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Background Chemotherapy for non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) has been challenging due to the possibility of the acute exacerbation of ILD as a life-threatening adverse effect. No acceptable regimen for such patients has been established. Therefore, we herein assessed our series of NSCLC patients with ILD who were treated with cisplatin plus etoposide (PE). Patients and methods The unresectable NSCLC patients with ILD detected on chest computed tomography (CT) who received PE at our department between December 2006 and December 2013 were retrospectively reviewed. Cisplatin (80 mg/m2, day 1) and etoposide (100 mg/m2, days 1 to 3) were administered every three weeks. Results Thirty-two consecutive NSCLC patients with ILD were evaluated. Twenty-four received PE as first-line treatment, while the other eight received it as second-line or later treatment. Twenty-three patients exhibited the usual pneumonitis (UIP) pattern, eight possible UIP pattern and one was inconsistent to UIP on CT. Grade 3/4 hematological toxicities were frequently seen, including neutropenia in 23 (74.2%). Febrile neutropenia was seen in six (19.4%) patients. Two patients experienced grade 2 pneumonitis after PE, but successfully recovered. The overall response rate was 31.2%. The median progression-free survival was 3.4 months and the median overall survival for all patients was 8.5 months. Conclusion PE treatment for unresectable NSCLC patients with ILD in our series was considered to be relatively safe, with an acceptable tumor response and survival. Obviously, careful patient selection and management are warranted. A prospective evaluation should also be performed.

Summary Background RET rearrangements are rare oncogenic alterations in non-small-cell lung cancer (NSCLC). Vandetanib is a multitargeted tyrosine kinase inhibitor exhibiting RET kinase activity. We aimed to assess the efficacy and safety of vandetanib in patients with advanced RET -rearranged NSCLC. Methods In this open-label, multicentre, phase 2 trial (LURET), patients with advanced RET -rearranged NSCLC continuously received 300 mg of oral vandetanib daily. RET -positive patients were screened using a nationwide genomic screening network of about 200 participating institutions. Primary endpoint was the independently assessed objective response in eligible patients. This study is registered with UMIN-CTR, number UMIN000010095. Findings Between Feb 7, 2013, and March 19, 2015, 1536 patients with EGFR mutation-negative NSCLC were screened, of whom 34 were RET -positive (2%) and 19 were enrolled. Among 17 eligible patients included in primary analysis, nine (53% [95% CI 28–77]) achieved an objective response, which met the primary endpoint. In the intention-to-treat population of all 19 patients treated with vandetanib, nine (47% [95% CI 24–71]) achieved an objective response. At the data cutoff, median progression-free survival was 4·7 months (95% CI 2·8–8·5). The most common grade 3 or 4 adverse events were hypertension (11 [58%]), diarrhoea (two [11%]), rash (three [16%]), dry skin (one [5%]), and QT prolongation (two [11%]). Interpretation Vandetanib showed clinical antitumour activity and a manageable safety profile in patients with advanced RET -rearranged NSCLC. Our results define RET rearrangement as a new molecular subgroup of NSCLC suitable for targeted therapy. Funding The Ministry of Health, Labour and Welfare of Japan and the Practical Research for Innovation Cancer Control from the Japan Agency for Medical Research and Development, AMED.

Objectives To evaluate patient-reported outcomes (PROs) from a phase 1/2 study (NCT01970865) in patients with anaplastic lymphoma kinase (ALK)- or ROS1-positive advanced non-small cell lung cancer (NSCLC) treated with lorlatinib 100 mg once daily. Materials and methods PRO measures, including global quality of life (QoL), functioning domains and symptoms, were assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the 13-item Lung Cancer (QLQ-LC13) module. Mean changes of absolute scores from baseline were assessed. Percentages of patients showing improvement, stability or worsening on each scale were reported, with a change of ≥10 points considered clinically meaningful (CM). Results 255 patients completed baseline and ≥1 post-baseline PRO assessment. Most patients had CM improvement (42.4 %) or stable (38.0 %) scores for global QoL. Functioning domains with the greatest proportion of patients with improved scores were role (37.6 %) and emotional (36.9 %); only one domain had more patients showing worsening than improving function (cognitive [24.3 % vs 22.4 %]). Most patients showed improved or stable scores for disease-related symptoms. No QLQ-C30 symptom domains had more patients worsening than improving. Symptoms on the QLQ-C30 scale with the greatest proportion of patients with improved scores were fatigue (49.4 %) and insomnia (46.3 %). Four QLQ-LC13 domains had more patients worsening than improving (two most affected were peripheral neuropathy [37.3 % vs 13.7 %] and alopecia [19.2 % vs 13.3 %]). Symptoms on the QLQ-LC13 scale with the greatest proportion of patients with improved scores were cough (42.7 %) and pain in other parts (32.9 %). Conclusions Lorlatinib treatment showed CM improvement from baseline in global QOL that was maintained over time. Additionally, there were improvements in physical, emotional, social, and role functioning. Improvements were shown in appetite loss and key symptoms such as pain, dyspnea, cough and fatigue; a worsening in peripheral neuropathy was noted.

BACKGROUND Capmatinib is a highly potent, selective MET-inhibitor known to cross the BBB, and intracranial activity with capmatinib has been previously reported. Updated results for overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and brain metastases (BM) activity from the GEOMETRY mono-1 study are presented here. METHODS GEOMETRY mono-1 is a phase 2, multi-cohort, multicenter study evaluating capmatinib in METΔex14-mutated or MET-amplified NSCLC patients. Patients (≥18 years) with ECOG PS 0–1, ALK-/EGFR-wt, and stage IIIB/IV NSCLC were eligible. Patients with asymptomatic BM were allowed. METΔex14-mutated patients were assigned to Cohorts 4 (1–2 prior lines of treatment) and 5b (treatment-naive) and received capmatinib 400mg BID. Endpoints by BIRC: ORR (primary, RECIST v1.1), DOR, and PFS. Ad hoc BIRC neuro-radiologic assessments of all Cohort 4 and 5b patients with baseline BM were performed. RESULTS As of April 15, 2019, 97 patients (Cohort 4: 69 patients; Cohort 5b: 28 patients) were evaluable for efficacy. BIRC assessments: ORR (95%CI): 40.6% (28.9–53.1) in Cohort 4; 67.9% (47.6–84.1) in Cohort 5b. Median DOR (95%CI): 9.7 (5.55–12.98) and 11.1 (5.55-NE) months and median PFS (95%CI): 5.4 (4.17–6.97) and 9.7 (5.52–13.86) months for Cohorts 4 and 5b, respectively. Of 13 evaluable patients with BM at baseline, 7 (54%) had intracranial response by BIRC, including 4 patients with complete resolution of brain lesions, and 12/13 had intracranial disease control. Responses in the brain were as fast as systemic responses. Most common treatment-related AEs (≥15%, all grades) across all cohorts (N=334): peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%); most AEs were grade 1/2. CONCLUSION These data confirm capmatinib to be a promising new treatment option for patients with METΔex14-mutated advanced NSCLC regardless of line of therapy, with deep and durable responses including in patients with brain metastases, and a manageable toxicity profile.

