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Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Background: Patients (pts) with HER2-positive locallyadvanced/metastatic breast cancer (LA/MBC) previously treated with pertuzumab(P)-containing regimens have few therapeutic options. The efficacy of Pre-treatment combined with trastuzumab (T)+chemotherapy as 3 or 4 -line chemotherapy was examined in such pts. Methods: Pts previously treated with P-containing regimens as1st/2nd-line treatment for LA/MBC were randomly assigned 1:1 to two groups(P+T+chemotherapy based on physicians’ choice (C) (PTC), and T+C (TC)),stratified by estrogen receptor status, previous P treatment duration, numberof previous chemotherapy regimens, and presence or absence of visceralmetastasis. The primary endpoint was investigator-assessed progression-freesurvival (PFS). Superiority of PTC to TC will be tested using a stratifiedlog-rank test that accounts for all stratification factors, and a one-sidedP-value of less than 0.05 will be considered an indicator of superiority. Thedistribution of PFS will be estimated using the Kaplan-Meier method. In addition,the hazard ratio and one-sided 95% CI of the therapeutic effect between thegroups will be calculated using the Cox proportional hazard model. Secondaryendpoints included independent reviewer assessed PFS, PFS in pts treated withT-DM1 as the latest regimen (PFS after T-DM1), objective response rate (ORR),overall survival (OS), safety, and health-related quality of life (HR-QoL). Results: Of the 219 pts enrolled, 217 (108 PTC, 109 TC) wereincluded in the intent-to-treat analysis. At the data cutoff (July 31, 2019),PFS and OS events were 184 (84.8%) and 84 (38.7%), respectively. Medianfollow-up time was 14.2 months (mo). Investigator-assessed PFS wassignificantly better in the PTC group (median PFS 5.3 vs. 4.2 mo; HR = 0.755[One-sided 95%CI upper limit, 0.967]; One-sided stratified log-rank test p =0.0217). Median PFS after T-DM1 (5.3 vs. 4.2 mo; HR = 0.801 [One-sided 95%CIupper limit, 1.061]; One-sided log-rank test p = 0.0952) and OS (28.8 vs. 23.4mo; HR = 0.713, [One-sided 95%CI upper limit, 1.026], One-sided log-rank test p= 0.062) tended to be longer in the PTC group, though further follow-up isneeded. The ORR with measurable disease (PTC (n = 90) 18.9% vs. TC (n = 92)19.6%) did not differ between the groups. The serious adverse event rate didnot differ between the groups (17.9% vs. 21.3%). There were no new safetysignals included cardiac events in the groups. In the comparison of HR-QoL bytime to deterioration analysis, there was no significant difference between thegroups in FACT-B trial outcome index (PTC 2.8 mo vs. TC 4.3 mo; HR = 1.274,log-rank test p = 0.2289).Conclusions: P re-treatment as 3 or 4 -line chemotherapy wasactive and feasible. P re-treatment can be a standard treatment option forpatients with HER2-positive LA/MBC previously treated with P.(ClinicalTrials.gov number: NCT02514681) Citation Format: Yutaka Yamamoto, Hiroji Iwata, Taira Naruto, Norikazu Masuda, Masato Takahashi, Tetsuhiro Yoshinami, Takayuki Ueno, Tatsuya Toyama, Takashi Yamanaka, Toshimi Takano, Masahiro Kashiwaba, Koichiro Tsugawa, Yoshie Hasegawa, Kenji Tamura, Hiroshi Tada, Fumikata Hara, Shigehira Saji, Satoshi Morita, Masakazu Toi, Shinji Ohno, Japan Breast Cancer Research Group. A randomized, open-label, phase III trial of pertuzumab re-treatment in HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab, trastuzumab, and chemotherapy: The Japan Breast Cancer Research Group-M05 (PRECIOUS) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-11.

Background: Synergistic antitumor effect of combined anti-PD-1 antibody and anti-VEGF agent has been expected, based on previous preclinical data. We have conducted NEWBEAT trial to evaluate efficacy of triple combination regimen of nivolumab + paclitaxel + bevacizumab in patients (pts)with HR+ HER2- MBC or metastatic TNBC, and clinical results were presented in SABCS 2019. A biomarker study (WJOG9917BTR) was conducted to evaluate the VEGF and immune status of these patients. Methods: HER2-negative breast cancer patients in the NEWBEAT trial were enrolled. To explore the biomarkers for the triple combination treatment, immune status and its dynamics were evaluated with multicolor flowcytometry, multiplex ELISA in peripheral blood before and after treatment. Results: Among the 57 patients who were enrolled to the NEWBEAT trial, 50 patients were registered to the biomarker study. The expression of Ki67 and inducible T-cell co-stimulator (ICOS) on T cells increased after treatment, indicating induction of the T cell proliferation and activation. In responder (defined as patients with progression-free survival longer than 1 year, n = 30), the number of naïve CD4+ T cells at pretreatment were higher and effector memory CD4+ T cells were lower than non-responder. On the other hand, CD86+ myeloid DC at pretreatment were lower in non-responder pts. The median concentration of VEGF-A in serum before treatment was 116.065 pg/ml (range: 0-740.23) and decreased below 37 pg/ml at day 8 after treatment. Although serum VEGF-A level is inversely correlated with clinical outcome of pts with anti-PD-1 antibody in previous reports, in this trial VEGF-A high subgroup had better objective response than VEGF-A low subgroup, suggesting that blockade of VEGF by bevacizumab may overcome immunosuppression via VEGF signaling. Interestingly, in recurrent pts , the number of VEGFR-2+ CD4+ T cells / Monocyte were higher, and PD-L1+ CD4+ T cells / Monocyte / myeloid Dendritic Cell tended to be higher than in de novo stage IV pts. These results suggested that immune status of recurrent pts were more immunosuppressive than de novo stage IV pts, and that it might be more effective by the combination therapy to block the VEGF and PD-1 pathways. Moreover, the changes of immune status and dynamics on CD8+ T cells were not observed, suggesting that the therapeutic strategy of breast cancer might require the re-activation of CD8+ effector T cells through the stimulation of antigen-presenting cells followed by modification of CD4+ helper T cells.Conclusions: Our analysis showed the different immune status depending stage, subtype and response in advanced breast cancer pts. The dynamic decrease of serum VEGF-A concentration and high expression of VEGFR-1 or VEGFR-2 in the immune suppressive cells in advanced breast cancer pts suggested that combination treatment with bevacizumab might clinically overcome the immune suppression via inhibition of VEGF-A. (UMIN000029590) Citation Format: Yukinori Ozaki, Shigehisa Kitano, Junji Tsurutani, Tsutomu Iwasa, Masato Takahashi, Toru Mukohara, Norikazu Masuda, Manabu Futamura, Hironobu Minami, Koji Matsumoto, Hidetaka Kawabata, Makiko Yamashita, Kenichi Yoshimura, Toshimi Takano. Immunological analysis of the combination therapy of nivolumab, paclitaxel and bevacizumab in patients with HER2-negative MBC in NEWBEAT trial (WJOG9917BTR) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-14.

Background Trastuzumab emtansine (T-DM1) treatment for human epidermal growth factor receptor-2 (HER2)-positive metastatic breast cancer after taxane with trastuzumab and pertuzumab is standard therapy. However, treatment strategies beyond T-DM1 are still in development with insufficient evidence of their effectiveness. Here, we aimed to evaluate real-world treatment choice and efficacy of treatments after T-DM1 for HER2-positive metastatic breast cancer. Methods In this multi-centre retrospective cohort study involving 17 hospitals, 325 female HER2-positive metastatic breast cancer patients whose post-T-DM1 treatment began between April 15, 2014 and December 31, 2018 were enrolled. The primary end point was the objective response rate (ORR) of post-T-DM1 treatments. Secondary end points included disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), and overall survival (OS). Results The median number of prior treatments of post-T-DM1 treatment was four. The types of post-T-DM1 treatments included (1) chemotherapy in combination with trastuzumab and pertuzumab (n = 102; 31.4%), (2) chemotherapy concomitant with trastuzumab (n = 78; 24.0%), (3), lapatinib with capecitabine (n = 63; 19.4%), and (4) others (n = 82; 25.2%). ORR was 22.8% [95% confidence interval (CI): 18.1–28.0], DCR = 66.6% (95% CI 60.8–72.0), median PFS = 6.1 months (95% CI 5.3–6.7), median TTF = 5.1 months (95% CI 4.4–5.6), and median OS = 23.7 months (95% CI 20.7–27.4). Conclusion The benefits of treatments after T-DM1 are limited. Further investigation of new treatment strategies beyond T-DM1 is awaited for HER2-positive metastatic breast cancer patients.

Background The bioavailability of lapatinib is affected by food, even following the 1 hour fast recommended by the package insert. We hypothesized that overnight fasting would minimize food‐drug interactions. Here, we investigated if lapatinib administration timing is associated with its tolerability, efficacy, and pharmacokinetics. Methods This is a retrospective cohort study utilizing the medical records of patients enrolled in the JBCRG‐16/Neo‐LaTH randomized phase 2 trial for breast cancer patients treated with lapatinib. Lapatinib administration timing was divided into three groups: before breakfast (BB), between meals (BM), and at bedtime (AB). Side effects (SE), treatment discontinuation rate (TDR), relative dose intensity (RDI), pathological complete response (pCR) rate, and lapatinib serum trough concentration were compared between groups. Results About 140 patients were included in this study: BB 15, BM 51, and AB 74. A reduced risk of diarrhea {adjusted hazard ratio (HR), 0.51, 95% confidence interval (CI), 0.27‐0.89, p = 0.018}, and rash {adjusted HR, 0.37; 95% CI, 0.17‐0.70, p = 0.002} was seen in BB versus AB. Fewer patients with low RDI (< 0.85/, The bioavailability of lapatinib is affected by food, even when following package insert information. In a retrospective cohort study that utilized the medical records of 140 patients enrolled in the JBCRG‐16/Neo‐LaTH randomized phase 2 trial for breast cancer who were treated with lapatinib, associations between the timing of lapatinib administration (before breakfast, between meals or at bedtime) and clinical outcomes such as toxicities likely due to lapatinib (diarrhea, skin rash and hepatotoxicity) and drug efficacy were evaluated. Lapatinib administration after overnight fasting reduced the incidence of drug‐related diarrhea and skin rash without diminishing its therapeutic efficacy by avoiding food‐drug interactions.

Purpose To investigate the effectiveness and safety of bevacizumab–paclitaxel combination therapy as first- or second-line chemotherapy for HER2-negative locally advanced or metastatic breast cancer in daily clinical practice. Methods In this prospective multicenter observational study, bevacizumab–paclitaxel was administered at the discretion of attending physicians. Cohorts A and B had hormone receptor-positive and triple-negative breast cancer (TNBC), respectively. Primary endpoint was overall survival (OS). Multivariate analyses were conducted to identify prognostic factors. Results Between November 2012 and October 2014, 767 patients were enrolled from 155 institutions across Japan. Effectiveness was analyzed in 754 eligible patients (cohort A, 539; cohort B, 215) and safety in 750 treated patients (median observation period, 19.7 months). Median OS (95% CI) was 21.7 (19.8–23.6) months in eligible patients; 25.2 (22.4–27.4) months and 13.2 (11.3–16.6) months in cohorts A and B, respectively; and 24.4 (21.9–27.2) months and 17.6 (15.2–20.0) months in patients receiving first- and second-line therapy, respectively. Factors affecting OS (hazard ratio 95% CI) were TNBC (1.75, 1.44–2.14), second-line therapy (1.35, 1.13–1.63), ECOG performance status ≥ 1 (1.28, 1.04–1.57), taxane-based chemotherapy (0.65, 0.49–0.86), cancer-related symptoms (0.56, 0.46–0.68), and visceral metastasis (0.52, 0.40–0.66). Incidences of grade ≥ 3 AEs hypertension, neutropenia, peripheral neuropathy, proteinuria, and bleeding were 35.7%, 27.2%, 7.2%, 3.7%, and 0.3%, respectively. Conclusions In Japanese clinical practice, combined bevacizumab–paclitaxel was as effective as in previous studies. Factors that independently predicted poor prognosis in the present study are consistent with those identified previously. Trial registration Trial no. UMIN000009086.

