A single-arm study evaluating bevacizumab, cisplatin, and paclitaxel followed by single-agent bevacizumab in Japanese patients with advanced cervical cancer.

BACKGROUND: Adding bevacizumab to chemotherapy for recurrent, persistent or metastatic cervical cancer significantly improved overall survival (primary endpoint), progression-free survival and overall response rate in the randomized Phase III GOG-0240 trial. However, data for bevacizumab-containing therapy are scarce in Japanese patients with advanced cervical cancer. METHODS: The primary objective of the single-arm multicenter Phase II JO29569 study was to evaluate the tolerability of paclitaxel (135 mg/m2 over 24 h or 175 mg/m2 over 3 h), cisplatin (50 mg/m2) and bevacizumab (15 mg/kg), administered every 3 weeks until disease progression or unacceptable toxicity in Japanese patients with stage IVB, persistent or recurrent cervical cancer. RESULTS: The seven treated patients received a median of nine (range 7-12) bevacizumab cycles and six (range 4-12) chemotherapy cycles. None of the predefined adverse events occurred during the tolerability evaluation period. The most common all-grade adverse events were alopecia, hypertension, decreased appetite, nausea and peripheral sensory neuropathy. There were no cases of fistula. The most common grade ≥3 adverse events were hypertension, neutrophil count decreased and neutropenia. Only one patient experienced febrile neutropenia. The overall response rate was 86% (95% confidence interval, 42-100%), including a complete response in one patient. At data cutoff, disease had progressed in one patient; bevacizumab therapy was ongoing in the remaining six. CONCLUSIONS: According to the specified primary objective, a regimen of cisplatin, paclitaxel and bevacizumab was tolerable in Japanese patients and demonstrated encouraging activity in this small single-arm study. Further study is warranted to confirm the safety and effectiveness of bevacizumab in Japanese patients with cervical cancer.

First-line bevacizumab plus paclitaxel in Japanese patients with HER2-negative metastatic breast cancer: subgroup results from the randomized Phase III MERiDiAN trial.

BACKGROUND: In the double-blind placebo-controlled randomized Phase III MERiDiAN trial (ClinicalTrials.gov NCT01663727), adding bevacizumab to paclitaxel for HER2-negative metastatic breast cancer (mBC) significantly improved progression-free survival (PFS; stratified hazard ratio [HR] 0.68, 99% confidence interval [CI], 0.51-0.91). We assessed the efficacy and tolerability of first-line bevacizumab-paclitaxel in the subset of Japanese patients in MERiDiAN. METHODS: Eligible patients had HER2-negative mBC previously untreated with chemotherapy. Plasma vascular endothelial growth factor (VEGF)-A was measured before randomization to paclitaxel 90 mg/m2 on Days 1, 8 and 15 with either placebo or bevacizumab 10 mg/kg on Days 1 and 15, repeated every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal. Stratification factors were: baseline plasma VEGF-A level, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary endpoints were investigator-assessed PFS in the intent-to-treat (ITT) population and in the subgroup with high plasma VEGF-A. This exploratory analysis evaluated efficacy and safety in the subpopulation treated in Japanese centers. RESULTS: Of 481 patients randomized in MERiDiAN, 54 (11%) were Japanese. The stratified PFS HR in the Japanese subgroup was 0.64 (95% CI, 0.29-1.40). Median PFS was 9.2 months with placebo-paclitaxel (n = 30) versus 12.7 months with bevacizumab-paclitaxel (n = 24). Bevacizumab was associated with increased incidences of Grade ≥3 neutropenia, peripheral sensory neuropathy and hypertension, but there was no Grade ≥3 proteinuria, bleeding or gastrointestinal perforation. CONCLUSIONS: Bevacizumab-paclitaxel efficacy in Japanese patients was consistent with the MERiDiAN ITT population. No new safety signals were seen and tolerability was consistent with previous experience.

Final overall survival in JO22903, a phase II, open-label study of first-line erlotinib for Japanese patients with EGFR mutation-positive non-small-cell lung cancer.