BACKGROUND: Pembrolizumab, an anti-programmed cell death-1 (PD-1) monoclonal antibody, has been shown to yield a durable response and significant survival benefit in some non-small cell lung cancer (NSCLC) patients. Recent studies have shown that the Controlling Nutritional Status (CONUT) score, a novel nutritional index, can be useful for predicting the prognosis in some malignancies. However, its usefulness in predicting the clinical outcome of immune-checkpoint inhibitor (ICI) treatment in patients with NSCLC has not been clarified. The aim of this study was to investigate the clinical significance of the CONUT score in NSCLC patients treated with pembrolizumab. METHODS: We conducted a retrospective analysis of the clinical data of 32 patients with advanced NSCLC who received pembrolizumab monotherapy. A cut-off CONUT score of 2 was used to categorize patients into low and high CONUT groups. We evaluated the relation between the clinicopathological factors including CONUT score and neutrophil-to-lymphocyte ratio (NLR) and the prognosis. RESULTS: Twenty-two patients were classified into the low CONUT score group, while 10 were classified into the high CONUT score group. In the univariate and multivariate analyses, the number of prior treatments and the CONUT score were found to independently predict progression-free survival (PFS) (P

The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17-0.71, P0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018).Patients aged ≥20 years who were ALK inhibitor-naïve and chemotherapy-naïve, or had received one prior chemotherapy regimen, were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily. The primary end point was IRF-assessed PFS. Secondary end points included OS and safety. All patients entered survival follow-up in July 2018.Median follow-up was 42.4 months for alectinib and 42.2 months for crizotinib. Sustained improvement in IRF-assessed PFS with alectinib was shown (HR 0.37, 95 % CI: 0.26-0.52; median PFS 34.1 months vs 10.2 months crizotinib). At the second interim OS analysis, superiority of alectinib to crizotinib could not be concluded (stratified HR 0.80, 99.8799 % CI: 0.35-1.82, stratified log-rank P = 0.3860; median OS not reached alectinib vs 43.7 months crizotinib). Fewer alectinib-treated patients experienced grade ≥3 adverse events (36.9 % vs 60.6 % crizotinib).At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues.

Summary Background Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. Methods An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG ( NCT02650401 ; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov , NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001). Findings Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. Interpretation Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. Funding Ignyta/F Hoffmann-La Roche.

Summary Background Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC. Methods We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0–2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov , NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001). Findings Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64–88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4–20·2). Median duration of response was 24·6 months (95% CI 11·4–34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred. Interpretation Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC. Funding Ignyta/F Hoffmann-La Roche.

Objective Adjuvant chemotherapy is standard of care for patients with completely resected stage IB, II and IIIA NSCLC. However, optimum chemotherapy regimen has not been determined. TORG0503 was undertaken to select a preferred platinum-based 3rd generation regimen in this clinical setting. Materials and methods Patients with completely resected stage IB, IIA, IIB or stage IIIA NSCLC were stratified by stage (IB/IIA vs. IIB/IIIA) and institutions, and randomized to receive 3 cycles of docetaxel (60 mg/m2) plus cisplatin (80 mg/m2) (arm A) or paclitaxel (200 mg/m2) plus carboplatin (AUC 6) (arm B) on day 1, every 3 weeks. The primary endpoint of the study was 2-year relapse free survival, and the key secondary endpoints included overall survival, feasibility and toxicity. Results 111 patients were randomized, 58 patients to arm A and 53 to arm B. Patient demographics were balanced between the two arms. 93 % (54/58) of patients on the arm A and 92 % (49/53) patients on the arm B completed the planned 3 cycles of chemotherapy. There was no treatment-related death in both arms. The 2 and 5 year relapse free survival was 74.5 % (95 %CI: 68.6–80.4) and 61.6 % in the arm A, and 72.0 % (95 %CI: 65.7–78.3) and 46.0 % in the arm B. The overall 2, 5-year survival was 89.7 %, 73.9 % in the arm A and 86.9 %, 67.5 % in the arm B. Conclusion Both docetaxel plus cisplatin and paclitaxel plus carboplatin are safe and feasible regimens as adjuvant chemotherapy. We choose docetaxel plus cisplatin as the control regimen for the next clinical trial.

Summary Background Resistance to first-generation and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is mediated by the emergence of the Thr790Met mutation in 50–60% of treated patients with non-small-cell lung cancer (NSCLC). We aimed to assess the safety and activity of nazartinib (EGF816), a third-generation EGFR TKI that selectively inhibits EGFR with Thr790Met or activating mutations (or both), while sparing wild-type EGFR, in patients with advanced EGFR-mutant NSCLC. Methods This phase 1 dose-escalation part of an open-label, multicentre, phase 1/2 study was conducted at nine academic medical centres located in Europe, Asia, and North America. Patients were included if they were aged 18 years or older and had stage IIIB–IV EGFR-mutant NSCLC (with varying statuses of EGFR mutation and previous therapy allowed), at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Nazartinib (at seven dose levels between 75 mg and 350 mg, in capsule or tablet form) was administered orally, once daily, on a continuous 28-day dosing schedule. A two-parameter Bayesian logistic regression model, guided by the escalation with overdose control principle, was implemented to make dose recommendations and estimate the maximum tolerated dose or recommended phase 2 dose of nazartinib (the primary outcome). This study is registered with ClinicalTrials.gov ( NCT02108964 ); enrolment to phase 1 is complete and the study is ongoing. Findings By Aug 31, 2017, 180 patients (116 [64%] women; median age 60 years (52–69); 116 [64%] with ECOG performance status 1) received nazartinib across seven dose levels: 75 mg (n=17), 100 mg (n=38), 150 mg (n=73), 200 mg (n=8), 225 mg (n=28), 300 mg (n=5), and 350 mg (n=11). Seven dose-limiting toxicities were observed in six (3%) patients who received 150 mg, 225 mg, or 350 mg nazartinib once daily. Although the maximum tolerated dose was not met, the recommended phase 2 dose was declared as 150 mg once daily (tablet). The most common adverse events, regardless of cause, were rash (all subcategories 111 [62%] patients, maculopapular rash 72 [40%], dermatitis acneiform 22 [12%]), diarrhoea (81 [45%]), pruritus (70 [39%]), fatigue (54 [30%]), and stomatitis (54 [30%]), and were mostly grades 1–2. Any-cause grade 3–4 adverse events were reported in 99 (55%) patients across all doses, the most common being rash (all subcategories grouped 27 [15%]), pneumonia (12 [7%]), anaemia (ten [6%]), and dyspnoea (nine [5%]). Serious adverse events suspected to be drug-related occurred in 16 (9%) patients. Interpretation Nazartinib has a favourable safety profile, with low-grade skin toxicity characterised by a predominantly maculopapular rash that required minimal dose reductions. Funding Novartis Pharmaceuticals Corporation.

