Time To Failure Of Strategy Research Articles

FU/FA maintenance therapy with or without panitumumab (pmab) in RAS wild-type metastatic colorectal cancer (mCRC) (PanaMa, AIO KRK 0212): Updated efficacy analyses.

3506 Background: The randomized open-label phase II PanaMa trial compared FU/FA with or without pmab maintenance after mFOLFOX6+pmab induction for RAS wild-type mCRC. Updated efficacy results of the Full Analysis Set are presented. Methods: Median progression-free survival (PFS), overall survival (OS), PFS of re-induction (PFS re-ind.), time to failure of strategy (TFS), and objective response rates (ORR) were compared by log-rank test / Cox regression and Fisher’s exact test. Results: PFS was significantly (8.8 vs. 5.8 months, HR=0.73 (95%CI 0.56 – 0.94), P=0.015) and OS numerically longer (29.9 vs. 24.7 months, HR=0.85 (95%CI 0.64 – 1.12), P=0.24). PFS re-ind. was significantly shorter after pmab maintenance (4.1 vs. 7.4 months, HR=1.93 (95%CI 1.33 – 2.82), P<0.001). TFS was comparable (17.1 vs. 15.7 months, HR=0.98 (95%CI 0.68 – 1.42), P=0.92). Molecular subgroups are displayed in Table 1. ORR of FU/FA+pmab was comparable to FU/FA during induction (74.4% vs. 76.4%, P=0.77), higher during maintenance (40.8% vs. 29.3%, P=0.06), but lower at re-induction (8.0% vs. 35.9%, P<0.001). Conclusions: PFS remained improved by the addition of pmab to FU/FA maintenance therapy, while OS was not significantly longer. Re-induction of pmab+mFOLFOX6 did not provide benefit following pmab maintenance regarding PFS. Clinical trial information: NCT01991873 . [Table: see text]

Real-world effect of bevacizumab and eribulin on metastatic breast cancer using a propensity score matching analysis.

Bevacizumab and eribulin are novel agents for the treatment of HER2-negative metastatic breast cancer (MBC); however, the choice between bevacizumab and eribulin for MBC can be difficult. The present study aimed to compare two treatment strategies, eribulin followed by bevacizumab and paclitaxel (BEV + PTX) versus BEV + PTX followed by eribulin, to determine whether the order of administration affects the outcome of MBC in the real world. A total of 180 patients who started BEV + PTX and eribulin treatment for HER2-negative MBC from August 2011 to June 2018 were selected. Of these, 84 patients were treated with both BEV + PTX and eribulin sequentially. To evaluate the influence of the sequential order, the efficacy of BEV + PTX followed by eribulin (B-E arm) was compared to treatment with the reverse sequence (E-B arm). The propensity score matching method (PSMA) was used to improve the robustness of the findings from the present study. A total of 60 cases analyzed received BEV + PTX or eribulin as either first- or second-line treatment. In the entire cohort, the median time to failure of strategy (TFS) was 16.8 and 9.9 months in the B-E and E-B arms, respectively [hazard ratio (HR)=0.515, 95% CI 0.298-0.889, P=0.017). A similar HR was derived from PSMA for TFS. Using PSMA, TFS was 16.9 and 9.9 months in the B-E and E-B arms, respectively (HR=0.491, 95% CI 0.253-0.952, P=0.031). These results suggested that when both bevacizumab and eribulin are administered, bevacizumab should be administered first and eribulin should be administered later to ensure the most effective use of each drug.

STRATEGIC-1: Multi-line therapy trial in unresectable wild-type KRAS/NRAS/BRAF metastatic colorectal cancer—A GERCOR-PRODIGE randomized open-label phase III study.

3504 Background: The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents have become available. Ultimately, strategy trials are needed to define the optimal use and the best sequencing of these agents. Methods: Patients with previously untreated RAS/BRAF wild-type unresectable mCRC were randomly assigned (1:1 ratio) to receive either FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab (arm A) or OPTIMOX-bevacizumab followed by FOLFIRI-bevacizumab followed by EGFR mab +/- irinotecan (arm B). This trial was designed as a superiority study (hypothesis arm B > arm A) with Duration of Disease Control (DDC) as primary endpoint, defined as the sum of PFS of each active sequence of treatment (Chibaudel B, J Clin Oncol, 2011). Secondary endpoints were overall survival (OS), Time to Failure of Strategy (TFS), Progression-free survival (PFS) and response rate (RECIST version 1.1) per sequence, salvage surgery rate, safety, and Quality of life (QoL). Results: Between October 2013 and May 2019, 263 eligible patients were randomized (arm A, n = 131; arm B, N = 132). After a median follow-up of 51.2 months (95% CI 43.3-57.4), 188 events for DDC were observed. Efficacy outcomes are presented in table. Median DDC was similar in both arms (HR 0.97, 95% CI 0.72-1.29; P = 0.805). Salvage surgery for metastasis (+/- radiofrequency ablation) was done in 36 (27.5%) patients in arm A and 28 (21.2%) in arm B. Median time until definitive deterioration of QoL (global health status) were 18.3 and 18.0 months (P = 0.628). The safety profiles were consistent with the established safety profiles of each treatment regimen. Conclusions: STRATEGIC-1 is the first randomized phase III study comparing multi-line standard treatment strategies in patients with KRAS/NRAS/BRAF wild-type mCRC. This study did not meet its primary endpoint of DDC. The treatment strategy starting with FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab led to higher response rates and to a trend for better median OS exceeding 3 years. These findings may add to our understanding of treatment sequencing in mCRC. Clinical trial information: NCT01910610. [Table: see text]

Phase III Clinical Trial for the Combination of Erlotinib Plus Ramucirumab Compared With Osimertinib in Previously Untreated Advanced or Recurrent Non–Small Cell Lung Cancer Positive for the L858R Mutation of EGFR: REVOL858R (WJOG14420L)

