Results from the randomized KEYNOTE-355 study of pembrolizumab plus chemotherapy for Asian patients with advanced TNBC.

In the phase 3 KEYNOTE-355 study (NCT02819518), pembrolizumab plus chemotherapy demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy among patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) and programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 10 tumors. We analyzed outcomes for the subgroup of patients enrolled in Asia in KEYNOTE-355. Patients received pembrolizumab 200 mg or placebo (2:1 randomization) every 3 weeks for 35 cycles plus investigator's choice chemotherapy. Primary endpoints were PFS per Response Evaluation Criteria in Solid Tumors version 1.1 and OS. Among patients enrolled in Hong Kong, Japan, Korea, Malaysia and Taiwan (pembrolizumab plus chemotherapy, n = 113; placebo plus chemotherapy, n = 47), 117 (73.1%) had PD-L1 CPS ≥ 1 and 56 (35.0%) had PD-L1 CPS ≥ 10. Median time from randomization to data cutoff (June 15, 2021) was 43.8 (range, 36.8‒53.2) months (intent-to-treat [ITT] population). Hazard ratios (HRs [95% CI]) for PFS in the CPS ≥ 10, CPS ≥ 1, and ITT populations were 0.48 (0.24‒0.98), 0.58 (0.37‒0.91), and 0.66 (0.44‒0.99), respectively. Corresponding HRs (95% CI) for OS were 0.54 (0.28‒1.04), 0.62 (0.40‒0.97), and 0.57 (0.39‒0.84). Grade 3/4 treatment-related adverse events (AEs) occurred in 77.9% versus 78.7% of patients with pembrolizumab plus chemotherapy versus placebo plus chemotherapy. No grade 5 AEs occurred. Clinically meaningful improvement in PFS and OS with manageable toxicity were observed with pembrolizumab plus chemotherapy versus placebo plus chemotherapy in patients enrolled in Asia with previously untreated, inoperable or metastatic TNBC.Trial registration: ClinicalTrials.gov, NCT02819518.

Preliminary results from ASCENT-J02: a phase 1/2 study of sacituzumab govitecan in Japanese patients with advanced solid tumors.

BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate approved outside Japan for second-line and later metastatic triple-negative breast cancer (mTNBC), based on the ASCENT study (NCT02574455). We report SG safety and efficacy in an open-label, phase 1/2 bridging study in Japanese patients with advanced solid tumors (ASCENT-J02; NCT05101096; jRCT2031210346). METHODS: Phase 1 was a standard 3 + 3 design. Patients received intravenous SG 6 mg/kg, escalating to 10 mg/kg, on Days 1 and 8 per 21-day cycle; primary endpoints were safety, incidence of dose-limiting toxicity/toxicities (DLTs), and determination of the recommended phase 2 dose (RP2D). In the multicohort phase 2 study, patients in the mTNBC cohort with previously treated disease received SG at the RP2D; primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; RECIST v1.1). Safety was a secondary endpoint. RESULTS: In phase 1 (N = 15), one DLT (grade 3 elevated transaminases) occurred with SG 10 mg/kg; RP2D was SG 10 mg/kg regardless of UGT1A1 status. In phase 2, 36 patients with mTNBC received SG 10 mg/kg. At median follow-up of 6.1 months, IRC-assessed ORR was 25.0% (95% CI 12.1-42.2; P = 0.0077). Median progression-free survival was 5.6 months (95% CI 3.9-not reached [NR]); median overall survival was NR. No treatment-emergent adverse events led to discontinuation or death. CONCLUSIONS: SG RP2D was established as 10 mg/kg in Japanese patients. SG showed efficacy in Japanese patients with previously treated mTNBC, a manageable safety profile, and no new safety signals, consistent with the previous ASCENT study.

