North East Japan Study Group Research Articles

A phase II study of first-line afatinib for patients aged \u226575 years with EGFR mutation-positive advanced non-small cell lung cancer: North East Japan Study Group trial NEJ027

BackgroundLung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC).MethodsThis was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review.ResultsIn total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75–91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5–19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2–not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported.ConclusionAlthough dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS.Trial registrationThe trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

A Phase II Study of Osimertinib Combined With Platinum Plus Pemetrexed in Patients With EGFR-Mutated Advanced Non–Small-cell Lung Cancer: The OPAL Study (NEJ032C/LOGIK1801)

BackgroundOsimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is now a standard treatment of previously untreated EGFR-mutated advanced non–small-cell lung cancer (NSCLC). However, disease progression occurs within 19 months of treatment. In the NEJ009 study, gefitinib plus carboplatin plus pemetrexed demonstrated significantly better progression-free and overall survival compared with gefitinib monotherapy. Furthermore, the Lung Oncology Group in Kyushu and North East Japan Study Group, major clinical trial groups in Japan, conducted a randomized phase II study to evaluate the efficacy and safety of second-line osimertinib plus carboplatin plus pemetrexed versus osimertinib monotherapy for patients with disease progression during first-line EGFR tyrosine kinase inhibitor therapy and the EGFR T790M resistance mutation (TAKUMI trial; trial registration no., jRCTs071180062). In the first treatment course for the initial 24 patients, no safety issues were reported in the combination arm. Thus, we have planned this phase II study to evaluate the safety and preliminary efficacy of osimertinib plus cisplatin/carboplatin plus pemetrexed therapy for patients with previously untreated EGFR-mutated NSCLC. Patients and MethodsA total of 66 patients will be enrolled, because this sample size will be adequate for assessing treatment safety and efficacy. The co-primary endpoints include safety and the objective response rate, and the secondary endpoints include the complete response rate, disease control rate, and progression-free survival. ConclusionsThis is the first study to explore the efficacy and safety of osimertinib combined with platinum-based chemotherapy in previously untreated NSCLC patients with EGFR-sensitizing mutations. Our findings could provide valuable information for phase III studies such as FLAURA2 and for developing treatment strategies for EGFR-mutated NSCLC.

Clinical Outcomes of Second-Line Chemotherapy in Patients with Previously Treated Advanced Thymic Carcinoma: A Retrospective Analysis of 191 Patients from the NEJ023 Study.

Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. We performed a multi-institutional, retrospective study named NEJ023 for patients with advanced thymic carcinoma. Patients without indications for curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions in the North East Japan Study Group. Demographic and clinicopathologic characteristics, data on treatment methods, and outcomes of second-line chemotherapy were obtained from medical records. In total, 191 patients were enrolled in this study. Second-line chemotherapy included platinum-based doublets in 57.6% of patients, other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide) in 13.6%, and monotherapy in 28.8%. The median follow-up time was 50.5 months, and the median overall survival (OS) from the start of second-line chemotherapy was 22.4 (95% confidence interval, 17.5-26.7) months. The average response rate (RR) was 20.0% overall; it was 21.6% for patients treated with platinum-based doublet chemotherapy, 13.6% for those treated with other multidrug chemotherapy, and 19.6% for those treated with single agent chemotherapy. There was no significant difference in OS between platinum-based doublet chemotherapy, other multidrug chemotherapy, and monotherapy (the median OS was 22.4, 25.7, and 21.4 months, respectively). The median OS was 22.4 months in patients with advanced thymic carcinoma treated with second-line chemotherapy. There were no significant differences in RR and OS between monotherapy and multidrug chemotherapy in this study. Owing to the rarity of this tumor, there is limited information about second-line chemotherapy for patients with previously treated advanced thymic carcinoma. This is the largest data for those patients treated with second-line chemotherapy. This study suggests there is no significant difference in efficacy between monotherapy and multidrug chemotherapy for previously treated advanced thymic carcinoma. This result can support the adequacy to select monotherapy as treatment of those patients.