Purpose To investigate whether palonosetron is better than granisetron in preventing chemotherapy‐induced nausea and vomiting (CINV) in a three‐drug combination with dexamethasone and fosaprepitant (Fos) in patients with breast cancer who are placed on anthracycline and cyclophosphamide (AC‐based regimen). Patients and Methods Chemo‐naive women with primary breast cancer were randomly administered either palonosetron 0.75 mg (day 1) or granisetron 1 mg (day 1) combined with dexamethasone (12 mg at day 1, 8 mg at day 2 and day 3) and Fos 150 mg (day 1) before receiving AC‐based regimen in a double‐blind study. The primary endpoint was the complete response (CR) rate of emesis in cycle 1 in the delayed phase. This was defined as neither vomiting nor rescue drug usage for emesis at >24‐120 hours after chemotherapy. Secondary endpoints were the CR in the acute/overall phase (0‐24/0‐120 hours, respectively, after chemotherapy), no nausea and vomiting, Patient‐Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO‐CTCAE), and safety. Results From December 2012 to October 2014, 326 patients were treated and evaluated (164/162 evaluable patients in granisetron/palonosetron arm, respectively). The CR during the delayed phase was 60.4% in the granisetron regimen and 62.3% in the palonosetron regimen. The CR during acute phase (73.2% vs 75.9%, respectively) and the CR during overall phase (54.9% in both regimens) were very identical. A significantly higher number of patients in the palonosetron arm were free from nausea during the delayed phase (28% vs 40.1%; P = .029). Adverse events were also identical, although infusion site reactions (ISR) were higher (20.3%‐23.3%) than preceding studies in both regimens. Conclusion In combination with dexamethasone and Fos, this study suggests that palonosetron is not better than granisetron in chemo‐naive patients with primary breast cancer receiving AC‐based regimen. Administration of Fos in peripheral veins after AC‐based regimen increased ISR., A randomized phase 3 trial compared palonosetron with granisetron as combination therapy with dexamethasone and fosaprepitant for chemotherapy‐induced nausea and vomiting prevention in breast cancer patients receiving anthracycline and cyclophosphamide. Although palonosetron was better than granisetron in terms of control of nausea in the delayed phase, the primary endpoint, CR in the delayed phase, was not statistically significant (62.3% vs 60.4%).

PURPOSE In patients taking tamoxifen, the CYP2D6 genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether CYP2D6 genotype–guided tamoxifen dosing in patients with hormone receptor–positive metastatic breast cancer could have an impact on the clinical outcome. METHODS Patients who needed first-line tamoxifen therapy were enrolled. Based on individual CYP2D6 genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes. RESULTS Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% v 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM v 51.1 nM; P < .0001) and were also higher compared with wt/wt patients (72.0 nM; P = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months ( P = .43). CONCLUSION In patients with CYP2D6-variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen.

Background [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is a novel antibody-drug conjugate with a humanized anti-HER2 antibody, peptide-based cleavable linker, and topoisomerase I inhibitor payload (MAAA-1181a). T-DXd has a drug-to-antibody ratio of ≈ 8, and the membrane permeability of the cleaved payload induces a cytotoxic bystander effect. In the phase 1 study (NCT02564900), T-DXd 5.4 and 6.4 mg/kg had a manageable safety profile and confirmed objective response rates (ORRs) of 59.5% in subjects with advanced HER2-positive breast cancer (BC) and 44% in subjects with BC with low HER2 expression. Methods This phase 1 study of T-DXd assessing the QTc interval (by 12-lead ECG) and pharmacokinetics (PK) in subjects with HER2-expressing metastatic BC (NCT03366428) was conducted at 7 study sites in Japan. Subjects received T-DXd 6.4 mg/kg IV infusion once every 3 weeks. Data cutoff (Dec 5, 2018) occurred after all subjects completed ≥ 3 cycles (C) or discontinued. Results 51 subjects enrolled and received T-DXd; all were female and Asian. Median age was 56 y (range, 31-79; ≥ 65 y, 25%); 8% were HER2-positive (IHC3+ or IHC2+/ISH+) and 92% were HER2-low (IHC1+, 73%; IHC 2+/ISH−, 12%); 75% were estrogen-receptor positive. Prior therapies included trastuzumab (24%), CDK4/6i (22%), T-DM1 (16%), and pertuzumab (16%); 67% had received > 5 lines of therapy. At data cutoff, 63% of subjects remained on treatment; primary reasons for discontinuation were disease progression (29%) and adverse events (AEs, 4%; grade [Gr] 2 pneumonitis and Gr 2 LVEF decrease). Median duration of survival follow-up was 4.8 months (range, 1.4-8.9). T-DXd 6.4 mg/kg was not associated with a clinically meaningful QTcF prolongation (change of > 10 ms); the upper bound of the 90% CI was < 10 ms at all assessments. The PK profile of total anti-HER2 antibody was similar to that of T-DXd; MAAA-1181a exposure was low. Some accumulation (35%) of T-DXd was observed from C 1-3 (Table); mean accumulation ratio for AUCtau at C 3 was consistent with the observed t1/2 of T-DXd. All subjects had treatment-emergent AEs (TEAEs; 67% Gr ≥ 3), most of which were gastrointestinal or hematologic disorders and primarily Gr 1 or 2. Most common Gr ≥ 3 TEAEs were neutrophil count decreased (45%), white blood cell count decreased (24%), anemia (10%), platelet count decreased (8%), lymphocyte count decreased (8%), and fatigue (6%). 2 subjects had serious TEAEs (Gr 2 nausea [drug related] and Gr 3 femur fracture [not drug related]). 1 subject had ILD (Gr 2 pneumonitis) and 4 had Gr 1 electrocardiogram QT prolonged. No grade 5 events occurred. The unconfirmed ORR (CR + PR) was 39% (95% CI, 26%-54%), with responses seen in HR+ (37%), HR− (46%), and HER2-low (IHC 1+, 43%; IHC 2+/ISH−, 20%) BC. Median time to response was 2.9 months (range, 1.2-4.4), and the duration of response was not yet reached. The disease control rate (CR + PR + SD ≥ 5 weeks from first dosing date) was 84% (95% CI, 82%-99%). Conclusion T-DXd 6.4 mg/kg was not associated with clinically relevant QTcF prolongation; the accumulation of T-DXd from C 1-3 was consistent with the elimination t1/2. T-DXd had a manageable safety profile, consistent with other studies. T-DXd showed preliminary antitumor activity with clinically meaningful responses in heavily pretreated subjects with metastatic HER2-expressing BC (mostly HER2-low), including HR+ and HR− disease. Pharmacokinetic Parameters for 3 Analytes by CycleMean (SD)Median (range)Cmax, μg/mLAUCtau, μg·d/mLt1/2, dTmax, hT-DXdCycle 1 (n = 51)179 (112)677 (141)5.82 (1.11)2.08 (1.55-7.02)Cycle 3 (n = 37)154 (23.3)905 (189)7.40 (1.48)2.12 (0.70-7.15)AR Cycle 3/ Cycle 1-1.35 (0.150)--Total Anti-HER2 AntibodyCycle 1 (n = 51)165 (110)752 (185)6.35 (2.01)2.07 (1.48-7.02)Cycle 3 (n = 37)142 (27.0)1030 (256)8.27 (1.97)2.07 (0.60-7.15)AR Cycle 3/ Cycle 1-1.36 (0.219)--MAAA-1181aCmax, ng/mLAUCtau, ng·d/mLt1/2, dTmax, hCycle 1 (n = 51)12.6 (4.49)39.0 (11.2)5.74 (1.29)6.93 (3.88-191.47)Cycle 3 (n = 37)9.60 (3.89)41.5 (13.8)6.57 (1.81)6.92 (1.95-70.65)AR Cycle 3/ Cycle 1-1.09 (0.194)--AR, accumulation ratio; AUCtau, area under plasma concentration-time curve over dosing interval; Cmax, maximum concentration; HER2, human epidermal growth factor receptor 2; t1/2, half-life; Tmax, time to maximum concentration. Citation Format: Toshinari Yamashita, Akihiko Shimomura, Toshimi Takano, Yasuaki Sagara, Junichiro Watanabe, Eriko Tokunaga, Kunika Kikumori, Emi Kamiyama, Takahiro Kamio, Ryo Nakamura, Tetsu Shinkai, Shunji Takahashi. A phase 1, multicenter, open-label study to assess the effect of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) on QTc and pharmacokinetics in subjects with HER2-expressing metastatic and/or unresectable breast cancer [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 P1-18-12.

Background: There are now many treatment options for estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, there are few reports indicating the optimal treatment sequence for this disease. Information to predict response to treatment is vital for personalized therapy and determining the most beneficial approach for individual patients. In this study, we attempted to determine predictive factors of response to hormonal therapy and survival outcomes using the large-scale databases constructed in the Safari study (UMIN000015168), a retrospective, multicenter cohort study involving 1,072 Japanese patients receiving fulvestrant 500mg for ER+ ABC. We examined the association between clinicopathological factors and time to failure (TTF) of fulvestrant in Japanese ABC patients. Methods: Among 1072 patients, 247 patients were selected for this study. Inclusion criteria was as follows: 1) patients treated with either SERM or AI in the adjuvant setting (AS) with known starting and finishing date of the treatment (patients relapsed on adjuvant treatment were excluded), 2) patients treated with SERM, AI and SERD in the metastatic setting (MS) as the first and the second line treatment. Influence of the adjuvant hormonal therapy on the TTF of the first line and the second line treatment and overall survival (OS) was assessed. Cox proportional hazards model was used for this analysis. Results: Patients treated with SERM in AS had significantly longer TTF of 1st line and 1st+2nd line of hormonal therapy in MS (1st line: HR 1.519, 95% CI 1.04-2.218, p=0.0307, 1st+2nd line: HR 2.372, 95% CI 1.584-3.551, p Conclusions: Interestingly, once AI-treated patients in AS have relapsed, their hormone sensitivity is lower and survival outcomes are worse compared with SERM-treated patients in AS in this cohort. Our results have consistency with the results of ABCSG-12 trial showing a pronounced higher risk of death for anastrozole-treated patients (Annals of Oncology 26: 313–320, 2015). Since it is a cohort of selected patients who were successfully treated with fulvestrant, prospective analysis would be therefore warranted. Citation Format: Takahiro Nakayama, Hidetoshi Kawaguchi, Norikazu Masuda, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Shigehira Saji, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Yutaka Yamamoto, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Influence of the adjuvant hormonal therapy on hormone sensitivity and survival outcomes in ER+ and HER2−advanced breast cancer: A subgroup analysis of the JBCRG-C06 Safari study [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 P5-11-11.

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 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.

Background: After the CONFIRM trial, fulvestrant 500 mg (F500) became a standard treatment for patients with estrogen receptor positive (ER+) advanced/metastatic breast cancer (AMBC). The JBCRG-C06 Safari study (UMIN 000015168) showed that earlier F500 use, a longer time from diagnosis to F500 use, and no prior chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with ER+ and HER2-negative AMBC (Kawaguchi H, et al. Breast Cancer Res Treat, 2017; Kawaguchi H, et al. Curr Med Res Opin, 2018). We had carried out subgroup analyses on real world data from the Safari study focusing on ER+ and HER2+ AMBC with the objective to examine further on potential interactions between TTF and the following: F500 single treatment or F500 with anti-HER2 therapy; presence or absence of visceral metastasis; progesterone receptor (PgR) status; and prior chemotherapy for AMBC. Material & methods: The Safari study was a retrospective, multicenter cohort study, conducted in 1072 patients at 16 sites in Japan for ER+ AMBC. Patients starting treatment with F500 between Nov 2011 and Dec 2014 were registered. After the data cleaning through the central review, 94 patients (9.6%) has been included in this sub-analysis among the 978 patients in which HER2 status was confirmed by the documentation. The relationship between baseline clinical/pathological factors, treatment line, and TTF (time from start to cessation of F500 treatment for any reason, including toxicity and death) were analyzed using Kaplan-Meier methods. Univariate analysis of TTF data was performed by Cox hazards model using: age, histological type, histological/nuclear grade, visceral-metastases, stage, PgR, period from AMBC diagnosis to F500 use, treatment line of F500, prior chemotherapy. Results: Median age at diagnosis of AMBC was 57.5yrs (33-85); 59(33-85) and 56.5(39-75) for F500 with/ without anti-HER2 therapy. Median age of fulvestrant start was 61yrs (35-96). 21.3% had de novo metastatic disease; 78.7% recurrent disease; 37.2% visceral metastases. All patients’ ER status was positive, and PgR status was positive in 65.9%, negative 25.5% respectively. HER2 IHC 3+ patients accounted for 44.7%, IHC 2+/1+ for 38.3%. In the case of IHC 2+/1+, HER2-positivity was confirmed by FISH. F500 alone was administered in 52 patients, while F500 with anti-HER2 therapy in 42 patients. At median follow up of 3.9 years, median TTF was 4.4m (95% CI: 3.3-5.7); 3.7m (95% CI: 2.9-5.9), 5.1m(95% CI: 3.6-6.4) for the F500 alone group, F500 with anti-HER2 therapy group respectively (p = 0.5973). F500 with/ without anti-HER2 therapy was administered in 1stor 2nd-line in 20 (21.3%), and ≥3rd-line in 74(78.7%) patients. Median TTF was 6.6m (95% CI: 4.6-8.5) and 3.7m (95% CI: 2.8-5.2) in the 1stor 2nd-line and ≥3rd-line respectively (p value:0.0145). Although no statistically significant difference was found, TTF tended to be shorter in the group receiving chemotherapy prior to F500 (median TTF: 3.7m vs 5.5m). No other clinical parameters including age, PgR status, metastatic sites were associated with the effectiveness. The median OS was 7.8-years (95% CI: 5.9-9.5), which had not been influenced by with/ without anti-HER2 therapy. The toxicity profile we observed was similar to that in the registration trial. Conclusions: Our findings suggest that F500 with/without anti-HER2 therapy appears to be effective also in the ER+ and HER2-positive ABMC setting which is consistent with the limited results previously published. Earlier line use of F500 use may be useful in HER2-positive patients as well as HER2-negative patients. Citation Format: Misato Hagi, Hidetoshi Kawaguchi, Norikazu Masuda, Shigehira Saji, Yutaka Yamamoto, Takahiro Nakayama, Kenjiro Aogi, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Daisuke Yotsumoto, Satoshi Morita, Masakazu Toi, Shinji Ohno. Outcomes of fulvestrant therapy among Japanese women with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of the JBCRG-C06 safari study [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 P5-11-13.

