Non-sq NSCLC Research Articles

Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC).

LBA109 Background: Options for advanced non-SQ NSCLC patients (pts) who progress after platinum-based doublet chemotherapy (PT-DC) are limited, with minimal improvement in overall survival (OS). We report results from a randomized, global phase III study of NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC and tyrosine kinase inhibitor, if eligible. Methods: Pts were randomized to NIVO 3 mg/kg Q2W (n=292) or DOC 75 mg/m2 Q3W (n=290) until progression or discontinuation due to toxicity/other reasons. Primary objective was OS; Secondary objectives were investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression, quality of life, and safety. Results: NIVO demonstrated superior OS (HR=0.73; 96% CI: 0.59, 0.89; P=0.00155) and improved ORR (19.2% vs 12.4%; P=0.0235). HR for PFS was 0.92 (95% CI: 0.77, 1.11; P=0.393). PD-L1 expression was associated with benefit from NIVO (Table). In PD-L1+ pts, NIVO showed improved efficacy across all endpoints at predefined 1%, 5%, and 10% cut- points. Grade 3–5 drug-related AEs occurred in 10.5% (30/287) of NIVO and 53.7% (144/268) of DOC pts. No deaths were related to NIVO vs 1 DOC-related death. After discontinuation, 42.1% of NIVO and 49.7% of DOC pts received subsequent systemic therapy. Conclusions: NIVO demonstrated superior OS vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC. The safety profile of NIVO 3 mg/kg Q2W was favorable vs DOC. NIVO demonstrated survival benefit across histologies in two randomized phase III trials. Clinical trial information: NCT01673867. [Table: see text]

A multicenter phase II study of S-1 combined with bevacizumab after platinum-based chemotherapy in patients with advanced non-squamous non-small cell lung cancer.

e19040 Background: The additional effects of bevacizumab (B) as first-line chemotherapy for non-squamous non-small cell lung cancer (Non-sq NSCLC) have been established. However, the efficacy of B ...

O3-9-1 - Weekly Paclitaxel in Combination with Bevacizumab in Patients with Non-Sq Nsclc Who Have Failed Previous Treatments

Backgrounds: Bevacizumab (BEV) in combination with paclitaxel (PTX) and carboplatin (Cb) has provided survival benefit for advanced non-small cell lung cancer (NSCLC) as first-line treatment. However, tri-weekly PTX therapy induce severe peripheral neuropathy frequently, and may deteriorate quality of life. Because of this toxicity, platinum plus pemetrexed regimen may be preferred as first-line treatment over Cb/PTX/BEV regimen. Weekly paclitaxel (w-PTX) regimen has proved to be effective and safe in a large number of clinical trials for advanced solid tumors. However, few clinical studies have focused on the comparison between w-PTX and tri-weekly PTX in advanced NSCLC. We previously reported that fractionated administration of paclitaxel may be less toxic and more active against advanced NSCLC in clinical trials. Furthermore, several studies have reported that combination chemotherapy of w-PTX and BEV proved survival benefit in patients with advanced breast cancer. Therefore, we conducted a phase II trial to evaluate the efficacy and toxicity for the combination chemotherapy of w-PTX and BEV in patients with advanced non-squamous (non-Sq) NSCLC who have failed previous treatment.Methods: Eligibility required ECOG performance status 0-2 and prior cytotoxic chemotherapy. The primary end point of the phase II study was the progression free survival (PFS). PTX was infused on days 1, 8 and 15, and BEV (15 mg/kg) was administered on day 1 of a 4-week cycle until PD. Toxicity evaluations were based on CTCAE (version 4).Results: Between September 2011 and January 2014 a total of 30 eligible patients were enrolled onto the study.Conclusions: This combination of w-PTX and BEV is both feasible and active in the treatment of patients with advanced non-Sq NSCLC. We will soon start a phase II study evaluating this combination as first-line treatment.

SY3-2 - Continuation Maintenance for Elderly Patients with Advanced Non-Small-Cell Lung Cancer(Nsclc)

The population of elderly NSCLC patients continues to increase with growing geriatric population, and more than 50% of Japanese patients with advanced NSCLC will be aged more than 75 years. It is thus important to establish modern standard treatment for those populations.Two randomized phase III trials (WJOTG9904, JCOG0803/WJOG4307L) consistently demonstrated that first-line single agent docetaxel (60 mg/m2 q3w) had encouraging survival outcomes with median survival time of 14.3 months and 14.8 months, respectively. Recently, French group published their phase III trials demonstrating that carboplatin (AUC 6) plus weekly paclitaxel (90 mg/m2) significantly improved overall survival (median of 10.3 versus 6.2 months, P < 0.001) comparing single agent gemcitabine or vinorelbine for advanced NSCLC patients aged 70-89 years, suggesting that carboplatin-based combination is beneficial to elderly patients. We are now conducting a randomized phase III trial (JCOG1210/WJOG7813L) comparing single agent docetaxel (60 mg/m2 q3w) vs carboplatin (AUC 5, q3w) plus pemetrexed (500 mg/m2 q3w up to 4 cyles) followed by pemetrexed continuation maintenance for advanced non-squamous (sq) NSCLC aged more than 75 years old. Pemetrexed continuous maintenance has recently emerged as a novel therapeutic paradigm for advanced non-sq NSCLC based on the phase III trial (PARAMOUNT) demonstrating prolonged overall survival as well as progression-free survival. Several clinical data suggest that pemetrexed continuation after platinum combination is feasible even for elderly patients with non-sq NSCLC. Together, how to apply these data to our clinical practice will be discussed at this symposium.