First Line Treatment with Erlotinib Plus Bevacizumab or with Erlotinib Alone in Patients with Advanced Non-Squamous Non-Small-Cell Lung Cancer Harboring EGFR Mutations (NEJ026): An Open-Label, Randomized, Multicenter, Phase 3 Study

Background: Resistance to first- or second-generation TKI monotherapy, the standard treatment for EGFR mutation-positive NSCLC, develops in less than a year. A phase II study comparing combination therapy of erlotinib and bevacizumab (BE) with erlotinib (E) monotherapy demonstrated the higher efficacy and safety of BE in patients. To validate these results, we have conducted a phase III study. Methods: The NEJ026 study was an open-label, randomized phase III clinical study. The patients with EGFR mutation-positive NSCLC were randomly allocated to a BE combination therapy or E monotherapy arm. In both arms, patients were orally administered 150 mg/day of erlotinib. In the BE arm, patients were additionally intravenously administered 15 mg/kg of bevacizumab every 21 days. The primary endpoint was progression-free survival (PFS). Interim analysis for evaluating efficacy was planned for when 67% of final events were attained. Findings: Between Jun 3, 2015 to Aug 31, 2016, 228 patients were enrolled. Preplanned interim analysis was performed on Sep 21, 2017. Median PFS for patients in the BE arm was 16·9 months (95% CI, 14·2-21·0), which was significantly superior to the value of 13·3 months (95% CI, 11·1-15·3) for patients in the E monotherapy arm. The response rates were 72·3% (95%CI 63·1-80·4) in the BE arm and 66·1% (95%CI 56·5-74·7) in the E arm. The rate of hypertension (45·5% vs 8·8%), proteinuria (32·1% vs 2·6%), and hemorrhage (25·9% vs 2·6%) significantly increased in the BE arm, but remained manageable. There were no treatment-related deaths. Interpretation: The results of this phase III study confirm that BE combination therapy can be a new standard treatment for patients with EGFR mutation-positive NSCLC. Clinical Trial Number: The trial was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; 000017069). Funding Statement: This study was funded by Chugai Pharmaceutical. The funding source gave its approval at the conception of this study and was involved in the provision of information; however, it was not involved in preparation of the protocol, analysis, and interpretation of the results. Declaration of Interests: HS reports grants from Chugai Pharmaceutical, AstraZeneca, and MSD, personal fees from Ono Pharmaceutical, Nippon Boehringer Ingelheim, Novartis Pharma, outside the submitted work. TF reports personal fees from AstraZeneca and Boehringer Ingelheim, outside the submitted work. NF has nothing to disclose. KW has nothing to disclose. SS reports personal fees from Chugai Pharma, AstraZeneca, Nippon Boehringer Ingelheim, MSD, Taiho Pharmaceutical, Pfizer, Eli Lilly and Company, and Novartis, non-financial support from Kyowa Hakko Kirin, Bristol-Myers Squibb, Ono Pharmaceutical, outside the submitted work. SI reports grants and personal fees from Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, MSD, Bristol-Myers Squib, Eli Lilly Japan, Taiho Pharmaceutical, and DAIICHI SANKYO COMPANY, outside the submitted work. NT has nothing to disclose. OY has nothing to disclose. MO reports and Research grants and clinical trial fee to my research at Hiroshima University was provided from Chugai Pharma. IN has nothing to disclose. KA has received honoraria from Ono Pharmaceutical, Bristol-Myers Squibb, AstraZeneca, and Chugai Pharmaceutical. Yukari T has nothing to disclose. YF reports personal fees from Chugai Pharmaceutical, and AstraZeneca, outside the submitted work. NM has nothing to disclose. GA has nothing to disclose. SW reports personal fees from AstraZeneca, Chugai Pharma, Bristol-Myers Squibb, Boehringer Ingelheim, Ono Pharmaceutical, and Taiho Pharmaceutical, outside the submitted work. MasakiM has nothing to disclose. KH reports personal fees from Chugai pharmaceuticals, during the conduct of the study; In addition, KH has a patent EGFR mutation detection method with royalties paid to LSI medience. TN reports grants from Chugai Pharmaceutical, during the conduct of the study. SM reports grants from North East Japan Study Group, during the conduct of the study; personal fees from Chugai Pharmaceutical, outside the submitted work. KK reports grants from Chugai Pharmaceutical, during the conduct of the study. MakotoMD reports personal fees from Chugai Pharmaceutical., during the conduct of the study; grants and personal fees from Boehringer Ingelheim, AstraZeneca, personal fees from Eli Lilly, outside the submitte Ethics Approval Statement: The study was conducted in compliance with the Helsinki Declaration and GCP Guidelines. Moreover, the study protocol was reviewed and approved by the central institutional review board (IRB). Although the primary endpoint was met and the independent data monitoring committee recommended that the study be ceased, we decided to continue our investigation to attain secondary and exploratory endpoints. The JO25567 study, however, was not designed to detect OS-related benefits and the OS analysis was additionally performed just for half of patients with consent. Therefore, a combined analysis of OS data from the NEJ026 and JO25567 studies was considered. To resolve any ethical issues with our approach, this study was continued after we notified all investigators of the results of our interim analysis and obtained permission for the addition of bevacizumab to the treatment regimen of patients in the E monotherapy arm.