Background: To evaluate the survival risk is an important factor to decide or treatment options for recurrent breast cancer patients with estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2 negative (HER2−), though there are not enough supporting reports from large-scale databases. The Safari study (UMIN000015168) is a newly conducted retrospective, multicenter cohort study including 1072 ER+ advanced breast cancer Japanese patients treated with fulvestrant 500 mg mostly as a second or later line hormonal therapy. The follow-up data of Safari study is evaluated to focus on any relationship between clinicopathological factors and post-recurrence survival (PRS) in ER+ HER2− recurrent breast cancer patients. Methods: PRS was defined as the duration from the date of initial treatment for recurrent breast cancer to death. The Cox hazards model was used to evaluate the relationship between the clinical factors and PRS. We also performed multivariate analysis on PRS using factors that showed a statistical difference (p < 0.15) in univariate analysis. Hazard ratios (HRs) with 95% confidence intervals (CIs) and p-values are described. All tests were two-sided and p Citation Format: Kenjiro Aogi, Hidetoshi Kawaguchi, Norikazu Masuda, Takahiro Nakayama, Keisei Anan, Yoshinori Ito, Shoichiro Ohtani, Nobuaki Sato, Shigehira Saji, Toshimi Takano, Eriko Tokunaga, Seigo Nakamura, Yoshie Hasegawa, Masaya Hattori, Tomomi Fujisawa, Satoshi Morita, Miki Yamaguchi, Hiroko Yamashita, Toshinari Yamashita, Yutaka Yamamoto, Daisuke Yotsumoto, Masakazu Toi, Shinji Ohno. Factors associated with prolonged post-recurrence survival in patients with postmenopausal estrogen receptor-positive breast cancer taking fulvestrant: A follow-up data of the JBCRG-C06 Safari study factors associated with prolonged post-recurrence survival in patients with postmenopausal estrogen receptor-positive breast cancer taking fulvestrant: A follow-up data of the JBCRG-C06 Safari study [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 P3-08-55.

Background Previous large trials of trastuzumab (TZM) demonstrated improved outcomes in patients with HER2-positive early breast cancer. However, its effectiveness and safety in Japanese patients is not yet clear. Recently, new anti-HER2 agents were developed to improve treatment outcomes, but the patient selection criteria remain controversial. Purpose The aim of this study was to evaluate the long-term effectiveness of TZM therapy as perioperative therapy for HER2-positive operable breast cancer in daily clinical practice and to create a recurrence prediction model for therapeutic selection. Methods An observational study was conducted in Japan (UMIN000002737) to observe the prognosis of women (n = 2024) with HER2-positive invasive breast cancer who received TZM for stage I–III C disease between July 2009 and June 2011. Moreover, a recurrence-predicting model was designed to evaluate the risk factors for recurrence. Results The 5- and 10-year disease-free survival (DFS) rates were 88.9 (95% CI 87.5–90.3%) and 82.4% (95% CI 79.2–85.6%), respectively. The 5- and 10-year overall survival (OS) rates were 96% (95% CI 95.1–96.9%) and 92.7% (95% CI 91.1–94.3%), respectively. Multivariate analysis revealed that the risk factors for recurrence were an age of ≥ 70 years, T2 or larger tumors, clinically detected lymph node metastasis, histological tumor diameter of > 1 cm, histologically detected lymph node metastasis (≥ n2), and the implementation of preoperative treatment. The 5-year recurrence rate under the standard treatment was estimated to be > 10% in patients with a score of 3 or greater on the recurrence-predicting model. Conclusion The recurrence-predicting model designed in this study may improve treatment selection of patients with stage I–III C disease. However, further studies are needed to validate the scores generated by this model.

The combination of bevacizumab and chemotherapy has greatly improved progression-free survival (PFS) and objective response rate (ORR) in HER2-negative metastatic breast cancer in many pivotal trials. However, risk–benefit balance related to bevacizumab addition could not be confirmed because of a lack of overall survival (OS) improvement. Therefore, we conducted a meta-analysis to evaluate multiple endpoints pertaining to bevacizumab use in metastatic breast cancer (MBC) treatment. We searched PubMed and Cochrane Library databases and included seven studies in our meta-analysis in which bevacizumab combined with chemotherapy was compared with chemotherapy alone in MBC. Compared to the chemotherapy-alone group, the combination treatment group had significantly improved PFS [hazard ratio (HR): 0.72, 95% CI 0.67–0.77, P

Purpose The standard of care in the neoadjuvant setting for human epidermal growth factor receptor 2 (HER2)-positive breast cancer is dual HER2-targeted therapy. However, a need to minimize treatment-related toxicity and improve pathological complete response (pCR) rates, particularly in luminal HER2-positive disease, exists. Methods Neopeaks, a randomized, phase 2 study, compared docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP; 6 cycles; group A), TCbHP (4 cycles) followed by trastuzumab emtansine + pertuzumab (T-DM1+P; 4 cycles; group B), and T-DM1+P (4 cycles; group C) regimens in HER2‐positive primary breast cancer patients; concurrent hormone therapy with T-DM1+P was administered in case of estrogen receptor positivity (ER+). Based on tumor shrinkage, nonresponders in group C were switched to 5-fluorouracil + epirubicin + cyclophosphamide (FEC; 4 cycles). Primary endpoint was pCR (comprehensive pCR ypN0 [ypT0-TisypN0]). Results Of 236 patients enrolled, 204 were randomized to groups A (n = 51), B (n = 52), and C (n = 101). In group C, 80 (79%) patients continued T-DM1+P following favorable response, whereas 21 (21%) nonresponders switched to FEC. pCR rate was numerically higher with the TCbHP → T-DM1+P regimen (71%) versus the standard TCbHP (57%) and T-DM1+P (57%) regimens. The rate in group C was higher among responders continuing T-DM1+P (63%) versus nonresponders who switched to FEC (38%). pCR rates after initial 4 cycles of T-DM1+P (group C; 57%) and standard TCbHP regimen (57%) were equivalent. pCR rate in patients with ER+ was significantly higher in group B (69%) than groups A (43%) and C (51%), but was comparable in patients with ER− (67–76%). Compared with the T-DM1-based arm, the incidence of adverse events was higher in the taxane-based arms. Conclusion In the neoadjuvant setting, the pCR rate with the standard TCbHP → T-DM1+P regimen was numerically better than the TCbHP regimen alone and significantly better in patients with ER+. Personalization of the T-DM1+P regimen could serve as a reasonable approach to minimize toxicity while maintaining efficacy. Trial registration ID: UMIN-CTR: UMIN000014649.

Background The original aim of this study was to evaluate the treatment sequence and anthracycline requirement in docetaxel, cyclophosphamide and trastuzumab therapy. After one death in the anthracycline-containing arm, the protocol was amended to terminate the randomization. The single-docetaxel, cyclophosphamide and trastuzumab arm was continued to examine the efficacy and safety of the anthracycline-free regimen. Methods Women with human epidermal growth factor receptor-2-positive, operable and primary breast cancer were randomized to receive 5-fluorouracil, epirubicin and cyclophosphamide (four cycles) followed by docetaxel, cyclophosphamide and trastuzumab (four cycles), or docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide, or docetaxel, cyclophosphamide and trastuzumab (six cycles). After the protocol amendment, patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm alone. The primary endpoint was a pathological complete response. Results In total, 103 patients were enrolled between September 2009 and September 2011: 21, 22 and 24 patients in the 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel, cyclophosphamide and trastuzumab; docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide and docetaxel, cyclophosphamide and trastuzumab arms, respectively, and 36 patients in the docetaxel, cyclophosphamide and trastuzumab arm after the protocol amendment. In total, 60 patients were allocated to the docetaxel, cyclophosphamide and trastuzumab arm, in which the pathological complete response rate was 45.8%, and disease-free survival at 3 years was 96.6%. Patients with stage I or IIA in the docetaxel, cyclophosphamide and trastuzumab arm showed good disease-free survival (100% at 3 years). The comparison of efficacy among the three arms was statistically underpowered. Left ventricular ejection fraction decreased significantly after 5-fluorouracil, epirubicin and cyclophosphamide followed by docetaxel–docetaxel, cyclophosphamide and trastuzumab (P = 0.017), but not after docetaxel, cyclophosphamide and trastuzumab followed by 5-fluorouracil, epirubicin and cyclophosphamide or docetaxel, cyclophosphamide and trastuzumab. Conclusions The pathological complete response rate for docetaxel, cyclophosphamide and trastuzumab was similar to previous reports of anthracycline-containing regimens. Docetaxel, cyclophosphamide and trastuzumab might be an option for primary systemic therapy in human epidermal growth factor receptor-2-positive early breast cancer. A larger confirmatory study is necessary., Neoadjuvant docetaxel, cyclophosphamide and trastuzumab provided a pathological complete response rate of 45.8% and 3-year disease-free survival of 96.6%, comparable to those of reported anthracycline-containing regimens. Docetaxel, cyclophosphamide and trastuzumab might be an option for human epidermal growth factor receptor-2-positive breast cancer.

Background Assessing survival risk is important for discussing treatment options with estrogen receptor-positive (ER+) advanced breast cancer (ABC) patients. However, there are few reports from large-scale databases on the survival risk factors in ER+ ABC. The Safari study (UMIN000015168) was a retrospective, multicenter cohort study involving 1072 Japanese patients receiving fulvestrant 500 mg mostly as a second- or later-line endocrine therapy for ER+ ABC. The follow-up data after the Safari study were examined, focusing on any relationship between clinicopathological factors and overall survival (OS) in ER+ ABC patients. Methods OS in patients with ER+ ABC was analyzed by univariate and multivariate analyses with a Cox proportional hazards model in this study. Results A total of 1031 cases were evaluable for OS analysis. Multivariate analysis showed that younger age ( Conclusions In ER+ ABC patients whose treatment history included fulvestrant, younger age, longer time from ABC diagnosis to fulvestrant use, no prior palliative chemotherapy use, PgR−, and lower histological or nuclear grade correlated positively with prolonged OS.

We conducted the Neo-LaTH study in which patients were randomized to different lengths of neoadjuvant induction anti-HER2 therapy with lapatinib and trastuzumab followed by weekly paclitaxel plus the anti-HER2 therapy, and in estrogen receptor (ER)-positive patients, with or without concurrent endocrine therapy. The use of endocrine therapy did not affect the response, comprehensive pathological complete response (CpCR) plus ypN0 rate was 57.6% and 30.3% in ER-negative and ER-positive patients, respectively. After surgery, patients received an anthracycline-based regimen based on physician’s choice, followed by trastuzumab for 1 year, and in ER-positive patients, endocrine therapy for 5 years. Here, we report the 5-year survival outcomes. Among the followed-up patients (n = 212), the 5-year disease-free survival (DFS), distant DFS, and overall survival rates were 87.8% [95% confidence interval (CI), 82.5–91.6%], 93.7% (95% CI, 89.3–96.3%), and 95.6% (95% CI, 91.7–97.7%), respectively, with no difference between ER-negative and ER-positive patients. The 5-year DFS rate was significantly higher in patients who had a CpCR plus ypN0 after neoadjuvant treatment than in those who did not (91.7% vs. 85.1%, p = 0.0387). The stratified analysis showed better survival outcomes in patients who had CpCRypN0 than in those who did not after neoadjuvant treatment, regardless of use of adjuvant anthracycline therapy.