Identification of peripheral blood test parameters predicting the response to palbociclib and endocrine therapy for metastatic breast cancer: a retrospective study in a single institution.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors have been used in endocrine therapy for patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. Although randomized trials have shown that combined therapies prolong progression-free survival (PFS) in comparison to endocrine monotherapy, the predictors of efficacy are unknown. This study aimed to identify the blood test parameters to predict the effects of palbociclib and endocrine therapy. METHODS: Seventy-nine patients treated with palbociclib and endocrine therapy between December 2017 and June 2022 were reviewed. We assessed PFS in patients according to factors evaluated based on patient characteristics and peripheral blood tests. RESULTS: Patients in the C-reactive protein (CRP)-high, lactate dehydrogenase (LDH)-high, and albumin (Alb)-low groups had significantly shorter PFS than those in the normal group. A multivariate analysis revealed that high LDH and low Alb levels were independent factors that affected PFS. The Alb-low group had an inferior disease control rate. Patients in the CRP-high, LDH-high, and Alb-low groups who received these therapies as first- or second-line treatments showed poor PFS. CONCLUSIONS: Several predictors of the efficacy of palbociclib and endocrine therapy were identified in the peripheral blood test parameters of patients with ER-positive and HER2-negative subtypes of metastatic breast cancer.

TP53 signature predicts pathological complete response after neoadjuvant chemotherapy for breast cancer: Observational and confirmational study using prospective study cohorts.

The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies. Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed. The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876-16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2- subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group. The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group.

Comparison of proportions and prognostic impact of pathological complete response between evaluations of representative specimen and total specimen in primary breast cancer after neoadjuvant chemoradiotherapy: an ancillary study of JCOG0306.

BACKGROUND: In JCOG0306 trial, a phase II study to examine the efficacy of neoadjuvant chemotherapy followed by radiation therapy (NAC-RT) to primary breast cancer, pathological complete response (pCR) was evaluated from specimens of the representative cross-section including the tumor center that had been accurately marked [representative specimen (RS) method]. In this ancillary study, we examined if the RS method was comparable to the conventional total specimen (TS) method, which is widely employed in Japan, to identify the pCR group showing excellent prognosis. METHODS: We obtained long-term follow-up data of 103 patients enrolled in JCOG0306 trial. As histological therapeutic effect, pCR (ypT0 and ypT0/is) and quasi-pCR [QpCR, ypT0/is plus Grade 2b (only a few remaining invasive cancer cells)] were evaluated with RS and TS methods. Concordance of pCR between these two methods and associations of the pCR with prognosis were examined. RESULTS: ypT0, ypT0/is, and QpCR were observed in 28 (27.2%), 39 (37.9%), and 45 (43.7%) patients with RS method, whereas these were 20 (19.4%), 25 (24.3%) and 40 (38.9%) with TS method, respectively. Between RS and TS methods, concordance proportions of ypT0 and ypTis were 92.2% and 86.4%, respectively. Risk of recurrence of ypT0/is group was lower than that of non-ypT0/is group (HR 0.408, 95% CI [0.175-0.946], P = 0.037) and risk of death of ypT0/is group was lower than that of non-ypT0/is group (HR 0.251, 95% CI [0.073-0.857], P = 0.027). The ypT0 and ypT0/is groups with RS method showed excellent prognosis similarly with those with TS method, and RS method was able to differentiate the OS and RFS between pCR and non-pCR than TS method significantly even if pCR was classified ypT0 or ypT0/is. With TS method, QpCR criteria stratified patients into the better and worse prognosis groupsmore clearly than pCR criteria of ypT0 or ypT0/is. CONCLUSIONS: RS method was comparable to TS method for the evaluation of pCR in the patients who received NAC-RT to primary breast cancer provided the tumor center was accurately marked. As pCR criteria with RS method, ypT0/is appeared more appropriate than ypT0.

Prognostic value of the 21-Gene Breast Recurrence Score® assay for hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer: subanalysis from Japan Breast Cancer Research Group-M07 (FUTURE trial).