1445P - A phase II study of first-line afatinib for patients aged 75 or older with EGFR mutation-positive advanced non-small cell lung cancer: North East Japan study group trial NEJ027

Lung cancer is most common among older individuals. However, polypharmacy and comorbidities, which are also more common in older individuals, can limit treatment options. Previous studies suggest that afatinib can be used safely and effectively in elderly patients. This study investigated the anti-tumour activity and safety profile of first-line afatinib in previously-untreated elderly Japanese patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). This was a single-arm, open-label, phase II study, performed in multiple centres in Japan. Previously untreated patients, aged ≥75 years, with EGFR mutation-positive (Del19 or L858R) advanced NSCLC were treated with afatinib 40 mg until disease progression or unacceptable toxicity. Adverse events (AEs) were managed with protocol-defined dose adjustments. The primary endpoint was objective response rate (ORR) by central review. In total, 38 patients received at least one dose of afatinib, and 37 were evaluable for response. Median age was 77.5 years (range 75–91), all patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 60.5% had Del19-positive disease. Median follow-up was 838 days. ORR was 75.7% (2 complete responses and 26 partial responses). Median progression-free survival was 14.2 months (95% confidence interval [CI], 9.5–19.0). Median overall survival (OS) was 35.2 months (95% CI, 35.2–not reached); the 2-year OS rate was 78.3%. The most common grade 3/4 treatment-related AEs (TRAEs) were diarrhoea (28.9%), paronychia (23.7%), and rash/acne (15.8%). Dose reductions due to TRAEs were reported in 78.9% of patients, and eight (21.1%) patients discontinued afatinib due to TRAEs. No treatment-related deaths were reported. Although dose adjustments were relatively common in this small group of Japanese patients aged ≥75 years with EGFR mutation-positive NSCLC, discontinuation occurred much less frequently, and most patients were able to stay on treatment for well over a year. Further, afatinib was associated with high response rates and prolonged PFS and OS. The trial is registered with Japan Registry of Clinical Trials (JRCT) as trial number 031180136 (date of initial registration: 19 February 2019), and the University Hospital Network (UMIN) as trial number 000017877 (date of initial registration: 11 June 2015).

Prognostic Factors and Efficacy of First-Line Chemotherapy in Patients with Advanced Thymic Carcinoma: A Retrospective Analysis of 286 Patients from NEJ023 Study.

