Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer.

BACKGROUND: In patients with early-stage triple-negative breast cancer, the phase 3 KEYNOTE-522 trial showed significant improvements in pathological complete response and event-free survival with the addition of pembrolizumab to platinum-containing chemotherapy. Here we report the final results for overall survival. METHODS: We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response and event-free survival. Overall survival was a secondary end point. RESULTS: Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. At the data-cutoff date (March 22, 2024), the median follow-up was 75.1 months (range, 65.9 to 84.0). The estimated overall survival at 60 months was 86.6% (95% confidence interval [CI], 84.0 to 88.8) in the pembrolizumab-chemotherapy group, as compared with 81.7% (95% CI, 77.5 to 85.2) in the placebo-chemotherapy group (P = 0.002). Adverse events were consistent with the established safety profiles of pembrolizumab and chemotherapy. CONCLUSIONS: Neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab resulted in a significant improvement, as compared with neoadjuvant chemotherapy alone, in overall survival among patients with early-stage triple-negative breast cancer. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.).

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.

Phase I/Ib Trial of Inavolisib Plus Palbociclib and Endocrine Therapy for PIK3CA-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced or Metastatic Breast Cancer.

PURPOSE: To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA-mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172). METHODS: Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability. RESULTS: Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response. CONCLUSION: Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.

Novel Approaches Needed: An Experimental Study with an Alternative to Mechanical Restraint.

Despite many calls to reduce or eliminate the use of mechanical restraint, it is still widely used in many countries. Studies using patient interviews have a very clear message: Patients experience mechanical restraint as the most humiliating intervention. There seems to be a lack of alternatives for violent patients if all other approaches to prevent the use of coercion have failed. We developed a method using 30 kg bags, originally designed for fitness purposes, to be attached to a patient's wrist or ankle under 1:1 supervision. The method was tested with 10 experienced nurses and de-escalation trainers. A video was made and presented to six outpatients who had previously experienced mechanical restraint. All participants were interviewed. Transcribed interviews were analysed using qualitative content analysis. All participants approved of the method as a milder and less humiliating alternative to mechanical restraint. The nurses' main concerns were the risk of falls and the use of the bags as weapons. The latter could be controlled by using an additional bag. Patients were generally positive, especially if there was a history of abuse. The method should be further developed to replace at least some mechanical restraints. As with all 'milder means', care should be taken to really replace restraint and not to introduce additional coercion.

HER2DX Genomic Assay in HER2-Positive Early Breast Cancer Treated with Trastuzumab and Pertuzumab: A Correlative Analysis from the PHERGain Phase II Trial.

PURPOSE: The purpose of this study was to assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab-pertuzumab (HP)-based therapy in HER2-positive (HER2+) early breast cancer. EXPERIMENTAL DESIGN: HER2DX was analyzed in baseline pretreatment tumors from the PHERGain trial. Patients with stage I-IIIA HER2+ early breast cancer were randomized to group A [docetaxel, carboplatin, and HP (TCHP)] and group B (HP ± endocrine therapy). PET response was evaluated after two cycles. Group A received TCHP for six cycles regardless of PET response. Group B continued with HP ± endocrine therapy for six cycles (PET responders) or with TCHP for six cycles (PET nonresponders). The primary objective of this retrospective study was to associate the HER2DX pathologic complete response (pCR) score with pCR. The secondary objective was the association of the HER2DX risk score with 3-year invasive disease-free survival (iDFS). RESULTS: HER2DX was performed on 292 (82.0%) tumors. The overall pCR rate was 38.0%, with pCR rates of 56.4% in group A and 33.8% in group B. In multivariable analysis including treatment and clinicopathologic factors, the HER2DX pCR score (continuous variable) significantly correlated with pCR [OR, 1.29; 95% confidence interval (CI), 1.10-1.54; P < 0.001]. HER2DX-defined pCR-high, -med, and -low groups exhibited pCR rates of 50.4%, 35.8%, and 23.2%, respectively (pCR-high vs. pCR-low OR, 3.27; 95% CI, 1.54-7.09; P < 0.001). In patients with residual disease, the HER2DX high-risk group demonstrated numerically worse 3-year iDFS than the low-risk group (89.8% vs. 100%; HR, 2.70; 95% CI, 0.60-12.18; P = 0.197). CONCLUSIONS: HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease.