Background: In this year, anti-programmed death-ligand 1 (PD-L1) antibody has been approved for PD-L1-positive metastatic triple-negative breast cancer by the U.S. Food and Drug Administration. The synergistic effect of the combination of anti-PD-L1 antibody, CDK4/6 inhibitor and endocrine therapy (ET) has been anticipated based on various preclinical data. A Phase Ib study (JPCE, NCT02779751) of abemaciclib plus pembrolizumab demonstrated manageable safety and promising anti-tumor activity in patients with HR-positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC). Therefore, we initiated this investigator-initiated trial to evaluate the efficacy and safety of the combination of nivolumab, abemaciclib and ET (letrozole [LET] or fulvestrant [FUL]) as a first or second-line treatment in patients with HR+, HER2- MBC. Trial Design: This is a multicenter, multi-cohort, nonrandomized, open-label Phase II study to evaluate the efficacy and safety of nivolumab in combination with abemaciclib and ET (LET or FUL) in patients with HR+, HER2- MBC. Since there is no safety data of the combination of nivolumab, abemaciclib and ET, we evaluate safety and tolerability of the combination therapy in the first 6 patients with predefined dose-limiting toxicities. Patients will receive nivolumab 240 mg/body on day 1, 15, abemaciclib 150mg twice daily, and either LET 2.5mg once daily (LET cohort) or FUL 500mg on day1, day15 (FUL cohort) every 4 weeks until disease progression, unacceptable toxicity, or patient refusal. Pre- or perimenopausal women must receive concomitant treatment with a gonadotropin-releasing hormone agonist. Eligibility Criteria: Key eligibility criteria for the LET cohort are: postmenopausal HR+, HER2- MBC with ECOG PS≤1, measurable disease, no prior systemic therapy. ET in the adjuvant setting is permitted if the patient has a disease-free interval > 12 months from the completion of ET. Key eligibility criteria for the FUL cohort are: HR+, HER2- MBC with ECOG PS≤1, measurable disease, no more than one ET or any prior chemotherapy for MBC. Patients are required to have a disease that progressed while receiving adjuvant ET, ≤ 12 months after adjuvant ET, or while receiving ET for MBC. Specific Aims: The primary endpoint is the objective response rate (ORR) and key secondary endpoints include progression-free survival, overall survival, and the safety of the protocol treatment. Statistical Design: The threshold and expected ORR of LET cohort are 55% and 75%, respectively, and 16 patients are needed to ensure a statistical power of 80% (α=0.20). The threshold and expected ORR of FUL cohort are 45% and 60%, respectively, and 32 patients are needed to ensure a statistical power of 80% (α=0.20). Target Accrual: A total of 53 patients (LET cohort: 18, FUL cohort: 35) will be enrolled and duration of enrollment will be 1 year and 4 months. This trial opened to accrual in June 2019. Clinical trial information: JapicCTI-194782. Contact Information: Jun Masuda, Toranomon Hospital, Tokyo, Japan, masu-j@toranomon.gr.jp Citation Format: Jun Masuda, Junji Tsurutani, Norikazu Masuda, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Masato Takahashi, Hiroji Iwata, Tsutomu Iwasa, Toru Mukohara, Kenichi Yoshimura, Takayuki Ueno, Toshimi Takano. Phase II study of nivolumab in combination with abemaciclib plus endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer (WJOG11418B, NEWFLAME 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 OT2-04-07.

Background: PD-1 inhibitors have been developed for various cancer types, including breast cancer. Potential synergistic effects of nivolumab, paclitaxel and bevacizumab in combination was reported in preclinical models. Therefore, we initiated this investigator-initiated trial to evaluate the efficacy and safety of nivolumab + paclitaxel + bevacizumab therapy for metastatic breast cancer (MBC) patients (pts).Methods: This is a Phase II, multi-center, single-arm study to evaluate the efficacy and safety of nivolumab + paclitaxel + bevacizumab combination therapy as a first-line treatment for pts with HER2— MBC. Patients received nivolumab 240 mg/body on day 1, 15, paclitaxel 90 mg/m2 on day1, 8, 15, and bevacizumab 10 mg/kg on day1, 15 every 4 weeks until disease progression or intolerable toxicity experienced. The primary endpoint is the objective response rate (ORR) by independent central assessment. Key secondary endpoints include disease control rate (DCR: CR+PR+SD), progression free survival (PFS), overall survival, and the toxicity. The threshold and expected ORR are 55% and 70%, respectively, and 47 patients are needed to ensure a statistical power of 80% (α=0.10). Results: From February 2018 to October 2018, 57 female HER2— MBC pts were enrolled. Thirty-nine pts (68%) were with hormone receptor-positive (HR+), and 18 pts (32%) were with triple negative breast cancer (TNBC). ORR based on investigator assessment was 75.4%, and DCR was 96.4%. ORR was 71.7% (28/39) in pts with HR+ breast cancer and 83.3% (15/18) in pts with TNBC. Median PFS was not reached with median follow-up time of 10.7 months, and PFS rate at 12 months was 75.8% (95%CI: 60.9-86.2). Median OS was not reached and OS rate at 12 months was 87.1% (95%CI: 70.7-94.9). Thirty-five pts (59%) were still under treatment at the data cut-off date (1st June 2019). All pts had ≥1 AE; 58% of pts had Grade 3 or 4 AEs and 17% of pts had Grade 3 or 4 immune related-AEs. Twenty two percent of pts had serious AEs (SAE), and 12% of pts had nivolumab-related SAEs. Among the pts with nivolumab-related SAEs, 71% of them had recovered from SAEs. No treatment-related death was observed. Primary endpoint of ORR by independent central assessment and subset analysis with PD-L1 expression on tumor tissue (CPS, TPS by 28-8 antibody and IC, TC by SP142 antibody) will be presented at the symposium. Conclusions: This is the first study showing the promising efficacy of Nivolumab in combination with paclitaxel plus bevacizumab as a first line treatment for HER2— MBC. This triple-combination strategy for breast cancer warrants further study. Clinical trial information: UMIN000030242.Funding: This trial is sponsored by Ono pharmaceutical company. ResponseTotal100% (N = 57)Partial response (PR)75.4% (N = 43)Stable disease (SD)21.1% (N = 12)Progressive disease (PD)1.7% (N = 1)Objective response rate (ORR)75.4% (N = 43)Disease control rate (DCR) :CR+PR+SD96.4% (N = 55) Citation Format: Yukinori Ozaki, Toru Mukohara, Junji Tsurutani, Masato Takahashi, Koji Matsumoto, Manabu Futamura, Norikazu Masuda, Shigehisa Kitano, Kenichi Yoshimura, Hironobu Minami, Toshimi Takano. A multicenter phase II study evaluating the efficacy of nivolumab plus paclitaxel plus bevacizumab triple-combination therapy as a first-line treatment in patients with HER2-negative metastatic breast cancer: WJOG9917B NEWBEAT 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 PD1-03.

Background: Docetaxel + Trastuzumab (H) + Pertuzumab (P) provided progression-free survival (PFS) and overall survival (OS) benefits in HER2-positive advanced or metastatic breast cancer (AMBC) in the CLEOPATRA study as a first-line therapy. However, long-term administration of docetaxel at a dose of 75 mg/m2 every 3 weeks in AMBC patients (pts) is difficult due to the toxicities. Eribulin mesylate (E) is a well-tolerated microtubule inhibitor, and we have reported the efficacy and safety of EHP regimen as first- and second-line therapy for AMBC in a multicenter, phase II study (JBCRG-M03/UMIN000012232). In this M06 study, we address the clinical question as to which is the better chemotherapy partner for HP as first line regimen, in terms of efficacy, toxicity and QOL. Methods: JBCRG-M06 is a multicenter open-label randomized phase III study for HER2-positive AMBC pts who have received no prior chemotherapy except for the HER2- Antibody-Drug Conjugate (ADC). Pts will be randomized 1:1 to E (1.4mg/m2 on day 1 and 8) + H (8 mg/kg loading dose followed by 6 mg/kg) +P (840 mg loading dose followed by 420 mg) q3wks or standard taxanes (docetaxel 75mg/m2 on day1 or paclitaxel 80mg/m2 on day 1, 8 and 15) + HP q3wks. Stratification factors for randomization are; presence of visceral metastases, number of prior taxanes on perioperative adjuvant treatment, and treatment with prior anti-HER2-ADC. Primary endpoint is PFS and secondary endpoints include overall response rate, duration of response, OS, patient-reported outcomes (PRO) relating to QOL and peripheral neuropathy, new-metastases free survival, and safety. Translational research to search for biomarker for individual precision therapy will be performed. Main eligibility criteria are as follows: pts with HER2-positive AMBC, female aged 20-70 years old, ECOG PS of 0-1, LVEF ≥ 50% at baseline and adequate organ function. Pts who had progressive MBC within 6 months after the end of primary adjuvant systemic chemotherapy are excluded. The sample size was calculated by type1 error (2-sided) of 0.05 and 80% power to estimate the noninferiority margin 1.33 with an expected median PFS of 14.2 months. The target number of pts is 480 recruited over the duration of 3-years. The first patient in was achieved on August 2017. (ClinicalTrials.gov Identifier:NCT03264547). Citation Format: Masuda N, Yamashita T, Saji S, Araki K, Ito Y, Takano T, Takahashi M, Tsurutani J, Koizumi K, Kitada M, Kojima Y, Sagara Y, Tada H, Iwasa T, Kadoya T, Iwatani T, Hasegawa H, Morita S, Ohno S. A phase III trial to compare eribulin mesylate + trastuzumab (H) + pertuzumab (P) with paclitaxel or docetaxel + HP for HER2-positive advanced or metastatic breast cancer (JBCRG-M06/ EMERALD) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-05.

Background: In recent years, anti-PD-1 antibody, an immune checkpoint inhibitor, has been developed for the treatment of various types of cancer, including breast cancer. Synergistic effects of nivolumab, paclitaxel and bevacizumab are expected, based on various preclinical data, when these drugs are administered in combination. A biomarker study is ongoing to evaluate the immune status of patients participating in the NEWBEAT trial, which is a phase II trial of nivolumab + paclitaxel + bevacizumab therapy as first-line treatment for patients with metastatic or recurrent HER2-negative breast cancer. Methods: HER2-negative breast cancer patients from the WJOG9917B (NEWBEAT) trial are enrolled in this biomarker study. To explore new biomarkers for combined treatment of breast cancer with immune-checkpoint inhibitors and anti-vascular endothelial growth factor antibodies, we propose to conduct multicolor immunohistochemistry (IHC) assays for immunomonitoring of the intra-tumor environment, such as the expressions of PD-L1, CD4 and CD8. Blood samples are collected before the start of treatment and at four time-points during the treatment, to determine, using a multicolor flow cytometry panel, the numbers of circulating immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells and tumor-associated macrophages (M2). In the NEWBEAT trial, patients receive nivolumab 240 mg/body on days 1 and 15, paclitaxel 90 mg/m2 on days 1, 8 and 15, and bevacizumab 10 mg/kg on days 1 and 15 every 4 weeks until disease progression. The primary endpoint is the objective response rate, and the key secondary endpoints include progression-free survival, overall survival, and toxicity of the protocol treatment. A total of 51 patients will be enrolled and the enrollment period will be one year. This trial opened to accrual in February 2018. Clinical trial registry number: UMIN000029590 Citation Format: Ozaki Y, Kitano S, Matsumoto K, Takahashi M, Mukohara T, Futamura M, Masuda N, Tsurutani J, Yoshimura K, Minami H, Takano T. Biomarker study of patients with HER2-negative metastatic breast cancer receiving combination therapy with nivolumab, bevacizumab and paclitaxel as first-line treatment (WJOG9917BTR) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-12-02.