The prognostic factors and the efficacy of first-line chemotherapy remain unclear in patients with advanced thymic carcinoma. We conducted a multi-institutional retrospective study named NEJ023 for patients with advanced thymic carcinoma. All patients without any indication of curative treatment were treated with chemotherapy from 1995 to 2014 at 40 institutions of the North East Japan Study Group. A total of 286 patients with advanced thymic carcinoma were analyzed. First-line chemotherapy included platinum-based doublets in 62.2% of the patients, monotherapy in 3.5%, and other multidrug chemotherapy (e.g., cisplatin, doxorubicin, vincristine, and cyclophosphamide [ADOC]) in 34.3%. The median follow-up period was 55.5 months, and the median overall survival (OS) from the start of first-line chemotherapy was 30.7 months (95% confidence interval, 25.9-35.9 months). There was no significant difference in OS among different first-line chemotherapy regimens (e.g., between carboplatin/paclitaxel and ADOC, median OS: 27.8 vs. 29.9 months). Masaoka-Koga stage IVa and volume reduction surgery were favorable prognostic factors for OS in the multivariate analysis using the Cox proportional hazards model. The efficacy of each first-line chemotherapy regimen for advanced thymic carcinoma did not vary significantly. Our results might support the adequacy of the use of carboplatin/paclitaxel as first-line chemotherapy for these patients. Because of its rarity, there is limited information about prognostic factors and efficacy of chemotherapy in patients with advanced thymic carcinoma. This is the largest data set for those patients treated with chemotherapy. This study suggests there is no significant difference in efficacy between carboplatin/paclitaxel and cisplatin/doxorubicin/vincristine/cyclophosphamide for advanced thymic carcinoma. This result can support the adequacy of the selection of platinum doublets as treatment for those patients, rather than anthracycline-based multidrug regimen.

Updated survival outcomes of NEJ005/TCOG0902: a randomised phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations

BackgroundThe North-East Japan Study Group (NEJ) 005/Tokyo Cooperative Oncology Group (TCOG) 0902 study has reported that first-line concurrent and sequential alternating combination therapies of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant non-small cell lung cancer. However, overall survival (OS) data were insufficient in the primary report because of the lack of death events.Patients and methodsProgression-free survival (PFS) and OS were re-evaluated at the final data cut-off point (March 2017) for the entire population (n=80).ResultsAt the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 77.5% of patients had died. Median PFS was 17.5 months for the concurrent regimen and 15.3 months for the sequential alternating regimen (P=0.13). Median OS was 41.9 and 30.7 months, respectively (P=0.036). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; P=0.34). Patients with Del19 tumours displayed relatively better OS (median: 45.3 vs 33.3 months, respectively) than those with L858R (31.4 vs 28.9 months, respectively). No severe adverse events, including interstitial lung disease, occurred in the period since the primary report.ConclusionsThis updated analysis confirms that PFS is improved with first-line combination therapy compared with gefitinib monotherapy and that the concurrent regimen, in particular, offers an OS benefit of 42 months in the EGFR-mutated setting. Our ongoing NEJ009 study will clarify whether this combination strategy can be incorporated into routine clinical practice.Trial registration numberUMIN C000002789, Post-results.

445P - Phase II study of efficacy of bevacizumab plus chemotherapy in management of malignant pleural effusion in non-squamous non-small cell lung cancer patients with malignant pleural effusion (MPE) unsuccessfully controlled by tube drainage or pleurodesis (NEJ-13-2 trial)