Introduction Thymic carcinoma (TC) is a rare cancer with a poor prognosis and limited treatment options, especially after relapse. Methods In this open-label, two-stage, multicentre, single-arm and phase II trial, the main eligibility criteria were unresectable or recurrent TC, an Eastern Cooperative Oncology Group–performance status of 0 or 1, progression after at least one chemo(radio)therapy and no history of autoimmune disease. Nivolumab was administered at a dose of 3 mg/kg every 2 weeks. The primary end-point was response rate (RR) as evaluated by central review using Response Evaluation Criteria In Solid Tumours (RECIST), version 1.1. The planned sample size was 15 for each stage, with a threshold RR of 5%, an expected RR of 20%, one-sided alpha of 5% and power of 80%. Results Between July 1 and August 16 2016, 15 patients were accrued in the first stage. Response was assessable in all patients, and 13 had squamous histology. Median follow-up time was 14.1 months (range: 2.4–17.5). The median number of nivolumab received was eight (range: 3–33). RR was 0% (95% confidential interval [CI]: 0–21.8). Eleven patients had stable disease (SD) including five patients with SD for 24 or more weeks. Median progression-free survival was 3.8 months (95% CI: 1.9–7.0). Two patients experienced immune-related serious adverse events (grade III aspartate aminotransferase (AST) increase and grade II adrenal insufficiency). Because the early termination criteria (less than one responder) were fulfilled during the first stage, the patient accrual was terminated. Conclusions Despite the small number of patients, nivolumab was unable to produce tumour shrinkage by RECIST in previously treated unresectable or recurrent TC.

Anaplastic lymphoma kinase (ALK) is one of the most attractive molecular targets for the treatment of patients with non-small-cell lung cancer. Treatment with ALK inhibitors is recognized as the standard-of-care for patients with ALK gene rearrangements, but it is important to appropriately select patients who will benefit from such treatment. Areas covered: In this article, we review the evidence regarding ALK testing. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and reverse transcription polymerase chain reaction (RT-PCR) are the representative methods for detecting ALK gene fusions. Among these diagnostic modalities, IHC in particular exhibits high sensitivity and specificity for the detection of ALK fusions when appropriately applied and interpreted. Expert commentary: Discrepancies have been reported between the results of IHC and FISH. However, it was revealed that patients with IHC-positivity and FISH-negativity may respond to alectinib, indicating that IHC can be used as a stand-alone method from a clinical standpoint for the identification of patients eligible for treatment with ALK inhibitors. In addition, differences between ALK variants have been reported to affect the prognosis and efficacy of ALK inhibitor-based treatments, and RT-PCR will likely increase in importance as a complementary tool.

9031 Background: Cytotoxic monotherapy is one of the standard treatments for elderly patients with advanced non-small cell lung cancer (NSCLC). Carboplatin plus nab-paclitaxel demonstrated significantly higher objective response rate (ORR) than carboplatin plus paclitaxel in patients with squamous histology and could improve overall survival (OS) in patients aged ≥70 years. Here, we compared carboplatin plus nab-paclitaxel with docetaxel in elderly patients with squamous NSCLC. Methods: The CAPITAL study is a multicenter, open-label, phase 3, randomized trial at 92 institutions in Japan. Eligible patients had advanced squamous NSCLC with no prior systemic chemotherapy, aged ≥70 years, and had an ECOG performance status of 0 or 1. Patients were randomized 1:1 to docetaxel 60 mg/m2 (D arm) or carboplatin AUC 6 mg/mL/min plus nab-paclitaxel 100 mg/m2 weekly (nab-PC arm) for each 21-day cycle. The primary endpoint was OS. This trial is registered with the UMIN Clinical Trials Registry (UMIN000019843) and the Japan Registry of Clinical Trials (jRCTs041180110). Results: Between December 2015 and August 2020, 196 patients were randomly assigned to the two treatment arms (D arm, n=98; nab-PC arm, n=98). The median follow-up and age were 11.5 months and 76 years (range: 70–88 years), respectively, and 87% of the patients were male. After the planned interim analysis, the independent data monitoring committee confirmed that the study met the primary endpoint of improved OS in August 2020, and this report represents the final analysis. The nab-PC arm showed significant superiority in OS versus the D arm (hazard ratio [HR], 0.52; 90% CI, 0.38-0.70; median, 16.9 vs. 10.9 months; p

9022 Background: The primary analysis of the J-ALEX (JapicCTI-132316) study for the ALK-inhibitor naïve ALK+ NSCLC demonstrated superior progression-free survival (PFS) in Japanese patients randomized to the ALC, compared with those assigned in the CRZ (HR 0.34, 99.7% CI 0.17–0.71, stratified log-rank p

9042 Background: Brigatinib is a next-generation ALK inhibitor with demonstrated activity against ALK mutations. We report primary analysis results with brigatinib in Japanese patients with ALK-positive NSCLC who have not previously been treated with an ALK TKI in the phase 2 J-ALTA study (NCT03410108). Methods: J-ALTA, a multi-cohort study, included a TKI-naive expansion cohort. Patients in the TKI-naive cohort received brigatinib 180 mg qd with 7-day lead-in at 90 mg. Primary endpoint was 12-month progression-free survival (PFS) as assessed by an independent-review committee (IRC). Secondary endpoints included confirmed objective response rate (ORR; IRC- and investigator-assessed); IRC-assessed PFS and duration of response (DoR); overall survival (OS); intracranial PFS (iPFS by IRC); and safety. Results: A total of 104 patients were enrolled in the whole study; of these, 32 patients had TKI-naive NSCLC (median age, 60.5 y; 94% had adenocarcinoma; 22% had baseline brain metastases; 25% received prior chemotherapy). As of September 29, 2020, median follow-up was 14.2 months and 27 patients remained on treatment. IRC-assessed 12-month PFS was 93% (90% CI, 79–98). Confirmed ORR was 97% (90% CI, 84–100) by IRC, with 2 complete responses and 29 partial responses. Median DoR as assessed by the IRC was not mature; median PFS, iPFS, and OS were not reached. In the TKI-naive cohort, treatment-emergent adverse events (TEAEs) were reported in all 32 patients (most common: increased creatine phosphokinase, 81%; hypertension, 59%; diarrhea, 47%). Grade ≥3 TEAEs were reported in 91% of patients in this cohort (most common: increased creatinine phosphokinase, 44%; hypertension, 34%; increased lipase, 19%) and 75% of all patients. Three cases (9.4%) of interstitial lung disease/pneumonitis were reported in the TKI-naive cohort; all were grade 1 and occurred after day 15 of brigatinib treatment. Dose discontinuations/interruptions/reductions due to AEs in the TKI-naive cohort were 0%/94%/66%, respectively, and in the total study population were 5%/72%/41%. AE frequency and profile were similar in the TKI-naive and overall cohorts. Conclusions: In the J-ALTA TKI-naive cohort, brigatinib demonstrated substantial efficacy and manageable safety in the Japanese patient population. Brigatinib remains one of the treatment options in Japanese patients. Clinical trial information: NCT03410108.