BACKGROUND: In Japan, the clinical efficacy of erlotinib monotherapy in epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer was demonstrated in the phase II JO22903 trial, which reported a median progression-free survival of 11.8 months. Here we report final overall survival data from JO22903. METHODS: JO22903 (JapicCTI-101085) was a single-arm, multicenter, phase II, open-label, non-randomized study of first-line erlotinib monotherapy in EGFR mutation-positive non-small-cell lung cancer. Eligible patients (≥20 years) with stage IIIB/IV or recurrent non-small-cell lung cancer and confirmed activating mutations of EGFR (exon 19 deletion or L858R point mutation in exon 21) received oral erlotinib 150 mg/day until disease progression or unacceptable toxicity. The primary endpoints were progression-free survival and safety; overall survival was a secondary endpoint. RESULTS: At the final analysis, 102 patients were included in the modified intent-to-treat population and 103 in the safety population. Median follow-up was 32.3 months. Median overall survival was 36.3 months (95 % confidence interval 29.4-not reached). Subgroup analyses of overall survival suggested that the presence of brain metastases was a negative prognostic factor (median overall survival 22.7 months, 95 % confidence interval 19.6-29.4). The impact on overall survival of using versus not using EGFR tyrosine kinase inhibitors in any line of treatment following disease progression was unclear (median 32.8 versus 36.3 months, respectively). No new safety issues were observed. CONCLUSION: In this survival update, single-agent erlotinib achieved a median overall survival of more than 3 years in patients with EGFR mutation-positive non-small-cell lung cancer.

Erlotinib for Japanese patients with activating EGFR mutation-positive non-small-cell lung cancer: combined analyses from two Phase II studies.

AIMS: We evaluated the efficacy and safety of erlotinib, and patient characteristics affecting progression-free survival (PFS), by analyzing data from two Phase II studies of first-line erlotinib in activating EGFR mutation-positive non-small-cell lung cancer. METHODS: Data were combined from patients who received first-line erlotinib monotherapy in JO22903 (single-arm study; JapicCTI-101085) and JO25567 (randomized study; JapicCTI-111390). RESULTS: Median PFS was 10.9 months in efficacy-evaluable patients (n = 177). Major adverse events were dermatologic; no new safety signals were observed. Baseline pleural/cardiac effusion notably affected PFS (yes median 8.0 months vs no median 15.3 months) as confirmed in multivariate analysis (hazard ratio: 0.38; 95% CI: 0.25-0.58). CONCLUSION: Efficacy and safety of erlotinib monotherapy were consistent with previous studies. Baseline pleural/pericardial effusion was associated with shorter PFS.

Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.

BACKGROUND: With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease. METHODS: In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390. FINDINGS: Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16·0 months (95% CI 13·9-18·1) with erlotinib plus bevacizumab and 9·7 months (5·7-11·1) with erlotinib alone (hazard ratio 0·54, 95% CI 0·36-0·79; log-rank test p=0·0015). The most common grade 3 or worse adverse events were rash (19 [25%] patients in the erlotinib plus bevacizumab group vs 15 [19%] patients in the erlotinib alone group), hypertension (45 [60%] vs eight [10%]), and proteinuria (six [8%] vs none). Serious adverse events occurred at a similar frequency in both groups (18 [24%] patients in the erlotinib plus bevacizumab group and 19 [25%] patients in the erlotinib alone group). INTERPRETATION: Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted. FUNDING: Chugai Pharmaceutical Co Ltd.

A DPC Database Study on the Safety of Atezolizumab/Bevacizumab/Carboplatin/Paclitaxel in Non-small Cell Lung Cancer in Japanese Patients.

