Publications by authors named "Norikazu Masuda"

225 Publications

Palbociclib as an early-line treatment for Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: a review of clinical trial and real-world data.

Int J Clin Oncol 2021 Oct 26. Epub 2021 Oct 26.

Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Breast cancer is the most common type of cancer among women worldwide and in Japan. The majority of breast cancers are hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2‒), and endocrine therapy is an effective therapy for this type of breast cancer. However, recent substantial advances have been made in the management of HR+/HER2‒ advanced breast cancer (ABC) with the advent of targeted therapies, such as cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, resulting in significant improvements in survival outcomes versus endocrine therapy alone. To evaluate the optimal use of palbociclib, a CDK4/6 inhibitor, in HR+/HER2- ABC, this review summarizes clinical trial and real-world data for palbociclib. In addition, current biomarker studies in palbociclib clinical research are reviewed. In Japanese patients, palbociclib was shown to be effective with a manageable safety profile, although differences were observed in the frequency of adverse event and dosing parameters. Current evidence supporting palbociclib as a first-line treatment strategy for patients with HR+/HER2‒ ABC in Asia, and specifically japan, is also discussed.
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http://dx.doi.org/10.1007/s10147-021-02013-8DOI Listing
October 2021

A phase II study of sequential treatment with anthracycline and taxane followed by eribulin in patients with HER2-negative, locally advanced breast cancer (JBCRG-17).

Breast Cancer Res Treat 2021 Sep 23. Epub 2021 Sep 23.

Department of Surgery, Breast Oncology, NHO Osaka National Hospital, Osaka, Japan.

Purpose: The sequence of taxanes (T) followed by anthracyclines (A) as neoadjuvant chemotherapy has been the standard of care for almost 20 years for locally advanced breast cancer (LABC). Sequential administration of eribulin (E) following A/T could provide a greater response rate for women with LABC.

Methods: In this single-arm, multicenter, Phase II prospective study, the patients received 4 cycles of the FEC regimen and 4 cycles of taxane. After the A/T-regimen, 4 cycles of E were administered followed by surgical resection. The primary endpoint was the clinical response rate. Eligible patients were women aged 20 years or older, with histologically confirmed invasive breast cancer, clinical Stage IIIA (T2-3 and N2 only), Stage IIIB, and Stage IIIC, HER2-negative.

Results: A preplanned interim analysis aimed to validate the trial assumptions was conducted after treatment of 20 patients and demonstrated that clinical progressive disease rates in the E phase were significantly higher (30%) than assumed. Therefore, the Independent Data Monitoring Committee recommended stopping the study. Finally, 53 patients were enrolled, and 26 patients received the A/T/E-regimen. The overall observed clinical response rate (RR) was 73% (19/26); RRs were 77% (20/26) in the AT phase and 23% (6/26) in the E phase. Thirty percent (8/26) of patients had PD in the E phase, 6 of whom had achieved cCR/PR in the AT phase. Reported grade ≥ 3 AEs related to E were neutropenia (42%), white blood cell count decrease (27%), febrile neutropenia (7.6%), weight gain (3.8%), and weight loss (3.8%).

Conclusion: Sequential administration of eribulin after the A/T-regimen provided no additional effect for LABC patients. Future research should continue to focus on identifying specific molecular biomarkers that can improve response rates.
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http://dx.doi.org/10.1007/s10549-021-06396-0DOI Listing
September 2021

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens.

Breast Cancer Res Treat 2021 Oct 23;189(3):665-676. Epub 2021 Sep 23.

Division of Breast Oncology and Surgery, Kaohsiung Medical University Chung-Ho Memorial Hospital, No.100, Tzyou 1st Road, Kaohsiung, 807, Taiwan.

Purpose: Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein.

Methods: 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m bid, day 1-14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m bid, day 1-14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety.

Results: 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity.

Conclusion: Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted.

Clinical Trial Registration: NCT01808573.
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http://dx.doi.org/10.1007/s10549-021-06313-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505315PMC
October 2021

Capecitabine in Combination with Endocrine Therapy as Maintenance Therapy after Bevacizumab Plus Paclitaxel Induction Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: KBCSG-TR1214.

Cancers (Basel) 2021 Aug 31;13(17). Epub 2021 Aug 31.

Department of Breast and Endocrine Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka-shi 541-8567, Osaka, Japan.

Optimal treatment strategies for hormone receptor (HR)-positive, HER2-negative advanced and/or metastatic breast cancer (AMBC) remain uncertain. We investigated the clinical usefulness of adding capecitabine to maintenance endocrine therapy after induction chemotherapy and the efficacy of reinduction chemotherapy. Patients who had received bevacizumab-paclitaxel induction therapy and did not have progressive disease (PD) were randomized to maintenance therapy with endocrine therapy alone (group E) or endocrine plus capecitabine (1657 mg/m/day on days 1-21, q4w) (group EC). In case of PD after maintenance therapy, patients received bevacizumab-paclitaxel reinduction therapy. Ninety patients were randomized. The median progression-free survival (PFS) under maintenance therapy (primary endpoint) was significantly longer in group EC (11.1 {95% CI, 8.0-11.8} months) than in group E (4.3 {3.6-6.0} months) (hazard ratio, 0.53; < 0.01). At 24 months from the induction therapy start, the overall survival (OS) was significantly longer in group EC than in group E (hazard ratio, 0.41; = 0.046). No difference was found in the time to failure of strategy (13.9 and 16.6 months in groups E and EC, respectively). Increased capecitabine-associated toxicities in group EC were tolerable. Addition of capecitabine to maintenance endocrine therapy may be a beneficial option after induction chemotherapy for HR-positive, HER2-negative AMBC patients.
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http://dx.doi.org/10.3390/cancers13174399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430728PMC
August 2021

Long-Term Outcomes of a Randomized Study of Neoadjuvant Induction Dual HER2 Blockade with Trastuzumab and Lapatinib Followed by Weekly Paclitaxel Plus Dual HER2 Blockade for HER2-Positive Primary Breast Cancer (Neo-Lath Study).