9111 Background: Capmatinib, a highly selective and potent MET inhibitor, was approved for patients (pts) with advanced MET exon 14 skipping mutation (METex14) NSCLC in the US and Japan, with the FoundationOne CDx (tissue NGS assay), based on results of the ongoing GEOMETRY mono-1 study (NCT02414139). Here, we report efficacy findings in pts from GEOMETRY mono-1, who were identified as METex14 using a next-generation sequencing (NGS)-based liquid biopsy test (LDx), which detects METex14 in circulating tumor (ct)DNA. Methods: During the GEOMETRY mono-1 study, pts were screened for METex14 status using a METex14 RT-PCR clinical trial assay (CTA) on FFPE tissue. Clinical validation of the LDx was performed using plasma samples from pts enrolled in the GEOMETRY mono-1 study, which include METex14-positive samples from Cohort (C)4 (pretreated) and C5b (treatment-naïve), in addition to METex14-negative samples from C1b, C2, and C3, and 21 tissue-matched NSCLC plasma samples from commercial sources to supplement the total number of METex14 deletion negative patients. Concordance of the CTA and LDx were evaluated by positive percent agreement (PPA) and negative percent agreement (NPA). This retrospective analysis reports overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS), all by BIRC, and overall survival (OS) in pts identified as METex14 by the LDx (data cutoff: Sep 18, 2020). Results: Of the 97 pts with METex14 NSCLC in C4 (n = 69) and C5b (n = 28), 88 pts had plasma volume ≥2.5 mL and cell free DNA ≥20 ng (minimum input); of these 57 were LDx positive (C4, n = 41; C5b, n = 16), 26 were negative; 5 had invalid sequencing results. Of the 97 CTA METex14-negative patients who met minimum input requirements, 88 were LDx negative and 9 had invalid sequencing results; none of the CTA METex14-negative pts (N = 97) were reported as positive by the LDx. The PPA and NPA for these were 68.7% (95% CI: 57.6%, 78.4%) and 100% (95% CI: 95.9%, 100%), respectively, when excluding LDx invalid results. In pts identified as METex14 positive by LDx, the ORR (95% CI) was 81.3% (54.4‒96.0; n = 16) in C5b and 48.8% (32.9‒64.9; n = 41) in C4; median DOR (95% CI) was 20.3 (4.2, NE; n = 13) months in C5b and 9.8 (4.2‒19.5; n = 20) months in C4; median PFS (95% CI) was 12.4 (4.5‒NE; n = 16) months in C5b and 5.4 (4.0‒6.6; n = 41) months in C4; median OS was 17.9 (9.8‒NE; n = 16) months in C5b and 13.6 (6.6‒23.3; n = 41) months in C4. Clinical findings in those identified as METex14 positive by LDx were comparable with those identified by the CTA. Conclusions: Current findings from the GEOMETRY mono-1 study support the activity of capmatinib in advanced NSCLC pts with METex14 identified using LDx. For pts identified as METex14-negative by the LDx, further testing should be performed on tissue samples, as a negative LDx result does not preclude a positive result by tissue biopsy. Clinical trial information: NCT02414139.

Introduction Taletrectinib (AB-106/DS-6051b) is an oral, potent selective ROS1 and pan-NTRK tyrosine kinase inhibitor (TKI). Preclinically, taletrectinib has activity against ROS1 G2032R solvent-front mutation. Methods Patients with ROS1+ NSCLC enrolled into two phase 1 studies conducted in United States (U101, NCT02279433) and Japan (J102, NCT02675491) were analyzed for objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors version 1.1, progression-free survival, and safety. Results A total of 22 patients with ROS1+ NSCLC out of the total 61 patients enrolled were analyzed. Taletrectinib was given at the oral dose of 400 mg, 600 mg, 800 mg, and 1200 mg once daily and 400 mg twice daily as part of the dose-escalation schema. Data cutoff was August 19, 2020. Median follow-up time for all 22 patients was 14.9 months (95% confidence interval [CI]: 4.1–33.8). A total of 18 patients with ROS1+ were assessable for response. The confirmed ORR for ROS1 TKI-naive patients (N = 9) was 66.7% (95% CI: 35.4–87.9) with a disease control rate of 100% (70.1–100). The confirmed ORR for crizotinib pretreated patients (N = 6) was 33.3% (95% CI: 9.7–70.0) with a disease control rate of 88.3% (95% CI: 443.6–97.0). The median progression-free survival for ROS1 TKI-naive patients (N = 11) was 29.1 months (95% CI: 2.6–not reached) and 14.2 months (95% CI: 1.5–not reached) for crizotinib-refractory only patients (N = 8). The most common treatment-related adverse events were alanine transaminase elevations (72.7%), aspartate transaminase elevations (72.7%), nausea (50.0%), and diarrhea (50.0%). Grade 3 or higher adverse events were alanine transaminase elevations (18.2%), aspartate transaminase (9.1%), and diarrhea (4.5%). Conclusions Taletrectinib (AB106/DS6051b) has a meaningful clinical activity in patients with advanced ROS1+ NSCLC who are ROS1 TKI-naive or crizotinib-refractory and a manageable safety profile.

Background Various polymorphisms have been detected in the UDP-glucuronosyltransferase 1A ( UGT1A ) gene, and UGT1A1 *28 and UGT1A1 *6 have important effects on the pharmacokinetics of irinotecan and the risk of severe toxicities during irinotecan therapy. This study was conducted to determine the maximum tolerated dose (MTD) of irinotecan chemotherapy according to the UGT1A1 genotype in previously treated lung cancer patients with the UGT1A1 *28 or UGT1A1 *6 polymorphism. Methods The eligibility criteria were as follows: lung cancer patients that had previously been treated with anticancer agents other than irinotecan, possessed the UGT1A1 *28 or UGT1A1 *6 polymorphism (group A included *28/*28, *6/*6, and *28/*6, and group B included *28 /− and *6 /−), were aged ≤75 years old, had a performance score of 0–1, and exhibited adequate bone marrow function. The patients were scheduled to receive irinotecan on days 1, 8, 15, 22, 29, and 36. Results Four patients were enrolled in this trial. Two patients were determined to be ineligible. The remaining two patients, who belonged to group B, received an initial irinotecan dose of 60 mg/m2, but did not complete the planned treatment because of diarrhea and leukopenia. Thus, in group B patients, 60 mg/m2 was considered to be the MTD of irinotecan. The study was terminated in group A because of poor case recruitment. Conclusions The MTD of irinotecan for previously treated lung cancer patients that are heterozygous for the UGT1A1 * 28 or UGT1A1 * 6 gene polymorphism is 60 mg/m2.

Summary We report pharmacokinetics, efficacy, and safety data for a new 150 mg alectinib capsule in ALK+ non-small-cell lung cancer in a multicenter, open-label pharmacologic study (JP28927). Eligible patients (≥20 years, locally advanced/metastatic ALK+ disease, ALK inhibitor-naive and -pretreated [including crizotinib refractory]) were randomized 1:1 to receive one of two sequences of alectinib 300 mg twice daily (comprising different schedules of 20/40 mg and 150 mg capsules) until investigator-determined lack of clinical benefit. Co-primary endpoints were: bioequivalence of alectinib 20/40 mg versus 150 mg; food effect with 150 mg; and safety. Thirty-five patients were enrolled; median treatment duration was 13.1 months (range 1.1−15.0). Under fasting conditions, exposure of the two formulations was similar; mean AUClast ± standard deviation 3230 ± 914 h•ng/mL versus 3710 ± 1040 h•ng/mL, respectively, for 150 mg versus 20/40 mg capsules. Food effect with 150 mg alectinib was negligible. Treatment-related adverse events in >20% of patients were constipation (31.4%), dysgeusia (25.7%), and decreased white blood cell and neutrophil count (22.9% each). No treatment-related grade 4/5 events occurred. Median time to response was 1.2 months (95% CI 1.1−2.1). For the full analysis set (n = 35) and crizotinib-failure subpopulations (n = 23), overall response rate was 70.0% (95% CI 50.6−85.3) and 65.0% (95% CI 40.8−84.6), and median progression-free survival was 13.9 months (95% CI 11.1−not reached) and 12.9 months (95% CI 3.9−not reached), respectively. The 150 mg capsule had a similar exposure profile to 20/40 mg capsules. Alectinib demonstrated promising efficacy and was well tolerated. This article is protected by copyright. All rights reserved.