INTRODUCTION: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) combination therapy is a standard of care for advanced non-squamous non-small cell lung cancer (NSQ-NSCLC); however, the lack of safety data limits its clinical application in Japan. METHODS: This study compared the safety of ABCP with that of bevacizumab, carboplatin, and paclitaxel (BCP) combination for the treatment of advanced NSQ-NSCLC in Japanese patients by evaluating the clinical background and incidence of adverse events (AEs) based on data extracted from the Diagnosis Procedure Combination (DPC) database. Incidence rates and restricted mean survival times (RMSTs) for up to 1 year were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. RESULTS: A search conducted using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes identified 350,987 patients, of whom 202 were included in the ABCP cohort and 232 in the BCP cohort. Among the 19 AEs, the incidence of skin disorder and febrile neutropenia (FN) was significantly higher in the ABCP cohort versus the BCP cohort. The adjusted incidence rate ratios were 2.65 [95% confidence interval (CI) 1.43-4.91] for skin disorder and 1.70 (95% CI 1.01-2.85) for FN. The adjusted RMST differences were - 64.2 days (95% CI - 93.0 to - 35.4 days) and - 46.0 days (95% CI - 73.5 to - 18.5 days) for skin disorder and FN, respectively. These results were comparable to those of other pivotal clinical trials. CONCLUSIONS: The findings of this DPC database study highlight the safety of ABCP in Japanese clinical practice, and this methodology may facilitate more efficient research in real-world settings. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000041507.

A DPC Database Study on the Safety of Atezolizumab/Carboplatin/Etoposide in Extensive-Disease Small Cell Lung Cancer in Japanese Patients.

INTRODUCTION: Atezolizumab, carboplatin, and etoposide (ACE) therapy is a standard of care for extensive-disease small cell lung cancer (SCLC); however, its safety data are scarce, limiting generalization to the Japanese population. METHODS: This study aimed to compare the safety of ACE versus carboplatin and etoposide (CE) therapies in Japanese patients using the Diagnosis Procedure Combination (DPC) database by comparing the incidence of adverse events (AEs). Retrospective data on clinical background and AEs were extracted from the DPC database. Incidence rates and restricted mean survival times (RMSTs) up to 6 months were analyzed for 19 clinically important AEs. Covariates were adjusted using the inverse probability weighting method. RESULTS: A total of 330,774 patients were identified using the International Statistical Classification of Diseases and Related Health Problems 10th Revision codes, of whom 277 were included in the ACE cohort and 478 in the CE cohort. Among the 19 AEs, the incidence of skin disorder and thyroid dysfunction was significantly higher in the ACE cohort compared with the CE cohort. The adjusted incidence rate ratios were 2.38 (95% confidence interval [CI] 1.04-5.43) for skin disorder and 6.92 (95% CI 2.00-23.89) for thyroid dysfunction. The adjusted RMST differences were - 8.2 days (95% CI - 16.0 to - 0.4 days) for skin disorder and - 8.8 days (95% CI - 15.7 to - 1.9 days) for thyroid dysfunction. CONCLUSIONS: This study provides evidence regarding the safety of ACE combination therapy in Japanese clinical practice using the DPC database, with results comparable to those reported in pivotal clinical trials. TRIAL REGISTRATION: UMIN Clinical Trials Registry ID UMIN000041508.

Biomarker analysis of the phase II JO25567 study comparing erlotinib with or without bevacizumab in first-line advanced EGFR+non-small-cell lung cancer.

Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), such as erlotinib, are standard-of-care for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC), but most patients progress within 1 year. Previously, we demonstrated that erlotinib plus bevacizumab (EB) improved progression-free survival (PFS) in patients with EGFR-positive non-squamous NSCLC in the randomized JO25567 study. To understand this effect, we conducted comprehensive exploratory biomarker analyses. Methods: Using blood and tissue specimens from patients enrolled in the JO25567 study, angiogenesis-related serum factors, plasma vascular endothelial growth factor-A (pVEGFA), angiogenesis-related gene polymorphisms, and messenger RNAs (mRNAs) in tumor tissue were analyzed. Interactions between potential predictors and treatment effect on PFS were analyzed in a Cox model. Continuous variable predictors were evaluated by multivariate fractional polynomial interaction methodology and subpopulation treatment effect pattern plotting (STEPP). Results: Overall, 152 patients treated with EB or erlotinib alone (E) were included in the analysis. Among 26 factors analyzed in 134 baseline serum samples, high follistatin and low leptin were identified as potential biomarkers for worse and better outcomes with EB, with interaction P values of 0.0168 and 0.0049, respectively. Serum concentrations of 12 angiogenic factors were significantly higher in patients with high follistatin. Low pVEGFA levels related to better outcomes with EB, interaction P=0.033. VEGF-A165a was the only predictive tissue mRNA, showing a similar trend to pVEGFA. No valid results were obtained in 13 polymorphisms of eight genes. Conclusions: EB treatment showed better treatment outcomes in patients with low pVEGFA and serum leptin, and limited efficacy in patients with high serum follistatin.