Background: Prospective and retrospective studies on intrapleural therapy of malignant pleural effusion (MPE) have reported that the success rate for controlling pleural effusion is 50% at 2.5 months. When pleurodesis is unsuccessful, the lung is not fully expanded after drainage before receiving effective chemotherapy. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of MPE. Here, a multicenter phase II trial was conducted to evaluate bevacizumab therapy in non-squamous NSCLC patients with unsuccessful management of MPE. Methods: Non-squamous NSCLC patients with MPE who had received unsuccessful tube drainage or pleurodesis received chemotherapy with bevacizumab (15 mg/kg) every 3 weeks. The primary endpoint was pleural effusion control rate (PECR), defined as the percentage of patients without reaccumulation of MPE for 8 weeks. The secondary endpoint was pleural Progression-free survival (PPFS), defined as PFS without reaccumulation of MPE. Results: Fifteen of 20 patients entered received a median of 4 cycles of carboplatin plus paclitaxel or pemetrexed including maintenance therapy with bevacizumab. The PECR was 80% of treated patients. PPFS was 16.6 months. The response rate and disease control rate were 45% and 80%, respectively, and the median PFS and overall survival (OS) were 9.8 months and 19.6 months, respectively. The patients with high VEGF (<1000pg/ml) in MPE had shorter PPFS (P = 0.01) and OS (P < 0.01). Toxicities of grade ≥3 included neutropenia (50.0%), thrombocytopenia (10.0%), proteinuria (10.0%) and hypertension (2.0%). Global QOL score investigated by EORTC QLQ-C30 favored in the patients without reaccumulation of MPE. Conclusions: The combination of bevacizumab with chemotherapy demonstrated efficacy with acceptable toxicities as a standard therapy in controlling MPE in patients with non-squamous NSCLC whose MPE was unsuccessfully controlled by tube drainage or pleurodesis. Clinical trial indentification: trial protocol number (NIH or European equivalent) is UMIN000006868. The release data is 10/12/2011. Legal entity responsible for the study: North East Japan Study Group Funding: None Disclosure: Y. Hosomi: Research funding from Chugai, MSD, Boheringer and Astrazeneca, H. Okamoto: Reserch funding from Chugai MSD Taiho AstraZeneca, Merck, Eli Lilly, Bristol and Astellas. K. Hagiwara: Patents, Royalties from LSI Medience, K. Kubota: Research funding from Chugai, Astrazeneca, Bheringer and Lilly. A. Gemma: Research fundung from Astrazeneca, Taiho, Chugai, MSD, Lilly and Bheringer. All other authors have declared no conflicts of interest.

Phase II study of efficacy of bevacizumab plus chemotherapy in management of malignant pleural effusion (MPE) in non-squamous non-small cell lung cancer (NSCLC) patients with MPE unsuccessfully controlled by tube drainage or pleurodesis (North East Japan Study Group Trial NEJ-013B-2).

e21660 Background: Prospective and retrospective studies on intrapleural therapy of malignant pleural effusion (MPE) have reported that the success rate for controlling pleural effusion was 50–70% at 2.5 months, and that the median post-pleurodesis survival time was 6-9 months. When pleurodesis is unsuccessful, and the lung is not fully expanded after drainage, the patients cannot receive effective chemotherapy. Vascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of MPE. Here, a multicenter phase II trial was conducted to evaluate bevacizumab therapy in non-squamous non-small cell lung carcinoma patients with unsuccessful management of MPE. Methods: Non-squamous NSCLC patients with MPE who had received unsuccessful tube drainage or pleurodesis received chemotherapy with bevacizumab (15 mg/kg) every 3 weeks. The primary endpoint was Pleural effusion control rate (PECR), defined as the percentage of patients without reaccumulation of MPE for 8 weeks. The secondary endpoint was pleural Progression-free survival (PPFS), defined as PFS without reaccumulation of MPE. Results: Fifteen of 20 patients entered received a median of 4 cycles of carboplatin plus paclitaxel or pemetrexed including maintenance therapy with bevacizumab. The PECR was 80% of treated patients (95% CI: 78-82%). PPFS was 16.6 months (95% CI: 11.46-21.80 months). The response rate (RR) and disease control rate (DCR) were 45% (95% CI: 39.6-50.4%), and 80% (95% CI: 78.0-82.0 %), respectively, and the median PFS and overall survival (OS) were 9.8 months (95% CI: 4.38-15.28 months) and 19.6 months (95% CI: 4.38-15.28 months), respectively. Toxicities of grade ≥3 included neutropenia (50.0%), thrombocytopenia (10.0%), proteinuria (10.0%), hypertension (2.0%), pulmonary embolism (5%). Conclusions: The combination of bevacizumab with chemotherapy demonstrated efficacy with acceptable toxicities in controlling MPE in patients with non-squamous NSCLC whose MPE was unsuccessfully controlled by tube drainage or pleurodesis.