PURPOSE: This study aimed to determine whether the 21-Gene Breast Recurrence Score® assay from primary breast tissue predicts the prognosis of patients with hormone receptor-positive and human epidermal growth factor 2-negative advanced breast cancers (ABCs) treated with fulvestrant monotherapy (Group A) and the addition of palbociclib combined with fulvestrant (Group B), which included those who had progression in Group A from the Japan Breast Cancer Research Group-M07 (FUTURE trial). METHODS: Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test and Cox regression analysis based on original recurrence score (RS) categories (Low: 0-17, Intermediate: 18-30, High: 31-100) by treatment groups (A and B) and types of ABCs (recurrence and de novo stage IV). RESULTS: In total, 102 patients [Low: n = 44 (43.1%), Intermediate: n = 38 (37.5%), High: n = 20 (19.6%)] in Group A, and 45 in Group B, who had progression in Group A were analyzed. The median follow-up time was 23.8 months for Group A and 8.9 months for Group B. Multivariate analysis in Group A showed that low-risk [hazard ratio (HR) 0.15, 95% confidence interval (CI) 0.04-0.53, P = 0.003] and intermediate-risk (HR 0.22, 95% CI 0.06-0.78) with de novo stage IV breast cancer were significantly associated with better prognosis compared to high-risk. However, no significant difference was observed among patients with recurrence. No prognostic significance was observed in Group B. CONCLUSION: We found a distinct prognostic value of the 21-Gene Breast Recurrence Score® assay by the types of ABCs and a poor prognostic value of the high RS for patients with de novo stage IV BC treated with fulvestrant monotherapy. Further validations of these findings are required.

Long-term outcomes of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1 + P) and docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) for HER2-positive primary breast cancer: results of the randomized phase 2 JBCRG20 study (Neo-peaks).

PURPOSE: The randomized phase 2 Neo-peaks study examined usefulness of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1 + P) following docetaxel + carboplatin + trastuzumab + pertuzumab (TCbHP) as compared with the standard TCbHP regimen. We previously reported that pCR rate after neoadjuvant therapy tended to be higher with TCbHP followed by T-DM1 + P. We conducted an exploratory analysis of prognosis 5 years after surgery. METHODS: Neoadjuvant treatment with TCbHP (6 cycles; group A), TCbHP (4 cycles) followed by T-DM1 + P (4 cycles; group B), and T-DM1 + P (4 cycles; group C, + 2 cycles in responders) were compared. Group C non-responders after 4 cycles were switched to an anthracycline-based regimen. We evaluated 5-year disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS). RESULTS: Data from 203 patients (50, 52, and 101 in groups A-C, respectively) were analyzed. No significant intergroup differences were found for DFS, DDFS, or OS. The 5-year DFS rates (95% CI) were 91.8% (79.6-96.8%), 92.3% (80.8-97.0%), and 88.0% (79.9-93.0%) in groups A-C, respectively. TCbHP followed by T-DM1 + P and T-DM1 + P with response-guided addition of anthracycline therapy resulted in similar long-term prognosis to that of TCbHP. CONCLUSIONS: In patients who achieved pCR after neoadjuvant therapy with T-DM1 + P, omission of adjuvant anthracycline may be considered, whereas treatment should be adjusted for non-pCR patients with residual disease. T-DM1 + P with response-guided treatment adjustment may be useful for minimizing toxicity. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: UMIN-CTR, UMIN000014649, prospectively registered July 25, 2014. Some of the study results were presented as a Mini Oral session at the ESMO Breast Cancer 2023 (Berlin, Germany, 11-13 May 2023).

Predictive Performance of Radiomic Features Extracted from Breast MR Imaging in Postoperative Upgrading of Ductal Carcinoma in Situ to Invasive Carcinoma.

PURPOSE: To investigate the predictive performance of radiomic features extracted from breast MRI for upgrade of ductal carcinoma in situ (DCIS) to invasive carcinoma. METHODS: This retrospective study included 71 women with DCIS lesions diagnosed preoperatively by biopsy. All women underwent breast dynamic contrast-enhanced (DCE) MRI of the breast, which included pre-contrast and five post-contrast phases continuously with a time resolution of 60s. Lesion segmentation was performed manually, and 144 radiomic features of the lesions were extracted from T2-weighted images (T2WI), pre-contrast T1-weighted images (T1WI), and post-contrast 1st, 2nd, and 5th phase subtraction images on DCE-MRI. Qualitative features of mammography, ultrasound, and MRI were also assessed. Clinicopathological features were evaluated using medical records. The least absolute shrinkage and selection operator (LASSO) algorithm was applied for features selection and model building. The predictive performance of postoperative upgrade to invasive carcinoma was assessed using the area under the receiver operating characteristic curve. RESULTS: Surgical specimens revealed 13 lesions (18.3%) that were upgraded to invasive carcinoma. Among clinicopathological and qualitative features, age was the only significant predictive variable. No significant radiomic features were observed on T2WI and post-contrast 2nd phase subtraction images on DCE-MRI. The area under the curves (AUCs) of the LASSO radiomics model integrated with age were 0.915 for pre-contrast T1WI, 0.862 for post-contrast 1st phase subtraction images, and 0.833 for post-contrast 5th phase subtraction images. The AUCs of the 200-times bootstrap internal validations were 0.885, 0.832, and 0.775. CONCLUSION: A radiomics approach using breast MRI may be a promising method for predicting the postoperative upgrade of DCIS. The present study showed that the radiomic features extracted from pre-contrast T1WI and post-contrast subtraction images in the very early phase of DCE-MRI were more predictable.