Cancers (Basel) 2021 Aug 9;13(16). Epub 2021 Aug 9.

Breast Cancer Unit, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin Sakyo-ku, Kyoto-shi 606-8507, Kyoto, Japan.

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 ( = 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%; = 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.
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http://dx.doi.org/10.3390/cancers13164008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394774PMC
August 2021

MONARCH 2: Subgroup Analysis of Patients Receiving Abemaciclib Plus Fulvestrant as First-Line and Second-Line Therapy for HR, HER2-Advanced Breast Cancer.

Clin Cancer Res 2021 Aug 10. Epub 2021 Aug 10.

Stanford University School of Medicine, Stanford, California.

Purpose: In MONARCH 2, abemaciclib plus fulvestrant significantly prolonged progression-free survival (PFS) and overall survival (OS) versus placebo plus fulvestrant in patients with hormone receptor positive (HR), HER2 advanced breast cancer. This exploratory analysis assessed the efficacy of abemaciclib plus fulvestrant across subgroups of patients receiving study therapy as first- or second-line treatment for metastatic disease.

Patients And Methods: Improvements were estimated using Cox models, and a test of interactions of subgroups with treatment was performed.

Results: The benefit in PFS [first-line, HR, 0.57; 95% confidence interval (CI), 0.45-0.73; second-line, HR, 0.48; 95% CI, 0.36-0.64] and OS (first-line, HR, 0.85; 95% CI, 0.64-1.14; second-line, HR, 0.66; 95% CI, 0.46-0.94) was observed across both subgroups, consistent with the intent-to-treat (ITT) population. In first-line patients (abemaciclib arm, = 265; placebo arm, = 133), the numerically largest effect on PFS and OS was observed in patients with primary resistance to endocrine therapy (ET; PFS, HR, 0.40; 95% CI, 0.26-0.63; OS, HR, 0.58; 95% CI, 0.35-0.97) and visceral disease (PFS, HR, 0.54; 95% CI, 0.39-0.73; OS, HR, 0.82; 95% CI, 0.58-1.20). In second-line patients (abemaciclib arm, = 170; placebo arm, = 86), a numerical benefit in PFS and OS was observed across primary and secondary ET resistance, with numerically more pronounced effects observed in patients with visceral disease (PFS, HR, 0.39; 95% CI, 0.27-0.57; OS, HR, 0.51; 95% CI, 0.33-0.81). Prolongation of time to second disease progression, time to chemotherapy, and chemotherapy-free survival was observed in both subgroups.

Conclusions: Consistent with the ITT population, a benefit in PFS and OS was observed across the first- and second-line subgroups in MONARCH 2.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4685DOI Listing
August 2021

Real-world effectiveness of post-trastuzumab emtansine treatment in patients with HER2-positive, unresectable and/or metastatic breast cancer: a retrospective observational study (KBCSG-TR 1917).

BMC Cancer 2021 Jul 9;21(1):795. Epub 2021 Jul 9.

Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan.

Background: Trastuzumab emtansine (T-DM1) is a second-line standard therapy for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Evidence regarding post-T-DM1 treatments is currently lacking. We evaluated the effectiveness of post-T-DM1 drug therapy in patients with HER2-positive, unresectable and/or metastatic breast cancer.

Methods: In this multicenter, retrospective, observational study, real-world clinical data of female patients with HER2-positive breast cancer who had a history of T-DM1 treatment were consecutively collected from five sites in Japan. We investigated the effectiveness of post-T-DM1 therapy by evaluating the real-world progression-free survival (rwPFS), time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Tumor response was assessed by investigators according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) guidelines. Subgroup and exploratory analyses according to background factors were also undertaken.

Results: Of the 205 patients who received T-DM1 treatment between 1 January 2014 and 31 December 2018, 128 were included in this study. Among the 128 patients analyzed, 105 (82%) patients received anti-HER2 therapy and 23 (18%) patients received regimens without anti-HER2 therapy. Median (95% confidence interval [CI]) rwPFS, TTF, and OS were 5.7 (4.8-6.9) months, 5.6 (4.6-6.4) months, and 22.8 (18.2-32.4) months, respectively. CBR and ORR (95% CI) were 48% (38.8-56.7) and 23% (15.1-31.4), respectively. Cox-regression analysis showed that an ECOG PS score of 0, a HER2 immunohistochemistry score of 3+, recurrent type, ≥12 month duration of T-DM1 therapy, and anti-HER2 therapy were independent variables for rwPFS. An exploratory subgroup analysis of regimens after T-DM1 showed that those with anti-HER2 therapy had a median rwPFS of 6.3 and those without anti-HER2 therapy had a median rwPFS of 4.8 months.

Conclusions: In the real-world setting in Japan, several post-T-DM1 regimens for patients with unresectable and/or metastatic HER2-positive breast cancer, including continuation of anti-HER2 therapy, showed some effectiveness; however, this effectiveness was insufficient. Novel therapeutic options are still needed for further improvement of PFS and OS in later treatment settings.

Trial Registration: UMIN000038296 ; registered on 15 October 2019.
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http://dx.doi.org/10.1186/s12885-021-08504-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268506PMC
July 2021

Clinical usefulness of eribulin as first- or second-line chemotherapy for recurrent HER2-negative breast cancer: a randomized phase II study (JBCRG-19).

Int J Clin Oncol 2021 Jul 23;26(7):1229-1236. Epub 2021 Apr 23.

Breast Oncology Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: Anthracycline (A) or taxane T-based regimens are the standard early-line chemotherapy for metastatic breast cancer (BC). A previous study has shown a survival benefit of eribulin in heavily pretreated advanced/recurrent BC patients. The present study aimed to compare the benefit of eribulin with treatment of physician's choice (TPC) as first- or second-line chemotherapy for recurrent HER2-negative BC.