IntroductionOsimertinib is a standard first-line treatment for non–small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor gene (EGFR). However, tumors with the L858R mutation appear to be less sensitive to EGFR–tyrosine kinase inhibitors (TKIs) than those with exon-19 deletions, and subgroup analysis of the FLAURA study revealed that osimertinib did not significantly prolong overall survival (OS) compared with gefitinib or erlotinib in patients with the L858R. The RELAY study revealed a similar high efficacy of combination therapy with erlotinib plus ramucirumab (E+RAM) in patients with L858R and in those with exon-19 deletions. Patients who acquire the TKI resistance–associated T790M mutation during E+RAM treatment can also expect to receive benefit from second-line osimertinib. We have therefore planned a phase III study to evaluate the clinical efficacy of E+RAM compared with osimertinib monotherapy for untreated patients with advanced NSCLC harboring L858R. Patients and MethodsA total of 230 patients will be enrolled. The primary end point is time to failure of strategy (TFS), which is defined for this study as the time from randomization of treatment until disease progression or death on osimertinib, or the time from randomization until first disease progression or death of the primary treatment when osimertinib is not administered in the E+RAM group. Secondary end points include OS and progression-free survival. ConclusionThis is the first phase III clinical trial to target only NSCLC patients with the L858R mutation. Its results may establish an optimal treatment for such individuals.

Comparison of time to failure of pembrolizumab plus chemotherapy versus pembrolizumab monotherapy: a consecutive analysis of patients having NSCLC with high PD-L1 expression

IntroductionThere are two treatment strategies for non-small cell lung cancer (NSCLC) exhibiting a high expression level of programmed death-ligand 1 (tumor proportion score ≥ 50%): pembrolizumab plus chemotherapy and monotherapy. We retrospectively compared their efficacy and safety.Materials and methodsWe reviewed the efficacy and safety of first-line pembrolizumab-containing regimens administered between 2017 and 2020 to consecutive patients. The patients were divided into a pembrolizumab plus chemotherapy group (Combo group) or monotherapy group (Mono group). To compare the efficacy, we monitored the time to failure of strategy (TFS) defined as the time from the start of treatment to the occurrence of one of the following events: the addition of any drug not included in the primary strategy, progression of cancer after complete therapy, progression and no subsequent therapy, or death, whichever occurred first. We used the propensity score matching (PSM) to reduce the bias.ResultsA total of 126 patients were identified (89 in the Mono group and 37 in the Combo group). PSM matched 36 individuals from each of the two groups. The overall response rate and median progression-free survival of the Combo group were better than those of the Mono group. However, the median TFS was almost the same (11.3 months vs. 14.9 months; hazard ratio 1.40 [95% confidence interval 0.62–3.15]). The frequency of all serious adverse effects was higher in the Combo group than in the Mono group.DiscussionDue to similar efficacy in TFS, both pembrolizumab plus chemotherapy and monotherapy are valid options for NSCLC.

Comparison of time to failure of pembrolizumab plus chemotherapy versus pembrolizumab monotherapy: A consecutive analysis of NSCLC patients with high PD-L1 expression.

9061 Background: There are two types of pembrolizumab-containing strategies for patients with non-small cell lung cancer (NSCLC) exhibiting a high expression level of programmed death-ligand 1 (PD-L1) (tumor proportion score [TPS] ≥50%): the early combination of pembrolizumab plus chemotherapy, and chemotherapy after pembrolizumab failure. Which strategy is superior, however, remains unclear. Comparing progression-free survival (PFS) or progression after the next therapy line (PFS2) in previous clinical trials has not allowed any conclusions regarding superiority to be made. Instead, the time to failure of strategy (TFS), which represents the time until disease exacerbation when the same number of drugs has been used, should be used to compare the two strategies. Methods: We consecutively reviewed the efficacy and safety of first-line, pembrolizumab-containing regimens administered between December 2017 and November 2020. We divided the patients who received pembrolizumab as a first-line treatment into two groups according to whether they received chemotherapy: a pembrolizumab plus chemotherapy group (combo group), and a pembrolizumab monotherapy group (mono group). TFS was defined as the PFS in the combo group and the PFS2 in the mono group. We used the propensity score matching (PSM) method to reduce the bias. Results: Of the 964 patients with advanced NSCLC who underwent first-line treatment, 126 with a PD-L1 TPS ≥50% were eligible for inclusion in this analysis (89 in mono group, 37 in combo group). PSM matched 36 people from each of the two groups. The median follow-up period was 16.2 months (range, 0.1-34.3 months). The patient backgrounds were similar. The overall response rate (ORR) of the combo group was higher than that of the mono group (69.4% vs. 50.0%). The median PFS (mPFS) in the combo group was longer (11.4 months vs. 6.0 months). However, the median TFS (mTFS) of the two groups was almost the same (11.4 months vs. 11.7 months). At the time of the analysis, the median overall survival had not been reached. The frequency of all immune-related serious adverse events (irSAE) was similar, however, that of all SAE and AE leading to treatment discontinuation were larger in the combo group. Conclusions: The ORR of the combo group was higher than that of the mono group; however, the TFS was similar. We suggest that pembrolizumab plus chemotherapy, which can increase toxicity, might be of value in patients, producing a clinically meaningful increase in the ORR.[Table: see text]

Planned drug holiday in a cohort study exploring the effect of lenvatinib on differentiated thyroid cancer.

