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JMIR Cancer Apr 2024Trastuzumab has had a major impact on the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Anti-HER2 biosimilars such as Ogivri...
Comparison of the Real-World Reporting of Symptoms and Well-Being for the HER2-Directed Trastuzumab Biosimilar Ogivri With Registry Data for Herceptin in the Treatment of Breast Cancer: Prospective Observational Study (OGIPRO) of Electronic Patient-Reported Outcomes.
BACKGROUND
Trastuzumab has had a major impact on the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Anti-HER2 biosimilars such as Ogivri have demonstrated safety and clinical equivalence to trastuzumab (using Herceptin as the reference product) in clinical trials. To our knowledge, there has been no real-world report of the side effects and quality of life (QoL) in patients treated with biosimilars using electronic patient-reported outcomes (ePROs).
OBJECTIVE
The primary objective of this prospective observational study (OGIPRO study) was to compare the ePRO data related to treatment side effects collected with the medidux app in patients with HER2-positive BC treated with the trastuzumab biosimilar Ogivri (prospective cohort) to those obtained from historical cohorts treated with Herceptin alone or combined with pertuzumab and/or chemotherapy (ClinicalTrials.gov NCT02004496 and NCT03578731).
METHODS
Patients were treated with Ogivri alone or combined with pertuzumab and/or chemotherapy and hormone therapy in (neo)adjuvant and palliative settings. Patients used the medidux app to dynamically record symptoms (according to the Common Terminology Criteria for Adverse Events [CTCAE]), well-being (according to the Eastern Cooperative Oncology Group Performance Status scale), QoL (using the EQ-5D-5L questionnaire), cognitive capabilities, and vital parameters over 6 weeks. The primary endpoint was the mean CTCAE score. Key secondary endpoints included the mean well-being score. Data of this prospective cohort were compared with those of the historical cohorts (n=38 patients; median age 51, range 31-78 years).
RESULTS
Overall, 53 female patients with a median age of 54 years (range 31-87 years) were enrolled in the OGIPRO study. The mean CTCAE score was analyzed in 50 patients with available data on symptoms, while the mean well-being score was evaluated in 52 patients with available data. The most common symptoms reported in both cohorts included fatigue, taste disorder, nausea, diarrhea, dry mucosa, joint discomfort, tingling, sleep disorder, headache, and appetite loss. Most patients experienced minimal (grade 0) or mild (grade 1) toxicities in both cohorts. The mean CTCAE score was comparable between the prospective and historical cohorts (29.0 and 30.3, respectively; mean difference -1.27, 95% CI -7.24 to 4.70; P=.68). Similarly, no significant difference was found for the mean well-being score between the groups treated with the trastuzumab biosimilar Ogivri and Herceptin (74.3 and 69.8, respectively; mean difference 4.45, 95% CI -3.53 to 12.44; P=.28).
CONCLUSIONS
Treatment of patients with HER2-positive BC with the trastuzumab biosimilar Ogivri resulted in equivalent symptoms, adverse events, and well-being as found for patients treated with Herceptin as determined by ePRO data. Hence, integration of an ePRO system into research and clinical practice can provide reliable information when investigating the real-world tolerability and outcomes of similar therapeutic compounds.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05234021; https://clinicaltrials.gov/study/NCT05234021.
PubMed: 38573759
DOI: 10.2196/54178 -
JAMA Network Open Apr 2024Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients...
IMPORTANCE
Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC).
OBJECTIVE
To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan.
DESIGN, SETTING, AND PARTICIPANTS
This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022.
EXPOSURE
Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose.
MAIN OUTCOMES AND MEASURES
Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR).
RESULTS
A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months.
CONCLUSIONS AND RELEVANCE
In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.
Topics: Humans; Middle Aged; Female; Breast Neoplasms; Capecitabine; Cohort Studies; Prospective Studies; Trastuzumab; Brain Neoplasms; Disease Progression; Receptor, ErbB-2; Oxazoles; Pyridines; Quinazolines
PubMed: 38568692
DOI: 10.1001/jamanetworkopen.2024.4435 -
The Oncologist Mar 2024According to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria, both immunohistochemical HER2 (3+) and HER2 (2+)/in situ...
Comparison of the Response to Neoadjuvant Therapy Between Immunohistochemistry HER2 (3+) and HER2 (2+)/ISH+ Early-Stage Breast Cancer: A Retrospective Multicenter Cohort Study.