Real-world progression-free survival and overall survival of palbociclib plus endocrine therapy (ET) in Japanese patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer in the first-line or second-line setting: an observational study.

BACKGROUND: A recent large real-world study conducted in the United States reported the effectiveness of palbociclib plus aromatase inhibitor in HR+/HER2- advanced breast cancer (ABC). However, local clinical practice and available medical treatment can vary between Japan and Western countries. Thus, it is important to investigate Japanese real-world data. This observational, multicenter study (NCT05399329) reports the interim analysis of effectiveness of palbociclib plus ET as first-line or second-line treatment for HR+/HER2- ABC by estimating real-world progression-free survival (rwPFS) and overall survival (OS) in Japanese routine clinical practice. METHODS: Real-world clinical outcomes and treatment patterns of palbociclib plus ET were captured using a medical record review of patients diagnosed with HR+/HER2- ABC who had received palbociclib plus ET in the first-line or second-line treatment across 20 sites in Japan. The primary endpoint was rwPFS; secondary endpoints were OS, real-world overall response rate, real-world clinical benefit rate, and chemotherapy-free survival. RESULTS: Of the 677 eligible patients, 420 and 257 patients, respectively, had received palbociclib with ET as first-line and second-line treatments. Median rwPFS (95% confidence interval) was 24.5 months (19.9-29.4) for first-line and 14.5 months (10.2-19.0) for second-line treatment groups. Median OS was not reached in the first-line group and was 46.7 months (38.8-not estimated) for the second-line group. The 36-month OS rates for de novo metastasis, treatment-free interval (TFI) ≥ 12 months, and TFI < 12 months were 80.2% (69.1-87.7), 82.0% (70.7-89.3), and 66.0% (57.9-72.9), respectively. CONCLUSION: The addition of palbociclib to ET was effective for treating HR+/HER2- ABC in Japanese routine clinical practice.

A Century of Change: Unraveling the Impact of Socioeconomic/Historical Milestones on Age at Menarche and Other Female Reproductive Factors in Japan.

BACKGROUND: Reproductive factors, such as age at menarche, are known to be associated with disease risk, but data on trends in these factors in Japan are limited. In this study, we investigated secular trends in reproductive factors and explored their potential association with socioeconomic and historical events. METHODS: We conducted a retrospective analysis of 62,005 Japanese women born between 1890 and 1991 using a survey conducted over 25 years. Trends in reproductive factors were analyzed using linear and joinpoint regression models, and their associations with major historical events involving Japan were evaluated. RESULTS: We found that the age at menarche showed a significant downward trend (P < 0.001) over the century. Three joinpoints were identified, in 1932 (15.23 years old), 1946 (13.48 years old), and 1959 (12.71 years old), which indicated that average age at menarche decreased by approximately 0.8% per year between 1932 and 1946, and then by 0.4% per year between 1946 and 1959, both of which were statistically significant. However, after 1959, age of menarche remained stable. Analyses of other reproductive factors found significant changes, including a decrease in parity and the number of babies breastfed, and an increase in age at first birth. CONCLUSION: Age at menarche showed a long-term downward trend in Japan, with significant change points in annual percent change. Other factors showed secular changes in trends as well. These change points were observed at the same time as historical events, namely wars and economic development, suggesting that socioeconomic and environmental changes at the population level affect reproductive factors in females.