6070 Background: Lenvatinib is now available for unresectable radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). However, toxicities are considerable and require frequent dose interruption and modification. Recently, planned drug holidays, which are dose interruptions in accordance with the timing of severe or intolerable adverse events, have been proposed to avoid severe adverse events due to lenvatinib (Tahara M.ESMO Open 2018). Our retrospective study demonstrated that progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who used planned drug holidays than those who did not (Matsuyama C et.al, 2020 Annual Meeting of the Japan Association of Endocrine Surgeons). Methods: In this prospective observational study, patients with curatively unresectable and progressive RAI-refractory DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities were permitted. Primary endpoint was OS, and secondary endpoints were time to treatment failure (TTF), time to failure of strategy (TFS), PFS with clinical progressive disease, response rate, quality of life, safety, and patient reports. This study was registered with UMIN Clinical Trials Registry (UMIN000022243). Results: 262 patients were accrued. Of 255 evaluable, 153 were female; median age was 70 (range 27.0-88.0); histology was papillary thyroid carcinoma/follicular thyroid carcinoma/poorly DTC in 204/45/4; previous therapy was surgery/RAI/molecular targeted drug in 246/164/14; reason for initiation of lenvatinib was disease progression/unsuitable for RAI in 241/4. 1-year OS was 85.6% (95%CI: 80.6-89.4%); 1-year TTF rate was 74.9% (95%CI: 69.1-79.8%); 1-year TFS rate was 80.8% (95%CI: 75.4-85.2%); and 1-year PFS rate was 84.4% (95%CI: 79.3-88.4%). Overall response by RECIST was 3 (1.2%) in CR and 151 (61.9%) in PR. Most common grade 3 or 4 toxicities were hypertension (61.4%), hand foot syndrome (10.2%), fatigue (9.1%), anorexia (8.3%) and diarrhea (4.7%). Grade 5 toxicities occurred in 4 patients (fistula, hypoxia, respiratory failure, trachea stenosis). Of 253 patients evaluable for efficacy, 73 used planned drug holidays. TTF, TFS and PFS were significantly longer in patients who used planned drug holiday than those who did not (Table). Conclusions: Planned drug holiday for lenvatinib demonstrated significantly better clinical outcomes, including TTF, TFS and PFS, than daily oral administration. These data further support use of a planned drug holiday in RAI-refractory DTC patients receiving lenvatinib. Clinical trial information: 000022243. [Table: see text]

XELOX or mFOLFOX6 chemotherapy combined with resection of primary lesion versus chemotherapy alone for colon cancer with unresectable metastases: A randomized clinical trial.

3590 Background: It is still controversial for colon cancer patients with unresectable metastases whether to resect the primary tumor when there are no symptoms of primary lesion. Methods: This is an open-label, single-center, prospective, randomized, controlled phase II trial. Colon cancer patients aged 18-80 years with unresectable metastases at enrollment will be randomly allocated to either resection group (group A) or chemotherapy group (group B), and stratified by tumor response and number of organ metastases, after receiving induction chemotherapy with 4 cycles of XELOX or 6 cycles of mFOLFOX6, excluding those with disease progression, lesions radically resectable, or primary lesion unresectable. Patients in group A received resection of primary lesion and then continued chemotherapy, and patients in group B just continued chemotherapy, both up to 4 cycles of XELOX or 6 cycles of mFOLFOX6, and capecitabine maintenance afterwards. If progression occurs 3 months after discontinuation of oxaliplatin and toxicity has recovered to grade I, the original regimen can be applied again. The primary endpoint was TFS (time to failure of strategy, defined as the time from randomization to secondary progression in patients received re-introduce of the induction chemotherapy regimen, or to first progression in patients without re-introduce of the original regimen). The secondary endpoints included progression-free survival (PFS, the time from randomization to first progression), overall survival (OS, the time from enrollment to death), and adverse events (AEs). Efficacy data were analyzed on an intention-to-treat (ITT) basis. This study is registered with ClinicalTrials.gov, number NCT02291744. Results: Between April, 2015, and July, 2020, 140 patients were enrolled, and 54 patients withdrew due to colon obstruction (16), perforation (1), disease progression (22), death (1), radical resection (3), or other reasons (11). Finally, 86 patients were randomized into group A (n = 42) or group B (n = 44). The median TFS was 143 days (95%CI: 104.9-181.1) in group A, and 196 days (95%CI: 96.5-295.5) in group B (HR:0.930 95%CI:0.589-1.468, p = 0.755). The median PFS was 147 days (95%CI: 105.7-188.3) in group A, and 206 days(95%CI:180.9-231.1) in group B (HR:0.831, 95%CI:0.522-1.323, p = 0.436). The median OS was 530 days (95%CI: 308.9-751.1) in group A, and 779 days (95%CI:626.3-931.7) in group B (HR:0.948 95%CI:0.554-1.622, p = 0.845). The incidence of treatment-related AEs was similar between two groups. Conclusions: Resection of primary tumor after induction chemotherapy could not bring survival benefits. It’s not recommended for patients without symptoms of primary lesion to receive primary tumor resection, but it also requires individualized treatment as colon obstruction or perforation occurred in some patients. Clinical trial information: NCT02291744.

Gender-dependent survival benefit from first-line irinotecan in metastatic colorectal cancer. Subgroup analysis of a phase III trial (XELAVIRI-study, AIO-KRK-0110)

BackgroundXELAVIRI compared sequential (Arm A) versus initial (Arm B) irinotecan in combination with fluoropyrimidine plus bevacizumab in patients with metastatic colorectal cancer, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown. The present analysis was performed to evaluate the effect of gender on treatment outcome and tolerability. MethodsThe study end-points overall response rate (ORR), progression-free survival (PFS), TFS and overall survival (OS) were evaluated in female versus male patients and in molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests. ResultsIn total, 281 male and 140 female patients (n = 421) were evaluated. Among the male patients, the ORR was 33.6% without and 58.3% with initial irinotecan (P < 0.001). PFS (hazard ratio [HR] 0.54; 95% confidence interval [CI] 0.42–0.69; P < 0.001) and OS (HR 0.63; 95% CI 0.47–0.85; P = 0.002) were also significantly better with initial irinotecan. Among the female patients, the ORR was 42.7% in Arm A and 43.1% in Arm B, PFS was similar (HR 1.09; 95% CI 0.76–1.55; P = 0.649) without and with initial irinotecan. A strong trend for inferior outcome with regard to OS with initial irinotecan was observed (HR 1.46; 95% CI 0.95–2.24; P = 0.081) and the trend reached significance in the multivariate analysis (HR 1.78; 95% CI 1.08–2.95; P = 0.02). Formal interaction of treatment and gender was observed for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). Treatment-related adverse events were not significantly different between male and female patients. ConclusionsThe present analysis suggests that gender interacts with efficacy of initial irinotecan when used in combination with fluoropyrimidines and bevacizumab. Although male patients derived a significant and clinically meaningful benefit from initial combination chemotherapy, this was not observed in female patients.