BACKGROUND
According to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria, both immunohistochemical HER2 (3+) and HER2 (2+)/in situ hybridization (ISH) amplified [HER2 (2+)/ISH+] breast cancers (BCs) fall under the HER2-positive BC category. However, there is a lack of studies exploring the difference of neoadjuvant therapeutic response between patients with HER2 (3+) and HER2 (2+)/ISH+ early BC. We aimed to evaluate the neoadjuvant therapeutic response, long-term outcome, and intrinsic subtype heterogeneity between HER2 (3+) and HER2 (2+)/ISH+ BC.
METHODS
We examined 2 distinct cohorts. Cohort 1 (C1) encompassed 2648 patients with HER2-positive early BC diagnoses, and they received neoadjuvant therapy (NT) and surgery between January 1, 2009 and December 31, 2022, from the Shanghai Jiao Tong University Breast Cancer Data Base. Cohort 2 (C2) comprised 135 patients with early-stage HER2-positive BC who underwent NT and surgery at Henan Cancer Hospital from January 1, 2021, to December 31, 2022. These patients had available genomic and transcriptomic data at their disposal. C1 and C2 were further categorized into 2 patient cohorts as follows: (1) patients with IHC HER2 (3+) early BC [HER2 (3+) group], (2) patients with HER2 (2+)/ISH+ early BC [HER2 (2+)/ISH+ group]. Among those excluded from the analysis were patients < 18 years or >80 years of age. Clinicopathological parameters, long-term outcomes, and intrinsic subtypes were analyzed.
RESULTS
In the C1 population, 83.7% had HER2 (3+) BC, while 16.3% had HER2 (2+)/ISH+ BC. Patients with HER2 (3+) had a significantly higher pathological complete response (PCR) rate (38.9%) than patients with HER2 (2+)/ISH+ (18.1%; P < .001), but the disease-free survival (DFS) was comparable after a median follow-up of 29 months (P = .556). The addition of trastuzumab or trastuzumab plus pertuzumab to neoadjuvant chemotherapy (NAC) improved PCR rates and DFS in HER2 (3+) BC but not in HER2 (2+)/ISH+ BC. In the C2 population, 97.75% HER2 (3+) and 52.17% HER2 (2+)/ISH+ were HER2 enriched (HER2E) subtype (P < .001). HER2E showed increased PCR rates compared to non-HER2E (P = .004).
CONCLUSIONS
Compared to HER2 (3+) BC, the limited effectiveness of neoadjuvant trastuzumab and pertuzumab therapy for HER2 (2+)/ISH+ BC is due to subtype heterogeneity. Reassessment of targeted therapy efficacy in patients with HER2 (2+)/ISH+ BC is essential.
PubMed: 38537665
DOI: 10.1093/oncolo/oyae047 -
International Journal of Clinical... Jun 2024Standard-of-care for HER2-positive metastatic breast cancer (HER2 + mBC) patients consists of trastuzumab ± pertuzumab with chemotherapy in first-line (1L), and...
PURPOSE
Standard-of-care for HER2-positive metastatic breast cancer (HER2 + mBC) patients consists of trastuzumab ± pertuzumab with chemotherapy in first-line (1L), and ado-trastuzumab emtansine (T-DM1) or the more recently approved trastuzumab deruxtecan (T-DXd) in second-line (2L). Contemporary data on treatment sequencing and real-world effectiveness is limited. This study aims to report 2L treatments and outcomes among HER2 + mBC patients in the United States (US).
METHODS
HER2 + mBC patients initiating 2L treatment (index date) between January 2014 and February 2021 were identified from the Syapse Learning Health Network (LHN) database. Summary statistics for patient characteristics, treatment received, reasons for 2L discontinuation and time to 2L-clinical outcomes are reported.
RESULTS
Of the 312 patients initiating 2L treatment, had a median age of 59 years (interquartile range [IQR], 50-66) at the start of 2L. The majority were white (69%) and had de novo mBC (62%). Top three 2L regimens included T-DM1 ± endocrine therapy (29%), trastuzumab/pertuzumab/taxane (10%) and T-DM1/trastuzumab (8%). Around 88% discontinued 2L and 63% received subsequent treatment. Median time-to-next-treatment was 10.6 months (95% CI, 8.8-13.3) and real-world progression-free-survival was 7.9 months (95% CI, 7.0-9.9). Among 274 patients who discontinued 2L, 47% discontinued due to progression and 17% because of intolerance/toxicity, respectively.
CONCLUSION
This real-world US study showed that approximately two-thirds of 2L patients received subsequent therapy and disease progression was the most common reason for 2L discontinuation highlighting the need for timely 2L treatment with the most efficacious drug to allow patients to achieve longer treatment duration and delayed progression.