Purpose The epidermal growth factor receptor (EGFR) tyrosine kinase has been an important target for non–small-cell lung cancer. Several EGFR tyrosine kinase inhibitors (TKIs) are currently approved, and both gefitinib and erlotinib are the most well-known first-generation EGFR-TKIs. This randomized phase III study was conducted to investigate the difference between these two EGFR-TKIs. Patients and Methods Previously treated patients with lung adenocarcinoma were randomly assigned to receive gefitinib or erlotinib. This study aimed to investigate the noninferiority of gefitinib compared with erlotinib. The primary end point was progression-free survival (PFS). Results Five hundred sixty-one patients were randomly assigned, including 401 patients (71.7%) with EGFR mutation. All baseline factors (except performance status) were balanced between the arms. Median PFS and overall survival times for gefitinib and erlotinib were 6.5 and 7.5 months (hazard ratio [HR], 1.125; 95% CI, 0.940 to 1.347; P = .257) and 22.8 and 24.5 months (HR, 1.038; 95% CI, 0.833 to 1.294; P = .768), respectively. The response rates for gefitinib and erlotinib were 45.9% and 44.1%, respectively. Median PFS times in EGFR mutation–positive patients receiving gefitinib versus erlotinib were 8.3 and 10.0 months, respectively (HR, 1.093; 95% CI, 0.879 to 1.358; P = .424). The primary grade 3 or 4 toxicities were rash (2.2% for gefitinib v 18.1% for erlotinib) and alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation (6.1%/13.0% for gefitinib v 2.2%/3.3% for erlotinib). Conclusion The study did not demonstrate noninferiority of gefitinib compared with erlotinib in terms of PFS in patients with lung adenocarcinoma according to the predefined criteria.

BACKGROUND Jumonji domain-containing 2B, JMJD2B, has been shown to play an important role in the pathogenesis of lung cancer cells. However, the significance of JMJD2B in patients with lung cancer remains to be elucidated. PATIENTS AND METHODS Seventy-eight patients with resected adenocarcinoma, whose data regarding oncogenic drivers in lung cancer were available, were included in the study. Immunohistochemical analysis was performed with a specific antibody for JMJD2B to investigate JMJD2B expression and the significance of JMJD2B expression in survival after surgery was evaluated. RESULTS Among the 78 patients, 50 (64%) exhibited JMJD2B immunopositivity. The overall survival (OS) of the 50 JMJD2B-positive patients after surgery was significantly inferior to that of the JMJD2B-negative patients (five-year survival=56.7% vs. 92.6%; log-rank: p=0.01). Multivariate analysis showed that JMJD2B positivity was an independent prognostic factor. CONCLUSION JMJD2B may be a novel prognostic factor for resected lung adenocarcinoma.

Summary Background Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. Methods We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m 2 on days 1 and 8, intravenous etoposide 60 mg/m 2 on days 1–3, and intravenous irinotecan 90 mg/m 2 on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m 2 on days 1–5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Findings Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0–35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7–20·6) than in the topotecan group (12·5 months, 10·8–14·9; hazard ratio 0·67, 90% CI 0·51–0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Interpretation Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer. Funding National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.

Background: Uridine 5′-diphospho-glucuronosyltransferase 1A1 (UGT1A1*27) is known to impair the effect of UGT in basic research; however, little clinical investigation has been conducted. To evaluate the effect of the UGT1A1*27 polymorphism in irinotecan therapy, we conducted a prospective study. Methods: Eligibility criteria included: lung cancer patients; scheduled irinotecan therapy doses of single ? 80, combination ? 50, radiation with single ? 50, or radiation with combination ? 40 mg/m2; age ? 20; and Eastern Cooperative Oncology Group performance score (PS) 0?2. Patients were examined for UGT1A1*28 and *6 polymorphisms and received irinotecan. When the UGT1A1*28 polymorphism was detected, a search for UGT1A1*27 was conducted. Fifty patients were enrolled, with 48 patients determined eligible. Results: UGT1A1 polymorphisms *28/*28, *6/*6, *28/*6, *28/?, *6/?, ?/? observed 0 (0%), 1 (2%), 1 (2%), 7 (15%), 17 (35%) and 22 (46%), respectively. UGT1A1*27 were examined in nine patients including one ineligible patient; however, no polymorphisms were found. The study ceased after interim analysis. In an evaluation of the side effects of irinotecan, patients with UGT1A1*28 and UGT1A1*6 polymorphisms had a higher tendency to experience febrile neutropenia than wild type (25% and 32% vs. 14%). Incidences of grade 3/4 leukopenia and neutropenia were significantly higher in patients with UGT1A1*28 polymorphisms compared with wild type (75% vs. 32%, P = 0.049; 75% vs. 36%, P = 0.039, respectively). Conclusion: Our prospective study did not locate the UGT1A1*27 polymorphism, suggesting that UGT1A1*27 does not significantly predict severe irinotecan toxicity in cancer patients., Thoracic Cancer, 7(4), pp.467-472; 2016

Background The Japan Guidelines of Lung Cancer Therapy recommend epidermal growth factor receptor-tyrosine kinase inhibitors as a first-line therapy for advanced/recurrent non-small cell lung cancer patients with epidermal growth factor receptor mutation. Although survival periods in recent reports of epidermal growth factor receptor-tyrosine kinase inhibitor treatment have been getting longer, the reasons why are unclear. We investigated the survival, prognostic factors and real-world treatment of non-small cell lung cancer patients with epidermal growth factor receptor mutation in clinical practice. Methods Non-small cell lung cancer patients (n = 1660) who started first-line treatment from January 2008 to December 2012 were enrolled. Patients were diagnosed with epidermal growth factor receptor mutation-positive advanced/recurrent non-small cell lung cancer by histology or cytology samples. The primary objective was to estimate overall survival. The secondary objectives were to determine prognostic factors, real-world treatment patterns and efficacy of gefitinib treatment. We calculated the treatment exposure rate for each treatment category using the following formula: exposure rate = person-years for the treatment category/total person-years × 100. Results The median overall survival was 30.8 months. Sex, age, histology, epidermal growth factor receptor mutation type, clinical stage and performance status affected overall survival. The exposure rates for all epidermal growth factor receptor-tyrosine kinase inhibitors, gefitinib and platinum-doublet chemotherapy were 62.1, 46.4 and 8.5% respectively. Overall 56.1% of patients were administered gefitinib as first-line therapy, and 39.0% were treated with ≥2 epidermal growth factor receptor-tyrosine kinase inhibitor regimens. The median progression-free survival in the first-line gefitinib group was 11.4 months. Factors affecting prognosis were sex, histology, clinical stage and performance status. Conclusion Epidermal growth factor receptor-tyrosine kinase inhibitors, especially gefitinib, are major components of the treatment regimens for epidermal growth factor receptor mutation-positive non-small cell lung cancer. Switching and re-challenging with epidermal growth factor receptor-tyrosine kinase inhibitors were also practiced in Japan.