Abstract P2-15-12: Effect of Bevacizumab and Eribulin for metastatic breast cancer in the real world evaluated using the propensity score matching analysis (PSMA) and inverse probability of treatment weighting analysis (IPTWA)

Abstract Background: Bevacizumab (BEV) + Paclitaxel (PTX) and Eribulin represent the most frequently agents for the treatment of HER2-negative metastatic breast cancer (MBC). Eribulin has improved overall survival (OS) in EMBRACE trials. On the other hand, BEV has improved progression free survival (PFS) in several clinical studies, but not revealed prolongation of OS in them. There are difficult situations in making a clinical decision of when to choose which treatment option.Purpose: The purpose of this study is to compare two treatment strategies, Eribulin followed by BEV + PTX versus BEV + PTX followed by Eribulin. We evaluated whether sequential order of treatment affects survival benefit in patients who have been treated with both BEV + PTX and Eribulin in the real world. Methods: All patients who started BEV + PTX and Eribulin treatment for MBC from Aug-2011 to Jun-2018 were selected. Among 264 patients recorded in the TBCRG (14 institutions of Research Group) database, 180 patients had HER2-negative MBC. Of these, 84 patients were treated with both BEV + PTX and Eribulin sequentially regardless of treatment line. To evaluate the influence of sequential order, we compared the efficacy of Eribulin followed by BEV + PTX (arm E-B) to treatment with the reverse sequence (arm B-E). We used the two different analytical approaches to rubstify the findings from this study. Results: 38 patients were treated with E-B and 46 patients with the B-E sequence. We analyzed 60 cases within 3rd-line. In the entire cohort, the median time to failure of strategy (TFS) was 9.9 and 16.8 months in arm E-B and arm B-E, respectively (HR = 0.503, 95%CI 0.298-0.889, p=0.017). The respective median OS was 17.2 and 28.0 months (HR = 0.663, 95%CI 0.349-1.261. p=0.21). Similar HRs were derived from the PSMA and IPTWA cohort in TFS. Using PSMA, TFS was 9.0 and 14.1 months in arm E-B and arm B-E, respectively (HR = 0.406, 95%CI 0.172-0.955, p=0.039). The respective median OS was 12.8 and 24.0 months (HR = 0.61, 95%CI 0.232-1.6, p=0.315). Using IPTWA, TFS was 10.2 and 14.8 months in arm E-B and arm B-E, respectively (HR = 0.621, 95%CI 0.423-0.913, p=0.015). The respective median OS was 17.5 and 24.0 months (HR = 0.86, 95%CI 0.547-1.352, p=0.513).Conclusion: These results suggest that when patients with HER2-negative MBC are treated with both BEV + PTX and Eribulin, patients with prior BEV + PTX treatment is more likely to show more significant difference in results benefit than patients who are treated with prior Eribulin treatment. Citation Format: Koshi Matsui, Mitsuharu Earashi, Takuya Nagata, Akemi Yoshikawa, Wataru Fukushima, Zensei Nozaki, Yasuko Tanada, Kaeko Oyama, Katsuo Shimada, Kaoru Kiyohara, Tetsuro Shimizu, Keiko Iwata, Toru Yoshida, Kiichi Maeda, Akiyoshi Nakakura, Satoshi Morita, Tsutomu Fujii. Effect of Bevacizumab and Eribulin for metastatic breast cancer in the real world evaluated using the propensity score matching analysis (PSMA) and inverse probability of treatment weighting analysis (IPTWA) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-12.

Abstract P2-15-01: A randomized, multicenter, phase II study evaluating the efficacy of interventional maintenance endocrine therapy with bevacizumab following fixed cycles of bevacizumab plus paclitaxel in advanced/metastatic ER-positive HER2-negative breast cancer: JBCRG-M04 BOOSTER trial