Methods: Patients with recurrent HER2-negative BC previously receiving anthracycline and taxane AT-based chemotherapy in the adjuvant or first-line setting were eligible for this open-label, randomized, parallel-group study. Patients were randomized 1:1 by the minimization method to receive either eribulin (1.4 mg/m on day one and eight of each 21-day cycle) or TPC (paclitaxel, docetaxel, nab-paclitaxel or vinorelbine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure (TTF), overall response rate (ORR), duration of response, and safety (UMIN000009886).

Results: Between May 2013 and January 2017, 58 patients were randomized, 57 of whom (26 eribulin and 31 TPC) were analyzed for efficacy. The median PFS was 6.6 months with eribulin versus 4.2 months with TPC (hazard ratio: 0.72 [95% confidence interval (CI), 0.40-1.30], p = 0.276). Median TTF was 6.0 months with eribulin versus 3.6 months with TPC (hazard ratio: 0.66 [95% CI, 0.39-1.14], p = 0.136). Other endpoints were also similar between groups. The most common grade ≥ 3 adverse event was neutropenia (22.2% with eribulin versus 16.1% with TPC).

Conclusions: Eribulin seemed to improve PFS or TTF compared with TPC without statistical significance. Further validation studies are needed.
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http://dx.doi.org/10.1007/s10147-021-01920-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213561PMC
July 2021

In Reply.

Oncologist 2021 07 19;26(7):e1286-e1287. Epub 2021 Apr 19.

Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1002/onco.13782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265353PMC
July 2021

Meta-analysis of nanoparticle albumin-bound paclitaxel used as neoadjuvant chemotherapy for operable breast cancer based on individual patient data (JBCRG-S01 study).

Breast Cancer 2021 Sep 3;28(5):1023-1037. Epub 2021 Apr 3.

Breast Oncology Center, Cancer Institute Hospital, Tokyo, 135-0063, Japan.

Background: Nanoparticle albumin-bound paclitaxel (nab-PTX), a novel taxane formulation, was developed to avoid cremophor/ethanol-associated toxicities including peripheral neuropathy and hypersensitivity. At least 35 phase II studies using combined nab-PTX and anthracycline in neoadjuvant settings are registered in Japan. We analyzed the efficacy and safety of nab-PTX based on patient characteristics in these studies.

Methods: We conducted a meta-analysis using individual patient data (IPD) to investigate the average efficacy of nab-PTX-containing regimens as neoadjuvant chemotherapy for operable breast cancer. IPD were provided by principal investigators who agreed to participate. The primary endpoint was pathological complete response (pCR) rate of each breast cancer subtype.

Results: We analyzed the data of 16 studies involving 753 patients. The overall crude frequencies of pCR (ypT0 ypN0, ypT0/is ypN0, and ypT0/is ypNX) were 18.1, 26.0, and 28.6%, respectively. Specifically, the frequencies were 6.7, 10.2, and 13.4% for luminal (n = 343); 40.5, 63.5, and 68.9% for human epidermal growth factor receptor 2 (HER2)-rich, (n = 74); 21.9, 40.6, and 42.7% for luminal/HER2 (n = 96); and 26.3, 31.5, and 32.3% for triple-negative breast cancers (TNBC) (n = 232). The multivariate analyses indicated that HER2 positivity, TNBC, high Ki-67, high nuclear grade, and weekly nab-PTX administration were significantly associated with the pCR. The proportion of hematological toxicities (neutropenia (39.7%) and leukopenia (22.5%)), peripheral sensory neuropathy (9.7%), myalgia (5.7%), and arthralgia (4.7%) was higher than grade 3 adverse events, but most patients recovered.

Conclusions: Nab-PTX is a safe and acceptable chemotherapeutic agent in neoadjuvant settings, particularly for aggressive cancers. UMIN-CTR#: UMIN000028774.
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http://dx.doi.org/10.1007/s12282-021-01238-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354972PMC
September 2021

Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy.

Breast Cancer 2021 Sep 1;28(5):1038-1050. Epub 2021 Apr 1.

Breast Cancer Unit, Breast Surgery, Graduate School of Medicine, Kyoto University Hospital, Kyoto University, 54 Shogoin-Kawaracho, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC).

Methods: Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety.

Results: In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380-1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390-1.463).

Conclusions: Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population.

Clinical Trial Registration: NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703 .
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http://dx.doi.org/10.1007/s12282-021-01239-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8354907PMC
September 2021

Patient-Reported Outcomes in Patients With -Mutated Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer From SOLAR-1.

J Clin Oncol 2021 Jun 29;39(18):2005-2015. Epub 2021 Mar 29.

Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France.

Purpose: In the phase III SOLAR-1 trial (NCT02437318), the PI3Kα-selective inhibitor and degrader alpelisib significantly improved median progression-free survival when added to fulvestrant in patients with phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ()-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. We assessed health-related quality of life using patient-reported outcome measures in these patients.

Materials And Methods: In the -mutant cohort, 341 patients were randomly assigned 1:1 to receive alpelisib 300 mg daily or placebo plus fulvestrant 500 mg on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Patient-reported outcomes were evaluated with the European Organisation for Research and Treatment of Cancer QoL of Cancer Patients and Brief Pain Inventory-Short Form questionnaires. Changes from baseline and time to 10% deterioration were analyzed using repeated measurement models and Cox models, respectively.

Results: Global Health Status/QoL and functional status were maintained from baseline (mean changes < 10 points) in the alpelisib (overall change from baseline [95% CI], -3.50 [-8.02 to 1.02]) and placebo arms (overall change from baseline [95% CI], 0.27 [-4.48 to 5.02]). Overall treatment effect in Global Health Status/QoL was not significantly different between arms (-3.77; 95% CI, -8.35 to 0.80; = .101). Time to 10% deterioration for Global Health Status/QoL was similar between arms (hazard ratio, 1.03; 95% CI, 0.72 to 1.48). Compared with placebo, deterioration in social functioning and in diarrhea, appetite loss, nausea or vomiting, and fatigue symptom subscales occurred with alpelisib. Numerical improvement in Worst Pain was observed with alpelisib versus placebo (42% 32%, week 24; = .090).