Brain Metastases Safely Treated with WBRT after Bevacizumab and Chemotherapy in NSCLC

Patients who had brain metastases following bevacizumab and chemotherapy (CT) for non-squamous, non—small cell lung cancer (non-Sq NSCLC) were safely treated with whole-brain radiotherapy, with a good response and symptom improvement.

First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status.

8024 Background: The fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody nivolumab has demonstrated durable responses and tolerability in patients (pts) with previously treated advanced NSCLC. Tumor PD-1 ligand (PD-L1) expression is being studied as a potential biomarker for nivolumab. We report interim phase I results of first-line nivolumab in chemotherapy-naïve advanced NSCLC pts. Methods: Pts with squamous (sq) or non-sq advanced NSCLC received nivolumab 3 mg/kg IV Q2W until progression or unacceptable toxicity (post-progression treatment allowed based on protocol-defined criteria). Responses (RECIST 1.1) were evaluated overall and according to tumor PD-L1 status (PD-L1+ = ≥5% tumor cells expressing PD-L1 [Dako immunohistochemistry assay]). Results on the first 20 pts are included. Results: After ≥6 months follow up, 17 pts (85%) experienced any-grade treatment-related adverse events (AEs), managed with standard algorithms. Treatment-related grade 3-4 AEs (3 pts, 15%) were AST or ALT elevations, hyperglycemia, and rash (n=1 each). No pneumonitis (any grade) was observed. Objective response rate (ORR) was 30% (Table); 5/6 responders (83%) achieved response by first scan (wk 11). Two pts had >80% target lesion reduction at 18 wks. Of 15 evaluable tumor samples, 9 were PD-L1+. ORR was 67% in PD-L1+ pts; no responses were observed in the 6 PD-L1- pts. Responses were durable (median duration of response [mDOR] not reached [NR]; 5 ongoing responses). Conclusions: In this phase I study, nivolumab led to early, durable responses in advanced NSCLC pts, with a tolerable safety profile. PD-L1 status appeared to correlate with ORR/progression-free survival (PFS). Follow up and responses of 30 additional treated pts will be reported. These data support further studies of first-line nivolumab monotherapy in advanced NSCLC. Clinical trial information: NCT01454102. ORR mDOR Median PFS n/N (%) wk (range) All pts 6/20 (30) NR (11.1+, 37.7+) 29.6 (5.9, 47.6+) Non-sq 4/11 (36) NR (36.1, 37.7+) 45.6 (9.6, 47.6+) Sq 2/9 (22) NR (11.1+, 27.9+) 15.1 (5.9, 37.9+) PD-L1+ 6/9 (67) NR (11.1+, 37.7+) NR (8, 47.6+) PD-L1- 0/6 n/a 23.1 (9.6, 47.3+) PD-L1 unknown 0/5 n/a 15.1 (5.9, 35.7+)

O1–146 - Rechallenge with EGFR-TKI after a Drug Holiday, Retrospective Study in Single Institution

Purpose: Patients with advanced non-squamous non-small cell lung cancer (Non-Sq NSCLC) harboring somatic EGFR mutations respond well to the EGFR tyrosine kinase inhibitor (TKI) in initial therapy. However, patients with an activating EGFR mutation who initially respond to EGFR-TKI eventually relapse with resistant disease. The molecular mechanism of resistance is poorly understood. The aim of this retrospective study was to investigate whether rechallenge with EGFR-TKI after a drug holiday was beneficial. Methods: We retrospectively reviewed the medical records of 22 patients with stage IV Non-Sq NSCLC who experienced progressive disease after 1st EGFR-TKI, were subsequently treated with cytotoxic drug and retreated with EGFR-TKI at renewed progression. Results: Twenty two patients (10 male, 12 female, median age 66 years(50-84 years), all adenocarcinoma, EGFR mutation status; Ex19 del./L858R/other/unknown=10/9/1/2) received treatment with 2nd EGFR-TKI. 1st response rate(RR), 1st disease control rate (DCR), 1st time to treatment failure(TTF) and 1st progression free survival(PFS) were 59%, 100%, 8.5M and 9.5M, respectively. 2nd RR, 2nd DCR, 2nd TTF and 2nd PFS were 0%, 72%, 7M and 7M, respectively. Median drug holidays of EGFR-TKI was 7.5M. Conclusions: Our findings suggest that rechallenge with 2nd EGFR-TKI is an option for patients with Non-Sq NSCLC who received a benefit from 1st EGFR-TKI and experienced progressive disease after cytotoxic chemotherapy.