Accuracy of algorithms to identify patients with a diagnosis of major cancers and cancer-related adverse events in an administrative database: a validation study in an acute care hospital in Japan.

OBJECTIVES: Validation studies in oncology are limited in Japan. This study was conducted to evaluate the accuracy of diagnosis and adverse event (AE) definitions for specific cancers in a Japanese health administrative real-world database (RWD). DESIGN AND SETTING: Retrospective observational validation study to assess the diagnostic accuracy of electronic medical records (EMRs) and claim coding regarding oncology diagnosis and AEs based on medical record review in the RWD. The sensitivity and positive predictive value (PPV) with 95% CIs were calculated. PARTICIPANTS: The validation cohort included patients with lung (n=2257), breast (n=1121), colorectal (n=1773), ovarian (n=216) and bladder (n=575) cancer who visited the hospital between January 2014 and December 2018, and those with prostate cancer (n=3491) visiting between January 2009 and December 2018, who were identified using EMRs. OUTCOMES: Key outcomes included primary diagnosis, deaths and AEs. RESULTS: For primary diagnosis, sensitivity and PPV for the respective cancers were as follows: lung, 100.0% (96.6 to 100.0) and 81.0% (74.9 to 86.2); breast, 100.0% (96.3 to 100.0) and 74.0% (67.3 to 79.9); colorectal, 100.0% (96.6 to 100.0) and 80.5% (74.3 to 85.8); ovarian, 89.8% (77.8 to 96.6) and 75.9% (62.8 to 86.1); bladder, 78.6% (63.2 to 89.7) and 67.3% (52.5 to 0.1); prostate, 100.0% (93.2 to 100.0) and 79.0% (69.7 to 86.5). Sensitivity and PPV for death were as follows: lung, 97.0% (84.2 to 99.9) and 100.0% (84.2 to 100.0); breast, 100.0% (1.3 to 100.0) and 100.0% (1.3 to 100.0); colorectal, 100.0% (28.4 to 100.0) and 100.0% (28.4 to 100.0); ovarian, 100.0% (35.9 to 100.0) and 100.0% (35.9 to 100.0); bladder, 100.0% (9.4-100.0) and 100.0% (9.4 to 100.0); prostate, 75.0% (19.4 to 99.4) and 100.0% (19.4 to 100.0). Overall, PPV tended to be low, with the definition based on International Classification of Diseases, 10th revision alone for AEs. CONCLUSION: Diagnostic accuracy was not so high, and therefore needs to be further investigated. TRIAL REGISTRATION NUMBER: University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000039345).

Erlotinib with or without bevacizumab as a first-line therapy for patients with advanced nonsquamous epidermal growth factor receptor-positive non-small cell lung cancer: Exploratory subgroup analyses from the phase II JO25567 study.

BACKGROUND: In the phase II JO25567 study (JapicCTI-111390), erlotinib plus bevacizumab demonstrated a significant clinical benefit in Japanese patients with epidermal growth factor receptor mutation-positive (EGFR+) non-small cell lung cancer (NSCLC). Here, we present an exploratory analysis investigating the impact of baseline pleural/pericardial effusion (PPE) on patient outcomes. METHODS: Patients with stage IIIB/IV or postoperative recurrent EGFR+ NSCLC were randomized 1:1 to receive erlotinib (150 mg/day) plus bevacizumab (15 mg/kg every 3 weeks) or erlotinib monotherapy. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety were evaluated according to the presence or absence of baseline PPE. RESULTS: The population comprised 152 patients, 66 with baseline PPE and 86 without. Median PFS was longer with erlotinib plus bevacizumab than with erlotinib alone, with (hazard ratio [HR] 0.45; 95% confidence interval [CI]: 0.25-0.82) or without (HR 0.62; 95% CI: 0.37-1.04) baseline PPE. Median OS was also prolonged with erlotinib plus bevacizumab relative to erlotinib regardless of the presence (HR 0.82; 95% CI: 0.46-1.47) or absence (HR 0.84; 95% CI: 0.46-1.55) of baseline PPE. ORR was higher with erlotinib plus bevacizumab (70.0%) than with erlotinib (55.6%) in patients with baseline PPE, but similar (68.9% vs. 70.7%) in patients without. Most common grade ≥3 adverse events were hypertension and rash in the erlotinib plus bevacizumab arm, and rash in the erlotinib arm, regardless of baseline PPE status. CONCLUSIONS: Erlotinib plus bevacizumab may be a beneficial treatment strategy in patients with EGFR+ NSCLC, especially for those with baseline PPE.