Neoadjuvant pembrolizumab+chemotherapy/adjuvant pembrolizumab for Early-Stage Triple-Negative breast cancer: Quality-of-Life results from randomized KEYNOTE-522 study.

BACKGROUND: In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab+chemotherapy then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522. METHODS: Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel+carboplatin then 4 cycles of doxorubicin (or epirubicin)+cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. EORTC QLQ-30 and QLQ-BR23 were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1/cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with ≥60%/80% completion/compliance were assessed using a longitudinal model (no alpha error assigned). RESULTS: Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab+chemotherapy [N = 762] vs placebo+chemotherapy [N = 383]) in LS mean change from baseline to week 21 in QLQ-C30 GHS/QoL, emotional functioning, and physical functioning were -1.04 (95% CI, -3.46 to 1.38), -0.69 (95% CI, -3.13 to 1.75), and -2.85 (95% CI, -5.11 to - 0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [N = 539] vs placebo [N = 308]) in LS mean change from baseline to week 24 were -0.41 (95% CI, -2.60 to 1.77), -0.60 (95% CI, -2.99 to 1.79), and -1.57 (95% CI, -3.36 to 0.21). CONCLUSIONS: No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab+chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo+chemotherapy in early-stage TNBC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03036488.

Impact of coadministration of proton-pump inhibitors and palbociclib in hormone receptor-positive/HER2-negative advanced breast cancer.

BACKGROUND: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study. METHODS: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive. RESULTS: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1-2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0-1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002). CONCLUSIONS: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC.

Health-related quality of life with sacituzumab govitecan in HR+/HER2- metastatic breast cancer in the phase III TROPiCS-02 trial.

BACKGROUND: The TROPiCS-02 study (NCT03901339) demonstrated that sacituzumab govitecan (SG) has superior clinical outcomes over treatment of physician's choice (TPC) chemotherapy in patients with hormone receptor-positive, human epidermal growth factor 2 receptor-negative (HR+/HER2-) metastatic breast cancer (mBC). Here, we present health-related quality of life (HRQoL) patient-reported outcome (PRO) findings from this study. PATIENTS AND METHODS: Eligible adults with HR+/HER2- mBC who previously received a taxane, endocrine-based therapy, a CDK4/6 inhibitor, and 2-4 lines of chemotherapy were randomized 1:1 to receive SG or TPC until progression or unacceptable toxicity. PROs were assessed at baseline and on day 1 of each cycle, using the European Organization for Research and Treatment of Cancer Quality-of-Life Core 30 (EORTC QLQ-C30), EQ-5D-5L, and PRO Common Terminology Criteria for Adverse Events (PRO-CTCAE). RESULTS: Compared to TPC, overall least square mean change from baseline was significantly better for SG for physical functioning and dyspnea, but worse for diarrhea. Time to first clinically meaningful worsening or death was significantly longer for SG in global health status/quality of life, physical functioning, fatigue, emotional functioning, dyspnea, insomnia, and financial difficulties of the EORTC QLQ-C30 and the EQ-VAS, but longer for TPC in diarrhea. Few patients in both arms reported experiencing any worsening to level 3 or 4 treatment-related symptomatic events during treatment, as assessed by 16 PRO-CTCAE items, except for diarrhea frequency and amount of hair loss, which favored TPC. CONCLUSIONS: SG was associated with an HRQoL benefit in most symptoms and functioning, compared with TPC. This supports the favorable profile of SG as a treatment option for patients with pretreated HR+/HER2- mBC.

Navigating practical challenges in immunotherapy for metastatic triple negative breast cancer.

Immunotherapy has revolutionized cancer therapy and now represents a standard of care for many tumor types, including triple-negative breast cancer. Despite the positive results that have led to the approval of immunotherapy in both early- and advanced-stage triple-negative breast cancer, pivotal clinical trials cannot address the myriad questions arising in everyday clinical practice, often falling short in delivering all the information that clinicians require. In this manuscript, we aim to address some of these practical questions, with the purpose of providing clinicians with a guide for optimizing the use of immune checkpoint inhibitors in the management of breast cancer patients and identifying opportunities for future research to clarify unresolved questions.