O3–097 - Phase II Study of Bevacizumab Plus CBDCA/PAC as First Line Chemotherapy for Non-SQ NSCLC with Malignant Pleural Effusion

O3–097 - Phase II Study of Bevacizumab Plus CBDCA/PAC as First Line Chemotherapy for Non-SQ NSCLC with Malignant Pleural Effusion

Survival analysis of induction cisplatin (CDDP)-docetaxel (DOC)-bevacizumab (BEV) chemotherapy followed by maintenance BEV-pemetrexed (PEM) therapy in advanced nonsquamous non-small cell lung cancer (NonSq NSCLC): A phase II trial from Okayama Lung Cancer Study Group 0903.

e19040 Background: BEV maintenance therapy and PEM maintenance therapy in platinum-based chemotherapy yield a significant survival advantage in CALGB and PARAMUNT trials, respectively, but each agent gave only modest impact on survival. We conducted a phase II trial of CDDP-DOC-BEV therapy followed by maintenance BEV-PEM therapy inchemo-naïve advanced NonSq NSCLC. Methods: Forty-one patients (pts) participated in the induction phase, specified as four cycles of induction CDDP (80 mg/m2), DOC (60 mg/m2) and BEV (15 mg/kg) on day 1 of a 21-day cycle. Pts who had not progressed during CDDP-DOC-BEV received maintenance BEV (15 mg/kg) and PEM (500 mg/m2) on day 1 of a 21-day cycle until disease progression. The primary endpoint was PFS, and the secondary endpoints included OS, toxicity, and response. Survival time was calculated from the date of registration. Results: Pt characteristics were as follows: median age: 62 yrs; 76% male; 32% PS 0; 73% stage IV; 93% Ad; 5% EGFR-mutant and 2% ALK-mutant. At the time of this analysis, 34 pts (83%) discontinued the treatment, mainly due to progressive disease (53%). The principal toxicity was myelosuppression (gr. 4 hematological: 21 pts [51%]), and grs. 3/4 febrile neutropenia was observed in 10 (24%) despite no treatment-related deaths. The objective response rate and disease control rate (DCR, % pts with CR/PR/SD) was 82.9% and 97.6%, respectively. Median follow-up time was 15.6 months, and 1-yr PFS rate was 34.2% with 95% confidence interval (CI) of 20.3-48.5%, which met the primary endpoint. Also, 1-yr OS rate was 75.6% (95%CI: 59.4-86.1%). Exploratory analysis for pts with both EGFR- and ALK-wild-typed NonSq NSCLC (n = 16) demonstrated 1-yr PFS and OS rates of 50.0% (24.5-71.1%) and 87.5% (58.6-96.7%), respectively. Also, pts with maintenance therapy (n = 34) had 1-yr PFS and OS rates of 41.2% (24.8-56.9%) and 82.4% (64.9-91.7%), respectively. Conclusions: CDDP-DOC-BEV followed by BEV-PEM maintenance seems highly effective despite moderately toxic profiles in chemo-naïve pts with advanced NonSq NSCLC. Clinical trial information: UMIN000004127.

WS4-4 - A Phase II Study of Pemetrexed in Chemotherapy-Naive Elderly Patients with Advanced Non-Squamous Non-Small-Cell Lung Cancer: Hanshin Oncology Group 003

ABSTRACT Background Single-agent chemotherapy (i.e. doxetaxel, gemcitabine or vinorelbine) is one of the standard treatments for elderly patients with advanced NSCLC. Pemetrexed has clinically equivalent efficacy, but with less toxicity compared with doxetaxel in the second-line setting of patients with advanced NSCLC. We conducted a phase II trial to evaluate the efficacy and safety of frontline pemetrexed in elderly patients with advanced non-squamous (non-Sq) NSCLC. Methods In this multicenter phase II trial, we recruited elderly patients with non-Sq NSCLC. Eligibility criteria were as follows: chemonaive; locally advanced or metastatic non-Sq NSCLC; age 75 or older; ECOG performance status 0-1; adequate organ function. Patients received pemetrexed (500 mg/m2) intravenously on day 1 every 3 weeks until disease progression had been confirmed. The primary end point was response rate (RR). The secondary end points included progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. The planned sample size was 45 patients. Results Between August 2009 and July 2011, 47 patients were enrolled. Median age was 79 years (range: 75–91), 57% (20 of 47) were male, 36% (17 of 47) had never smoked, 85% (40 of 47) had adenocarcinoma, 72% (34 of 47) had stage IV and 41% (16 of 39) had EGFR tyrosine kinase activating mutation. Median number of cycles was 4 (1 to 15). RR was 13.3% (95% CI: 5.1, 26.8), DCR was 66.7% (95% CI: 51.0, 80.0), PFS was 4.9 months (95% CI: 3.0, 6.2 months), median OS was not reached. The most frequent treatment-related AEs were anemia, fatigue, hypocalcemia, mostly grade 1/2. Treatment-related grade 3/4 AEs were reported in 17.8% of patients (mostly neutropenia and fatigue). No treatment-related death occurred. Conclusions The efficacy and limited side-effects of pemetrexed are promising in elderly patients with non-Sq NSCLC.

