis of PEMVITASTART shows simultaneous B12-FAS initiation with pemetrexed-based chemotherapy is feasible with acceptable non hematological toxicity profile.

Clinical trial identification

NCT02679443 First received: February 1, 2016 Last updated: April 22, 2017 Last verified: April 2017

Legal entity responsible for the study

PGIMER, Chandigarh

Funding

PGIMER, Chandigarh

Disclosure

All authors have declared no conflicts of interest.

Background

Osimertinib is a 3^rd generation, CNS-active EGFR-TKI that potently and selectively inhibits both EGFRm and EGFR T790M resistance mutations. FLAURA (NCT02296125) is a PhIII, double-blind, randomised study assessing efficacy and safety of osimertinib vs SoC EGFR-TKI in first-line pts with EGFRm advanced NSCLC. We present results of an Asian subset (Asian pts enrolled at Asian sites) of FLAURA.

Methods

Eligible pts: ≥18 yrs (Japan: ≥20 yrs), no prior EGFR-TKI/systemic anti-cancer therapy for advanced disease, with Ex19del/L858R EGFRm advanced NSCLC. Neurologically stable pts with CNS mets were allowed, provided definitive treatment/steroids were completed for ≥2 weeks. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or SoC EGFR-TKI (gefitinib 250 mg or erlotinib 150 mg qd po), stratified by mutation status (Ex19del/L858R) and race (Asian/non-Asian). Primary endpoint: progression-free survival (PFS) by RECIST v1.1, by investigator. Data cutoff: 12 June 2017.

Results

322 Asian pts (Chinese n = 46, Japanese n = 120, other Asian n = 156) received treatment. Baseline characteristics were generally balanced across arms.

PFS benefit was broadly consistent across predefined subgroups (HR ranging from 0.48–0.68). Median total treatment duration (range): 15.5 (0.5–25.5) mo with osimertinib; 11.7 (0–26.2) with SoC. All causality adverse events (AEs), by investigator: osimertinib, 99% (Gr ≥ 3, 40%); SoC, 99% (Gr ≥ 3, 48%). AEs leading to discontinuation: osimertinib, 15%; SoC, 21%. Most common all causality AEs with osimertinib: diarrhoea (54% [Gr ≥ 3, 2%]), paronychia (40% [1%]); SoC: diarrhoea (54% [3%]), dermatitis acneiform (53% [6%]).

Conclusions

Results in Asian pts with EGFRm advanced NSCLC were consistent with the overall results of the FLAURA study. First-line osimertinib demonstrated superior efficacy over SoC. There were no new safety findings.

Clinical trial identification

NCT02296125

Legal entity responsible for the study

AstraZeneca

Funding

AstraZeneca

Disclosure

B.C. Cho: Research funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST; Consulting role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Yuhan, Pfizer, Eli Lilly. V. Sriuranpong: Received only clinical trial related support from Astra Zeneca. F. Imamura: Research fund, Honoraria from AstraZeneca. Y. Ohe: Honoraria: AstraZeneca, Chugai, Lilly, Ono, BMS, Daiichi-Sankyo, Nipponkayaku, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho Research; Funding: AstraZeneca, Chugai, Lilly, ONO, BMS, Kyorin, Dainippon- Sumitomo, Pfizer, Taiho, Novartis, Merck Serono; Consulting Or Advisory Role: AstraZeneca, Chugai, Lilly, Ono, Novartis. N. Nogami: Meiji Seika Pharma Co., Ltd. AstraZeneca Pfizer Inc. Bristol-Myers Squibb Ono Pharmaceutical Co., Ltd. Kyowa Hakko Kirin Taiho Phamaceutical Co., Ltd. Chugai Pharmaceutical Co., Ltd Eli Lilly Japan Boehringer Ingelheim. T. Kurata: Honoraria; AstraZenaca Research funding; AstraZeneca. I. Okamoto: Grants and personal fees from AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Taiho Pharmaceutical, Boehringer Ingelheim, and Pfizer Japan. C. Zhou: Lecture honoraria: Eli Lily, AstraZeneca, Roche, Pfizer, Sanofi, Boehringer Ingelheim, Henrui; Ad Board: Roche, Boehringer Ingelheim, AstraZeneca. H. Mann, M. Saggese: Employee of AstraZeneca.

All other authors have declared no conflicts of interest.

Table: LBA6_PR

Background

ROS1 rearrangement has been identified in 1-2% of NSCLC cases. Noninvasive genotyping of driver genes and monitoring of tumor dynamics help make better personalized therapeutic decisions. The aim of this study is to investigate the feasibility and performance of capture-based sequencing on ROS1 fusion detection, we developed a targeted region capture combined sequencing panel to detect and quantify rearrangement events, along with other driver mutation variants in plasma.