Real world study of sacituzumab govitecan in metastatic triple-negative breast cancer in the United Kingdom.

BACKGROUND: Treatment options for pre-treated patients with metastatic triple-negative breast cancer (mTNBC) remain limited. This is the first study to assess the real-world safety and efficacy of sacituzumab govitecan (SG) in the UK. METHODS: Data was retrospectively collected from 16 tertiary UK cancer centres. Pts had a diagnosis of mTNBC, received at least two prior lines of treatment (with at least one being in the metastatic setting) and received at least one dose of SG. RESULTS: 132 pts were included. Median age was 56 years (28-91). All patients were ECOG performance status (PS) 0-3 (PS0; 39, PS1; 76, PS2; 16, PS3;1). 75% (99/132) of pts had visceral metastases including 18% (24/132) of pts with CNS disease. Median PFS (mPFS) was 5.2 months (95% CI 4.5-6.6) with a median OS (mOS) of 8.7 months (95% CI 6.8-NA). The most common adverse events (AEs) were fatigue (all grade; 82%, G3/4; 14%), neutropenia (all grade; 55%, G3/4; 29%), diarrhoea (all grade; 58%, G3/4, 15%), and nausea (all grade; 38%, G3/4; 3%). SG dose reduction was required in 54% of pts. CONCLUSION: This study supports significant anti-tumour activity in heavily pre-treated pts with mTNBC. Toxicity data aligns with clinical trial experience.

Contribution of tumour and immune cells to PD-L1 expression as a predictive biomarker in metastatic triple-negative breast cancer: exploratory analysis from KEYNOTE-119.

The efficacy of pembrolizumab monotherapy versus chemotherapy increased with increasing programmed death ligand 1 (PD-L1) expression, as quantified by combined positive score (CPS; PD-L1 expression on both tumour cells and immune cells) in patients with previously treated metastatic triple-negative breast cancer (mTNBC) in the phase 3 KEYNOTE-119 study. This exploratory analysis was conducted to determine whether the expression of PD-L1 on tumour cells contributes to the predictive value of PD-L1 CPS in mTNBC. PD-L1 expression in tumour samples was assessed using PD-L1 IHC 22C3 pharmDx and quantified using both CPS and tumour proportion score (TPS; PD-L1 expression on tumour cells alone). Calculated immune cell density (CID) was defined as CPS minus TPS. The ability of each scoring method (CPS, TPS, and CID) to predict clinical outcomes with pembrolizumab was evaluated. With pembrolizumab, the area under the receiver operating characteristic curve was 0.69 (95% CI = 0.58-0.80) for CPS, 0.55 (95% CI = 0.46-0.64) for TPS, and 0.67 (95% CI = 0.56-0.77) for CID. After correction for cutoff prevalence, CPS performed as well as, if not better than, CID with respect to predicting objective response rate, progression-free survival, and overall survival. Data from this exploratory analysis suggest that, although PD-L1 expression on immune cells alone is predictive of response to programmed death 1 blockade in mTNBC, adding tumour PD-L1 expression assessment (i.e. CPS, which combines immune cell and tumour cell PD-L1 expression) may improve prediction. PD-L1 CPS thus remains an effective and broadly applicable uniform scoring system for enriching response to programmed death 1 blockade with pembrolizumab in mTNBC as well as other tumour types.

Optimal [18F]FDG PET/CT Cutoff for Pathologic Complete Response in HER2-Positive Early Breast Cancer Patients Treated with Neoadjuvant Trastuzumab and Pertuzumab in the PHERGain Trial.