Conclusion: In SOLAR-1, there was no statistical difference in deterioration of Global Health Status/QoL between arms, whereas symptom subscales favored placebo for diarrhea, appetite loss, nausea or vomiting, and fatigue, known side effects of alpelisib. Treatment decisions must consider efficacy and tolerability; taken with clinical efficacy, these results support the benefit-risk profile of alpelisib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative -mutated advanced breast cancer.
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http://dx.doi.org/10.1200/JCO.20.01139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210974PMC
June 2021

Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial.

Breast Cancer Res Treat 2021 Jul 25;188(1):117-131. Epub 2021 Mar 25.

Breast Cancer Unit, Kyoto University Hospital, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Purpose: To investigate clinical usefulness of eribulin-based neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) patients.

Methods: Patients in group A (aged < 65 years with homologous recombination deficiency, HRD, score ≥ 42, or those at any age with germline BRCA mutation, gBRCAm) were randomized to 4 cycles of paclitaxel plus carboplatin (group A1) or eribulin plus carboplatin (group A2), followed by 4 cycles of anthracycline. Patients in group B (aged < 65 years with HRD score < 42, or aged ≥ 65 years without gBRCAm) were randomized to 6 cycles of eribulin plus cyclophosphamide (group B1) or eribulin plus capecitabine (group B2); non-responders to the first 4 cycles of the eribulin-based therapy received anthracycline. Primary endpoint was pCR rate (ypT0-is, ypN0; centrally confirmed). Main secondary endpoint was safety.

Results: The full analysis set comprised 99 patients. The pCR rate was 65% (90% CI, 46%-81%) and 45% (27%-65%) in groups A1 and A2, respectively, and 19% (8%-35%) in both groups B1 and B2. No major difference was seen in secondary endpoints, but peripheral neuropathy incidence was 74% in group A1, whereas it was 32%, 22%, and 26% in groups A2, B1, and B2, respectively.

Conclusions: In patients aged < 65 years with high HRD score or gBRCAm, weekly paclitaxel plus carboplatin and eribulin plus carboplatin followed by anthracycline resulted in a pCR rate of > 60% and > 40%, respectively, suggesting potential usefulness of patient stratification using HRD; pCR tended to be low in patients with HRD-negative tumors. Neurotoxicity was less frequent with the eribulin-based regimen.

Trial Registration: The study has been registered with the University Hospital Medical Information Network Clinical Trials Registry ( http://www.umin.ac.jp/ctr/index-j.htm ) with unique trial number UMIN000023162. The Japan Breast Cancer Research Group trial number is JBCRG-22.
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http://dx.doi.org/10.1007/s10549-021-06184-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233289PMC
July 2021

Abemaciclib in combination with endocrine therapy for East Asian patients with HR+, HER2- advanced breast cancer: MONARCH 2 & 3 trials.

Cancer Sci 2021 Jun 1;112(6):2381-2392. Epub 2021 May 1.

Stanford University, Stanford, CA, USA.

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double-blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression-free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P < .001; median: 21.2 vs 11.6 months) and MONARCH 3 (HR, 0.326; 95% CI, 0.200 to 0.531, P < .001; median: not reached vs 12.82 months). Diarrhea (MONARCH 2: 90%; MONARCH 3: 88%) and neutropenia (MONARCH 2: 68%; MONARCH 3: 58%) were the most frequent adverse events observed in the East Asian populations. Abemaciclib exposures and PK were similar in East Asians and the non-East Asian populations of both trials. Abemaciclib in combination with ET in the East Asian populations of MONARCH 2 and MONARCH 3 provided consistent results with the ITT populations, demonstrating improvements in efficacy with generally tolerable safety profiles for patients with HR+, HER2- advanced breast cancer.
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http://dx.doi.org/10.1111/cas.14877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177785PMC
June 2021

Clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with ductal carcinoma in situ (DCIS): a multi-institutional retrospective cohort study.

Breast Cancer 2021 Jul 18;28(4):896-903. Epub 2021 Feb 18.

Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.

Background: We conducted a prospective study with the intention to omit surgery for patients with ductal carcinoma in situ (DCIS) of the breast. We aimed to identify clinicopathological predictors of postoperative upstaging to invasive ductal carcinoma (IDC) in patients preoperatively diagnosed with DCIS.

Patients And Methods: We retrospectively analyzed patients with DCIS diagnosed through biopsy between April 1, 2010 and December 31, 2014, from 16 institutions. Clinical, radiological, and histological variables were collected from medical records.

Results: We identified 2,293 patients diagnosed with DCIS through biopsy, including 1,663 DCIS (72.5%) cases and 630 IDC (27.5%) cases. In multivariate analysis, the presence of a palpable mass (odds ratio [OR] 1.8; 95% confidence interval [CI] 1.2-2.6), mammography findings (≥ category 4; OR 1.8; 95% CI 1.2-2.6), mass formations on ultrasonography (OR 1.8; 95% CI 1.2-2.5), and tumor size on MRI (> 20 mm; OR 1.7; 95% CI 1.2-2.4) were independent predictors of IDC. Among patients with a tumor size on MRI of ≤ 20 mm, the possibility of postoperative upstaging to IDC was 22.1%. Among the 258 patients with non-palpable mass, nuclear grade 1/2, and positive for estrogen receptor, the possibility was 18.1%, even if the upper limit of the tumor size on MRI was raised to ≤ 40 mm.

Conclusion: We identified four independent predictive factors of upstaging to IDC after surgery among patients with DCIS diagnosed by biopsy. The combined use of various predictors of IDC reduces the possibility of postoperative upstaging to IDC, even if the tumor size on MRI is larger than 20 mm.
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http://dx.doi.org/10.1007/s12282-021-01225-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213581PMC
July 2021

Adjuvant S-1 plus endocrine therapy for oestrogen receptor-positive, HER2-negative, primary breast cancer: a multicentre, open-label, randomised, controlled, phase 3 trial.