Background: Programmed cell death-1 inhibitors have been developed for various cancer types. Potential synergistic effects of nivolumab, bevacizumab, and paclitaxel (triple therapy) were observed in preclinical models, but triple therapy has not been evaluated for metastatic breast cancer (mBC) in clinical trials. Methods: This investigator-initiated, phase 2, multicentre, single-arm study (WJOG9917B) was performed to evaluate the efficacy and safety of triple therapy in the first-line setting for patients with human epidermal growth factor receptor 2 (HER2)-negative mBC. Treatment was continued until disease progression or intolerable toxicity. The primary endpoint was the percentage of patients with a centrally assessed objective response. Key secondary endpoints included disease control, progression-free survival (PFS), overall survival (OS), and toxicities. This study was registered on the UMIN registry (ID: UMIN000030242). Findings: Between February 2018 and October 2018, 57 females with HER2-negative mBC patients were enrolled. An objective response was seen in 39 of 56 patients (70%, 95% confidence interval [CI] 55·9%–81·2%), which met the primary endpoint. Disease control was achieved in 55 patients (98%, 95% CI 90·4%–100%). The median PFS was 14·8 months (95% CI, 11·0 to not reached), with a median follow-up of 13·9 months. The estimated OS at 12 months was 88% (95% CI 76·4%–94·0%). Median OS was not reached. Adverse drug reactions of grade 3 or 4 occurred in 33 of 57 patients (58%). There were no treatment-related deaths. Immune-related adverse events occurred in 43 of 57 patients (75%), with grade 3 or 4 events in eight patients (14%). Interpretation: Nivolumab, bevacizumab, and paclitaxel as first-line triple therapy showed promising efficacy and manageable toxicity in patients with HER2-negative mBC. Registration: This study was registered on the UMIN registry (ID: UMIN000030242). Funding: Ono Pharmaceutical Company. Declaration of Interests: Y. Ozaki reports research funds from Ono Pharmaceutical in relation to this work; and personal fees from Chugai outside the submitted work. J. Tsurutani reports research funds from Ono Pharmaceutical in relation to this work; grants from Daiichi Sankyo, Kyowa Kirin, Chugai, Pfizer, Eisai, Nippon Kayaku, and Eli Lilly; consulting fees from Asahi Kasei; lecture fees from Eisai, Chugai, Taiho, Daiichi Sankyo, Eli Lilly, Pfizer, Nippon Kayaku, Novartis, and AstraZeneca, support for attending meetings from Eisai and Daiichi Sankyo; and participation on advisory boards for Daiichi Sankyo, Eisai, AstraZeneca, and Eli Lilly outside the submitted work. T. Mukohara reports research funds from Ono Pharmaceutical in relation to this work; and grants from Daiichi Sankyo, Sysmex, MSD, Pfizer, Eisai, Chugai, Novartis, Sanofi, Seagen, and AstraZeneca; lecture fees from Eisai, Novartis, Chugai, Eli Lilly, AstraZeneca, and Kyowa Kirin outside the submitted work. T. Iwasa reports research funds from Ono Pharmaceutical in relation to this work. M. Takahashi reports research funds from Ono Pharmaceutical in relation to this work; and personal fees from AstraZeneca, Eli Lilly, Eisai, and Pfizer outside the submitted work. Y. Tanabe reports grants provided to the institution from Ono Pharmaceutical, outside of the submitted work. H. Kawabata reports research funds from Ono Pharmaceutical in relation to this work; and research funds from MSD, Daiichi Sankyo, Novartis, Taiho, and Chugai outside the submitted work. N. Masuda reports research funds from Ono Pharmaceutical in relation to this work; grants from Chugai and Eisai; personal fees, honoraria, and research funding provided to the institution from Chugai, AstraZeneca, Pfizer, Eli Lilly, Eisai, Takeda, Kyowa Kirin, Novartis, and Daiichi Sankyo; and research funding provided to the institution from MSD, Nippon Kayaku, and Sanofi outside of the submitted work. M. Futamura reports research funds from Ono Pharmaceutical in relation to this work; and personal fees from Chugai, Taiho, Takeda, Novartis, and Eisai outside the submitted work. H. Minami reports research funds from Ono Pharmaceutical in relation to this work; grants from Ono Pharmaceutical, Asahi Kasei Pharma, Astellas, Bayer, Boehringer Ingelheim, Bristol- Myers Squibb, Chugai, Daiichi Sankyo, Sumitomo Dainippon, Eisai, Kyowa Kirin, Merck Serono, MSD, Nippon Shinyaku, Sanofi, Takeda, CSL Behring, Nippon Kayaku, Shionogi, Taiho, Eli Lilly, Novartis, and Mitsubishi Tanabe; personal fees and funding for clinical trials from Ono Pharmaceutical, Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, MSD, Pfizer, Taiho, and Novartis; personal fees from Celgene, Sumitomo Dainippon, Eisai, Janssen, Kyowa Kirin, Merck Serono, Otsuka, Sanofi, Takeda, Genomic Health, AbbVie, and Eli Lilly; and funding for clinical trials from AstraZeneca and Amgen outside the submitted work. K. Matsumoto reports research funds from Ono Pharmaceutical in relation to this work; grants from MSD, Chugai, Icon Japan, Eisai, Ono Pharmaceutical, AstraZeneca, and Novartis; and personal fees from MSD, Chugai, Eisai, Ono Pharmaceutical, AstraZeneca, Novartis, Eli Lilly, AbbVie, Kyowa Kirin, Centurion, and Taiho outside the submitted work. K. Yoshimura reports research funds from Ono Pharmaceutical in relation to this work; and personal fees and lecture fees from AstraZeneca, Eisai, Otsuka, Nippon Kayaku, Eli Lilly, Novartis, Boehringer Ingelheim, and Chugai outside the submitted work. S. Kitano reports research funds from Ono Pharmaceutical in relation to this work; joint research funds/contract research expenses for clinical trials from Ono Pharmaceutical, Boehringer Ingelheim, and Chugai; joint research funds from Daiichi Sankyo, Eisai, Astellas, Gilead Sciences, Takara Bio, and PACT Pharma; contract research expenses for clinical trials from Regeneron and MSD; and grants from the Japan Agency for Medical Research and Development (AMED) and Japan Society for the Promotion of Science (JSPS); consulting fees from Immunity Research; lecture fees and participation on advisory boards for Ono Pharmaceutical, AstraZeneca, Chugai, Pfizer, Boehringer Ingelheim, Novartis, Daiichi Sankyo, MSD, Sumitomo Dainippon, Eisai, Bristol-Myers Squibb, Regeneron, and GSK; lecture fees from Sanofi, Taiho, and Ayumi Pharmaceutical; participation on advisory boards for Rakuten Medical; and comment fees from Pharmaceuticals and Medical Devices Agency (PMDA) outside the submitted work. T. Takano reports research funds from Ono Pharmaceutical in relation to this work; grants provided to the institution from Chugai, Daiichi Sankyo, Ono Pharmaceutical, MSD, and Eisai; and lecture fees from Chugai, Daiichi Sankyo, Eisai, Kyowa Kirin, Pfizer, Eli Lilly, and Celltrion Healthcare outside the submitted work. Ethics Approval Statement: This trial was conducted according to Good Clinical Practice and the Declaration of Helsinki, and was approved by institutional review boards at all participating sites.

PURPOSE The role of maintenance therapy for gastric (GC) or gastroesophageal junction cancer (GEJC) is unclear. We investigated avelumab (anti–programmed death ligand-1 [PD-L1]) maintenance after first-line induction chemotherapy for GC/GEJC. PATIENTS AND METHODS JAVELIN Gastric 100 was a global, open-label, phase III trial. Eligible patients had untreated, unresectable, human epidermal growth factor receptor 2–negative, locally advanced or metastatic GC or GEJC. Patients without progressive disease after 12 weeks of first-line chemotherapy with oxaliplatin plus a fluoropyrimidine were randomly assigned 1:1 to avelumab 10 mg/kg every 2 weeks or continued chemotherapy, stratified by region (Asia v non-Asia). The primary end point was overall survival (OS) after induction chemotherapy in all randomly assigned patients or the PD-L1–positive randomly assigned population (≥ 1% of tumor cells; 73-10 assay). RESULTS A total of 805 patients received induction; 499 were randomly assigned to avelumab (n = 249) or continued chemotherapy (n = 250). Median OS was 10.4 months (95% CI, 9.1 to 12.0 months) versus 10.9 months (95% CI, 9.6 to 12.4 months) and 24-month OS rate was 22.1% versus 15.5% with avelumab versus chemotherapy, respectively (hazard ratio [HR], 0.91; 95% CI, 0.74 to 1.11; P = .1779). In the PD-L1–positive population (n = 54), the HR for OS was 1.13 (95% CI, 0.57 to 2.23; P = .6352). In an exploratory analysis of the PD-L1–positive population, defined as combined positive score ≥ 1 (22C3 assay; n = 137), median OS was 14.9 months (95% CI, 8.7 to 17.3 months) with avelumab versus 11.6 months (95% CI, 8.4 to 12.6 months) with chemotherapy (unstratified HR, 0.72; 95% CI, 0.49 to 1.05). With avelumab and chemotherapy, treatment-related adverse events (TRAEs) occurred in 149 (61.3%) and 184 (77.3%) patients, including grade ≥ 3 TRAEs in 31 (12.8%) and 78 (32.8%) patients, respectively. CONCLUSION JAVELIN Gastric 100 did not demonstrate superior OS with avelumab maintenance versus continued chemotherapy in patients with advanced GC or GEJC overall or in a prespecified PD-L1–positive population.

PURPOSE NALA (ClinicalTrials.gov identifier: NCT01808573 ) is a randomized, active-controlled, phase III trial comparing neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), plus capecitabine (N+C) against lapatinib, a reversible dual TKI, plus capecitabine (L+C) in patients with centrally confirmed HER2-positive, metastatic breast cancer (MBC) with ≥ 2 previous HER2-directed MBC regimens. METHODS Patients, including those with stable, asymptomatic CNS disease, were randomly assigned 1:1 to neratinib (240 mg once every day) plus capecitabine (750 mg/m2 twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m2 twice a day 14 d/21 d). Coprimary end points were centrally confirmed progression-free survival (PFS) and overall survival (OS). NALA was considered positive if either primary end point was met (α split between end points). Secondary end points were time to CNS disease intervention, investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate, safety, and health-related quality of life (HRQoL). RESULTS A total of 621 patients from 28 countries were randomly assigned (N+C, n = 307; L+C, n = 314). Centrally reviewed PFS was improved with N+C (hazard ratio [HR], 0.76; 95% CI, 0.63 to 0.93; stratified log-rank P = .0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; P = .2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% v 29.2%; P = .043). ORRs were N+C 32.8% (95% CI, 27.1 to 38.9) and L+C 26.7% (95% CI, 21.5 to 32.4; P = .1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; P = .0004). The most common all-grade adverse events were diarrhea (N+C 83% v L+C 66%) and nausea (53% v 42%). Discontinuation rates and HRQoL were similar between groups. CONCLUSION N+C significantly improved PFS and time to intervention for CNS disease versus L+C. No new N+C safety signals were observed.

The PRECIOUS study (UMIN000018202) is being conducted as a multicenter, randomized, open-label Phase III study to determine if retreatment with pertuzumab is more effective than conventional treatment in HER2-positive locally advanced (LA)/metastatic breast cancer (MBC) patients previously treated with pertuzumab, trastuzumab and chemotherapy. Patients are randomized 1:1 into chemotherapy plus trastuzumab with or without pertuzumab groups. The latest regimen before enrollment did not include pertuzumab, and the number of previous chemotherapy regimens for LA/MBC did not exceed three. The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints include independent reviewer-assessed progression-free survival, progression-free survival in patients treated with trastuzumab emtansine as the latest regimen, response rate, response duration, overall survival, safety and health-related quality of life. Target accrual is 370 patients, allowing the observation of 325 events, yielding an 80% power for detection of a hazard ratio of 0.739 with a one-sided 5% level of significance.

Background The optimal choice of antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) needs to be clarified. This study assessed the efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy (HEC). Methods Randomized trials that compared different antiemetic regimens were included from MEDLINE. Quality was assessed using the Cochrane risk-of-bias tool. We followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Data were pooled using random-effects models. We conducted indirect comparisons using network meta-analysis of a Bayesian model. The main outcomes were the odds ratio (OR) for overall complete response (CR [i.e., no emesis and no rescue]). Safety was assessed from the trial description. All statistical tests were two-sided. Findings We systematically reviewed 24 randomized control trials (12,104 participants), which compared 12 different antiemetic regimens. Palonosetron (PAL) 0·75 mg (PAL0·75) + dexamethasone (Dex); aprepitant (APR) + a serotonin-3 receptor antagonist (5HT3) + Dex; and APR + PAL (0·25 mg or 0·50 mg) + Dex were more favorable than the reference regimen (OR, 1·51; 95% credibility interval [95%CrI], 1·18-1·91; OR, 1·78; 95%CrI, 1·58-2·05; and OR, 2·28; 95%CrI, 1·66-3·18, respectively). The oral combination of netupitant and palonosetron (NEPA) was more effective than conventional regimens (OR, 2·39; CrI, 1·73-3·30). Olanzapine (OLZ)-containing regimens were apparently the most effective: the ORs of OLZ + 5HT3 + Dex, OLZ + PAL + Dex, and OLZ + APR + 5HT3 + Dex were 2·78, 2·58, and 4·98, respectively. Interpretation The regimens of PAL0·75 + Dex, APR + 5HT3 + Dex, and APR + PAL + Dex were more favorable in conventional regimens (i.e., regimens without NEPA or OLZ), which support the NCCN guideline strategy. NEPA could be a better choice than conventional regimens. OLZ-containing regimens could be an optimal choice; thus, more trials need to be accumulated. Citation Format: Yokoe T, Hayashida T, Nagayama A, Seki T, Takahashi M, Takano T, Abe T, Kitagawa Y. Comparative effectiveness of antiemetic regimens for highly emetogenic chemotherapy-induced nausea and vomiting: A systematic review and network meta-analysis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-14-11.