Updated survival outcomes of NEJ005/TCOG0902, a randomized phase II study of concurrent (C) versus sequential alternating (S) gefitinib and chemotherapy in previously untreated non-small cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations.

9038 Background: North East Japan Study Group (NEJ) 005/ Tokyo Cooperative Oncology Group (TCOG) 0902 study has demonstrated that first-line concurrent (C) and sequential alternating (S) combination therapies of EGFR tyrosine kinase inhibitor (gefitinib) plus platinum-based doublet chemotherapy (carboplatin/pemetrexed) offer promising efficacy with predictable toxicities for patients with EGFR-mutant NSCLC (ASCO2014, Ann Oncol 2015). However, overall survival (OS) data were insufficient because of the lack of death events in the primary report. Methods: Progression-free survival (PFS) and OS were re-evaluated at the final data cutoff point (November 2016) for the entire population (N = 80). Results: At the median follow-up time of 35.6 months, 88.8% of patients had progressive disease and 72.5% of patients had died. Median PFS was 17.5 months for the C regimen and 15.3 months for the S regimen (p = 0.13). Median OS time was 43.3 with the C regimen and 30.7 months with the S regimen (p = 0.018). Updated response rates were similar in both groups (90.2% and 82.1%, respectively; p = 0.34). Patients who had common mutations showed no significant differences in PFS according to type of mutation. Patients with Del19 displayed relatively better OS (median: 45.3 and 33.3 months for C and S regimens) than those with L858R (31.4 and 28.9 months). No severe adverse events including interstitial lung disease have occurred during the follow-up period since the primary report. Conclusions: This updated analysis has confirmed that PFS is improved with first-line combination therapies compared to that with gefitinib monotherapy, and the C regimen in particular offers an overall survival benefit of 43 months in the EGFR-mutated setting. Our on-going NEJ009 study will clarify whether this combinational strategy can be incorporated into routine clinical practice. Clinical trial information: UMIN000002789.

SC15.04 The Japanese Perspective

In Japan, several cooperative study groups, such as Japan Clinical Oncology Group (JCOG), West Japan Oncology Group (WJOG), North East Japan Study Group (NEJ), Thoracic Oncology Research Group (TORG), Tokyo Cooperative Oncology Group (TCOG), Oncology Group in Kyushu (LOGiK), Okayama Lung Cancer Study Group (OLCSG) and so on are conducting investigator initiated cooperative clinical studies for lung cancer. Phase 3 studies are mainly conducted by JCOG, WJOG and NEJ. JCOG and WJOG are conducting intergroup phase 3 studies for lung cancer. More recently, multi-group phase 3 studies are also started. JCOG is a multicenter clinical study group for cancer treatment fully funded by the national research grants in Japan. The goal of the JCOG is to establish effective standard treatments for various types of malignant tumors by conducting nationwide multicenter clinical trials, and to improve the quality and outcome of the management of cancer patients. JCOG consists of 16 subgroups and JCOG Lung Cancer Study Group (JCOG-LCSG) consists of 44 institutions, was established in 1982. JCOG also have JCOG Lung Cancer Surgical Study Group (JCOG-LCSSG) established in 1986. Only JCOG is supported by no industries but National Cancer Center and grants of Japan Agency for Medical Research and Development (AMED). Thus, JCOG studies are conducting completely independent from pharmaceutical companies. Other groups are supported by mainly pharmaceutical companies and grants of AMED. JCOG-LCSG has been conducting many randomized trials for small cell lung cancer and elderly non-small cell lung cancer. In case of JCOG-LCSG, protocol concepts are discussing in the group meeting held every 3 months. The protocol concept agreed in the group meeting will discuss in JCOG Protocol Review Committee and finally approved by JCOG Steering Committee. Kawano Y, Okamoto I, Fukuda H, et al. Current status and future perspectives of cooperative study groups for lung cancer in Japan. Respir Investig 52: 339-347, 2014. Japan Clinical Oncology Group, West Japan Oncology Group, Investigator initiated multicenter clinical study

A phase II study of bevacizumab with carboplatin-pemetrexed in non-squamous non-small cell lung carcinoma patients with malignant pleural effusions: North East Japan Study Group Trial NEJ013A