Time-series blood cytokine profiles correlate with treatment responses in triple-negative breast cancer patients.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most heterogeneous breast cancer subtype. Partly due to its heterogeneity, it is currently challenging to stratify TNBC patients and predict treatment outcomes. METHODS: In this study, we examined blood cytokine profiles of TNBC patients throughout treatments (pre-treatment, during chemotherapy, pre-surgery, and 1 year after the surgery in a total of 294 samples). We analyzed the obtained cytokine datasets using weighted correlation network analyses, protein-protein interaction analyses, and logistic regression analyses. RESULTS: We identified five cytokines that correlate with good clinical outcomes: interleukin (IL)-1α, TNF-related apoptosis-inducing ligand (TRAIL), Stem Cell Factor (SCF), Chemokine ligand 5 (CCL5 also known as RANTES), and IL-16. The expression of these cytokines was decreased during chemotherapy and then restored after the treatment. Importantly, patients with good clinical outcomes had constitutively high expression of these cytokines during treatments. Protein-protein interaction analyses implicated that these five cytokines promote an immune response. Logistic regression analyses revealed that IL-1α and TRAIL expression levels at pre-treatment could predict treatment outcomes in our cohort. CONCLUSION: We concluded that time-series cytokine profiles in breast cancer patients may be useful for understanding immune cell activity during treatment and for predicting treatment outcomes, supporting precision medicine. 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 the unique trial number UMIN000023162. The association Japan Breast Cancer Research Group trial number is JBCRG-22. The clinical outcome of the JBCRG-22 study was published in Breast Cancer Research and Treatment on 25 March 2021. https://doi.org/10.1007/s10549-021-06184-w .

Changes in cell-free DNA after short-term palbociclib and fulvestrant treatment for advanced or metastatic hormone receptor-positive and human epidermal growth factor 2-negative breast cancer.

PURPOSE: Here, we investigated the potential predictive and elucidating efficacy of cell-free DNA (cfDNA) changes on clinical outcomes and biological effects, respectively, after short-term palbociclib and fulvestrant treatment for patients with hormone receptor (HR)-positive and human epidermal growth factor 2 (HER2)-negative advanced or metastatic breast cancer (ABC). METHODS: In this secondary analysis of the Japan Breast Cancer Research Group-M07 (FUTURE) trial, blood cfDNA was obtained before palbociclib treatment and on day 15 of cycle one (28-day cycle). Target enrichment was performed using next-generation sequencing; progression-free survival (PFS) was compared based on cfDNA changes between baseline and day 15 of cycle one after combination therapy. RESULTS: Fifty-six patients (112 paired blood samples) were examined. The median follow-up time was 8.9 months. PIK3CA (30.4%, 17/56), FOXA1 (30.4%, 17/56), and ESR1 (28.6%, 16/56) were most frequently mutated at baseline. The number of mutated genes was significantly decreased on day 15 compared with that at baseline (paired t test: P value = 0.025). No significant difference was observed in PFS (decrease group, 7.9 m vs the others, 9.3 m; log-rank P value = 0.75; hazard ratio, 1.13; 95% confidence interval, 0.53-2.41). Among patients without previous aromatase inhibitor treatment (n = 15), three (20%) had ESR1 mutations after progression to fulvestrant. CONCLUSION: No significant association was observed between changes in mutated genes after short-term palbociclib and fulvestrant treatment and disease progression; a significant reduction in cfDNA mutation level was observed on day 15 of cycle one. Clinical meanings of cfDNA should be investigated in the future trials.

Overall survival in Japanese patients with ER+/HER2- advanced breast cancer treated with first-line palbociclib plus letrozole.