Background Dual blockade of HER2 promises increased pathological complete response (pCR) rate compared with single blockade in the presence of chemotherapy for HER2-positive (+) primary breast cancer. Many questions remain regarding optimal duration of treatment and combination impact of endocrine therapy for luminal HER2 disease. Methods We designed a randomised phase II, five-arm study to evaluate the efficacy and safety of lapatinib and trastuzumab (6 weeks) followed by lapatinib and trastuzumab plus weekly paclitaxel (12 weeks) with/without prolongation of anti-HER2 therapy prior to chemotherapy (18 vs. 6 weeks), and with/without endocrine therapy in patients with HER2+ and/or oestrogen receptor (ER)+ disease. The primary endpoint was comprehensive pCR (CpCR) rate. Among the secondary endpoints, pCR (yT0-isyN0) rate, safety, and clinical response were evaluated. Results In total, 215 patients were enrolled; 212 were included in the full analysis set (median age 53.0 years; tumour size = T2, 65%; and tumour spread = N0, 55%). CpCR was achieved in 101 (47.9%) patients and was significantly higher in ER− patients than in ER+ patients (ER− 63.0%, ER+ 36.1%; P = 0.0034). pCR with pN0 was achieved in 42.2% of patients (ER− 57.6%, ER+ 30.3%). No significant difference was observed in pCR rate between prolonged exposure groups and standard groups. Better clinical response outcomes were obtained in the prolongation phase of the anti-HER2 therapy. No surplus was detected in pCR rate by adding endocrine treatment. No major safety concern was recognised by prolonging the anti-HER2 treatment or adding endocrine therapy. Conclusions This study confirmed the therapeutic impact of lapatinib, trastuzumab, and paclitaxel therapy for each ER− and ER+ subgroup of HER2+ patients. Development of further strategies and tools is required, particularly for luminal HER2 disease. Electronic supplementary material The online version of this article (10.1007/s12282-018-0839-7) contains supplementary material, which is available to authorized users.

Summary Background Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population. Methods We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m 2 , paclitaxel 175 mg/m 2 , or 75 mg/m 2 docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on vs ≥5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807. Findings Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6–15·5; n=116] vs 10·6 months [8·4–12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63–1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6–13·2]; HR 0·57, 95% CI 0·26–1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3–4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients). Interpretation Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting. Funding F Hoffmann-La Roche, Genentech.

The JBCRG-C06 Safari study showed that earlier fulvestrant 500 mg (F500) use, a longer time from diagnosis to F500 use, and no prior palliative chemotherapy were associated with significantly longer time to treatment failure (TTF) among Japanese patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC). The objective of this sub-group analysis was to further examine data from the Safari study, focusing on ER + and human epidermal growth factor receptor-negative (HER2-) cases.The Safari study (UMIN000015168) was a retrospective, multi-center cohort study, conducted in 1,072 patients in Japan taking F500 for ER + ABC. The sub-analysis included only patients administered F500 as second-line or later therapy (n = 960). Of these, 828 patients were HER2-. Results Multivariate analysis showed that advanced age (≥65 years; p = .035), longer time (≥3 years) from ABC diagnosis to F500 use (p .001), no prior chemotherapy (p .001), and F500 treatment line (p .001) were correlated with prolonged TTF (median = 5.39 months).In ER+/HER2- patients receiving F500 as a second-line or later therapy, treatment line, advanced age, no prior palliative chemotherapy use, and a longer period from ABC diagnosis to F500 use were associated with longer TTF.

Background: In patients with HER2-positive metastatic breast cancer (MBC) who progressed on trastuzumab (H)-based therapy, both continuing H beyond progression and switching to lapatinib (L) in combination with chemotherapy are valid options. However, it is unclear which strategy is more effective and how we can select a proper strategy in each patient. Methods: We conducted an open label, multicenter, randomized phase II trial to comparatively evaluate efficacy and safety of H + capecitabine (X) (HX) or L + X (LX) in women with HER2-positive MBC who were previously treated with taxanes and progressed on H-containing regimens. Patients treated with more than two chemotherapy regimens for MBC were excluded. Those treated with pertuzumab and/or T-DM1 were allowed to enroll in this study. Patients with brain metastases were also included if they are asymptomatic. Patients received H (4mg/kg loading then 2mg/kg weekly or 8mg/kg loading then 6mg/kg every 3 weeks) and X (2500 mg/m2/day on days 1-14 every 3weeks) in HX arm and L (1250 mg/day) and X (2000 mg/m2/day on days 1-14 every 3weeks) in LX arm until progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR), proportion of subjects progressing with brain metastases as site of first progression, and safety.We also assessed biomarkers in tumor tissues and circulating cell-free DNA. Results: Between May 2011 and December 2014, 86 patients (43 in HX arm and 43 in LX arm) were enrolled in this study. Median age was 58 years (range 34-81), ECOG performance status was 0 (63%), 1 (35%), or 2 (2%), 63% had hormone receptor-positive disease, 15% had brain metastases, 56% had relapsed after primary surgery, and 23% had received adjuvant or neo-adjuvant trastuzumab. Median follow-up time was 44.6 months. Median PFS was 6.1 months in HX arm and 7.1 months in LX arm (hazard ratio 0.81 90% CI 0.55-1.21; p=0.39), median OS was 31.0 months in HX arm and not reached in LX arm (hazard ratio 0.58 95% CI 0.26-1.31; p=0.18), ORR was 40% in HX arm and 41% in LX arm (p=1.00), disease control rate was 73% in HX arm and 92% in LX arm (p=0.038), and proportion of subjects progressing with brain metastases as site of first progression was 5% in HX arm and 5% in LX arm. Grade 3-4 toxicities included hand-foot syndrome (21% in HX arm and 21% in LX arm) and diarrhea (9% in HX arm and 16% in LX arm). In subgroup analyses, PFS benefit in LX arm compared to HX arm was significantly larger among patients who had received previous systemic treatment for metastatic disease for less than 1 year (interaction p=0.007). Subgroup analyses by biomarkers will be presented at the meeting. Conclusions: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, lapatinib + capecitabine tended to yield better PFS and OS than trastuzumab beyond progression + capecitabine, although they were not statistically significant.Background: In patients with HER2-positive metastatic breast cancer (MBC) who progressed on trastuzumab (H)-based therapy, both continuing H beyond progression and switching to lapatinib (L) in combination with chemotherapy are valid options. However, it is unclear which strategy is more effective and how we can select a proper strategy in each patient. Methods: We conducted an open label, multicenter, randomized phase II trial to comparatively evaluate efficacy and safety of H + capecitabine (X) (HX) or L + X (LX) in women with HER2-positive MBC who were previously treated with taxanes and progressed on H-containing regimens. Patients treated with more than two chemotherapy regimens for MBC were excluded. Those treated with pertuzumab and/or T-DM1 were allowed to enroll in this study. Patients with brain metastases were also included if they are asymptomatic. Patients received H (4mg/kg loading then 2mg/kg weekly or 8mg/kg loading then 6mg/kg every 3 weeks) and X (2500 mg/m2/day on days 1-14 every 3weeks) in HX arm and L (1250 mg/day) and X (2000 mg/m2/day on days 1-14 every 3weeks) in LX arm until progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS) and secondary endpoints included overall survival (OS), objective response rate (ORR), proportion of subjects progressing with brain metastases as site of first progression, and safety.We also assessed biomarkers in tumor tissues and circulating cell-free DNA. Results: Between May 2011 and December 2014, 86 patients (43 in HX arm and 43 in LX arm) were enrolled in this study. Median age was 58 years (range 34-81), ECOG performance status was 0 (63%), 1 (35%), or 2 (2%), 63% had hormone receptor-positive disease, 15% had brain metastases, 56% had relapsed after primary surgery, and 23% had received adjuvant or neo-adjuvant trastuzumab. Median follow-up time was 44.6 months. Median PFS was 6.1 months in HX arm and 7.1 months in LX arm (hazard ratio 0.81 90% CI 0.55-1.21; p=0.39), median OS was 31.0 months in HX arm and not reached in LX arm (hazard ratio 0.58 95% CI 0.26-1.31; p=0.18), ORR was 40% in HX arm and 41% in LX arm (p=1.00), disease control rate was 73% in HX arm and 92% in LX arm (p=0.038), and proportion of subjects progressing with brain metastases as site of first progression was 5% in HX arm and 5% in LX arm. Grade 3-4 toxicities included hand-foot syndrome (21% in HX arm and 21% in LX arm) and diarrhea (9% in HX arm and 16% in LX arm). In subgroup analyses, PFS benefit in LX arm compared to HX arm was significantly larger among patients who had received previous systemic treatment for metastatic disease for less than 1 year (interaction p=0.007). Subgroup analyses by biomarkers will be presented at the meeting. Conclusions: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, lapatinib + capecitabine tended to yield better PFS and OS than trastuzumab beyond progression + capecitabine, although they were not statistically significant. Citation Format: Takano T, Tsurutani J, Takahashi M, Yamanaka T, Sakai K, Ito Y, Fukuoka J, Kimura H, Kawabata H, Tamura K, Matsumoto K, Aogi K, Sato K, Nishio K, Nakagawa K, Saeki T. A randomized phase II trial of trastuzumab + capecitabine versus lapatinib + capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes: WJOG6110B/ELTOP [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-14.

Background: In neoadjuvant dual HER2 blockade, over 30% of patients fail to complete treatment as planned because of lapatinib-induced diarrhea, rash, and hepatotoxicity. Lapatinib bioavailability, which affects both efficacy and toxicity, is influenced by prandial conditions. Methods: To investigate the association between lapatinib dosage timing and toxicity, we reviewed the medical records of patients who were enrolled in the JBCRG-16/Neo-LaTH randomized phase II multicenter trial evaluating the efficacy and safety of neoadjuvant 1000 mg/day lapatinib (La) and trastuzumab (T) therapy for 6 or 12 weeks followed by 750 mg/day La, T and weekly paclitaxel for 12 weeks in Japanese patients with primary HER2 positive breast cancer. Lapatinib dosage timing was divided into three groups: after overnight fasting, between meals, and at bedtime. We also measured serum lapatinib concentrations at steady state and dosage timing on the day prior to pharmacokinetic blood sampling. The primary endpoint was to investigate the association between lapatinib dosage timing and frequency of ≥grade 2 diarrhea. The secondary endpoint was to assess the association between dosage timing and other toxicities, pharmacokinetics, efficacy, and treatment discontinuation. Statistical analyses performed included one-way ANOVA, Welch's test and logistic regression. Results: Out of 213 patients enrolled in JBCRG-16/Neo LaTH, we obtained dosage timing data from 143 (67%) patients: 16 (11%) after overnight fasting, 53 (37%) between meals, and 74 (52%) at bedtime. Serum lapatinib concentrations were obtained in 34/143 (24%) of patients. Dosage timing was not associated with ≥grade 2 diarrhea (8/16 (50%) after overnight fasting, 18/53 (34%) between meals, and 26/74 (35%) at bedtime; p = 0.48). However, multivariate analysis revealed that the after overnight fasting group is less likely to develop acne-like rash during La + T treatment regardless of age, BMI, or treatment. Multivariate logistic regression analysis of factors predicting rash during La + T treatmentFactor Adjusted odds ratio95% confidence intervalp valueAge (years)≥55Reference In addition, serum lapatinib trough concentration and it's variability were significantly reduced in the after overnight fasting group (mean ± standard deviation (SD) = 0.35 ± 0.15 µg/ml, coefficient of variation (CV) = 42.7%) as compared to the others (mean ± SD = 0.77 ± 0.44 µg/ml, CV = 57.8%) (p Conclusions: These data suggest that overnight fasting stabilizes the bioavailability of lapatinib, which may aid in managing lapatinib-induced rash without diminishing its therapeutic efficacy. Citation Format: Tsuda M, Ishiguro H, Toriguchi N, Masuda N, Bando H, Ohgami M, Homma M, Morita S, Yamamoto N, Kuroi K, Takano T, Shimizu S, Toi M. Duration of fasting before taking lapatinib is associated with skin toxicity in neoadjuvant treatment of HER2 positive breast cancer: A cohort study from JBCRG-16/Neo-LaTH [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-11-07.

Highlights • Systemic or adjuvant chemotherapy is internationally accepted as a standard treatment for patients with metastatic or postoperative colorectal cancer, respectively. • Moreover, recent studies have demonstrated that preoperative chemotherapy improves the outcome of patients with CRC with liver metastases. • However, little is known about the effect and safety of preoperative FOLFOX and panitumumab combined chemotherapy for initially unresectable, locally advanced colon cancer without distant metastases., Introduction FOLFOX and panitumumab combined chemotherapy plays an important role for metastatic colorectal cancer. However the usefulness of this regimen for neoadjuvant therapy is unclear. Case report A 67-year-old man with abdominal pain and pneumaturia was diagnosed with RAS wild-type sigmoid colon cancer with urinary bladder invasion and colovesical fistulas. Because the cancer was considered to be unresectable, a transverse-loop colostomy was performed. Colonoscopy and computed tomography revealed a marked reduction in the size of the primary tumor after six courses of FOLFOX4 (oxaliplatin, leucovorin, and 5-fluorouracil) plus panitumumab. Laparoscopic sigmoidectomy and partial cystectomy were then performed. The pathological findings based on the resected specimen showed almost complete replacement of the tumor by fibrous tissue, with only a few degenerated tumor glands persisting in the submucosa. The patient’s postoperative course was uneventful and he was doing well, without disease recurrence, after 36 months of follow up. Conclusion To our knowledge, this is the first report of a successful curative resection in a patient with initially unresectable, locally advanced colorectal cancer who was treated with FOLFOX4 combined with panitumumab.