Lancet Oncol 2021 01;22(1):74-84

Cancer Institute Hospital, Tokyo, Japan.

Background: Oral fluoropyrimidines, such as S-1, have been shown to have a role in controlling disease progression in metastatic breast cancer. We examined adjuvant treatment with S-1 in patients with oestrogen receptor (ER)-positive and HER2-negative primary breast cancer.

Methods: We did a multicentre, open-label, randomised, controlled, phase 3 trial in 139 sites (137 hospitals and two clinics). Eligible patients were women aged 20-75 years with histologically diagnosed stage I to IIIB invasive breast cancer (intermediate to high risk of recurrence). Patients were temporarily registered at participating institutions and biopsy or surgical samples were collected and sent for central pathological assessment. Patients received 5 years of standard adjuvant endocrine therapy (selective oestrogen receptor modulators with or without ovarian suppression and aromatase inhibitors) with or without 1 year of S-1. Oral S-1 80-120 mg/day was administered twice a day for 14 days with 7 days off. Randomisation (1:1) using the minimisation method was done with six stratification factors (age, axillary lymph node metastasis at surgery or sentinel lymph node biopsy, preoperative or postoperative (neoadjuvant or adjuvant) chemotherapy, preoperative endocrine therapy, proportion of ER-positive cells, and study site). The primary endpoint was invasive disease-free survival, in the full analysis set (all randomly assigned patients, excluding those with significant protocol deviations). The safety analysis set consisted of all patients who received at least one dose of study treatment. Here, we report the results from the interim analysis at the data cutoff date Jan 31, 2019. This trial is registered with Japan Registry of Clinical Trials, jRCTs051180057, and the University hospital Medical Information Network, UMIN000003969.

Findings: Between Feb 1, 2012, and Feb 1, 2016, 1930 patients were enrolled in the full analysis set, 957 (50%) received endocrine therapy plus S-1 and 973 (50%) received endocrine therapy alone. Median follow-up was 52·2 months (IQR 42·1-58·9). 155 (16%) patients in the endocrine therapy alone group and in 101 (11%) patients in the endocrine therapy plus S-1 group had invasive disease-free survival events (hazard ratio 0·63, 95% CI 0·49-0·81, p=0·0003). As the primary endpoint was met at interim analysis, the trial was terminated early. The most common grade 3 or worse adverse events were decreased neutrophil count (72 [8%] of 954 patients in the endocrine therapy plus S-1 group vs seven [1%] of 970 patients in the endocrine therapy alone group), diarrhoea (18 [2%] vs none), decreased white blood cells (15 [2%] vs two [<1%]), and fatigue (six [<1%] vs none). Serious adverse events were reported in nine (1%) of 970 patients in the endocrine therapy alone group and 25 (3%) of 954 patients in the endocrine therapy plus S-1 group. There was one (<1%) possible treatment-related death in the endocrine therapy plus S-1 group due to suspected pulmonary artery thrombosis.

Interpretation: These data suggest that this combination of S-1 with endocrine therapy could be a potential treatment option for this intermediate and high-risk group of patients with ER-positive, HER2-negative primary breast cancer.

Funding: Public Health Research Foundation (Japan), Taiho Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(20)30534-9DOI Listing
January 2021

[Ⅰ.Capecitabine for Adjuvant Therapy in Breast Cancer].

Authors:
Norikazu Masuda

Gan To Kagaku Ryoho 2020 Dec;47(12):1673-1677

Dept. of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital.

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December 2020

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial.

Lancet 2020 12;396(10265):1817-1828

Barts Cancer Institute, Centre for Experimental Cancer Medicine and Queen Mary University of London, London, UK.

Background: Pembrolizumab monotherapy showed durable antitumour activity and manageable safety in patients with metastatic triple-negative breast cancer. We aimed to examine whether the addition of pembrolizumab would enhance the antitumour activity of chemotherapy in patients with metastatic triple-negative breast cancer.

Methods: In this randomised, placebo-controlled, double-blind, phase 3 trial, done in 209 sites in 29 countries, we randomly assigned patients 2:1 with untreated locally recurrent inoperable or metastatic triple-negative breast cancer using a block method (block size of six) and an interactive voice-response system with integrated web-response to pembrolizumab (200 mg) every 3 weeks plus chemotherapy (nab-paclitaxel; paclitaxel; or gemcitabine plus carboplatin) or placebo plus chemotherapy. Randomisation was stratified by type of on-study chemotherapy (taxane or gemcitabine-carboplatin), PD-L1 expression at baseline (combined positive score [CPS] ≥1 or <1), and previous treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting (yes or no). Eligibility criteria included age at least 18 years, centrally confirmed triple-negative breast cancer; at least one measurable lesion; provision of a newly obtained tumour sample for determination of triple-negative breast cancer status and PD-L1 status by immunohistochemistry at a central laboratory; an Eastern Cooperative Oncology Group performance status score 0 or 1; and adequate organ function. The sponsor, investigators, other study site staff (except for the unmasked pharmacist), and patients were masked to pembrolizumab versus saline placebo administration. In addition, the sponsor, the investigators, other study site staff, and patients were masked to patient-level tumour PD-L1 biomarker results. Dual primary efficacy endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS of 10 or more, CPS of 1 or more, and intention-to-treat populations. The definitive assessment of progression-free survival was done at this interim analysis; follow-up to assess overall survival is continuing. For progression-free survival, a hierarchical testing strategy was used, such that testing was done first in patients with CPS of 10 or more (prespecified statistical criterion was α=0·00411 at this interim analysis), then in patients with CPS of 1 or more (α=0·00111 at this interim analysis, with partial alpha from progression-free survival in patients with CPS of 10 or more passed over), and finally in the intention-to-treat population (α=0·00111 at this interim analysis). This study is registered with ClinicalTrials.gov, NCT02819518, and is ongoing.