BACKGROUND: An open-label, single-arm, Japanese phase 2 study (J-Ph2) investigated the efficacy and safety of first-line (1L) palbociclib (PAL) + letrozole (LET) in postmenopausal Japanese women with ER+/HER2- advanced breast cancer (ABC). In the final analysis, median progression-free survival was 35.7 months (95% CI 21.7-46.7); but overall survival (OS) data were immature. Here, we report the findings from a follow-up study of J-Ph2 (NCT04735367) evaluating OS and subsequent therapy in these Japanese women. METHODS: Patients (N = 42) who participated in J-Ph2 were enrolled in the OS follow-up study. The primary endpoint was OS and secondary endpoints included type and duration of subsequent therapy. RESULTS: Patients were a median age of 62.5 years; 48% had visceral metastases. At a median follow-up of 89.7 months, the median OS was 85.4 months (95% CI 64.3-not estimable). Median OS was longer in patients with nonvisceral versus visceral metastases (not reached vs 67.3 months), or with treatment-free interval > 12 months versus ≤ 12 months (85.4 vs 45.4 months), or with treatment duration ≥ 24 months versus < 24 months (not reached vs 47.5 months). Of patients who received a first subsequent therapy (81%), most (67%) continued endocrine-based therapy, while 7% received chemotherapy. The median duration of the first subsequent therapy was 8.3 months (95% CI 3.9-12.2), and the median chemotherapy-free survival was 69.1 months (95% CI 24.2-85.4). CONCLUSIONS: In this population of Japanese women with ER+/HER2- ABC, median OS was over 7 years with 1L PAL + LET, supporting the use of 1L PAL + endocrine therapy. TRIAL NUMBER: NCT04735367.

Health-Related Quality of Life With Pembrolizumab+Chemotherapy Versus Placebo+Chemotherapy for Advanced Triple-Negative Breast Cancer: KEYNOTE-355.

BACKGROUND: In KEYNOTE-355 (NCT02819518), addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced triple-negative breast cancer (TNBC) with tumor PD-L1 combined positive score (CPS) ≥10. We report patient-reported outcomes (PROs) from KEYNOTE-355. METHODS: Patients were randomized 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator's choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin). QLQ-C30, QLQ-BR23, and EQ-5D visual analogue scale (VAS) were prespecified. PROs were analyzed for patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. Change in PRO scores from baseline were assessed at week 15 (latest time point at which completion/compliance rates were ≥60%/≥80%). Time to deterioration (TTD) in PROs was defined as time to first onset of ≥ 10-point worsening in score from baseline. RESULTS: PRO analyses included 317 patients with tumor PD-L1 CPS ≥10 (pembrolizumab plus chemotherapy; n = 217; placebo plus chemotherapy, n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (GHS/QoL; least-squares mean difference, -1.81 [95% CI, -6.92 to 3.30]), emotional functioning (-1.43 [-7.03 to 4.16]), physical functioning (-1.05 [-6.59 to 4.50]), or EQ-5D VAS (0.18 [-5.04 to 5.39]), and no between-group difference in TTD in QLQ-C30 GHS/QoL, emotional functioning, or physical functioning. CONCLUSIONS: Together with the efficacy and safety findings, PRO results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced TNBC with tumor PD-L1 (CPS ≥10).

Efficacy and safety of pegfilgrastim biosimilar MD-110 in patients with breast cancer receiving chemotherapy: Single-arm phase III.

INTRODUCTION: Pegfilgrastim is indicated to decrease the incidence of chemotherapy-induced febrile neutropenia. It is the first granulocyte-colony stimulating factor approved for prophylactic use regardless of carcinoma type and is marketed in Japan as G-LASTA (Kyowa Kirin Co., Ltd., Tokyo, Japan). MD-110 is a biosimilar of pegfilgrastim. This phase III, multicenter, open-label, single-arm study investigated the efficacy and safety of MD-110 in early-stage breast cancer patients receiving neoadjuvant or adjuvant myelosuppressive chemotherapy. METHODS: A total of 101 patients received the study drug. Each patient received docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 (TC) for four cycles on day 1 of each cycle. MD-110 (3.6 mg) was administered subcutaneously on day 2 of each cycle. The primary efficacy endpoint was the duration of severe neutropenia during cycle 1 (days with absolute neutrophil count < 500/mm3 ). The safety endpoints were adverse events and the presence of antidrug antibodies. RESULTS: The mean (SD) duration of severe neutropenia for MD-110 was 0.2 (0.4) days. The upper limit of the two-sided 95% confidence interval for the mean duration of severe neutropenia was 0.2 days, below the predefined threshold of 3.0 days. The incidence of febrile neutropenia, the secondary efficacy endpoint, was 6.9% (7/101). Adverse events, occurring in more than 50% of patients, were alopecia, constipation, and malaise, which are common side effects of TC chemotherapy. Antidrug antibodies were negative in all patients. CONCLUSION: MD-110 was effective against chemotherapy-induced neutropenia. No additional safety concern, compared with the originator, was observed in patients with breast cancer receiving TC chemotherapy.(JapicCTI-205230).

Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3-Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3-Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial.

PURPOSE: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in breast cancer; high expression is associated with an adverse prognosis. Patritumab deruxtecan (HER3-DXd) is an investigational HER3-targeted antibody-drug conjugate that is being evaluated as a novel treatment in HER3-expressing advanced breast cancer in the U31402-A-J101 study. METHODS: Adults with disease progression on previous therapies were eligible. Patients in the dose-escalation, dose-finding, and dose-expansion parts received HER3-DXd 1.6-8.0 mg/kg intravenously once every 3 weeks or one of two alternative dosing regimens. In the dose-escalation part, the primary objectives were to determine the maximum tolerated dose and recommended dose for expansion (RDE). The safety and efficacy of the RDE were assessed during dose expansion. RESULTS: One hundred eighty-two enrolled patients received ≥1 dose of HER3-DXd. Patients had a median of five previous therapies for advanced disease. Efficacy results are reported across clinical subtypes: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer (n = 113; objective response rate [ORR], 30.1%; median progression-free survival [mPFS], 7.4 months), triple-negative breast cancer (n = 53; ORR, 22.6%; mPFS, 5.5 months), and HER2-positive breast cancer (n = 14; ORR, 42.9%; mPFS, 11.0 months). Objective responses were observed in cancers with HER3-high and HER3-low membrane expression. Dose-limiting toxicities observed during dose selection were decreased platelet count and elevated aminotransferases. In dose expansion, GI and hematologic toxicities were the most common treatment-emergent adverse events (TEAEs) observed. Grade ≥3 TEAEs were observed in 71.4% of patients, and 9.9% discontinued treatment because of TEAEs. Three grade 3 and one grade 5 treatment-related interstitial lung disease events occurred. CONCLUSION: HER3-DXd demonstrated a manageable safety profile and durable efficacy in heavily pretreated patients across clinical subtypes. These data warrant further evaluation of HER3-DXd in patients with HER3-expressing metastatic breast cancer.

A risk-based subgroup analysis of the effect of adjuvant S-1 in estrogen receptor-positive, HER2-negative early breast cancer.

PURPOSE: The Phase III POTENT trial demonstrated the efficacy of adding S-1 to adjuvant endocrine therapy for estrogen receptor-positive, HER2-negative early breast cancer. We investigated the efficacy of S-1 across different recurrence risk subgroups. METHODS: This was a post-hoc exploratory analysis of the POTENT trial. Patients in the endocrine-therapy-only arm were divided into three groups based on composite risk values calculated from multiple prognostic factors. The effects of S-1 were estimated using the Cox model in each risk group. The treatment effects of S-1 in patients meeting the eligibility criteria of the monarchE trial were also estimated. RESULTS: A total of 1,897 patients were divided into three groups: group 1 (≤ lower quartile of the composite values) (N = 677), group 2 (interquartile range) (N = 767), and group 3 (> upper quartile) (N = 453). The addition of S-1 to endocrine therapy resulted in 49% (HR: 0.51, 95% CI: 0.33-0.78) and 29% (HR: 0.71, 95% CI 0.49-1.02) reductions in invasive disease-free survival (iDFS) events in groups 2 and 3, respectively. We could not identify any benefit from the addition of S-1 in group 1. The addition of S-1 showed an improvement in iDFS in patients with one to three positive nodes meeting the monarchE cohort 1 criteria (N = 290) (HR: 0.47, 95% CI: 0.29-0.74). CONCLUSIONS: The benefit of adding adjuvant S-1 was particularly marked in group 2. Further investigations are warranted to explore the optimal usage of adjuvant S-1.

Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial).

BACKGROUND: Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies. METHODS: This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers. RESULTS: From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy. CONCLUSIONS: Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs. TRIAL REGISTRATION NUMBER: JapicCTI-194782, jRCT2080224706, UMIN000036970.