SummaryBackground This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.

Patients with advanced esophageal cancer frequently experience dysphagia and dyspnea, and relief of such symptoms is important. We wished to clarify the efficacy of endoscopic stent placement in patients with dysphagia or dyspnea caused by advanced esophageal cancer. A database of patients with esophageal cancer who underwent esophageal and airway stent insertion between 2005 and 2012 was analyzed retrospectively. Effects and complications of stent insertion, and survival after stent insertion, were investigated. Eighteen patients were treated by esophageal (n = 10) and/or airway (n = 9) stent placement. Marked improvements in food intake were recognized in eight patients after esophageal stenting. Marked improvements in breathing were observed in all patients after airway stenting. Dysphagia scores in the esophageal stent group as well as dyspnea grades in Common Terminology Criteria for Adverse Events v4.0 (CTCAE 4.0) in the airway stent group were significantly improved (p = 0.0078). In the esophageal stent group, major complications (CTCAE grade ≥3) occurred in seven of ten patients (70 %). In the airway stent group, major complications occurred in three of nine patients (33 %). Median survival of all 18 patients was 87.5 (range 13–1952) days after esophageal and/or airway stent placement. Stent placement is effective for the improvement of malignant dysphasia and dyspnea caused by advanced esophageal cancer.

Purpose Investigate the safety and tolerability of AZD5363 and define a recommended dose for evaluation in Japanese patients with advanced solid malignancies. Methods AZD5363 was administered orally as a single dose, and then the dose was escalated to twice daily (bid) in separate continuous (every day) and intermittent (4 days on, 3 days off [4/3] or 2 days on, 5 days off [2/5]) dosing schedules to reach recommended doses defined by dose-limiting toxicity (DLT). Doses for continuous, 4/3, and 2/5 intermittent dosing schedules were 80–400, 360–480, and 640 mg, respectively, and were informed by results from an equivalent study in Caucasian patients. Results Forty-one patients received AZD5363. DLTs were only experienced with continuous dosing. 97.6 % of patients reported at least one adverse event (AE); most common were diarrhea (78.0 %), hyperglycemia (68.3 %), nausea (56.1 %), and maculopapular rash (56.1 %). Grade ≥3 AEs were reported by 63.4 % of patients. Exposure of AZD5363 was generally dose proportional for both single and multiple doses. Single-dose pharmacokinetics of AZD5363 was generally predictive of multiple-dose pharmacokinetics. Confirmed partial responses were reported by two patients, both of whom were Akt1 (E17K) mutation positive. One patient in the 480 mg bid 4/3 dosing cohort maintained partial response for >2 years. Conclusions Intermittent dosing of AZD5363 was more tolerable than continuous dosing. 480 mg bid intermittent 4/3 dosing for AZD5363 monotherapy was selected for further investigation. Preliminary evidence of antitumor activity was observed. Akt1 (E17K) is a potent driver mutation that may predict clinical response to AZD5363.

Summary Background The combination of nedaplatin, a cisplatin derivative, and docetaxel showed promising activity for advanced squamous cell lung carcinoma in a previous phase 1–2 study. We compared nedaplatin plus docetaxel with cisplatin plus docetaxel in patients with previously untreated advanced or relapsed squamous cell lung carcinoma to determine effects on overall survival. Methods We did a randomised, open-label, phase 3 study at 53 institutions in Japan. Eligibility criteria included pathologically proven squamous cell lung cancer with stage IIIB/IV or postoperative recurrence, age 20–74 years, Eastern Cooperative Oncology Group performance status of 0–1, no previous chemotherapy or recurrence more than a year after previous adjuvant chemotherapy, and adequate organ function. Patients were randomly assigned (1:1) to 100 mg/m 2 nedaplatin and 60 mg/m 2 docetaxel intravenously, or 80 mg/m 2 cisplatin and 60 mg/m 2 docetaxel, every 3 weeks for four to six cycles (at the treating oncologist's discretion). Randomisation was done centrally at the West Japan Oncology Group data centre via a computer-generated allocation sequence with dynamic minimisation that balanced stage (IIIB/IV or postoperative recurrent), sex, and institution. The primary endpoint was overall survival in the modified intention-to-treat population (ie, all patients who were randomly assigned and met the inclusion criteria). Safety analyses were done in all randomly assigned patients who received at least one dose of the study regimen. This trial is registered with the UMIN Clinical Trials Registry, number UMIN000002015, and is closed to new participants. Findings Between July 6, 2009, and July 26, 2012, 355 patients were randomly assigned. 349 patients were included in the modified intention-to-treat analysis (177 in the nedaplatin group and 172 in the cisplatin group). Overall survival was significantly longer in the nedaplatin group (median 13·6 months, 95% CI 11·6–15·6) than in the cisplatin group (11·4 months,10·2–12·2; hazard ratio 0·81, 95% CI 0·65–1·02; p=0·037, one-sided stratified log-rank test). Grade 3 or worse nausea (seven of 177 patients in the nedaplatin group and 25 of 175 in the cisplatin group), fatigue (six vs 20), hyponatraemia (24 vs 53), and hypokalaemia (four vs 15) were more frequent in the cisplatin group than in the nedaplatin group, whereas grade 3 or worse leucopenia (98 vs 77), neutropenia (146 vs 123), and thrombocytopenia (16 vs none) were more frequent in the nedaplatin group than in the cisplatin group. Treatment-related deaths occurred in four and three patients in nedaplatin and cisplatin groups, respectively. Interpretation Overall survival was significantly longer with nedaplatin plus docetaxel than with cisplatin plus docetaxel, and the regimens had different safety profiles. Nedaplatin plus docetaxel could be a new treatment option for advanced or relapsed squamous cell lung cancer. Funding West Japan Oncology Group and Sanofi.

Introduction Sorafenib monotherapy has shown benefits in phase II trials as third-/fourth-line treatment in patients with non-small-cell lung cancer (NSCLC). Methods The phase III, multinational, double-blind, placebo-controlled Monotherapy admInistration of Sorafenib in patientS wIth nOn-small-cell luNg cancer (MISSION) trial randomized patients with advanced relapsed/refractory NSCLC, following two or three prior treatment regimens, to sorafenib 400 mg twice a day (n = 350) or matching placebo (n = 353) plus best supportive care. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS) and time to progression. Epidermal growth factor receptor and KRAS mutation status was analyzed in archival tumor and/or circulating tumor DNA from blood samples obtained during screening. Results Median OS was similar in the sorafenib and placebo groups (8.2 versus 8.3 mo; hazard ratio [HR], 0.99; 95% confidence interval [CI], 0.84–1.17; p = 0.47). Median PFS (2.8 versus 1.4 mo; HR, 0.61; 95% CI, 0.51–0.72; p p p = 0.002) and PFS (2.7 versus 1.4 mo; HR, 0.27; 95% CI, 0.16–0.46; p Conclusions Third-/fourth-line sorafenib therapy did not significantly increase OS in patients with relapsed/refractory NSCLC, despite significantly increasing PFS.