Findings: Between Jan 9, 2017, and June 12, 2018, of 1372 patients screened, 847 were randomly assigned to treatment, with 566 patients in the pembrolizumab-chemotherapy group and 281 patients in the placebo-chemotherapy group. At the second interim analysis (data cutoff, Dec 11, 2019), median follow-up was 25·9 months (IQR 22·8-29·9) in the pembrolizumab-chemotherapy group and 26·3 months (22·7-29·7) in the placebo-chemotherapy group. Among patients with CPS of 10 or more, median progression-free survival was 9·7 months with pembrolizumab-chemotherapy and 5·6 months with placebo-chemotherapy (hazard ratio [HR] for progression or death, 0·65, 95% CI 0·49-0·86; one-sided p=0·0012 [primary objective met]). Median progression-free survival was 7·6 and 5·6 months (HR, 0·74, 0·61-0·90; one-sided p=0·0014 [not significant]) among patients with CPS of 1 or more and 7·5 and 5·6 months (HR, 0·82, 0·69-0·97 [not tested]) among the intention-to-treat population. The pembrolizumab treatment effect increased with PD-L1 enrichment. Grade 3-5 treatment-related adverse event rates were 68% in the pembrolizumab-chemotherapy group and 67% in the placebo-chemotherapy group, including death in <1% in the pembrolizumab-chemotherapy group and 0% in the placebo-chemotherapy group.

Interpretation: Pembrolizumab-chemotherapy showed a significant and clinically meaningful improvement in progression-free survival versus placebo-chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer.

Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
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http://dx.doi.org/10.1016/S0140-6736(20)32531-9DOI Listing
December 2020

Relationships between pathological factors and long-term outcomes in patients enrolled in two prospective randomized controlled trials comparing the efficacy of oral tegafur-uracil with CMF (N·SAS-BC 01 trial and CUBC trial).

Breast Cancer Res Treat 2021 Feb 1;186(1):135-147. Epub 2020 Dec 1.

Chuo University, Tokyo, Japan.

Purpose: To evaluate the efficacies of cyclophosphamide, methotrexate, and fluorouracil (CMF) and tegafur-uracil (UFT) as adjuvant therapy in patients with resected stage I-IIIA breast cancer by immunohistochemistry (IHC)-based subtype and to determine the relationships between clinicopathological factors and long-term outcomes.

Methods: A pooled analysis of the randomized controlled N·SAS-BC 01 and CUBC studies was conducted. Expression of hormone receptors (HRs; estrogen and progesterone receptors), human epidermal growth factor receptor 2 (HER2), and Ki67were assessed by IHC. Tumor-infiltrating lymphocytes (TILs) and nuclear/histological grades were determined by hematoxylin and eosin staining. Relapse-free survival (RFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and hazard ratios were determined by Cox model adjusted for baseline tumor size and nodal status.

Results: A total of 689 patients (342 CMF and 347 UFT) were included in the analyses with a median follow-up of 11.1 years. There was no significant difference in RFS or OS between the two cohorts (RFS: 0.96 [95% confidence interval: 0.71-1.30], log-rank test p = 0.80; OS: 0.93 [0.64-1.35], p = 0.70). There was no difference in RFS or OS between the two cohorts for HR+/HER2- and HR+/HER2+ subtypes. RFS was significantly longer in patients treated with UFT compared with CMF in patients with HR-/HER2+ subtype (0.30 [0.10-0.88], p = 0.03). A high TILs level was associated with a better OS compared with low TILs level (p = 0.02).

Conclusions: This long-term follow-up study showed that RFS and OS were similar in patients with luminal-type breast cancer treated with CMF and UFT.
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http://dx.doi.org/10.1007/s10549-020-06018-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940338PMC
February 2021

Rechallenge of anti-PD-1/PD-L1 antibody showed a good response to metastatic breast cancer: a case report.

Immunotherapy 2021 02 23;13(3):189-194. Epub 2020 Nov 23.

Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka 5400006, Japan.

Rechallenge of immune checkpoint inhibitors has been reported for neoplasms other than breast cancer. Reported here is a case of a 55-year old woman diagnosed as having triple-negative right breast cancer with multiple metastases including lung. Atezolizumab and nab-paclitaxel were administered followed by epirubicin-cyclophosphamide. With subsequent eribulin, the overall best response was progressive disease, and curative surgical resection was performed. Three months after surgery (1.5 years after initial response of lung metastasis), right lung metastasis emerged at a site different from baseline. Based on the microsatellite instability-high status, pembrolizumab was administered and showed a good response. The patient has been treated with pembrolizumab, maintaining partial response, for over 9 months, which suggests the benefit of immune checkpoint inhibitors rechallenge in breast cancer.
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http://dx.doi.org/10.2217/imt-2020-0242DOI Listing
February 2021

Overnight fasting before lapatinib administration to breast cancer patients leads to reduced toxicity compared with nighttime dosing: a retrospective cohort study from a randomized clinical trial.

Cancer Med 2020 12 23;9(24):9246-9255. Epub 2020 Oct 23.

Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

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/<0.6) were in the BB group (BB 13% / 0%, BM 22% / 3.9%, AB 24% / 14%, p = 0.70 / 0.11). pCR was not diminished (p = 0.75). BB group had the lowest serum lapatinib concentration and variability (mean ±SD were 0.35 ± 0.15, 0.65 ± 0.32, 0.96 ± 0.43 µg/ml).

Conclusions: Compared to bedtime administration, lapatinib administration after overnight fasting reduces its toxicity without diminishing its therapeutic efficacy.
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http://dx.doi.org/10.1002/cam4.3528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774723PMC
December 2020

Analysis of subsequent therapy in Japanese patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer who received palbociclib plus endocrine therapy in PALOMA-2 and -3.