Potential value of ctDNA monitoring in metastatic HR + /HER2 - breast cancer: longitudinal ctDNA analysis in the phase Ib MONALEESASIA trial.

BACKGROUND: There is increasing interest in the use of liquid biopsies, but data on longitudinal analyses of circulating tumor DNA (ctDNA) remain relatively limited. Here, we report a longitudinal ctDNA analysis of MONALEESASIA, a phase Ib trial evaluating the efficacy and safety of ribociclib plus endocrine therapy (ET) in Asian patients with hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer. METHODS: MONALEESASIA enrolled premenopausal and postmenopausal Japanese and postmenopausal non-Japanese Asian patients. All patients received ribociclib with ET (letrozole, fulvestrant, or tamoxifen with goserelin). ctDNA was analyzed using a targeted next-generation sequencing panel of 572 cancer-related genes and correlated by best overall response (BOR). RESULTS: Five hundred seventy-four cell-free DNA samples from 87 patients were tested. The most frequently altered genes at baseline included PIK3CA (29%) and TP53 (22%). Treatment with ribociclib plus ET decreased ctDNA in most patients at the first on-treatment time point, regardless of dose or ET partner. Patients with partial response and stable disease had lower ctDNA at baseline that remained low until data cutoff if no progressive disease occurred. Most patients with progressive disease as the best response had higher ctDNA at baseline that remained high at the end of treatment. For patients with partial response and stable disease with subsequent progression, ctDNA increased towards the end of treatment in most patients, with a median lead time of 83 days (14-309 days). In some patients with BOR of partial response who experienced disease progression later, specific gene alterations and total ctDNA fraction increased; this was sometimes observed concurrently with the development of new lesions without a change in target lesion size. Patients with alterations in PIK3CA and TP53 at baseline had shorter median progression-free survival compared with patients with wild-type PIK3CA and TP53, 12.7 and 7.3 months vs 19.2 and 19.4 months, respectively (P = .016 and P = .0001, respectively). CONCLUSIONS: Higher ctDNA levels and PIK3CA and TP53 alterations detected at baseline were associated with inferior outcomes. On-treatment ctDNA levels were associated with different patterns based on BOR. Longitudinal tracking of ctDNA may be useful for monitoring tumor status and detection of alterations with treatment implications. TRIAL REGISTRATION: ClinicalTrials.gov NCT02333370 . Registered on January 7, 2015.

Fulvestrant with or without anti-HER2 therapy in patients in a postmenopausal hormonal state and with ER-positive HER2-positive advanced or metastatic breast cancer: A subgroup analysis of data from the Safari study (JBCRG-C06).

BACKGROUND: The role of endocrine therapy in the treatment of patients in a postmenopausal hormonal state and with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer (AMBC) is unclear. METHODS: We analyzed the data from 94 patients with ER-positive HER2-positive AMBC enrolled in the Safari study (UMIN000015168), a retrospective cohort study of 1072 ER-positive AMBC patients in a postmenopausal hormonal state who received fulvestrant 500 mg (F500): (1) to compare time to treatment failure (TTF) and overall survival (OS) by treatment group, and TTF by treatment line; (2) in patients who received endocrine therapy (including F500) or anti-HER2 therapy as initial systemic therapy before chemotherapy, to investigate relations between TTF for the first-line therapy or time to chemotherapy (TTC) and OS; (3) to investigate factors associated with OS. RESULTS: The TTF was longer in the patients treated with F500 as first- or second-line therapy (n = 20) than in those who received later-line F500 therapy (n = 74) (6.6 vs. 3.7 months; HR, 1.98; p = 0.014). In the 59 patients who received endocrine therapy or anti-HER2 therapy as initial systemic therapy before chemotherapy, those with TTC ≥3 years had longer median OS than those with TTC <3 years (10.5 vs. 5.9 years; HR, 0.32; p = 0.001). Longer TTC was associated with prolonged OS. CONCLUSIONS: In patients with ER-positive HER2-positive AMBC enrolled in the Safari study, TTF was longer in patients who received F500 as first- or second-line therapy. In patients who received chemotherapy-free initial systemic therapy, the prolonged OS in those with TTC ≥3 years suggests that this value may be a helpful cut-off for indicating clinical outcomes.