The PHERGain trial investigated the potential of metabolic imaging to identify candidates for chemotherapy deescalation in human epidermal growth factor receptor 2 (HER2)-positive, invasive, operable breast cancer with at least 1 breast lesion evaluable by [18F]FDG PET/CT. [18F]FDG PET/CT responders were defined as patients with an SUVmax reduction (ΔSUVmax) of at least 40% in all of their target lesions after 2 cycles of trastuzumab and pertuzumab (HP) (with or without endocrine therapy). In total, 227 of 285 patients (80%) included in the HP arm showed a predefined metabolic response and received a total of 8 cycles of HP (with or without endocrine therapy). Pathologic complete response (pCR), defined as ypT0/isN0, was achieved in 37.9% of the patients. Here, we describe the secondary preplanned analysis of the best cutoff of ΔSUVmax for pCR prediction. Methods: Receiver-operating-characteristic analysis was applied to look for the most appropriate ΔSUVmax cutoff in HER2-positive early breast cancer patients treated exclusively with neoadjuvant HP (with or without endocrine therapy). Results: The ΔSUVmax capability of predicting pCR in terms of the area under the receiver-operating-characteristic curve was 72.1% (95% CI, 65.1-79.2%). The optimal ΔSUVmax cutoff was found to be 77.0%, with a 51.2% sensitivity and a 78.7% specificity. With this cutoff, 74 of 285 patients (26%) would be classified as metabolic responders, increasing the pCR rate from 37.9% (cutoff ≥ 40%) to 59.5% (44/74 patients) (P < 0.01). With this optimized cutoff, 44 of 285 patients (15.4%) would avoid chemotherapy in either the neoadjuvant or the adjuvant setting compared with 86 of 285 patients (30.2%) using the original cutoff (P < 0.001). Conclusion: In the PHERGain trial, an increased SUVmax cutoff (≥77%) after 2 cycles of exclusive HP (with or without endocrine therapy) achieves a pCR in the range of the control arm with chemotherapy plus HP (59.5% vs. 57.7%, respectively), further identifying a subgroup of patients with HER2-addicted tumors. However, the original cutoff (≥40%) maximizes the number of patients who could avoid chemotherapy.

3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial.

BACKGROUND: PHERGain was designed to assess the feasibility, safety, and efficacy of a chemotherapy-free treatment based on a dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab in patients with HER2-positive early breast cancer (EBC). It used an 18fluorine-fluorodeoxyglucose-PET-based, pathological complete response (pCR)-adapted strategy. METHODS: PHERGain was a randomised, open-label, phase 2 trial that took place in 45 hospitals in seven European countries. It randomly allocated patients in a 1:4 ratio with centrally confirmed, HER2-positive, stage I-IIIA invasive, operable breast cancer with at least one PET-evaluable lesion to either group A, where patients received docetaxel (75 mg/m2, intravenous), carboplatin (area under the curve 6 mg/mL per min, intravenous), trastuzumab (600 mg fixed dose, subcutaneous), and pertuzumab (840 mg loading dose followed by 420 mg maintenance doses, intravenous; TCHP), or group B, where patients received trastuzumab and pertuzumab with or without endocrine therapy, every 3 weeks. Random allocation was stratified by hormone receptor status. Centrally reviewed PET was conducted at baseline and after two treatment cycles. Patients in group B were treated according to on-treatment PET results. Patients in group B who were PET-responders continued with trastuzumab and pertuzumab with or without endocrine therapy for six cycles, while PET-non-responders were switched to receive six cycles of TCHP. After surgery, patients in group B who were PET-responders who did not achieve a pCR received six cycles of TCHP, and all patients completed up to 18 cycles of trastuzumab and pertuzumab. The primary endpoints were pCR in patients who were group B PET-responders after two treatment cycles (the results for which have been reported previously) and 3-year invasive disease-free survival (iDFS) in patients in group B. The study is registered with ClinicalTrials.gov (NCT03161353) and is ongoing. FINDINGS: Between June 26, 2017, and April 24, 2019, a total of 356 patients were randomly allocated (71 patients in group A and 285 patients in group B), and 63 (89%) and 267 (94%) patients proceeded to surgery in groups A and B, respectively. At this second analysis (data cutoff: Nov 4, 2022), the median duration of follow-up was 43·3 months (range 0·0-63·0). In group B, the 3-year iDFS rate was 94·8% (95% CI 91·4-97·1; p=0·001), meeting the primary endpoint. No new safety signals were identified. Treatment-related adverse events and serious adverse events (SAEs) were numerically higher in patients allocated to group A than to group B (grade ≥3 62% vs 33%; SAEs 28% vs 14%). Group B PET-responders with pCR presented the lowest incidence of treatment-related grade 3 or higher adverse events (1%) without any SAEs. INTERPRETATION: Among HER2-positive EBC patients, a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. This strategy identified about a third of patients who had HER2-positive EBC who could safely omit chemotherapy. FUNDING: F Hoffmann-La Roche.