Topics: Humans; Female; Breast Neoplasms; Middle Aged; Receptor, ErbB-2; Aged; United States; Trastuzumab; Antineoplastic Combined Chemotherapy Protocols; Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Retrospective Studies; Neoplasm Metastasis; Progression-Free Survival; Treatment Outcome; Camptothecin; Immunoconjugates
PubMed: 38528295
DOI: 10.1007/s10147-024-02492-5 -
Asian Journal of Surgery Mar 2024
Real-world clinical study of Trastuzumab biosimilar (Zercepac) and Pertuzumab (Perjeta) in combination with chemotherapy for neoadjuvant treatment of HER-2-positive breast cancer.
PubMed: 38522990
DOI: 10.1016/j.asjsur.2024.03.063 -
European Journal of Cancer (Oxford,... May 2024In 2-5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy...
BACKGROUND
In 2-5% of patients with colorectal cancer (CRC), human epidermal growth factor 2 (HER2) is amplified or overexpressed. Despite prior evidence that anti-HER2 therapy confers clinical benefit (CB) in one-third of these patients, it is not approved for this indication in Europe. In the Drug Rediscovery Protocol (DRUP), patients are treated with off-label drugs based on their molecular profile. Here, we present the results of the cohort 'trastuzumab/pertuzumab for treatment-refractory patients with RAS/BRAF-wild-type HER2amplified metastatic CRC (HER2+mCRC)'.
METHODS
Patients with progressive treatment-refractory RAS/BRAF-wild-type HER2+mCRC with measurable disease were included for trastuzumab plus pertuzumab treatment. Primary endpoints of DRUP are CB (defined as confirmed objective response (OR) or stable disease (SD) ≥ 16 weeks) and safety. Patients were enrolled using a Simon-like 2-stage model, with 8 patients in stage 1 and 24 patients in stage 2 if at least 1/8 patients had CB. To identify biomarkers for response, whole genome sequencing (WGS) was performed on pre-treatment biopsies.
RESULTS
CB was observed in 11/24 evaluable patients (46%) with HER2+mCRC, seven patients achieved an OR (29%). Median duration of response was 8.4 months. Patients had undergone a median of 3 prior treatment lines. Median progression-free survival and overall survival were 4.3 months (95% CI 1.9-10.3) and 8.2 months (95% CI 7.2-14.7), respectively. No unexpected toxicities were observed. WGS provided potential explanations for resistance in 3/10 patients without CB, for whom WGS was available.
CONCLUSIONS
The results of this study confirm a clinically significant benefit of trastuzumab plus pertuzumab treatment in patients with HER2+mCRC.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Proto-Oncogene Proteins B-raf; Receptor, ErbB-2; Trastuzumab
PubMed: 38471288
DOI: 10.1016/j.ejca.2024.113988 -
MedComm Mar 2024Triple-positive breast cancer (TPBC) poorly responds to current standard neoadjuvant therapy (trastuzumab plus pertuzumab and chemotherapy). Our previous MUKDEN 01 study...
Triple-positive breast cancer (TPBC) poorly responds to current standard neoadjuvant therapy (trastuzumab plus pertuzumab and chemotherapy). Our previous MUKDEN 01 study showed a promising total pathological complete response (tpCR) rate of 30.4% with neoadjuvant pyrotinib (pan-human epidermal growth factor receptor tyrosine kinase inhibitor) plus dalpiciclib (cyclin-dependent kinase 4/6 inhibitor) and letrozole, but the efficacy remains suboptimal. This pilot study (NCT05228951) explored adding trastuzumab to this triplet neoadjuvant regimen in patients with stage II-III TPBC. The primary endpoint was tpCR (ypT0/is, ypN0) rate. Between February 2022 and June 2022, 12 patients were enrolled, and seven (58%; 95% confidence interval [CI], 27.7%-84.8%) patients achieved tpCR. The rate of residual cancer burden (RCB) 0-I was 75% (95% CI, 46.8%-91.1%). The objective response rate (ORR) was 92% (95% CI, 64.6%-98.5%). Mean Ki-67 level was significantly reduced from 45.0% (95% CI, 19.5%-70.5%) at baseline to 17.2% (95% CI, 0.7%-33.7%) after neoadjuvant therapy ( = 0.03). The most common grade 3 adverse events were diarrhea (four [33%]) and decreased neutrophil count (three [25%]). No grade 4 adverse events or treatment-related deaths occurred. This four-drug neoadjuvant regimen shows promising pathological response with an acceptable safety profile in patients with TPBC. A randomized controlled trial (NCT05638594) of this regimen is being conducted.