Methods

We screened 2617 patients with NSCLC for ROS1 rearrangements, and collected blood samples from 67 of them with confirmed ROS1 rearrangements based on their tissue biopsies. We obtained longitudinal blood samples of 16 ROS1 positive NSCLC patients after crizotinib treatment for disease monitoring.

Results

In total, we identified 62 genetic alterations with a median of 3.9 mutations per patient. 93% of patients still exhibit rearrangements, and 31% of patients acquired ROS1 required point mutations. Besides other known resistance mechanisms, we identified CDKN2A mutations in 19% of patients. Interestingly, we also observed TERT, PTPRD, NFE2L2 and OR5L2 mutations in ROS1 required point mutations negative patients, which were restricted to crizotinib resistance. In addition to detecting ROS1 rearrangements, we also detected one kind of crizotinib resistant mutations, ROS1 G2032R from 5 patients. ROS1 rearrangements were successfully blood samples detected in 42 of 67 patients at baseline with 62.7% sensitivity and 100% specificity. ctDNA concentration correlates with responses and disease progression, reflecting its ability as a biomarker.

Conclusions

The suitable sensitivity and the high specificity between tissue and plasma ROS1 determination supports the blood-based ROS1 rearrangements testing to determinate the eligibility of NSCLC patients for crizotinib treatment. Blood is a good screening substitute when tumor tissue is absent or insufficient for testing ROS1 rearrangements to guide crizotinib treatment in NSCLC. ROS1 rearrangement in blood could be used to recommend crizotinib treatment, but the blood negativity should be confirmed with other sample, biopsy tissue, pleural effusion, etc.

Legal entity responsible for the study

Wang Wenxian

Funding

None

Disclosure

All authors have declared no conflicts of interest.

Background

The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1–2% of non-small cell lung cancer (NSCLC). Alectinib (300 mg BID) has been approved for the treatment of anaplastic lymphoma kinase (ALK) fusion-positive NSCLC in Japan; it also has a high activity against RET in vitro. A global trial showed the efficacy and safety of alectinib (600 mg BID) in ALK fusion-positive NSCLC patients. Therefore, we conducted a phase 1/2 study of alectinib to establish the recommended dose and examine its activity in RET fusion-positive NSCLC patients.

Methods

This study is a single-arm, open-label, multi-institutional phase I/II trial. RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy were recruited. In the phase 1 portion (step 1) using 3 + 3 design to establish the recommended dose, alectinib (cohort 1/2: 600 mg/450 mg BID) was orally administered in a 21-day cycle. Dose-limiting toxicity (DLT) was evaluated during the first cycle. Here, we present data for the phase 1 portion of the study; phase 2 is ongoing. This study is registered at the UMIN Clinical Trials Registry (UMIN000020628).

Results

We enrolled 10 patients (2 patients previously treated with RET-TKIs, vandetanib and/or lenvatinib) in step 1, and 9 patients could be evaluated. In cohort 1, we observed 5 DLTs (grade 3 rash, increased aspartate aminotransferase, erythema multiforme, thromboembolic event, and increased CPK) in 3 of 6 patients. In accordance with the protocol, we moved to cohort 2 and observed no DLTs in 3 patients. The most commonly reported adverse events (occurring in ≥ 30% of patients) in step 1 were constipation, increased creatinine, increased CPK, and myalgia. Serious adverse events reported in one patient in cohort 1 were grade 3 biliary tract infection and grade 2 lower limb muscle weakness.

Conclusions

On the basis of DLTs, we determined alectinib 450 mg BID as the recommended dose for phase 2. Phase 2 is ongoing.

Clinical trial identification

UMIN000020628.

Legal entity responsible for the study

Seiji Yano

Funding

the Japan Agency for Medical Research and Development, AMED

Disclosure

T. Seto, K. Goto, S. Yano: Speaker honoraria and research funding from Chugai Pharmaceutical Co, Ltd.

All other authors have declared no conflicts of interest.

Background

Primary results of EAST-LC trial in previously-treated NSCLC demonstrated the non-inferiority in terms of overall survival (OS) of S-1 to DOC in Asia. Here we present PROs, an important consideration in assessing the benefit of particular anticancer therapies.

Methods

1154 patients were randomly assigned either S-1 (80–120 mg/day on days 1–28 every 42-days) or DOC (60 mg/m2 in Japan, 75 mg/m2 in other countries, on day 1 every 21 days). The EORTC QLQ-C30 and QLQ-LC13 were administered at baseline, every 6 weeks and end of treatment. Repeated measures mixed-effect modal was performed by overall scores and change from baseline scores.