Background Trastuzumab (Tmab), pertuzumab (Pmab), and taxane has been a standard first-line treatment for recurrent or metastatic human epidermal growth factor (HER2)-positive breast cancer (HER2+ mBC) but has some safety issues due to taxane-induced toxicities. This has led to ongoing efforts to seek less toxic alternatives to taxanes that are equally effective when used in combination with Tmab plus Pmab. This study aims to show the non-inferiority of eribulin, a non-taxane microtubule inhibitor, against taxane, as a partner for dual HER2 blockade. Methods/design This multicenter, randomized, open-label, parallel-group, phase III study will involve a total of 480 Japanese women with HER2+ mBC who meet the following requirements: (1) age 20–70 years; (2) no prior cytotoxic chemotherapy (excluding trastuzumab-emtansine) for mBC; (3) ≥ 6 months after prior neoadjuvant or adjuvant cytotoxic chemotherapy; (4) presence of any radiologically evaluable lesion; (5) left ventricular ejection fraction ≥ 50%; (6) Eastern Cooperative Oncology Group performance status score of 0 or 1; (7) adequate organ function; and (8) life expectancy of at least 6 months. They will be randomized 1:1 to receive eribulin (1.4 mg/m2 on days 1 and 8) or taxane (docetaxel 75 mg/m2 on day 1 or paclitaxel 80 mg/m2 on days 1, 8, and 15) in combination with Tmab (8 mg/kg then 6 mg/kg) plus Pmab (840 mg then 420 mg) on day 1 of each 21-day cycle. The treatment will be continued until disease progression or unmanageable toxicity. The primary endpoint is progression-free survival as per investigator according to RECIST v1.1 criteria. Key secondary endpoints include objective response rate, overall survival, quality of life and safety. Non-inferiority will be tested with two margins of 1.33 and 1.25 in a stepwise manner. If non-inferiority is shown with a margin of 1.25, superiority will then be tested. Discussion If this study shows the non-inferiority, or even superiority, of Tmab, Pmab, and eribulin against the existing taxane-containing regimen, this new regimen may become a standard first- or second-line treatment option for HER2+ mBC in Japan. Trial registration ClinicalTrials.gov, ID: NCT03264547. Registered on 28 June 2017.

This randomized phase II trial compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab plus FOLFIRI as second-line chemotherapy for wild-type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) and to explore the values of oncogenes in circulating tumor DNA (ctDNA) and serum proteins as predictive biomarkers. Patients with WT KRAS exon 2 mCRC refractory to first-line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI. Of 121 randomly assigned patients, 117 were eligible. Median overall survival (OS) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [hazard ratio (HR), 1.16; 95% CI, 0.76-1.77], respectively. Progression-free survival (PFS) was also similar (HR, 1.14; 95% CI, 0.78-1.66). KRAS, NRAS, and BRAF status using ctDNA was successfully examined in 109 patients, and mutations were identified in 19 patients (17.4%). Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations (P for interaction = 0.026 in OS and 0.054 in PFS). OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor-A (VEGF-A) levels and worse in those with low levels (P for interaction = 0.016). Second-line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.

Background While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy. Methods To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions. Results The study population consisted of 277 patients who had received a median of 10 doses (range, 1–79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77–4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF. Conclusions We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.

Background: In patients taking tamoxifen, the CYP2D6 genotype causes different exposure of active metabolite endoxifen. There is a high frequency of CYP2D6 decreased-function variant in Asian populations. Therefore, we prospectively evaluated whetherCYP2D6 genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact in the clinical outcome. Methods: In this randomized, open-label, multicenter, phase 2 study, patients who needed first-line tamoxifen therapy were enrolled in Japan. Based on individual CYP2D6 genotype, patients heterozygous (wt/V) or homozygous (V/V) for variant alleles of decreased or no-function were randomly assigned (1:1) to tamoxifen at increased dose (40 mg daily, ID arm) or regular dose (20 mg daily, RD arm), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was progression-free survival (PFS) rate at 6-month. The secondary endpoints included PFS and correlation of (Z)-endoxifen concentration with clinical outcomes. Findings: Between December 2012 and July 2016, 186 patients were enrolled. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6-month were not significantly different between ID and RD arms (67·6% vs. 66·7%). The serum trough concentrations of (Z)-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89·2 nM vs. 51·1 nM; P < 0.0001) and were also higher compared with wt/wt patients (72·0 nM; P = 0·0452). No significant difference in (Z)-endoxifen concentrations was observed between patients with and without progression at 6-month (p = 0·43). Interpretation: In patients with CYP2D6 variant alleles, increasing tamoxifen dosing did not achieve higher PFS rate at 6-month. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen. Clinical Trial Number: This study is registered with UMIN Clinical Trials Registry, number UMIN000009155. Funding Statement: This study was supported by grants from the Project for Development of Innovative Research on Cancer Therapeutics and from the Tailor-made Medical Treatment Program (BioBank Japan Project) funded by the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and the AMED under Grant Number 17ck0106191h0003). Declaration of Interests: YF reports grants from the Japan Agency for Medical Research and Development (AMED). MK reports grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT). KT reports grants from AstraZeneca and Daiichi-Sankyo outside the submitted work. CKI, MT, and YT report personal fees from AstraZeneca outside the submitted work. TT and JT report grants and personal fees from Daiichi-Sankyo outside the submitted work. SS reports grants and personal fees from AstraZeneca, and personal fees from Daiichi-Sankyo outside the submitted work. TY and YF report personal fees from AstraZeneca and Daiichi-Sankyo outside the submitted work. NTU reports grants from Daiichi-Sankyo outside the submitted work. YT reports personal fees from Meiji Seika Pharma outside the submitted work. All other authors declare no competing interests. Ethics Approval Statement: We obtained written informed consent from each patient before participation. The trial followed the ethical principles of the Declaration of Helsinki and Japanese Ethical Guidelines and Clinical Research. This study protocol and any amendments thereof were approved by an independent Ethics Committee or Institutional Review Board at each institution.

Background: Although tamoxifen (TAM) plus ovarian function suppression (OFS) is one of standard adjuvant treatments in premenopausal women with hormone receptor-positive breast cancer, the optimal duration of OFS has not been clearly established. Patients and Methods: We retrospectively reviewed data of premenopausal patients with breast cancer, who received TAM and OFS (goserelin or leuprorelin) as adjuvant therapy between February 2004 and April 2015. The primary analysis was to compare disease-free survival (DFS) between patients who received OFS shorter than 3 years and those who received OFS longer than 3 years. The analyses were performed with Cox proportional hazards models and propensity score matching models. Results: We analyzed 206 premenopausal patients with hormone receptor-positive breast cancer. Median follow-up time was 56 months. Median age was 42 years (range, 24-52 years). Twenty six per cent of the patients had positive axillary nodes and 30% had received neo-adjuvant or adjuvant chemotherapy. Median duration of OFS was 26 months. Duration of OFS was shorter than three years (OFS < 3y) in 74% patients, and longer than three years (OFS > 3y) in 26% patients. Patients with node-positive disease were more in OFS > 3y group than in OFS < 3y group, and more patients received chemotherapy in OFS > 3y group than in OFS < 3y group. 5-year disease-free survival (DFS) was 96.1%. DFS in patients aged ≤ 40 years and aged > 40 years were 91.8% and 99.0%, respectively (p=0.0223). Propensity score matching model showed that DFS was not significantly different between patients in OFS < 3y group and those in OFS > 3y group (97.4%, 91.6%; p=0.2406). In patients aged ≤ 40 years and/or those who received chemotherapy, 5-year DFS was 96.7% in OFS < 3y group, 90.1% in OFS > 3y group (p=0.3011). Conclusions: Our data suggest that OFS < 3y is not inferior to OFS > 3y for premenopausal women with hormone receptor-positive breast cancer as adjuvant endocrine therapy. A randomized trial is needed to establish the optimal OFS duration for these patients. Citation Format: Ozaki Y, Tamura N, Utiyama M, Masuda J, Koganemaru S, Miura Y, Tanabe Y, Ogura T, Kadowaki M, Miura D, Kawabata H, Takano T. Duration of ovarian function suppression for premenopausal women with hormone receptor-positive breast cancer: Retrospective study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-11.

Background: The standard treatment for estrogen receptor-positive, HER2-negative inoperable and/or recurrent breast cancers is a combination of endocrine therapy and a CDK4/6 inhibitor (abemaciclib). When abemaciclib is administered, 80%-90% of patients experience diarrhea, resulting in the reduction of patient QOL and compliance. Loperamide is recommended for abemaciclib-induced diarrhea as well as chemotherapy induced diarrhea. However, previous reports showed that approximately 40% patients had constipation due to supportive treatment of loperamide. Moreover, the side effects of molecular targeted drugs, including abemaciclib, are not clear in the mechanism, and the effectiveness of coping therapy similar to chemotherapy and the treatment for side effects have not been clearly established. Thus developing new measures to effectively manage abemaciclib-induced diarrhea is an important clinical task, especially prevention of diarrhea without increasing adverse events such as constipation will be important to maintain QOL of patients receiving abemaciclib. Trial Design: This is a multicenter, randomized, open-label Phase II study to evaluate the efficacy and safety of probiotics (bifidobacterial formulation) and trimebutine maleate in treatment of abemaciclib-induced diarrhea. Both Arms A and B will receive hormone therapies (selected by physician in charge*) as directed along with abemaciclib 150 mg bid over the course of 28 days, and simultaneously to initiation of abemaciclib administration, will be given two pills of Biofermin® tid in Both Arms. Once patients experience diarrhea that is grade 6 or greater on the Bristol scale (higher grade than loose stool), salvage therapy using loperamide will be administered in Arm A. In contrast, participants from Arm B will be administered 100 mg trimebutine maleate. Thereafter, following meals, trimebutine maleate tid will be given throughout the trial period of 28 days. Eligibility Criteria: Key eligibility criteria for this trial are: Histologically diagnosed estrogen receptor-positive, HER2-negative breast cancer. Stage IIIB/IIIC breast cancer that is not subjected to surgery for curative intent, Stage IV breast cancer suitable for endocrine therapy. No prior treatment with CDK 4/6 inhibitors, and any type and number of previous treatments will be allowed in the selection criteria except CDK4/6 inhibitors. Specific Aims: The primary endpoint is the percentage of patients who experienced Grade 2 or greater diarrhea during the trial duration of 28 days and key secondary endpoints include safety, frequency and duration of all-grade diarrhea, frequency of emesis and constipation, comparative usage of loperamide in Arms A and B, and QOL/PRO in the 28-day study duration Statistical Design: By using the 40% threshold as the null hypothesis, appropriate statistical analysis will be performed based on a binomial distribution. The significance level will be 2.5%, determined using a one-tailed test. Interval estimation will be appropriately deduced from a binomial distribution. If either arm shows a significant reduction compared with the threshold value, as secondary validation, intergroup comparison of the primary endpoint percentage of diarrhea onset will be performed. In this case, the significance level will be 10%, determined using a two-tailed test. Target Accrual: A total of 50 patients will be enrolled and duration of enrollment will be 1 year. This trial will open to accrual in September 2019. Contact Information: Hiroko Masuda, Showa University Hospital, Tokyo, Japan, hmasuda@med.showa-u.ac.jp Citation Format: Hiroko Masuda, Tsutomu Iwasa, Toru Mukohara, Shinya Tokunaga, Koji Matsumoto, Naoki Niikura, Yasuaki Sagara, Yasuo Miyoshi, Akihiko Shimomura, Masato Takahashi, Takeshi Nagashima, Mihoko Doi, Manabu Futamura, Kenichi Yoshimura, Toshimi Takano, Junji Tsurutani. Phase II study of trimebutine maleate and probiotics for abemaciclib-induced diarrhea in patients with ER-positive and HER2-negative advanced breast cancer (MERMAID) WJOG11318B [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 OT2-02-09.