Breast Cancer 2021 Mar 21;28(2):335-345. Epub 2020 Oct 21.

Kyoto University Graduate School of Medicine, 54, Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

Background: In the double-blind, phase 3 PALOMA-2 and PALOMA-3 studies, palbociclib plus endocrine therapy (ET) demonstrated significant improvement in progression-free survival versus placebo plus ET in patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative advanced breast cancer. This analysis assessed subsequent treatment patterns after palbociclib therapy in Japanese patients enrolled in the PALOMA-2 and PALOMA-3 studies.

Methods: PALOMA-2 included postmenopausal women who had not received prior systemic therapy for advanced disease. PALOMA-3 included pre- or postmenopausal women who had progressed on previous ET. Types of subsequent therapy were assessed, and treatment durations of subsequent therapy were estimated using the Kaplan-Meier method.

Results: Japanese patients were enrolled in PALOMA-2 (n = 46) and PALOMA-3 (n = 35). In both studies, the most common first subsequent therapy was ET (PALOMA-2, 77% in the palbociclib group and 75% in the placebo group; PALOMA-3, 55% and 43%, respectively), followed by chemotherapy (PALOMA-2, 18% and 8%; PALOMA-3, 32% and 57%). The median (95% CI) duration of first subsequent therapy was 6.4 (2.3‒13.9) months with palbociclib plus letrozole and 6.7 (2.8‒13.0) months with placebo plus letrozole in PALOMA-2 and 3.8 (2.4‒5.7) months with palbociclib plus fulvestrant and 9.7 (1.0‒not estimable) months with placebo plus fulvestrant in PALOMA-3.

Conclusions: The types of first subsequent therapy received by Japanese patients in the palbociclib plus ET and placebo plus ET groups were similar. Further evaluation of subsequent therapy data in the real-world setting is warranted considering the small sample size of this analysis.
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http://dx.doi.org/10.1007/s12282-020-01162-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925474PMC
March 2021

Management of Abemaciclib-Associated Adverse Events in Patients with Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Safety Analysis of MONARCH 2 and MONARCH 3.

Oncologist 2021 01 9;26(1):e53-e65. Epub 2020 Oct 9.

Mayo Clinic, Rochester, Minnesota, USA.

Background: Abemaciclib demonstrated efficacy in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Here we provide a comprehensive summary of the most common adverse events (AEs), their management, and whether AEs or dose reductions influenced progression-free survival (PFS), in the MONARCH 2 and 3 trials.

Materials And Methods: Incidence of the most clinically relevant AEs, management, and outcomes were summarized. Time-dependent covariate analyses examined the impact of dose reductions on PFS. PFS was estimated for patients with and without early onset of diarrhea or neutropenia.

Results: The most frequently reported AE was diarrhea, with clinically significant diarrhea (grade ≥2) reported for 42.8% of patients taking abemaciclib. Median time to onset was 1 week, and duration ranged from 6 to 12 days, depending on grade and study. Diarrhea was adequately managed by antidiarrheal medication (72.8%), dose omissions (17.3%), and reductions (16.7%). The highest rates of grade ≥2 diarrhea were observed in the first cycles and decreased in subsequent cycles. Neutropenia (grade ≥3) occurred in 25.4% of abemaciclib-treated patients. Neutropenia resolved with dose omissions (16.8%) and/or dose reductions (11.2%). Incidence of febrile neutropenia (0.7%) or other relevant grade ≥3 hematological events (<9%) was low. Venous thromboembolic events (5.3%) were primarily treated with anticoagulants. Interstitial lung disease/pneumonitis (3.4%) was treated with corticosteroids and/or antibiotics. PFS benefit of abemaciclib was not impacted by dose reductions or early onset of toxicities.

Conclusion: Abemaciclib was generally well tolerated. The most common AEs were effectively managed by supportive medications, and/or dose adjustments, with no detriment to PFS.

Implications For Practice: Treatment with abemaciclib plus fulvestrant or nonsteroidal aromatase inhibitors is generally well tolerated in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. In MONARCH 2 and MONARCH 3, any-grade diarrhea and grade ≥3 neutropenia were effectively managed with supportive medication and/or dose adjustment. Venous thromboembolic events were treated with anticoagulants and did not often require treatment discontinuation. Interstitial lung disease/pneumonitis was infrequent and treated with corticosteroids and/or antibiotics. Clinicians should be aware of and implement management strategies, including dose adjustments according to local labels, for commonly occurring and serious adverse events to ensure continued treatment and optimize clinical benefit/risk ratio.
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http://dx.doi.org/10.1002/onco.13531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794176PMC
January 2021

The efficacy and safety of pertuzumab plus trastuzumab and docetaxel as a first-line therapy in Japanese patients with inoperable or recurrent HER2-positive breast cancer: the COMACHI study.

Breast Cancer Res Treat 2021 Jan 13;185(1):125-134. Epub 2020 Sep 13.

Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan.

Purpose: In the CLEOPATRA study of patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent or metastatic breast cancer, the Japanese patient subgroup did not demonstrate the improved progression-free survival (PFS) of pertuzumab plus trastuzumab and docetaxel vs. placebo that was seen in the overall population. Therefore, COMACHI was conducted to confirm the efficacy and safety of this treatment regimen in this patient subgroup.

Methods: This was a phase IV study of pertuzumab plus trastuzumab and docetaxel in Japanese patients with histologically/cytologically confirmed inoperable or recurrent HER2-positive breast cancer. All patients received pertuzumab, trastuzumab, and docetaxel intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary endpoint was investigator-assessed PFS. Secondary endpoints were overall survival (OS), investigator-assessed objective response rate, and duration of response (DoR). Safety was also assessed.