A plain language summary of the TROPiCS-02 study in patients with breast cancer (HR-positive/HER2-negative).

WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment for certain types of advanced or metastatic breast cancer. One common type of breast cancer has at least 1 of 2 hormone receptors (HR positive) and does not have human epidermal growth factor 2 (HER2 negative). The HR and HER2 receptors are known to influence how severe a case of breast cancer is. Certain treatments will only work if a specific receptor is present on breast cancer cells. HR-positive/HER2-negative advanced or metastatic breast cancer can be treated with sacituzumab govitecan. This is a summary of the results of the TROPiCS-02 study. This study compared sacituzumab govitecan with standard chemotherapy in participants with HR-positive/HER2-negative advanced or metastatic breast cancer. WHAT WERE THE RESULTS?: The study showed that participants treated with sacituzumab govitecan lived significantly longer without their cancer getting worse than participants treated with chemotherapy. Participants also survived significantly longer and their tumors became significantly smaller in more participants treated with sacituzumab govitecan than with chemotherapy. In general, participants treated with sacituzumab govitecan were more likely to have side effects and had more severe side effects. These side effects included low levels of a type of white blood cell known as neutrophils and diarrhea. Oncologists (doctors that treat cancer) know of these side effects as they are common among people being treated for cancer. Doctors can control these side effects by following standard treatment guidelines and the package insert for sacituzumab govitecan. Participants treated with sacituzumab govitecan maintained their sense of well-being and ability to do daily activities (quality of life) longer than participants treated with chemotherapy. It also took longer for fatigue and other symptoms of cancer to worsen in participants treated with sacituzumab govitecan compared with chemotherapy. WHAT DO THE RESULTS MEAN?: Sacituzumab govitecan is more effective than standard chemotherapies for people who have already received multiple treatments for HR-positive/ HER2-negative advanced breast cancer. The side effects from sacituzumab govitecan could generally be managed well by doctors. Although there were more side effects with sacituzumab govitecan than with chemotherapy, they were generally mild to moderate.

First-Line Ipatasertib, Atezolizumab, and Taxane Triplet for Metastatic Triple-Negative Breast Cancer: Clinical and Biomarker Results.

PURPOSE: To evaluate a triplet regimen combining immune checkpoint blockade, AKT pathway inhibition, and (nab-) paclitaxel as first-line therapy for locally advanced/metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: The single-arm CO40151 phase Ib study (NCT03800836), the single-arm signal-seeking cohort of IPATunity130 (NCT03337724), and the randomized phase III IPATunity170 trial (NCT04177108) enrolled patients with previously untreated mTNBC. Triplet therapy comprised intravenous atezolizumab 840 mg (days 1 and 15), oral ipatasertib 400 mg/day (days 1-21), and intravenous paclitaxel 80 mg/m2 (or nab-paclitaxel 100 mg/m2; days 1, 8, and 15) every 28 days. Exploratory translational research aimed to elucidate mechanisms and molecular markers of sensitivity and resistance. RESULTS: Among 317 patients treated with the triplet, efficacy ranged across studies as follows: median progression-free survival (PFS) 5.4 to 7.4 months, objective response rate 44% to 63%, median duration of response 5.6 to 11.1 months, and median overall survival 15.7 to 28.3 months. The safety profile was consistent with the known toxicities of each agent. Grade ≥3 adverse events were more frequent with the triplet than with doublets or single-agent paclitaxel. Patients with PFS >10 months were characterized by NF1, CCND3, and PIK3CA alterations and increased immune pathway activity. PFS <5 months was associated with CDKN2A/CDKN2B/MTAP alterations and lower predicted phosphorylated AKT-S473 levels. CONCLUSIONS: In patients with mTNBC receiving an ipatasertib/atezolizumab/taxane triplet regimen, molecular characteristics may identify those with particularly favorable or unfavorable outcomes, potentially guiding future research efforts.

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).

Impact of pembrolizumab versus chemotherapy on health-related quality of life in patients with metastatic triple-negative breast cancer: results from the phase 3 randomised KEYNOTE-119 study.