Results

QOL questionnaire compliance was over 90% at baseline. The difference in least squares (LS) means of QLQ-C30 global health status was 2.454 (95% CI -0.124 to 5.033; P = 0.0621). The QOL score was -7.506 (-9.811to -5.201) for S-1 and -9.96 (-12.158 to -7.762) for DOC. The difference in LS means of QLQ LC-13 module partially comprises of diarrhea, decreased appetite, alopecia and peripheral neuropathy was 0.144 (95% CI -2.144 to 2.432; P = 0.9016), 5.511 (95% CI 2.320 to 8.703; P = 0.007), -46.02 (95% CI -49.616 to -42.424; P < 0.0001) and -6.947 (95%CI -9.998 to -4.052; P < 0.0001), respectively. An improvement from baseline was observed with S-1 versus DOC for alopecia and peripheral neuropathy while small difference in diarrhea and decreased appetite. The adverse events of any grade diarrhea and decreased appetite were higher in the S-1 group (37.4% vs. 18.2%, P < 0.0001; 52.7% vs. 37.9%, P = 0.0012 in S-1 and DOC groups, respectively). Alopecia and peripheral sensory neuropathy were as followed; (1.9%vs 46.8%; 4.7% vs 16.6% in S-1 and DOC group, respectively). The other PROs will also be presented.

Conclusions

Small differences in PROs in gastrointestinal toxicity items (diarrhea and decreased appetite) were observed and these toxicities were higher in patients treated with S-1. In contrast, large differences in DOC related alopecia and peripheral neuropathy remained in PROs. The observed differences in PROs may provide a rationale in selecting S-1 over docetaxel.

Legal entity responsible for the study

Taiho Pharmaceutical Co., Ltd

Funding

Taiho Pharamaceutical Co., Ltd.

Disclosure

R. Soo: Grants: AstraZeneca; Personal fee: AstraZeneca, Taiho, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, BMS. T.S.K. Mok: Grants and personal fee: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, SFJ, Roche, MSD, Clovis Oncology, BMS; Personal fee: Genentech, Eli Lilly, Amgen, Janssen, GSK, PrIME Oncology, Merck Serono, BioMarin, ACEA Biosciences, Vertex, Aveo & Biodesix, Prime Oncology, OncoGenex Pharmaceutical, OncoGenex Technologies, PeerVoice, and geneDecode; Holds stock in Sanomics limited. L. Zhang: Grants: AstraZeneca, BMS, Pfizer. S. Lu: Grants and personal fee: AstraZeneca, Boehringer Ingelheim, Roche Hutchison, MediPharma, genomiCare, Pfizer. J.C-H. Yang: Personal fee: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, AstraZeneca, Astellas, MSD, Merck Serono, Pfizer, Novartis, Clovis Oncology, Celgene, Innopharma, Merrimack. K. Nakagawa: Grants: Oncotherapy Science, EPS Associates, Quintiles, Japan Clinical Research Operations; Grants and personal fee: Taiho, Takeda, Eli Lilly, Eisai, MSD, Ono, Daiichi-Sankyo, Chugai, AstraZeneca, Astellas. N. Yamamoto: Grants and personal fee: Taiho. H. Nokihara: Grants and personal fee: Taiho, Boehringer Ingelheim, AstraZeneca, Ono, Eli Lilly, Chugai; Grants: Merck Serono, Pfizer, Eisai, Novartis, Daiichi Sankyo, GSK, Yakult, Quintiles, Astellas; Personal fee:Sanofi, BMS. S. Sugawara: Personal fee: Chugai, Pfizer, Nippon Boehringer Ingelheim, Taiho, AstraZeneca, Eli Lilly, Novartis, Kyowa Hakko Kirin, Bristol-Myers Squibb, Ono. M. Nishio: Grants: Novartis, Astellas; Grants and personal fee: Ono, Chugai, Bristol-Myers Squibb, Taiho, Eli Lilly, Pfizer, AstraZeneca. T. Takahashi: Grants and personal fee: AstraZeneca, Eli Lilly Japan, Chugai, Ono; Grants from Takeda, MSD; Personal fee: Boehringer Ingelheim Japan. K. Goto: Grants: MSD, Quintiles, GSK, OxOnc, Sumitomo Dainippon, Takeda, Astellas, Eisai, Amgen Astellas Biopharma, Merck Serono, AbbVie Stemcentrx, Riken Genesis; Grants and personal fee: AstraZeneca, Taiho, Chugai, BMS, Nippon Boehringer Ingelheim, Ono, Pfizer, Kyowa Hakko Kirin, Eli Lilly Japan, Novartis, Daiichi-Sankyo; Personal fee: Yakult Honsha, Abbott Japan. Y. Ichinose: Grants: Takeda Bio Development Center; Grants and personal fee: Taiho, Chugai; Personal fee: Kyowa Hakko Kirin, Taisho Toyama, Pfizer, Ono, Eli Lilly, Kaketsuken. S. Morita, T. Tamura: Personal fee: Taiho.