BackgroundVascular endothelial growth factor (VEGF) plays a pivotal role in the pathogenesis of malignant pleural effusion (MPE). Here, a multicenter phase II trial to evaluate bevacizumab in non-squamous non-small cell lung carcinoma patients with MPE was conducted. MethodsPatients having MPE with no prior treatment and performance status of 0–2 received carboplatin (area under the curve: AUC 6; up to 6 cycles) and pemetrexed (500mg/m2) with bevacizumab (15mg/kg) every 3 weeks. The primary endpoint was the control rate of MPE without pleurodesis at 8 weeks after treatment. VEGF levels in plasma and MPE were measured by enzyme immunoassay. ResultsOf 30 patients entered (median 66 years; 24 males; adenocarcinoma; 4 epidermal growth factor receptor: EGFR mutations), 28 patients (2 withdrawn patients) were given a median of 4 cycles of carboplatin, and 68% of the patients received maintenance pemetrexed with bevacizumab (median 8 cycles). At eight weeks, MPE was controlled without pleurodesis in 93% of treated patients (95% confidence interval: 77–99%). At the median follow-up time of 12.8 months, 78.6% of the cases required no pleurodesis. Response rate was 46%, and median progression-free survival (PFS) and overall survival (OS) were 8.2 months and 18.6 months, respectively. Toxicities of grade ≥3 included neutropenia (28.6%), thrombocytopenia (28.6%), proteinuria (3.6%), and hypertension (3.6%). Assessment of VEGF levels before treatment indicated that patients with low VEGF (<1000pg/ml) in MPE frequently needed pleurodesis (p=0.011), and that high VEGF (≥100pg/ml) in plasma was indicative of poor prognosis in the context of PFS (p=0.012). ConclusionThe combination of bevacizumab with carboplatin and pemetrexed demonstrated efficacy with acceptable toxicities in patients with MPE.

First-line gefitinib for elderly patients with advanced NSCLC harboring EGFR mutations. A combined analysis of North-East Japan Study Group studies

Objective: To assess outcomes of elderly patients with advanced NSCLC harboring an EGFR mutation treated with gefitinib, as well as safety and impact on quality of life (QoL).Methods: We performed a retrospective analysis of pooled data from one Phase III and two Phase II studies of 71 patients aged ≥ 70 years with a performance status of 0 – 2. The main outcome measures were progression-free survival (PFS), overall survival (OS) and response rate (RR), as well as incidence of adverse events and time to 9.1% deterioration in QoL.Results: Median PFS (14.3 vs 5.7 months, p < 0.001) and overall RR (73.2 vs 26.5%, p < 0.001) in the gefitinib group were superior to those in the standard chemotherapy group, whereas median OS was not significantly different (30.8 vs 26.4 months, p = 0.42). Elevation of aspartate transaminase and/or alanine transaminase (18.3%) was the most common adverse event, and one treatment-related death (pneumonitis) occurred. Time to 9.1% deterioration in the QoL domains of pain and dyspnea, anxiety, and daily functioning was similar between the two age groups.Conclusion: First-line gefitinib is efficacious with acceptable toxicity in relatively fit elderly patients with advanced NSCLC harboring an EGFR mutation.

1259P - GEFITINIB for Non-Small Cell Lung Cancer (NSCLC) with Minor EGFR Mutations: A Retrospective Study from the North East Japan Study Group (NEJ)