Abstract Background: The standard chemotherapy treatment strategy for patients with advanced/metastatic breast cancer (ABC) is the continuation of the same drug until tumor progression. However, despite continued antitumor effects, continuation of a drug often becomes difficult because of cumulative adverse events, such as peripheral neuropathy. Methods: This multicenter, randomized, Phase II study in patients with estrogen receptorpositive (ER+) human epidermal growth factor receptor 2-negative (HER2−) ABC aimed to compare 2 treatment strategies following induction therapy with 4-6 cycles of the combined use of weekly paclitaxel (wPTX) and bevacizumab (BV). Patients in Arm A continued with wPTX+BV, whereas patients in Arm B were switched from wPTX to maintenance endocrine therapy (endocrine+BV) until disease progression, followed by wPTX+BV re-induction. The primary endpoint was time to failure of strategy (TFS), defined as the time from randomization to a qualifying event (addition of a new agent not in the primary regimen, progressive disease during or after planned therapy, or death). Secondary endpoints were overall survival (OS), progression-free survival, safety, and quality of life (QoL). Sequential plasma and serum biomarkers were analyzed for predicting/monitoring the response. Result: Of 160 patients enrolled to receive induction therapy with wPTX+BV, 125 patients responded to treatment (complete response [CR], partial response [PR], or stable disease) and were randomized to either of the 2 treatment arms. Median follow-up was 21.3 months. Aromatase inhibitor (AI), fulvestrant, or AI with a luteinizing hormonereleasing hormone (LH-RH) analogue was used as maintenance endocrine therapy. The primary endpoint of TFS was 8.87 months (95% CI: 5.68-13.80) in the wPTX+BV continued group (Arm A) and 16.82 months (95% CI: 12.88-18.99) in the maintenance endocrine+BV group (Arm B) (hazard ratio [HR], 0.51; p&amp;lt;0.001). In Arm B, 52% of patients received wPTX+BV re-induction upon progression with maintenance therapy. Although the OS data were not yet mature, a trend of OS benefit was noted in a subset of patients in the maintenance group (Arm B) who achieved an objective response (CR or PR) to induction chemotherapy (HR, 0.75; 95% CI: 0.34-1.62). Health-related QoL data and biomarker analysis with IMPACT assay will be presented at the symposium. Conclusion: This is the first study showing the benefit of maintenance endocrine therapy in patients with ER+ HER2− advanced breast cancer who responded to a fixed dose of chemotherapy. (UMIN: UMIN000012179; ClinicalTrials.gov: NCT01989780) Funding: Chugai Pharmaceutical CO., LTD. Citation Format: Shigehira Saji, Masahiro Kitada, Toshimi Takano, Masahiro Takada, Tohru Ohtake, Tatsuya Toyama, Yuichiro Kikawa, Yoshie Hasegawa, Tomomi Fujisawa, Masahiro Kashiwaba, Takanori Ishida, Rikiya Nakamura, Yutaka Yamamoto, Uhi Toh, Hiroji Iwata, Norikazu Masuda, Naruto Taira, Satoshi Morita, Shinji Ohno, Masakazu Toi. A randomized, multicenter, phase II study evaluating the efficacy of interventional maintenance endocrine therapy with bevacizumab following fixed cycles of bevacizumab plus paclitaxel in advanced/metastatic ER-positive HER2-negative breast cancer: JBCRG-M04 BOOSTER trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-01.

571P - Randomized phase III study of sequential treatment with capecitabine or 5-fluorouracil (FP) plus bevacizumab (BEV) followed by the addition with oxaliplatin (OX) versus initial combination with OX+FP+ BEV in the first-line chemotherapy for metastatic colorectal cancer: The C-cubed study

BackgroundThe C-cubed study investigates the optimal treatment strategy in patients with untreated metastatic colorectal cancer (mCRC). We tested the superiority of a sequential treatment of FP+BEV followed by OX+FP+BEV (arm A: OX “wait & go”) at first progression to a combination treatment of OX+FP+BEV (arm B: OX “stop & go”), trial information: UMIN000015405. MethodsThe Primary endpoint was time-to-failure of strategy (TFS). A target sample size of 304 patients was considered sufficient to validate an expected Hazard Ratio (HR) for TFS of arm A compared with arm B with 80% power and 2-sided 5% α in case of a true HR value of<0.69. Secondary endpoints included overall response rate, overall survival (OS), progression-free survival, and safety. ResultsBetween Dec 2014 and Sep 2016, 311 patients were enrolled, and 302 patients were randomized either to receive the arm A (n=151) or B (n=151) as a full analysis set (FAS). Superiority of TFS in the arm A was established in this study (HR, 0.475; 95% CI, 0.362–0.623; p<0.0001). OSs in the arms A and B were not considered significantly different (HR, 0.930; 95% CI, 0.666–1.298). The patient population was predominantly positive for RAS mutant tumors (RAS MT) compared with that for RAS wild-type tumors (RAS WT), but this did not confer any clinical disadvantage in TFS to either arms (see table for details). We will present additional data associated with RAS status and differences between capecitabine and 5-fluorouracil at the meeting.Table571PTableTableEndpointArm A, “wait & go” (n=151) Months (95%CI)Arm B, “stop & go” (n=151) Months (95%CI)p-value (log rank)TFS (FAS)15.2 (12.5 – 17.2)7.6 (6.2 – 9.5)<.0001OS (FAS)27.5 (24.4 – 32.7)29.4 (24.1 – 36.0)0.6692FactorRAS WT (n=112) Months (95%CI)RAS MT (n=167) Months (95%CI)p-value (log rank)TFSArm A14.0 (11.2 – 19.0)15.3 (12.4 – 17.2)0.3126Arm B7.8 (7.0 – 10.5)7.4 (5.2 – 9.6)0.1615OSArm A27.5 (22.6 – NC)28.0 (23.4 – 32.7)0.3143Arm B34.7 (24.5 – NC)24.3 (19.1 – 32.8)0.0265 ConclusionsThe sequential “wait & go” strategy for OX was superior in TFS compared with the combinational “stop & go” accompanying with the equal survival benefit of nearly 30 months. Thus, the sequential approach with FP+BEV followed by OX is deemed an acceptable treatment strategy for patients with mCRC. Clinical trial identificationUMIN000015405. Legal entity responsible for the studyJapan South West Oncology Group (JSWOG). FundingChugai Pharmaceutical Co., Ltd. DisclosureT. Nagasaka: Speaker Bureau / Expert testimony: Eli Lilly Japan. Y. Shindo: Research grant / Funding (institution): Chugai; Research grant / Funding (institution): MSD; Research grant / Funding (self): Ono; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Lilly. A. Tsuji: Honoraria (institution): Daiichi Sankyo; Honoraria (institution), Speaker Bureau / Expert testimony: Taiho Pharmaceutical; Honoraria (institution), Speaker Bureau / Expert testimony: Chugai Pharma; Honoraria (institution), Speaker Bureau / Expert testimony: Merck Serono; Honoraria (institution), Speaker Bureau / Expert testimony: Takeda Pharmaceutical; Honoraria (institution): Bristol-Myers Squibb Japan. Y. Tsuji: Honoraria (institution): Bayer Co. Ltd; Honoraria (institution): Merck Serono Co. Ltd; Honoraria (institution): Eli Lilly Japan; Honoraria (institution): Chugai Pharmaceutical Co. Ltd; Honoraria (institution): Taiho Pharmaceutical Co. Ltd; Honoraria (institution): Ono Pharmaceutical Co. Ltd; Honoraria (institution): Takeda Pharmaceutical Co. Ltd; Honoraria (institution): Medicon Co. Ltd. H. Mishima: Research grant / Funding (institution): Chugai Pharmaceutical Co. Ltd. All other authors have declared no conflicts of interest.