Background: The JIPANG study is a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) versus vinorelbine /cisplatin (Vnr/Cis) for completely resected stage II-IIIA non-squamous non-small-cell lung cancer (Ns-NSCLC)(UMIN000006737, jRCTs041180023). This phase III study did not meet the primary endpoint (recurrence-free survival, RFS) but Pem/Cis had a similar efficacy to Vnr/Cis with a better tolerability as postoperative adjuvant chemotherapy for Ns-NSCLC patients. Patients without EGFR mutation detected by IVD kits showed favorable outcome (longer RPF) by Pem/Cis compared with Vnr/Cis. Tumor mutation burden (TMB) is thought to be associated with the amount of tumor neoantigen and to have a predictive value of immune checkpoint inhibitors. However, the relationship between EGFR and other mutation status, and TMB in NSCLC remains unclear and the relevance of TMB to cytotoxic chemotherapy is not yet fully understood. Purpose: The aim of this exploratory study was to investigate relationship between tumor mutation profiles, including TMB and clinical outcome (RFS), of Pem/Cis vs Vnr/Cis for completely resected stage II-IIIA Ns-NSCLC in the JIPANG study (UMIN000006737, jRCTs041180023). Materials and Methods: FFPE tumor tissues (n=385) were obtained from the patients in the JIPANG study. Mutation status of tissue DNA was analyzed by targeted deep sequencing (Comprehensive cancer panel, CCP). TMB was evaluated by mutations per megabase (mut/Mb). Results: Assay success rate of CCP was 99.2% (374/385). EGFR (37.2%, 139/374) mutations were detected frequently in Ns-NSCLC. Patients without any EGFR mutations experienced longer RFS in the Pem/Cis arm (median; not reached) compared with Vnr/Cis arm (52.6 mo) as reported previously. Median value of TMB of all tumor samples was 9.4 (2.5-83.8). Tumors with EGFR mutations had lower TMB values than EGFR wild type (TMB median; 8.5 vs 11.0, p Conclusions: TMB value was lower in Ns-NSCLC tissues harboring EGFR mutation. TMB was predictive of RPF benefit with Pem/Cis vs Vnr/Cis in Ns-NSCLC. Based on this exploratory analysis, further investigation of TMB combined with EGFR mutation status as a predictive biomarker for chemotherapy as well as immune checkpoint inhibitors is warranted. Citation Format: Masahiro Tsuboi, Kazuto Nishio, Kazuko Sakai, Hirotsugu Kenmotsu, Takeharu Yamanaka, Toshiaki Takahashi, Koichi Goto, Haruko Daga, Norihiko Ikeda, Takashi Seto, Shinichi Toyooka, Hiroshi Date, Tetsuya Mitsudomi, Isamu Okamoto, Hideo Saka, Hiroaki Okamoto, Yuichi Takiguchi, Nobuyuki Yamamoto. Tumor mutation burden as a biomarker of relapse free survival of non-squamous non-small cell lung cancer treated with PEM/CDDP in adjuvant setting (the JIPANG-TR) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2052.

9537 Background: Brigatinib is an ALK inhibitor with demonstrated activity against ALK resistance mutations. To evaluate efficacy and safety in Japanese patients with ALK-positive non-small cell lung cancer (NSCLC), a prospective, single-arm, phase 2 study was conducted. We report the efficacy and safety of brigatinib in patients who have progressed on alectinib with or without prior crizotinib and of those who previously received up to two ALK tyrosine kinase inhibitors (TKIs) with or without prior chemotherapy. Methods: A safety evaluation lead-in was followed by an expansion stage of an ALK TKI-naïve and two ALK TKI-refractory cohorts. The refractory cohorts included patients with stage IIIB, IIIC, or IV NSCLC with ALK rearrangements. This report describes efficacy results from the post-alectinib patients in the expansion cohort and safety results from all refractory patients. The primary endpoint was confirmed objective response rate (ORR) assessed by IRC, secondary endpoints included duration of response (DoR), progression-free survival (PFS), disease control rate (DCR), and intracranial ORR (iORR). Brigatinib was administered at 180 mg QD with 90 mg QD lead-in for the first 7 days, and efficacy was evaluated every 8 weeks. Results: A total of 72 patients were enrolled in 28 sites, including a cohort of 47 patients with prior alectinib, with/without crizotinib between January 2018 and September 2019. The primary analysis of brigatinib in this cohort (data cut-off date 26 September 2019) demonstrated an IRC-assessed, confirmed ORR of 30% and a median DoR of 6.1 months. The median PFS was 7.3 months. Clinically meaningful intracranial efficacy was also observed (see table). Grade ≥3 TEAEs included blood creatine phosphokinase increase (18.1%), lipase increase (13.9%), hypertension (11.1%), amylase increase (4.2%), and pneumonitis (1.4%). Brigatinib also showed anti-tumor activity in patients with refractory secondary mutations in the ALK kinase domain, including G1202R, I1171N, V1180L, and L1196M. Conclusions: Brigatinib showed clinically meaningful efficacy in Japanese patients refractory to prior alectinib (first line or post crizotinib), regardless of prior chemotherapy. The safety profile of brigatinib was consistent with prior studies and no new safety findings were identified. Clinical trial information: NCT03410108 . [Table: see text]

9527 Background: The phase III RELAY study (NCT02411448) showed significantly improved progression-free survival (PFS) for RAM+ERL vs PL+ERL in 449 pts with previously untreated EGFR mutation-positive metastatic NSCLC (median PFS 19.4 vs 12.4 mo, HR 0.591 [95% CI 0.461–0.760], p

Immune therapy opened a new era in treatment of advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) targeting the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) pathway have achieved great success over conventional cytotoxic chemotherapy.

Introduction Approximately one-half of patients with epidermal growth factor receptor (EGFR) mutation-positive advanced/metastatic non-small-cell lung cancer (NSCLC) develop resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) due to a secondary T790M mutation. This study investigated the pattern of T790M testing after EGFR TKI treatment in a real-world setting in Japan. Method This prospective observational study enrolled patients with EGFR mutation-positive advanced/metastatic NSCLC who reported disease progression during treatment with first- or second-generation EGFR TKIs. Data regarding sampling methods for T790M mutation testing (plasma sample, cytology or tissue biopsy) and the treatment strategies after disease progression were recorded prospectively. Results A total of 236 patients were included in the study (female, 67.4%; median age, 73.0 years), and 205 patients (86.9%) underwent rebiopsy by any of the three possible methods: plasma sampling in 137 patients (58.1%) and tissue/cytology sampling in 68 patients (28.8%) during the first rebiopsy. Overall, 80.6% of the tissue/cytology samples contained tumor cells, and 40% of these samples were positive for the T790M mutation. T790M mutations were detected in only 19.7% of plasma samples. Of the 199 patients who underwent T790M testing, 61 (30%) tested positive, and 56 (91.8%) subsequently received osimertinib. Conclusion Among the 87% of Japanese patients who underwent rebiopsy after progressing on treatment with a first- or second-generation EGFR TKI, approximately 30% tested positive for the T790M mutation and were eligible to receive osimertinib. Although plasma sampling is non-invasive, this rebiopsy method is less sensitive for T790M detection compared with tissue or cytology sampling (UMIN identifier: UMIN000024928). Funding AstraZeneca Japan. Electronic supplementary material The online version of this article (10.1007/s40487-018-0064-8) contains supplementary material, which is available to authorized users.