ABSTRACT Background In NSCLC, the sensitive mutations of epidermal growth factor receptor (EGFR), such as exon 19 deletion and L858R point mutation, are predictors of response to EGFR tyrosine kinase inhibitors (TKIs). However, it is still uncertain whether minor EGFR mutations are associated with sensitivity to EGFR-TKIs. Materials and methods Retrospective review of 221 EGFR mutated (exon 19 deletion, L858R, G719X and L861Q) patients who were treated with gefitinib in a NEJ002 study was performed. We identified 7 patients with G719X and 3 patients with L861Q. Results Among 10 patients harboring minor EGFR mutations (G719X or L861Q), 5 patients were treated with gefitinib as the 1st line treatment, and 5 patients were treated with carboplatin/paclitaxel as the 1st line chemotherapy, and then received gefitinib as the 2nd line treatment. Only 2 patients showed PR, 4 achieved SD, and 4 had PD with gefitinib treatment. The overall response rate was 20% and the disease control rate was 60%. The overall survival (OS) from enrollment was significantly shorter in patients with minor mutations (median OS, 12 months (95% CI, 5.8 - 30.5)) compared to patients with 19 deletion or L858R (median OS, 28 months (95% CI, 24.1 – 33.2), P = 0.0057). Tendency of longer progression free survival and OS were observed in minor EGFR mutation patients who received carboplatin/paclitaxel as the 1st line treatment (median PFS, 5.3 months (95% CI, 3.7 – 8.9) and median OS, 22.8 months (95% CI, 9.9 – 41.8)) compared to those who were treated with gefitinib as the 1st line treatment (median PFS, 2.2 months (95% CI, 0.5 – 10.6), P = 0.997 and median OS, 11.9 months (95% CI, 5.8 – 22.6), P = 0.1021). Conclusions Our results indicate that NSCLC patients with G719X or L861Q minor EGFR mutations are less responsive to gefitinib than those with 19 deletion or L858R. Disclosure All authors have declared no conflicts of interest.

Quality of Life with Gefitinib in Patients with EGFR-Mutated Non-Small Cell Lung Cancer: Quality of Life Analysis of North East Japan Study Group 002 Trial

For non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, first-line gefitinib produced a longer progression-free survival interval than first-line carboplatin plus paclitaxel but did not show any survival advantage in the North East Japan 002 study. This report describes the quality of life (QoL) analysis of that study. Chemotherapy-naïve patients with sensitive EGFR-mutated, advanced NSCLC were randomized to receive gefitinib or chemotherapy (carboplatin and paclitaxel). Patient QoL was assessed weekly using the Care Notebook, and the primary endpoint of the QoL analysis was time to deterioration from baseline on each of the physical, mental, and life well-being QoL scales. Kaplan-Meier probability curves and log-rank tests were employed to clarify differences. QoL data from 148 patients (72 in the gefitinib arm and 76 in the carboplatin plus paclitaxel arm) were analyzed. Time to defined deterioration in physical and life well-being significantly favored gefitinib over chemotherapy (hazard ratio [HR] of time to deterioration, 0.34; 95% confidence interval [CI], 0.23-0.50; p < .0001 and HR, 0.43; 95% CI, 0.28-0.65; p < .0001, respectively). QoL was maintained much longer in patients treated with gefitinib than in patients treated with standard chemotherapy, indicating that gefitinib should be considered as the standard first-line therapy for advanced EGFR-mutated NSCLC in spite of no survival advantage.

A randomized trial of postoperative UFT therapy in p stage I, II non-small cell lung cancer: North-east Japan Study Group for Lung Cancer Surgery

Objective: A prospective randomized trial was performed to investigate the prognostic advantage of postoperative adjuvant chemotherapy in patients with resected stage I–II non-small cell lung cancer (NSCLC). Patients and methods: From March 1992 to December 1994, 221 patients with completely resected stage I–II primary NSCLC were enrolled and randomly assigned to two groups, as follows: 2-year oral administration of Uracil plus Tegafur (UFT) (adjuvant group, 109 patients), and surgical treatment alone (control group, 110 patients). Results: The overall 5-year survival rates were 79% for the adjuvant group and 75% for the control group, and there was no statistical significance. The 5-year disease-free survival rates were 78% for the adjuvant group and 71% for the control group, and there was also no statistical significance. There have been seen no severe complications in the adjuvant group. The mean total dosages of UFT were about 75% of maximum basic amount. Conclusions: The UFT regimen was feasible. However, we have not observed any survival benefit in the adjuvant group. Larger trials are needed to confirm the effect of UFT to patients with resected NSCLC.