Gender and survival benefit from initial irinotecan in metastatic colorectal cancer: Analysis of the XELAVIRI (AIOKRK0110) study.

3559 Background: XELAVIRI compared initial vs sequential irinotecan (iri) in combination with fluoropyrimidine (FP) plus bevacizumab (bev) in patients (pts) with mCRC, trial identification: NCT01249638. In the full analysis set of the study, non-inferiority of time to failure of strategy (TFS) was not shown (primary endpoint). Pts with RAS/BRAF wildtype (wt) tumors benefitted from initial iri. Methods: The study endpoints objective response rate (ORR), progression-free survival (PFS), time to failure of strategy (TFS) as well as overall survival (OS) were evaluated in female vs. male pts as well as molecular subgroups (i.e. RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests. Results: Of 421 patients, 281/140 were male/female. In male patients, ORR was 33.6% without and 58.3% with initial iri (P &lt; 0.001). PFS (HR: 0.54 (95%CI 0.42-0.69) P &lt; 0.001) and OS (HR: 0.63 (95%CI 0.47-0.85), P = 0.002), were also significantly better with initial iri. In the subgroup analysis, this effect was especially pronounced in pts with RAS/BRAF wt tumors. In female pts, ORR was 43% in both arms, PFS was similar (HR: 1.09 (95%CI 0.76-1.55), P = 0.65) without and with initial iri. In OS, a strong trend for inferior outcome with initial iri was seen (HR: 1.46 (95%CI 0.95-2.24), P = 0.08) that reached significance in the multivariate analysis (HR: 1.73 (95%CI 1.04-2.86, P = 0.034). Female patients with RAS/BRAF wt tumors did not benefit from initial iri (HR 1.05 (95% CI 0.46-2.41), P = 0.903 for OS). Formal interaction of treatment and gender was seen for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). There were some trends for more pronounced toxicities in female pts treated with Irinotecan. Conclusions: This unplanned exploratory analysis suggests that gender might interact with efficacy of initial iri when used in the context of FP and bev. While especially male RAS wild-type patients derived a significant and clinically meaningful benefit from initial use of iri, this was not observed in female patients with RAS wt tumors. Clinical trial information: NCT01249638.

Gender and survival benefit from initial irinotecan in metastatic colorectal cancer: Analysis of the XELAVIRI (AIOKRK0110) study.

549 Background: XELAVIRI compared initial versus sequential irinotecan (iri) in combination with fluoropyrimidine (FP) plus bevacizumab (bev) in patients (pts) with mCRC, trial identification: NCT01249638. In the full analysis set of the study, non inferiority of time to failure of strategy (TFS) of the sequential use could not be demonstrated (primary endpoint). Methods: The secondary endpoints overall response rate (ORR), progression-free survival (PFS) as well as overall survival (OS) were evaluated in female versus male pts as well as molecular subgroups (RAS mutational status). Interaction of treatment and gender was tested by likelihood ratio tests. Results: Of 421 patients, 281/140 were male/female. In female pts, ORR was 43% in both arms, PFS was 8.9 (95% CI 6.8-11.1) versus 10.1 (95% CI 8.5-11.8) months (HR: 1.09 (95% CI 0.76-1.55), P = 0.65) in pts with initial iri versus pts without initial iri, respectively. In females, a trend for inferior OS with initial iri was seen: 21.8 (95% CI 14.8-28.8) months with initial iri versus 28.4 (95% CI 21.9-34.9) months without initial iri (HR: 1.46 (95% CI 0.95-2.24), P = 0.08). This difference was significant in the multivariate analysis (HR: 1.73 (95% CI 1.04-2.86, P = 0.034). Male pts benefitted across all analysed endpoints from initial iri: ORR was 58.3% with initial iri and 33.6% without iri (P &lt; 0.001), PFS was 10.1 (95% CI 9.2-11.0) versus 7.4 (95% CI 6.3-8.5) months (HR: 0.54 (95% CI 0.42-0.69) P &lt; 0.001) and OS 23.9 (95% CI 19.1- 28.6) versus 20.5 (95% CI 18.1-22.9) months (HR: 0.63 (95% CI 0.47-0.85), P = 0.002), with initial iri versus without initial iri, respectively. Interaction of treatment and gender was seen for ORR (P = 0.018), PFS (P = 0.002) and OS (P = 0.001). Additional data including treatment and toxicities will be presented at the meeting. Conclusions: This unplanned exploratory analysis suggests that gender might interact with efficacy of initial iri when used in the context of FP and bev. While male patients derived a significant and clinically meaningful benefit from initial use of iri, this was not observed in female patients. Clinical trial information: NCT01249638.