Assessing Pathologic Response in Resected Lung Cancers: Current Standards, Proposal for a Novel Pathologic Response Calculator Tool, and Challenges in Practice.

The efficacy of neoadjuvant treatment for NSCLC can be pathologically assessed in resected tissue. Major pathologic response (MPR) and pathologic complete response (pCR), defined as less than or equal to 10% and 0% viable tumor cells, respectively, are increasingly being used in NSCLC clinical trials to establish them as surrogate end points for efficacy to shorten time to outcome. Nevertheless, sampling and MPR calculation methods vary between studies. The International Association for the Study of Lung Cancer recently published detailed recommendations for pathologic assessment of NSCLC after neoadjuvant treatment, with methodology being critical. To increase methodological rigor further, we developed a novel MPR calculator tool (MPRCT) for standardized, comprehensive collection of percentages of viable tumor, necrosis, and stroma in the tumor bed. In addition, tumor width and length in the tumor bed are measured and unweighted and weighted MPR averages are calculated, the latter to account for the varying proportions of tumor beds on slides. We propose sampling the entire visible tumor bed for tumors having pCR regardless of size, 100% of tumors less than or equal to 3 cm in diameter, and at least 50% of tumors more than 3 cm. We describe the uses of this tool, including potential formal analyses of MPRCT data to determine the optimum sampling strategy that balances sensitivity against excessive use of resources. Solutions to challenging scenarios in pathologic assessment are proposed. This MPRCT will facilitate standardized, systematic, comprehensive collection of pathologic response data with a standardized methodology to validate studies designed to establish MPR and pCR as surrogate end points of neoadjuvant treatment efficacy.

Erlotinib Plus Bevacizumab Phase ll Study in Patients with Advanced Non-small-Cell Lung Cancer (JO25567): Updated Safety Results.

INTRODUCTION: The phase II JO25567 study compared the efficacy and safety of erlotinib plus bevacizumab vs. erlotinib alone as first-line therapy for advanced epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). OBJECTIVE: Our objective is to provide updated analyses of safety and the assessment of manageability of specific adverse events. METHODS: Patients with stage IIIB/IV or recurrent, non-squamous, EGFR mutation-positive NSCLC were randomized to receive erlotinib plus bevacizumab or erlotinib. The primary endpoint was progression-free survival. Adverse event frequency rates, predictability and manageability, reasons for discontinuation, time to onset, and outcomes of specific adverse events were analyzed. RESULTS: The safety analysis population comprised 152 randomized patients (75 erlotinib plus bevacizumab; 77 erlotinib) who received at least one dose of study drug between February 2011 and March 2012. There was no difference in overall incidence of serious adverse events between arms, but more grade 3 or higher adverse events were reported with erlotinib plus bevacizumab (90.7%) than with erlotinib (53.2%), primarily due to grade 3 hypertension. Hypertension was controllable with antihypertensive medications in most cases. Proteinuria and bleeding were also more frequently reported with erlotinib plus bevacizumab than with erlotinib but were manageable and did not lead to early discontinuations. CONCLUSIONS: The addition of bevacizumab to erlotinib prolonged progression-free survival in EGFR mutation-positive NSCLC. Follow-up safety data were consistent with the known safety profiles of both erlotinib and bevacizumab in NSCLC; this combination appeared to be manageable, and treatment was well tolerated. JapicCTI-111390.