All other authors have declared no conflicts of interest.

Background

Programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry (IHC) is a predictive factor for anti–PD-1/PD-L1 monoantibodies. However, intertumoral heterogeneity of PD-L1 expression and its accordance between resected tissue and biopsy tissue or cytological tumor samples remains controversial.

Methods

A total of 72 patients who consecutively undergone primary lung cancer resection and were diagnosed as pulmonary adenosquamous carcinoma were included. PD-L1 expression level was assessed by IHC (PD-L1: Clone E1L3N; Cell Signaling #13684) in different histological component of both primary and lymph node tissues respectively.

Results

With a 5% of cutoff, PD-L1 expression was 20.8%, 33.3% in adenomatous and squamous cell component respectively. When various cutoffs including 0.01, 0.05, 0.10 were used, the PD-L1 expression was discrepant in 26.4%, 19.4%, 12.5% cases respectively. With combination of the expression in tumor cells (TC) and tumor-infiltrated lymphocytes (TILs), discrepancies between two histological components were observed in 13.9%, 22.2%, 30.6% cases repectively. Of 38 lymphatic metastasis cases, there were 4 types of lymphatic node histology including adenocarcinoma, squamous cell, adenosquamous and a mixture of above. By different histological component and cutoff value, the concordances of PD-L1 expression were in 74.1%, 80.0%, 88.9% cases for adenomatous cell component and 90.0%, 80.0%, 85.0% cases for squamous cell component respectively. In addition, the discrepancy of adenocarcinoma histological subtype accounts for the lower concordant rate in adenomatous component.

Conclusions

PD-L1 expression showed a high discrepancy among adenomatous component and squamous cell components. In contrast, PD-L1 was highly consistent between paired histological types of lymph node and the primary lesion, which may suggest that the intrinsic genomic features plays important role in the PDL1 heterogeneously expression.

Legal entity responsible for the study

Tongji Pulmonary Hospital, Tongji University

Funding

Shanghai Municipal Education Commission

Disclosure

All authors have declared no conflicts of interest.Table 1.1: 396O

PD-L1 difference between adenomatous and squamous components

Background

Whether low molecular-weight heparins impact the survival of cancer patients remains controversial. We assessed the effect of tinzaparin on survival of patients with resected early-stage non-small cell lung cancer (NSCLC)

Methods

Patients with completely resected stage I, II or IIIA NSCLC were randomized within 8 weeks of surgery to usual care with or without tinzaparin 100 IU/kg daily for 12 weeks. The primary outcome was overall survival (OS). All clinical outcomes were centrally and blindly adjudicated.

Results

From August 2007 to June 2013, 549 patients were randomized to tinzaparin (n = 269) or control (n = 280). A total of 359 (65.4%) and 190 (34.6%) patients had stage I and II-III disease, respectively, and 220 patients (40.1%) received adjuvant chemotherapy. Median follow-up was 5.7 years. There was no significant difference in OS between groups (Hazard Ratio [HR], 1.24; 95% Confidence Interval [CI], 0.92 to 1.68; P = 0.17). Five-year OS was 74.2% (95% CI, 68.9% to 79.9%) and 68.2% (95% CI, 62.5% to 74.4%) in the control and tinzaparin groups, respectively. There was no difference in the cumulative incidence of recurrence between groups (subdistribution HR 0.94; 95% CI, 0.68 to 1.30; P = 0.70). In patients who received adjuvant chemotherapy, OS was lower in the tinzaparin group (HR, 1.78; 95%CI, 1.13 to 2.81; P = 0.013). Two patients in the tinzaparin group experienced serious bleeding during the treatment period.

Conclusions

Adjuvant tinzaparin at a dose of 100 IU/kg/d for 12 weeks had no detectable impact on overall and recurrence-free survival of patients with completely resected stage I-IIIA NSCLC.

Clinical trial identification

NCT00475098

Legal entity responsible for the study

Hôpital Européen Georges Pompidou, Paris, France

Funding

Leo Pharma

Disclosure

All authors have declared no conflicts of interest.