Evaluation of time to failure of strategy as an alternative surrogate endpoint in patients with lung cancer with EGFR mutations

BackgroundEpidermal growth factor receptor (EGFR) is one of the most common oncogenes in non-small cell lung cancer (NSCLC). EGFR-tyrosine kinase inhibitor (TKI) and platinum-doublet chemotherapy (PT) are effective regimens in patients with NSCLC harbouring EGFR mutations. Among these patients, progression-free survival (PFS) has been used as a surrogate endpoint; however, it may not correlate with overall survival (OS) due to crossover. Time to failure of strategy (TFS) has been proposed as an alternative endpoint in advanced colorectal cancer clinical trials where multiple effective therapies are provided either in combination or sequentially. Nevertheless, it remains unclear whether TFS is useful in lung cancer trials.Patients and methodsWe retrospectively reviewed patients with NSCLC harbouring EGFR mutations who chose a treatment strategy consisting of EGFR-TKI and PT as the initial two regimens at the National Cancer Center Hospital. We evaluated the relationship between PFS and OS and between TFS and OS.ResultsBetween May 2005 and April 2015, a total of 374 patients were diagnosed with NSCLC harbouring EGFR mutations. Among them, 158 patients were eligible for analysis. The median PFS, TFS and OS of the patients were 11.2 months (95% CI 9.9 to 12.6), 21.3 months (95% CI 18.6 to 26.2) and 36.6 months (95% CI 32.0 to 41.8), respectively. OS and TFS, but not PFS, were better in patients who received PT then EGFR-TKI compared with those who received the opposite schedule. The non-parametric Spearman’s rank correlation coefficients (r) between PFS and OS and between TFS and OS were 0.54 and 0.85, respectively.ConclusionsThis is the first report describing TFS data among patients with NSCLC with EGFR mutations who received EGFR-TKI and PT as the initial two regimens. TFS was acceptable as a surrogate endpoint for OS. Further validation in clinical trials is needed.

A randomized phase III clinical trial of sequential capecitabine or 5-FU plus bevacizumab (Cape/5-FU+Bmab) followed by Cape/5-FU plus oxaliplatin plus Bmab (CapeOX/mFOLFOX6+Bmab) versus combination CapeOX/mFOLFOX6+Bmab in advanced colorectal cancer: The C-cubed (C3) study.

TPS872 Background: Less intensive regimens, focusing on survival and disease control, may be better first-line treatments in unresectable metastatic colorectal cancer (mCRC). Several randomized trials suggested that sequential cytotoxic agents in mCRC may improve overall survival compared with combination chemotherapy. This study investigated whether sequential treatment with Bmab-based first-line therapy with oxaliplatin has superior efficacy to combination treatment for unresectable mCRC. Methods: This study is a two-arm, multicenter, open-label, randomized phase III trial in Japan, comparing the efficacy and safety of sequential Cape/5-FU+Bmab with escalation to CapeOX/mFOLFOX6+Bmab versus combination CapeOX/mFOLFOX6+Bmab as the first-line treatment of mCRC. The primary endpoint is Time to failure of strategy (TFS). In the sequential arm (Arm A: oxaliplatin ‘wait-and-go’), treatment escalation from Cape/5-FU+Bmab to CapeOX/mFOLFOX6+Bmab is recommended for progressive disease. In the combination arm (Arm B: oxaliplatin ‘stop-and-go’), de-escalation from CapeOX/mFOLFOX6+Bmab to Cape/5-FU+Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6+Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin, not caused by oxaliplatin-associated toxicity, after 12 weeks of treatment. A target sample size of 304 evaluable patients is considered sufficient to detect a hazard ratio of 0.69 for the TFS of the sequential ‘wait-and-go’ approach compared with the combination ‘stop-and go’ approach with 80% power and a 2-sided significance level of 5%. From December 2014 to September 2016, 311 patients were enrolled across 81 centers in Japan. The follow-up period is until March 2018, and results are expected in 2019, and results are expected in 2019. Clinical trial information: 000015405.

Clinical Relevance of Alternative Endpoints in Colorectal Cancer First-Line Therapy With Bevacizumab: A Retrospective Study

BackgroundWe studied the relationship between intermediate criteria and overall survival (OS) in metastatic colorectal cancer (mCRC) patients who received first-line chemotherapy with bevacizumab. Patients and MethodsWe assessed OS, progression-free survival (PFS), duration of disease control (DDC), the sum of the periods in which the disease did not progress, and the time to failure of strategy (TFS), which was defined as the entire period before the introduction of a second-line treatment. Linear correlation and regression models were used, and Prentice criteria were investigated. ResultsWith a median follow-up of 57.6 months for 216 patients, the median OS was 24.5 months (95% confidence interval [CI], 21.3-29.7). The median PFS, DDC, and TFS were 8.9 (95% CI, 8.4-9.7), 11.0 (95% CI, 9.8-12.4), and 11.1 (95% CI, 10.0-13.0) months, respectively. The correlations between OS and DDC (Pearson coefficient, 0.79 [95% CI, 0.73-0.83], determination coefficient, 0.62) and OS and TFS (Pearson coefficient, 0.79 [95% CI, 0.73-0.84], determination coefficient, 0.63) were satisfactory. Linear regression analysis showed a significant association between OS and DDC, and between OS and TFS. Prentice criteria were verified for TFS as well as DDC. ConclusionDDC and TFS correlated with OS and are relevant as intermediate criteria in the setting of patients with mCRC treated with a first-line bevacizumab-based regimen.