BACKGROUND: In KEYNOTE-119 (ClinicalTrials.gov, NCT02555657), overall survival (primary end-point) was similar between pembrolizumab and chemotherapy in patients with previously treated metastatic triple-negative breast cancer (TNBC), although the pembrolizumab treatment effect increased with tumour PD-L1 expression. We report results of prespecified health-related quality of life (HRQoL) analyses from KEYNOTE-119. METHODS: Eligible patients were randomised 1:1 to pembrolizumab 200 mg Q3W intravenously for up to 35 cycles or treatment of physician's choice per local/country guidelines. Prespecified exploratory end-points were the change from baseline in HRQoL (EORTC QLQ-C30, QLQ-BR23) and to characterise utilities (EQ-5D-3L). Time to deterioration (TTD) was the time from start of treatment to first onset of a ≥10-point worsening from baseline. RESULTS: HRQoL analyses included 187 patients with tumour PD-L1 combined positive score (CPS) ≥10. Changes from baseline at 6 weeks (primary analysis time point) were directionally better with pembrolizumab versus chemotherapy for QLQ-C30 GHS/QoL (between-group difference in least-squares mean scores of 4.21 [95% CI, -1.38 to 9.80]), QLQ-C30 functional scales (physical, role, cognitive, social), QLQ-C30 symptom scales/items (fatigue, nausea/vomiting, dyspnoea, appetite loss), and QLQ-BR23 symptom scales/items (systemic therapy side-effects, upset by hair loss). Median TTD was directionally longer for pembrolizumab versus chemotherapy for QLQ-C30 QHS/QoL (4.3 versus 1.7 months), QLQ-C30 nausea/vomiting (7.7 versus 4.8 months), and QLQ-BR23 systemic therapy side-effects (6.1 versus 3.4 months). Minimal treatment differences were observed for other HRQoL end-points. CONCLUSIONS: HRQoL results were consistent with clinical outcomes and appeared to be driven by results for patients with tumour PD-L1 CPS ≥10.

Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: In the phase 3 KEYNOTE-522 study, addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab significantly increased pathologic complete response (pCR) and event-free survival (EFS) vs neoadjuvant chemotherapy in patients with early triple-negative breast cancer. Objective: To evaluate efficacy and safety outcomes for patients enrolled in East/Southeast Asia (Asia) in KEYNOTE-522. Design, Setting, and Participants: KEYNOTE-522, a multicenter, double-blind, randomized clinical trial, enrolled 1174 patients between March 7, 2017, and September 13, 2018. For interim EFS and overall survival (OS) analyses (data cutoff, March 23, 2021), median follow-up was 39.8 months (range, 30.4-46.9 months) for pembrolizumab plus chemotherapy and 40.8 months (range, 30.1-46.9 months) for placebo plus chemotherapy. Data cutoff for pCR analysis was September 24, 2018. This secondary analysis included adults enrolled in Asia with newly diagnosed, previously untreated, nonmetastatic triple-negative breast cancer (tumor stage T1c and nodal stage N1-2 or tumor stage T2-4 and nodal stage N0-2) and Eastern Cooperative Oncology Group performance status of 0 to 1, regardless of programmed cell death ligand 1 (PD-L1) status. Intervention: Patients were randomized 2:1 to 4 cycles of pembrolizumab (200 mg every 3 weeks) or placebo plus carboplatin and paclitaxel and another 4 cycles of pembrolizumab or placebo plus doxorubicin or epirubicin and cyclophosphamide before surgery. After definitive surgery, patients received pembrolizumab or placebo every 3 weeks for 9 cycles or until recurrence or unacceptable toxic effects. Main Outcomes and Measures: The main outcome was pCR (no evidence of primary tumor after neoadjuvant therapy or carcinoma in situ after neoadjuvant therapy and no regional lymph node involvement after neoadjuvant therapy) at the time of definitive surgery and EFS. Results: A total of 216 of 1174 randomized patients (all female; median [range] age, 46.0 [24.0-71.0] years) were from Korea, Japan, Taiwan, and Singapore (136 in the pembrolizumab plus chemotherapy group and 80 in the placebo plus chemotherapy group). Of these patients, 104 (76.5%) in the pembrolizumab plus chemotherapy group and 60 (75.0%) in the placebo plus chemotherapy group had a tumor PD-L1 combined positive score of 1 or greater. Pathologic complete response was 58.7% (95% CI, 46.7%-69.9%) with pembrolizumab plus chemotherapy and 40.0% (95% CI, 26.4%-54.8%) with placebo plus chemotherapy; benefit was observed regardless of PD-L1 status. Thirteen patients (9.6%) in the pembrolizumab plus chemotherapy group and 20 patients (25.0%) in the placebo plus chemotherapy group had EFS events (hazard ratio, 0.35; 95% CI, 0.17-0.71). The 36-month EFS rate was 91.2% (95% CI, 85.0%-94.9%) with pembrolizumab plus chemotherapy and 77.2% (95% CI, 66.3%-85.0%) with placebo plus chemotherapy. Grade 3 to 4 treatment-related adverse events occurred in 109 patients (80.1%) receiving pembrolizumab plus chemotherapy and 64 patients (81.0%) receiving placebo plus chemotherapy. Conclusions and Relevance: In this subgroup analysis of patients enrolled in Asia in KEYNOTE-522, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab led to clinically meaningful improvements in pCR and EFS vs neoadjuvant chemotherapy alone. These findings support the use of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as a standard-of-care therapy for patients in Asian countries with early triple-negative breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03036488.

Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2-) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables. METHODS: In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2- locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339. FINDINGS: At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4-18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0-15·7] vs 11·2 months [10·1-12·7]; hazard ratio [HR] 0·79, 95% CI 0·65-0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03-2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61-0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60-0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. INTERPRETATION: Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2- metastatic breast cancer. FUNDING: Gilead Sciences.

TROPION-Breast02: Datopotamab deruxtecan for locally recurrent inoperable or metastatic triple-negative breast cancer.

Despite recent treatment advances, the prognosis for patients with locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) remains poor. The antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) is composed of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a stable, cleavable linker. The phase III TROPION-Breast02 trial in patients previously untreated for locally recurrent inoperable or metastatic TNBC, who are not candidates for PD-1/PD-L1 inhibitors is evaluating efficacy and safety of Dato-DXd versus investigator's choice of chemotherapy (ICC). Approximately 600 patients will be randomized 1:1 to Dato-DXd 6 mg/kg iv. every 3 weeks or ICC (paclitaxel, nab-paclitaxel, carboplatin, capecitabine or eribulin mesylate). Dual primary end points are progression-free survival by blinded independent central review and overall survival.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is hard to treat. Tumors lack receptors for estrogen and progesterone, which means that standard endocrine therapy is ineffective, and it does not express HER2, so HER2 therapies are also not appropriate. However, the majority of TNBC tumors do possess a cell surface protein called TROP2 which provides a way of directing treatment inside tumor cells that is more selective than traditional chemotherapy. Datopotamab deruxtecan (Dato-DXd) is a drug that consists of two parts: datopotamab (an antibody) and DXd (the cancer-cell killing toxic component), which are joined via a stable linker. Datopotamab binds to the TROP2 protein found on TNBC tumors and is taken into the cell. The linker is then broken and releases DXd, which kills the tumor cell. By binding to cancer cells before releasing the payload, treatment is directed to the tumor, minimizing side effects in the rest of the body. The TROPION-Breast02 study aims to discover whether Dato-DXd is more effective than standard-of-care chemotherapy, allowing patients with TNBC to live longer without their breast cancer getting worse. This study is also looking at how Dato-DXd may affect patients' overall functioning and quality of life. TROPION-Breast02 will recruit approximately 600 patients who: Have cancer that has spread from the original site (metastatic), or cancer that returned to the same site (locally recurrent) that cannot be surgically removed Have not received any prior treatment for this stage of cancer Cannot receive an alternative type of anticancer treatment called PD-(L)1 inhibitors Had any length of time between their last treatment with the aim of cure and return of their disease Eligible patients will be randomly assigned to a treatment group in equal numbers to either Dato-DXd or an appropriate chemotherapy (one of five available options, chosen by the treating doctor). Each patient will generally continue to receive their designated treatments if the tumor is controlled by the drug, there are no unacceptable side effects, or the patient chooses to stop treatment. Clinical Trial Registration: NCT05374512 (ClinicalTrials.gov).