We describe a 77-year-old Japanese woman who presented with three nodule shadows in three different lobes of the right lung, without evidence of lymph node metastasis or distant metastasis. All three tumors were surgically resected. The pathological diagnosis was synchronous multiple primary lung cancer: pT2aN0M0, pStageIB. Based on a differing epidermal growth factor receptor (EGFR) mutation status, no lymph node metastasis, and no distant metastasis, the tumors were characterized as synchronous triple primary rather than intrapulmonary metastases. At eight months after surgery, a new lesion emerged in the right lower lobe. Given that the most advanced tumor had an EGFR del-19 mutation, the patient was orally administered afatinib. Since then, the treatment response of the patient has been assessed as stable disease (SD) for about two years. This is a very rare case of resected triple synchronous primary lung cancer on the same lung side in which the lesions all had a different EGFR mutation status, and this report highlights the clinical utility of surgical resection of multifocal lung nodules without lymph node metastasis or distant metastasis in order to optimize therapy for patients with known driver mutations.

Background Most pts with EGFR mutation-positive (EGFRm) NSCLC develop first-line (1L) EGFR-TKI resistance. Previous analyses of US insurance databases have studied healthcare utilisation and expenditure in pts with EGFRm NSCLC starting first-/second-generation (1G/2G) EGFR-TKIs. We examined treatment patterns and survival rates among pts with locally advanced/metastatic NSCLC, who received 1L 1G/2G EGFR-TKIs, in a retrospective analysis of data from the MarketScan Commercial and Medicare Supplemental databases (all US census regions). We also assessed the effect of central nervous system metastases (CNS mets) on survival rates. Methods Pts ≥18 yrs with EGFRm NSCLC who received 1L 1G/2G EGFR-TKI were analysed from date of first lung cancer diagnosis (index date) through a variable-length follow-up period. Pts included had ≥1 pharmacy claim for 1G/2G EGFR-TKI on/within 60 days post index, and ≥2 non-diagnostic claims with a diagnosis code for lung cancer within 90 days of each other between 1/1/2015 and 31/3/2018. Excluded: pts receiving chemotherapy suitable for SCLC. Data were stratified by CNS mets status. Data that could be linked to the social security administration (SSA) death file were used for mortality analyses. Results Of 578 pts (median age 63 yrs, 64% female), 275 (48%) had CNS mets and 303 (52%) had no CNS mets. Of the pts with CNS mets, 149 (54%) discontinued 1L EGFR-TKI, of whom 124 (83%) initiated 2L therapy; 121 (40%) pts with no CNS mets discontinued 1L, 85 (70%) of whom initiated 2L therapy. The most frequently prescribed 1L EGFR-TKI was erlotinib (n = 414, 72%). Overall, at 1L, 6% of pts received an add-on therapy, bevacizumab (n = 17, 3%) being the most common. The most frequent 2L therapy was osimertinib (n = 96, 46%). In pts with available SSA mortality data, unadjusted mortality rates were 138 and 92 deaths per 1000-person-years, for pts with (n = 179) and without (n = 202) CNS mets, respectively. Conclusions Most pts who discontinued 1L treatment commenced 2L; with osimertinib as most frequent. Pts with no CNS mets had numerically lower mortality rates than pts with CNS mets. Editorial acknowledgement Charlotte Terry, MSc, from iMed Comms, funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines. Legal entity responsible for the study AstraZeneca. Funding AstraZeneca. Disclosure R. Soo: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Taiho; Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Yuhan. T. Seto: Honoraria (self): Astellas, AstraZeneca, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novartis, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific, ; Research grant / Funding (institution): AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Nippon Boehringer Ingelheim, Novartis, Pfizer Japan, Takeda, Bayer Yakuhin, Daiichi Sankyo, Kissei Pharmaceutical, LOXO Oncology, Merck Serono. J.E. Gray: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Takeda, Inviata; Advisory / Consultancy: AstraZeneca, Squibb, Celgene, Takeda, Inviata; Research grant / Funding (institution): Array, Merck, AstraZeneca, Genentech, Boehringer Ingelheim, Bristol-Myers Squibb. P. Karimi: Full / Part-time employment: AstraZeneca. A. Taylor: Full / Part-time employment: AstraZeneca. W. Sawyer: Full / Part-time employment, Full time Contractor: AstraZeneca. E. Thiel: Research grant / Funding (institution): AstraZeneca. E. Marchlewicz: Research grant / Funding (institution): AstraZeneca. M. Brouillette: Research grant / Funding (institution): AstraZeneca.

Background We previously reported that toxicities were tolerable and manageable in both arms; however, febrile neutropenia was more frequently observed in the CDDP+S-1 arm. Response rate was 60%/64%. Here, we present primary analysis of 2-year survival data. Methods Patients were randomly assigned to receive CDDP+S-1 (CDDP 60mg/m2, d1, and S-1 80mg/m2, d1-14, q4w, up to 4 cycles) or CDDP+PEM (CDDP 75mg/m2, d1, and PEM 500mg/m2, d1, q3w, up to 4 cycles) combined with TRT 60Gy in 30 fractions. The primary endpoint was 2-year progression-free survival (PFS) rate. The sample size was set at 100 patients. Results Between Jan 2013 and Oct 2016, 102 patients were enrolled in this study from 9 institutions in Japan. All 102 patients were eligible and assessable, of whom 52 were assigned to CDDP+S-1 and 50 to CDDP+PEM. Baseline characteristics were similar (CDDP+S-1/CDDP+PEM): median age (range) 64.5 (39-73)/63.5 (32-74) years; women, n = 17 (33%)/n=17 (34%); stage IIIB, n = 21 (40%)/n=20 (40%); ECOG PS of 1, n = 14 (27%)/n=14 (28%); never smoker, n = 12 (23%)/n=12 (24%); and adenocarcinoma, n = 47(90%)/n=45(90%); activating EGFR mutation, n = 9 (17%)/n=4 (8%); ALK fusion, n = 2 (4%)/n=3 (6%). A total of 72 PFS events were observed at the data cut-off (28 November 2018). After a median follow-up of 32.1 months, median PFS was 12.7/13.8 months (HR = 1.16, 95% CI, 0.73-1.84, p = 0.538), and 2-year PFS rate was 36.5% (95% CI, 23.5-49.6)/32.1% (95%CI, 18.9-45.4). After a median follow-up of 34.6 months, 44 OS events were observed. Median OS was 48.3/59.1 months (HR = 1.05, 95%CI, 0.58-1.90, p = 0.883), and 2-year OS rate was 69.2% (95%CI, 56.7-81.8)/66.4% (95%CI, 53.0-79.9). 27 patients in each arm received post-study chemotherapy including EGFR-TKIs (n = 7/n=5), ALK-TKIs (n = 0/n=3), and immunocheckpoint inhibitors (n = 6/n=10). Conclusions 2-year PFS rate in the CDDP+S-1 arm was better than that in the CDDP+PEM arm. We will select the CDDP+S-1 arm as the investigational arm in a future phase III study.