PubMed: 38469548
DOI: 10.1002/mco2.505 -
Breast Cancer (Dove Medical Press) 2024In this observational study, we analyzed the treatment patterns and clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive...
BACKGROUND
In this observational study, we analyzed the treatment patterns and clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) who developed brain metastases during their disease in a 2.7 million-member public health-provider in Israel.
METHODS
Newly diagnosed patients with mBC who initiated first-line treatment between January 2013 and June 2021 were identified. Time on treatment (ToT) and overall survival (OS) were assessed at a minimum of 6 months follow-up (cutoff: December 2021).
RESULTS
We identified a total of 61 patients: 98.4% females, median age 50 years (IQR = 44-63), 85% invasive ductal tumors, 44% hormone receptor positive, 51% performance status 0-1. The median duration of follow-up was 6.2 years. All patients initiated a combination treatment of trastuzumab, pertuzumab, and chemotherapy (TPC), and 72% moved to second-line treatment during the study follow-up period (82% ado-trastuzumab emtansine). The median ToT for first-line and second-line treatments were 16.9 months (95% CI = 13.9-27.7) and 7.9 months (95% CI = 5.6-10.9), respectively. The median overall survival (OS) was 45.5 months (95% CI = 35.4-71.2) from the initiation of first-line treatment. When considering the timing of brain metastases, the median OS was 36.3 months (95% CI = 10.0-NR) for those diagnosed upfront (n = 15, 25%), 59.1 months (95% CI = 32.5-NR) for those diagnosed while on TPC (n = 25, 41%), and 40.8 months (95% CI = 35.4-NR) for those diagnosed at a later stage (n = 21, 34%). The median OS from brain metastases diagnosis was 25.1 months (95% CI = 17.0-34.6).
CONCLUSION
Patients with upfront brain involvement at the time of mBC diagnosis had shorter survival compared to those who started TPC without brain metastases. Nonetheless, the overall results from this study compare favorably with previous studies and contribute to understanding the value of traditional treatment options, which will serve as a baseline for future treatment strategies in the real-world setting.
PubMed: 38464505
DOI: 10.2147/BCTT.S439158 -
Research Square Feb 2024HER2(+) metastatic breast cancer (mBC) is one of the most aggressive and lethal cancer types among females. While initially effective, targeted therapeutic approaches...
PURPOSE
HER2(+) metastatic breast cancer (mBC) is one of the most aggressive and lethal cancer types among females. While initially effective, targeted therapeutic approaches with trastuzumab and pertuzumab antibodies and antibody-drug conjugates (ADC) lack long-term efficacy against HER2(+) mBC and can cause severe systemic toxicity due to off-target effects. Therefore, the development of novel targeted delivery platforms that minimize toxicity and increase therapeutic efficacy is critical to the treatment of HER2(+) breast cancer (BC). A pretargeting delivery platform can minimize the non-specific accumulation and off-target toxicity caused by traditional one-step delivery method by separating the single delivery step into a pre-targeting step with high-affinity biomarker binding ligand followed by the subsequent delivery step of therapeutic component with fast clearance. Each delivery component is functionalized with bioorthogonal reactive groups that quickly react , forming cross-linked clusters on the cell surface, which facilitates rapid internalization and intracellular delivery of therapeutics.
PROCEDURES
We have successfully developed a click chemistry-based pretargeting platform for HER2(+) BC enabling PET-MR image guidance for reduced radiation dose, high sensitivity, and good soft tissue contrast. Radiolabeled trastuzumab and superparamagnetic iron-oxide carriers (uSPIO) were selected as pretargeting and delivery components, respectively. HER2(+) BT-474 cell line and corresponding xenografts were used for and studies.
RESULTS
An enhanced tumor accumulation as well as tumor-to-organ accumulation ratio was observed in pretargeted mice up to 24 h post uSPIO injection. A 40% local T decrease in the pretargeted mice tumor was observed within 4 h, and an overall 15% T drop was retained for 24 h post uSPIO injection.
CONCLUSIONS
Prolonged tumor retention and increased tumor-to-organ accumulation ratio provided a solid foundation for pretargeted image-guided delivery approach for applications.
PubMed: 38464126
DOI: 10.21203/rs.3.rs-3974001/v1 -
Nature Communications Mar 2024The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response... (Randomized Controlled Trial)
Randomized Controlled Trial
The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.
Topics: Female; Humans; Adjuvants, Immunologic; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Receptor, ErbB-2; Trastuzumab
PubMed: 38461323
DOI: 10.1038/s41467-024-45591-7