IS7-11 - Post-Marketing Clinical Study of Pemetrexed (PEM) Combined with Carboplatin (CBDCA) Followed by Maintenance PEM in Patients with Non-Squamous Non-Small Cell Lung Cancer (non-sq NSCLC): 18-Month Follow-up Data

ABSTRACT Objectives and methods The aim of this study was to evaluate the efficacy and safety of PEM (500 mg/m2 day 1, q3w)/CBDCA (AUC 6 day 1, q3w) followed by PEM maintenance therapy in chemo-naive patients with non-sq NSCLC. This reports the analysis results using data collected up to 18 months after last patient entered treatment (data cutoff, January 2012). Results The study included 69 men and 40 women (n = 109) with a median age of 63 years. Of the 109 patients, stage IIIB, IV and recurrent disease were observed in 33 (30%), 72 (66%) and 4 (4%) patients, respectively. A total of 75 patients (69%) completed four cycles of the induction phase by PEM/CBDCA combination therapy and 60 patients (55%) moved to the PEM maintenance phase. Relative dose intensities were 88.8% for PEM and 89.5% for CBDCA during the induction phase, and 89.4% for PEM maintenance. The overall response rate and disease control rate were 34.9% and 72.5% for the entire study period (n = 109), and 3.3% and 48.3% for the maintenance phase (n = 60), respectively. Median progression-free survival was 5.6 months after beginning PEM/CBDCA and 3.9 months after beginning PEM maintenance. In the entire study period, the most common toxic effects were anorexia (75%), nausea (74%) and fatigue (68%). Grade 3–4 neutropenia, thrombocytopenia and anemia were 56%, 41% and 29%, respectively. Newly emerged or deteriorated toxic effects during the maintenance phase were rarely observed. There were no treatment-related deaths. Updated study data including overall survival will be reported at the conference. Conclusions PEM/CBDCA followed by PEM maintenance therapy had a manageable safety profile. These results suggested efficacy in these patients with non-sq NSCLC.

P2-031 - An Investigation into P/B-Maintenance Therapy Following Combined Therapy with Carboplatin (C) + Pemetrexed (P) + Bevacizumab (B) as the Primary Treatment against Non-SQ NSCLC

ABSTRACT Background After performing the PARAMOUNT study, the significant prolongation of PFS was observed when conducting maintenance therapy with the single agent of P alone following cisplatin (CDDP) + P therapy. Upon an AVAPERL study, P/B-maintenance therapy exhibited a better PFS than the single agent of B alone following CDDP/P/B. Purpose The safety and efficacy was investigated regarding conducting P/B-maintenance therapy following primary treatment with C/P/B. Methods C AUC 5 + P 500 mg/m2 + B 15 mg/kg were administered in 3-week intervals at a maximum of six courses to PS 0–3, stage IV, non-Sq NSCLC patients of ≥20 with no history of prior treatment who maintained adequate organ function. Maintenance therapy with P/B was conducted in non-PD cases at 3-week intervals until they became PD. Outcome There were seven cases (December 2009 to November 2010) of men/women: 5/2, with a median age of 64 years old (47–76), PS 0/1/3: 2/3/2 and adenocarcinoma/large cell carcinoma: 6/1. The antitumor effect was: CR/PR/SD/PD: 0/5/1/1, RR = 71%, median PFS = 8.9 M and OS = 15 M, which was slightly better compared with the RR = 66%, PFS = 8.4 M of 17 cases that simultaneously underwent P following C/P in our institute. Regarding toxicity, neutropenia with G2 or more tended to be common compared with the C/P group, but other hematotoxicities were to the same extent. Two cases of G2 hypertension and one case of G2 ILD were observed with non-hematological toxicity, but it was rapidly improved by steroids. Among the seven cases, six cases completed the six courses of C/P/B, then switched over to P/B-maintenance therapy. Conclusion C/P/B therapy exhibited high safety and efficacy, thus suggesting that it may become one regimen for the primary treatment of non-Sq NSCLC.