Sequential administration of XELOX and XELIRI is effective, feasible and well tolerated by patients with metastatic colorectal cancer

Sequential administration of the chemotherapy regimes capecitabine and oxaliplatin (XELOX) and capecitabine and irinotecan (XELIRI) in the first- to second-line treatment setting would allow patients to be managed more easily in an outpatient unit. However, a small number of studies have raised concerns of cumulative adverse events as a consequence of the continuous use of capecitabine. To investigate this, the present study conducted a retrospective review of 81 consecutive metastatic colorectal cancer (mCRC) patients treated with the oxaliplatin, fluorouracil and leucovorin-irinotecan, fluorouracil and leucovorin (FOLFOX-FOFIRI/F-F) regimen (n=40) or the XELOX-XELIRI (X-X) regimen (n=41) in first- to second-line chemotherapy in Saitama Medical Center between 2006 and 2012. The disease control rate (DCR), the progression free survival (PFS), the overall survival (OS) and the time to failure of strategy (TFS) from first to second-line chemotherapy, as well as adverse events, were assessed and compared between patients receiving X-X or F-F. A total of 10 and 20 patients were additionally treated with bevacizumab in the F-F and X-X regimens, respectively, during first or second-line chemotherapy. There was no significant difference in DCR and the median PFS between the two regimens for first or second-line chemotherapy. There was no significant difference in the median OS and TFS between the two regimens (OS=24.5 and TFS=14 months in the F-F vs. 23.2 and 12.0 months in the X-X). Regarding adverse events, 45.0% of patients (18/40) exhibited grade 3-4 neutropenia throughout treatment with F-F. Whilst, 15.0% of patients (6/41) exhibited grade 3 hypertension throughout treatment with X-X, which was effectively controlled by a single antihypertensive drug. The results show that sequential administration of X-X is as effective and feasible as F-F treatment, while additionally reducing the frequency of infusion visits and eliminating the need for a central venous access device or home infusion pump, thereby offering a more convenient treatment option to patients with mCRC.

595P - Correlation between alternative endpoints and overall survival in metastatic colorectal cancer patients eligible to a maintenance strategy

In this study, our first aim was to assess the relation between different intermediate criteria and overall survival (OS) in patients treated for a metastatic colorectal cancer (mCRC) receiving a first-line chemotherapy associated with bevacizumab. We collected retrospective data from patients with mCRC treated with 1st-line chemotherapy (generally FOLFIRI-FOLFOX regimen) plus bevacizumab between January 2006 and December 2012. We assessed the following time to event endpoints: OS; progression free survival (PFS); duration of disease control (DDC), the sum of the periods in which the disease did not progress, and the time to failure of strategy (TFS), the whole period before the introduction of second-line treatment. Linear correlation and linear regression models were used to study relations between OS and TFS, and OS and DDC, respectively. Prentice criteria for surrogacy were investigated. We included 216 patients from 6 centers. 91 (42%) patients received a maintenance strategy. With a median follow-up of 57.6 (43.6-94.0) months, median OS was 24.5 (21.3-29.7) months, median PFS was 8.9 (8.4-9.7) months, median DDC was 11.0 (9.8-12.4) months, and median TFS was 11.1 (10.0-13.0) months. Pearson coefficient (coeff) was 0.79 (CI 95% 0.73-0.83) and determination coeff was 0.62, suggesting of a satisfactory correlation between OS and DDC. Similarly, the correlation between OS and TFS was rather satisfactory with a Pearson coeff at 0.79 (CI 95% 0.73-0.84) and a determination coeff at 0.63. Linear regression analysis showed a significant association between OS and DDC, and between OS and TFS, respectively. These relationships can be modeled by the formulas: cube root (SG) = 0.9547 + 0,8286 cubic root (DDC) and cubic root (SG)= 0.9655 +0,8186 cubic root (TFS). Considering resection of metastases as the treatment, Prentice criteria were verified for both TFS and DDC. DDC and TFS were correlated to OS and Prentice criteria were validated for both endpoints. This makes them relevant as intermediate criteria, in the setting of patients with mCRC treated with 1st-line bevacizumab-based regimen.

Maintenance therapy with biweekly cetuximab (C) in the first-line treatment of metastatic colorectal cancer (mCRC): The NORDIC 7.5 study (NCT00660582), by the Nordic Colorectal Cancer Biomodulation Group.

3538 Background: NORDIC 7.5 is a multi-center phase II trial of Nordic FLOX plus biweekly C followed by maintenance C in first-line treatment of mCRC, KRASwild-type (KRASwt). The aim was to complement the data of the NORDIC VII trial, arm C (Tveit et al, ASCO GI 2011). Specifically, the goal was to substantiate efficacy and safety of biweekly C as maintenance therapy and to assess time to failure of strategy (TFS) as an end-point in maintenance therapy studies. Methods: Patients had KRASwt, measurable, non-resectable mCRC; no prior chemotherapy for metastases; WHO PS 0-2 and good organ function. Patients received 8 courses of FLOX (bolus 5FU/folinic acid days 1 + 2 with oxaliplatin day 1 every 2 weeks) plus biweekly C (500 mg/m2 every 2 weeks) for 16 weeks followed by biweekly C as maintenance therapy until progression (PD). After at least 2 months of maintenance therapy, patients restarted FLOX plus biweekly C at the time of RECIST PD, and continued until a second RECIST PD. The primary endpoint was response rate (RR). Eighty-six patients were planned to confirm a response rate of 60%. While awaiting the results of Nordic VII, we amended the protocol to include 150 patients. Secondary endpoints included PFS, OS, resection rate, and safety. TFS was an explorative endpoint. Results: From July 2008 to September 2010, 152 KRASwt patients were included in 11 Nordic centers. Results were updated December 2011. Median age 64 years; 94% PS 0-1. RR 62%, median PFS 8.0 months, median OS 23.2 months, median TFS 11.9 months. Ten patients (15%) had R0-resection of metastasis. FLOX + C was re-introduced in 47 of 85 patients (55%) who were candidates for re-treatment and was started median 18 days after PD. Median duration of re-introduction was 5 months (1-29), 9 patients (20%) had response. Elevated baseline platelets and neutrofiles were associated with poor OS. The most common grade 3/4 non-hematologic AEs in were diarrea (9%), skin rash (9%), infection without neutropenia (7%), and fatigue (7%) Conclusions: Maintenance therapy with biweekly cetuximab is an encouraging strategy with efficacy and toxicity comparable to weekly cetuximab.