Results: At final analysis, median investigator-assessed PFS was 22.8 months (95% CI 16.9-37.5). From first dose, OS rate at 1 year was 97.7%; and at 2 and 3 years were 88.5% and 79.1%, respectively. Of the 118 patients with measurable disease at baseline, response rate was 83.9% (95% CI 77.3-90.5) and median investigator-assessed DoR was 26.3 months (95% CI 17.1-not evaluable). Treatment was well tolerated, with no new safety signals detected.

Conclusions: Our results suggest similar efficacy and safety for pertuzumab plus trastuzumab and docetaxel in Japanese patients compared with the overall population of CLEOPATRA, providing further support for this combination therapy as standard of care for Japanese patients with inoperable or recurrent HER2-positive breast cancer.
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http://dx.doi.org/10.1007/s10549-020-05921-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843485PMC
January 2021

Efficacy of the eribulin, pertuzumab, and trastuzumab combination therapy for human epidermal growth factor receptor 2-positive advanced or metastatic breast cancer: a multicenter, single arm, phase II study (JBCRG-M03 study).

Invest New Drugs 2021 02 24;39(1):217-225. Epub 2020 Aug 24.

Department of Surgery (Breast Surgery), Graduate School of Medicine Kyoto University, Kyoto, Japan.

Purpose To date, it is not clear which anticancer agent is useful in combination with trastuzumab and pertuzumab As the first and second selective regimens for advanced or metastatic breast cancer (AMBC), this multicenter, open-label, phase II trial (JBCRG-M03: UMIN000012232) presents a prespecified analysis of eribulin in combination with pertuzumab and trastuzumab. Methods We enrolled 50 patients with no or single prior chemotherapy for HER2-positive AMBC during November 2013-April 2016. All patients received adjuvant or first-line chemotherapy with trastuzumab and a taxane. The treatment comprised eribulin on days 1 and 8 of a 21-day cycle and trastuzumabplus pertuzumab once every 3 weeks, all administered intravenously. While the primary endpoint was the progression-free survival (PFS), secondary endpoints were the response rate and safety. Results Of 50 patients, 49 were eligible for safety analysis, and the full analysis set (FAS) included 46 patients. We treated 8 (16%) and 41 (84%) patients in first- and second-line settings, respectively. While 11 patients (23.9%) had advanced disease, 35 (76.1%) had metastatic disease. The median PFS was 9.2 months for all patients [95% confidence interval (CI): 7.0-11.4]. In the FAS, 44 patients had the measurable lesions and the complete response rate (CR) was 17.4%, and partial response rate (PR) was 43.5%. The grade 3/4 adverse events were neutropenia (5 patients, 10.2%), including febrile neutropenia (2 patients, 4.1%), hypertension (3 patients, 6.1%), and other (1 patient). The average of the left ventricular ejection fraction did not decline markedly. No symptomatic left ventricular systolic dysfunction was observed. Conclusions In patients with HER2-positive AMBC, eribulin, pertuzumab, and trastuzumab combination therapy exhibited substantial antitumor activity with an acceptable safety profile. Hence, we have started a randomized phase III study comparing eribulin and a taxane in combination with pertuzumab and trastuzumab for the treatment of HER2-positive AMBC. Trial registration ID: UMIN-CTR: UMIN000012232.
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http://dx.doi.org/10.1007/s10637-020-00991-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851001PMC
February 2021

Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.

J Clin Oncol 2020 09 17;38(27):3138-3149. Epub 2020 Jul 17.

Graduate School of Medicine, Gunma University, Gunma, Japan.

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/m twice a day 14 d/21 d) with loperamide prophylaxis, or to lapatinib (1,250 mg once every day) plus capecitabine (1,000 mg/m 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 0059). The OS HR was 0.88 (95% CI, 0.72 to 1.07; 2098). Fewer interventions for CNS disease occurred with N+C versus L+C (cumulative incidence, 22.8% 29.2%; 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; 1201); median DoR was 8.5 versus 5.6 months, respectively (HR, 0.50; 95% CI, 0.33 to 0.74; .0004). The most common all-grade adverse events were diarrhea (N+C 83% L+C 66%) and nausea (53% 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.
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http://dx.doi.org/10.1200/JCO.20.00147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499616PMC
September 2020

Ribociclib, a CDK 4/6 inhibitor, plus endocrine therapy in Asian women with advanced breast cancer.

Cancer Sci 2020 Sep 28;111(9):3313-3326. Epub 2020 Jul 28.

National Hospital Organization, Osaka National Hospital, Osaka, Japan.

The ongoing, Phase Ib MONALEESASIA study is evaluating the efficacy and safety of ribociclib plus endocrine therapy in Asian patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Eligible patients from Japan, Hong Kong, and Singapore were enrolled in this 2-phase study consisting of a dose-escalation phase to determine the maximum-tolerated dose and the recommended Phase II dose of ribociclib plus letrozole, and a dose-expansion phase to evaluate safety and tolerability of ribociclib plus letrozole, fulvestrant, or tamoxifen. An exploratory biomarker analysis evaluating expression of target genes was also conducted. In the dose-escalation phase, the maximum-tolerated/recommended Phase II doses of ribociclib were lower in Japanese patients (300 mg) than in Asian non-Japanese patients (600 mg). Ribociclib plus endocrine therapy at the recommended Phase II dose had a manageable safety profile, with neutropenia and elevated liver transaminases being the most common adverse events leading to dose modifications or discontinuations, and it demonstrated evidence of clinical activity in both Japanese and Asian non-Japanese patients. Preliminary efficacy in Asian populations is similar to that observed in White populations studied in previous ribociclib (MONALEESA) trials. Biomarker analysis demonstrated suppression of pharmacodynamic biomarker gene expression, indicating inhibition of target genes by ribociclib combined with endocrine therapy. Results from the ongoing study support the use of ribociclib in combination with letrozole in Asian non-Japanese patients at the same dose (600 mg) as White patients. In Japanese patients, a lower dose of ribociclib (300 mg) should be considered. Clinicaltrials.gov: NCT02333370.
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http://dx.doi.org/10.1111/cas.14554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469771PMC
September 2020
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