Background It is important to control chemotherapy-induced nausea and vomiting (CINV) to maintain dose intensity and patients' quality of life. The National Comprehensive Cancer Network guidelines suggest combination therapy of antiemetic agents. The growing number of antiemetic regimens, and in particular the growing use of regimens containing antagonists to the Nk-1 receptor (NK1RAs) and the antipsychotic drug olanzapine (OLZ), call for the re-evaluation of the optimal regimen for CINV. This study assessed the efficacy and safety of antiemetic regimens for highly emetogenic chemotherapy, using Bayesian network meta-analysis. Methods Randomized trials that compared different antiemetic regimens were included. We strictly followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The main outcomes were the odds ratio (OR) for overall complete response (absence of vomiting). We conducted network meta-analysis within a Bayesian model to combine the direct and indirect evidence. Safety was assessed from the trial description. All statistical tests were two-sided. Results We systematically reviewed 27 randomized control trials (13,356 participants), which compared 12 different antiemetic regimens: serotonin-3 receptor antagonist (5HT3), 5HT3 + dexamethasone (Dex), palonosetron (PAL), PAL + Dex, PAL at 0.75 mg (PAL0.75), PAL0.75 + Dex, NK1RA + 5HT3 + Dex, NK1RA + PAL + Dex, an oral combination of netupitant and palonosetron (NEPA) + Dex, OLZ + 5HT3 + Dex, OLZ + PAL + Dex, and OLZ + NK1RA + 5HT3 + Dex. An NK1RA + 5HT3 + Dex regimen and an NK1RA + palonosetron + Dex regimen gave a higher complete response (CR) rate than the reference regimen, 5HT3 + Dex (OR, 1.75; 95% credibility interval [95% CrI], 1.56-1.97, and OR, 2.25; 95% CrI, 1.66-3.03, respectively). A regimen containing NEPA was more effective in producing CR than conventional regimens without NEPA or olanzapine. Further analysis, based on the surface under the cumulative ranking probability curve, indicated that olanzapine-containing regimens were the most effective in producing CR. Conclusion Our meta-analysis supports the conclusion that olanzapine-containing regimens are the most effective for CINV of highly emetogenic chemotherapy. We confirmed that NK1RA + PAL + Dex is the most effective of conventional regimens. Substituting olanzapine for an Nk-1 receptor antagonist may offer a less costly and more effective alternative for patients. Implications for practice Nausea and vomiting during chemotherapy often pose difficulties for patients and doctors, making it hard to continue the proper therapy and to maintain the quality of life. This article gives insights into the optimal choice of medicine to treat nausea during chemotherapy. The findings reported here provide readers with a robust efficacy ranking of antinausea medicine, which can be used as a reference for the best possible treatment. Furthermore, the 70% less costly drug, olanzapine, is suggested to be equally effective to aprepitant in reducing nausea and vomiting. The possibility of offering a cost-effective treatment to a wider range of the population is discussed.

Locally advanced non-small-cell lung cancer (NSCLC) is curable. Standard treatment is concurrent chemoradiotherapy, but its efficacy with cytotoxic agents seems to reach a plateau. Among patients with advanced NSCLC who have epidermal growth factor receptor (EGFR) mutation, EGFR-tyrosine kinase inhibitor is the key drug. Thus, a similar strategy should be tested in patients with locally advanced NSCLC who have EGFR mutation. This single arm, phase II study aims to explore the efficacy and tolerability of gefitinib with concurrent thoracic radiotherapy in patients with unresectable stage III NSCLC harboring EGFR mutations. The primary endpoint is progression-free survival rate at 2 years. The secondary endpoints are overall response rate, progression-free survival, overall survival, and safety. A total of 27 patients will be enrolled in this trial.

Background Regorafenib is a multi-kinase inhibitor, which was shown to be effective for patients with metastatic colorectal cancer refractory to standard therapies. However, its patterns of response has not yet been fully understood. Methods Clinical records of 10 patients who received regorafenib for evaluable colorectal liver metastases were reviewed. Response to chemotherapy was evaluated with the RECIST and morphologic response criteria, and its clinical relevance was analyzed. Results All patients received multiple lines of fluorouracil-based chemotherapy before regorafenib. The median follow-up duration after introduction of regorafenib was 4.9 months (range, 2 to 12.5 months). Median number of chemotherapy cycles was 2 (range, 1 to 15). In size-based response evaluation, 4 patients presented SD and 6 patients showed PD according to the RECIST. In non-size-based response evaluation, 3 patients were classified as optimal morphologic response and 7 patients were categorized as suboptimal morphologic response. Patients who presented optimal morphologic response showed significantly longer progression-free survival compared with those presented suboptimal response (median, 4.9 months vs. 0.7 months; P = 0.028), while size-based response evaluation could not well stratify patient prognosis. Conclusion Non-size-based CT morphologic response could be a potential alternative response marker for patients treated with regorafenib. Electronic supplementary material The online version of this article (10.1186/s12885-018-4067-5) contains supplementary material, which is available to authorized users.

Background Five-weekly S-1 plus cisplatin (SP5) is one of the standard first-line regimens for advanced gastric cancer (GC), proven in a Japanese phase III study. To enhance the dose intensity of cisplatin, 3-weekly S-1 plus cisplatin (SP3) was developed. Patients and methods This multicenter, randomized, open-label, phase III study evaluated whether SP3 (S-1 80 mg/m2/day on days 1–14 and cisplatin 60 mg/m2 on day 1) was noninferior/superior to SP5 (S-1 80–120 mg/day on days 1–21 and cisplatin 60 mg/m2 on day 1 or 8) in terms of progression-free survival (PFS). Chemotherapy-naive patients with metastatic, recurrent gastric or gastroesophageal junction adenocarcinoma were randomized 1 : 1 to receive either SP3 or SP5. The trial is registered at ClinicalTrials.gov (NCT00915382). Results Between February 2009 and January 2012, 625 patients were randomized at 42 sites in Korea and Japan. With a median follow-up duration of 32.4 months (range, 13.3–48.6 months) in surviving patients, SP3 was not only noninferior but also superior to SP5 in terms of PFS [median 5.5 versus 4.9 months; hazard ratio (HR) = 0.82; 95% confidence interval (CI) 0.68–0.99; P = 0.0418 for superiority). There was no difference in overall survival (OS) between the groups (median 14.1 versus 13.9 months; HR = 0.99; 95% CI 0.81–1.21; P = 0.9068). In patients with measurable disease, the response rates were 60% in the SP3 arm and 50% in the SP5 arm (P = 0.065). Both regimens were generally well tolerated, but grade 3 or higher anemia (19% versus 9%) and neutropenia (39% versus 9%) were more frequent in SP3. Conclusions SP3 is superior to SP5 in terms of PFS. However, since the improvement in PFS was only slight and there was no difference in OS, both SP3 and SP5 can be recommended as first-line treatments for patients with advanced GC.

Purpose Pegfilgrastim is a pegylated form of filgrastim, a recombinant protein of granulocyte colony-stimulating factor, that is used to reduce the risk of febrile neutropenia (FN). Here, we report the results of a phase III trial of pegfilgrastim in breast cancer patients receiving docetaxel and cyclophosphamide (TC) chemotherapy. Methods We conducted a double-blind, placebo-controlled, randomized trial to determine the efficacy of pegfilgrastim in reducing the risk of FN in early-stage breast cancer patients. A total of 351 women (177 in the pegfilgrastim group and 174 in the placebo group) between 20 and 69 years of age with stage I–III invasive breast carcinoma who were to receive TC chemotherapy (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) as either neoadjuvant or adjuvant therapy were enrolled; 346 of these patients were treated with either pegfilgrastim (n = 173) or placebo (n = 173). Results The incidence of FN was significantly lower in the pegfilgrastim group than in the placebo group (1.2 vs. 68.8 %, respectively; P

Background/aim Tolerability and safety of trastuzumab emtansine (T-DM1) was investigated in Japanese patients with HER2-positive advanced breast cancer who were previously treated with chemotherapy and trastuzumab. Patients and methods Patients with inoperable or recurrent breast cancer who were previously treated with chemotherapy and trastuzumab in adjuvant and/or metastatic disease were included. T-DM1 3.6 mg/kg was administered intravenously every 21 days. The administration dosage or schedule of T-DM1 was modified based on laboratory tests on the administration day. Results Among 232 patients analyzed, adverse events were reported in 228 patients (98.3%); five patients (2.2%) discontinued due to adverse events and twenty patients (8.6%) had serious adverse events. The most commonly reported grade ≥3 adverse event of special interest was thrombocytopenia (69 patients; 29.7%), followed by hepatotoxicity (26 patients; 11.2%). Conclusion T-DM1 was well tolerated in Japanese patients with HER2-positive advanced breast cancer and no new safety signals were observed.

Five-weekly S-1 plus cisplatin (SP) therapy is the standard care for advanced gastric or esophagogastric junction cancer (GC/EGJC) in East Asia. However, its efficacy and safety when combined with trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive advanced GC/EGJC remains unclear. Patients received 5-weekly SP therapy (S-1 at 40–60 mg twice daily for 21 days plus cisplatin at 60 mg/m2 on day 8, every 5 weeks) plus trastuzumab therapy (first dose of 8 mg/kg, then 6 mg/kg every 3 weeks). The primary end point was the response rate, and the secondary end points included progression-free survival, overall survival, safety, and serum biomarker levels. Forty-four patients were enrolled. The response rate, progression-free survival, and overall survival were 61% (95% confidence interval 46–76%), 5.9 months, and 16.5 months respectively. The commonest grade 3 or grade 4 adverse events were neutropenia (30%) and anorexia (25%). A significantly higher response rate (92% vs 43%; P = 0.008) and longer progression-free survival (median 14.5 months vs 4.2 months; P = 0.028) were observed in patients with high (n = 14) compared with low (n = 17) pretreatment serum neuregulin 1 levels. Five-weekly SP therapy combined with trastuzumab therapy showed a good antitumor response and acceptable toxicity in HER2-positive advanced GC/EGJC. Serum neuregulin 1 might be associated with the efficacy of this treatment regimen.

For metastatic breast cancer (MBC), many drugs including chemotherapy, endocrine therapy, and molecular-targeted therapy have been widely used, and there remain many clinical questions on optimal use of these agents. In patients with HER2-positive MBC, anti-HER2 agents such as trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine (T-DM1) are used, and trastuzumab + pertuzumab + taxane (HPT) for first-line treatment and T-DM1 for second-line treatment have been established as the standard of care by CLEOPATRA study and EMILIA study, respectively. New anti-HER2 agents such as neratinib, margetuximab, and anti-HER2 antibody-drug conjugates (ADC) are under development. In patients with HER2-negative, estrogen receptor (ER)-positive MBC, many molecular-targeted agents such as CDK4/6 inhibitors, mTOR inhibitors, PI3K inhibitors, Akt inhibitors, and HDAC inhibitors are studied in combination with endocrine therapy. Also in patients with triple negative breast cancer (TNBC), many promising agents are under development. Although TNBC is defined by the lack of expression of ER and HER2, from now on, we should not treat this subtype as "disease characterized by lack" but "disease characterized by gain". The third or more targets other than ER and HER2 have been suggested and many drugs designed to affect such targets have been studied. Immune checkpoint inhibitors and PARP inhibitors have been investigated mostly in TNBC. Among each subtype, several smaller subtypes have been identified and found to differentially respond to specific drugs. We must efficiently develop appropriate classification and treatment to establish "precision medicine". In this education lecture, I want to discuss current standard of care, perspectives of new drug development, and future direction of precision medicine.

e12022 Background: PCP is rare complication of ddAC-ddP. DEX is plausible risk factor for PCP. Dose and duration of DEX against CINV is changing over time as other anti-emetic drugs (5HT3 RA, NK1 RA, and olanzapin) became available. Then DEX usage varies widely in each hospitals. ASCO/IDSA guideline recommends preventive ST for patients receiving 20 mg or more predonisone equivalents daily for more than one month, although evidence is lacking in patients receiving ddAC-ddP. This study is to investigate relation between DEX usage, preventive ST, and risk of PCP for patients receiving ddAC-ddP. Methods: This study is preplanned analysis of WJOG9016B (UMIN000024992) which investigated relative dose intensity of ddAC-ddP supported by 3.6 mg (approved dose in Japan) of pegfilgrastim. Eligible pts were HER2 negative PBC with stage I to IIIc, going to start ddAC-ddP and younger than 65 y.o.. DEX usage and preventive ST usage were discrete to treating physicians. Results: From Jan. 2017 to Jan. 2018, 92 pts were registered and 91 pts were in the FAS set, because one patients turned out be ineligible after registration. All patients received DEX for prevention of delayed CINV. Median total dose of DEX during ddAC was 112 mg (range; 80 to 212 mg), which was equal to 13.3 mg (9.52 mg–24.76 mg) predonisone equivalents daily. Only five of them (5.4%) received more than 20 mg predonisone equivalents daily. Twenty patients received preventive ST. Three patients developed PCP. None of them with preventive ST developed PCP (0%), whereas three of patients without ST developed PCP (4.2%). These three patients received total DEX dose during ddAC at 80 mg, 112 mg, and 112 mg, respectively. Conclusions: ST was highly effective for PCP prevention for patients receiving ddAC-ddP, if DEX used against delayed CINV. Without ST prevention, the risk of PCP was 4.2 %, which was higher than threshold (3.5%) proposed in ASCO/ IDSA guidelines. The threshold of steroid dose leading to the risk of PCP might be lower than 20 mg or more predonisone equivalents daily in patients receiving ddAC-ddP. Clinical trial information: UMIN000024992.