Pertuzumab Research Articles (Page 1)

738P Impact of prior anti-EGFR therapy (EGFRi) on efficacy of pertuzumab (PER) plus trastuzumab (TRA) for HER2-positive (HER2+) metastatic colorectal cancer (mCRC): TRIUMPH/MyPathway integrated analysis

Abstract Introduction: The paucity of real-world data (RWD) imposes barriers to evidence-based decision making for managing patients (pts) with HER2+ unresectable (u)/metastatic (m) breast cancer (BC). We present current treatment practices and associated survival outcomes in HER2+ u/mBC pts in routine clinical care from the Brazil cohort of the HER2 REAL retrospective study (NCT04857619). Method: Adult pts (≥18 years [yrs]) diagnosed with HER2+ u/mBC (index date) since Jan 2017 having ≥12 months (mo) follow-up data from diagnosis and completing ≥1-line of therapy (LOT) were enrolled based on medical chart review (data cut-off 31 Oct 2022). The primary endpoint was treatment patterns. Secondary endpoints included demographic and clinicopathologic characteristics, real-world median progression-free survival (mPFS), and median overall survival (mOS). Survival outcomes were calculated using Kaplan Meier method and presented as median (95% confidence interval [CI]). Data for the first 3 LOTs are presented. Results: Of the 152 pts screened, 78.9% (120) were analyzed; some pts (21.0% [32]) were excluded from the final dataset due to insufficient proof of HER2 positivity or not completing ≥1 LOT in the metastatic setting. Median (range) age was 53 (25–85) yrs with 99.2% (119) females; 55.9% with available data (52/93) were postmenopausal. The median (range) time from initial BC diagnosis to index date was 18 (0–424) mo. Of those with available data at index date, 62.1% (41/66) had moderately differentiated tumors with 90.4% (66/73) having ductal histology; 29.2% (35/120) reported hormone receptor positivity (estrogen receptor: 65.7% [23/35]; progesterone receptor: 34.3% [12/35]) while data were unavailable for the rest. Of 86 pts with available data, 24 pts (27.9%) reported a family history of BC. Overall, 62.0% (62/100) with available data had visceral metastasis and 20.0% (20/100) had CNS metastases. LOT1 was received by 89.2% (107/120); 13 eligible pts were excluded because their LOT1 start date was >30 days before index date. LOT2 was received by 67.5% (81/120) pts, and LOT3 by 30.0% (36/120). Treatment attrition rates were 19.6% (21/107) after LOT1, 33.3% (27/81) after LOT2, and 11.1% (4/36) after LOT3. The top regimen in LOT1 was trastuzumab (TRA) + pertuzumab (PTZ) + chemotherapy (CT) reported in 35.5% (38/107), in LOT2 was trastuzumab emtansine (T-DM1) reported in 16.0% (13/81), and in LOT3 was TRA + CT reported in 27.8% (10/36). With a median follow-up of 35.1 (95% CI: 1.5–167.1) mo, the 2-yr survival rate was 52.0%; mOS was not estimable overall. For TRA+PTZ+CT in LOT1, real-world mPFS was 14.1 (95% CI: 9.2–21.7) mo, and for T-DM1 in LOT2, real-world mPFS was not estimable. The main reason for treatment discontinuation was disease progression (51.4% [55/107] in LOT1, 45.7% [37/81] in LOT2, and 36.1% [13/36] in LOT3); 7, 3, and 1 pt discontinued treatment due to toxicity in LOT1, LOT2, and LOT3, respectively. Conclusion: This real-world analysis of HER2+ advanced or u/mBC showed that only a minority of pts followed the recommended guideline-directed medical therapy for the disease. These suboptimal treatment patterns are, at least partially, possibly due to access barriers and need to be further explored. These findings are in line with those reported in the HER2 REAL global dataset. This analysis highlights the need for a comprehensive study of real-world treatment patterns as they do not seem to reflect results observed in randomized clinical trials. Identification of the possible hindrances towards optimization of standard of care practices is an essential step for improving outcomes in this pt population. Citation Format: Carlos Barrios, Soo Chin Lee, Wei-Pang Chung, Tainan, Taiwan., Roger K.C. Ngan, Seock-Ah Im, Rina Hui, Eduardo H Cronemberger, Graziela Dal Molin, Sabina Aleixo, Antonio Matsuda, Teresa Tung. Real-world Treatment for HER2-positive (HER2+) Metastatic Breast Cancer Patients and Compliance to Guideline Recommendations: HER2 REAL Brazil Cohort [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-05-25.

e13009 Background: PERT-IJS is a proposed biosimilar to reference pertuzumab (PERT). This study assessed the pharmacokinetic (PK) equivalence, safety, tolerability, and immunogenicity of PERT-IJS compared with EU-approved PERT (EU-PERT) and US-licensed PERT (US-PERT) and EU-PERT versus US-PERT. Methods: In this double-blind, three-arm, parallel group, Phase 1 study, healthy male subjects were randomized 1:1:1 to 60±5 mins of a single 420 mg intravenous infusion of PERT-IJS (n = 50), EU-PERT (n = 50), or US-PERT (n = 49). Sentinel dosing with one subject from each treatment arm was performed initially to ensure optimal safety. PK, safety, and immunogenicity were evaluated for 91 days after dosing. The primary endpoint was area under the serum concentration–time curve (AUC) from time 0 to infinity (AUC 0-∞ ), and secondary endpoints were maximum serum concentration (C max ) and AUC from time 0 to the last measurable concentration at time t (AUC 0-t ) for pertuzumab. The pre-defined equivalence criterion was a 90% confidence interval (CI) of 80.00–125.00% for ratios of geometric least squares means (LSMs) among the test and reference products. Safety data were collected throughout the study and analyzed descriptively. Results: A total of 149 subjects, mean age 41.6 years, were randomized to the study treatments. The 90% CIs of the ratios of geometric LSMs were within the pre-defined bioequivalence interval of 80.00-125.00% for the primary and secondary endpoints (Table). Safety and tolerability profiles were also comparable among the treatment groups. The anti-drug antibody rates were comparable in all three treatment groups. Conclusions: This study demonstrated PK bioequivalence as well as comparable safety, tolerability, and immunogenicity between PERT-IJS versus EU-PERT/US-PERT and EU-PERT versus US-PERT in healthy male subjects. Clinical trial information: 2022-001691-34 . Statistical results of pertuzumab pharmacokinetics parameters. Treatment Comparison PK Parameter Geometric Least Squares Means Ratio 90% Confidence Interval PERT-IJS/EU-PERT AUC 0-∞ (mcg·h/mL) 0.97 91.48%-103.34% PERT-IJS/US-PERT AUC 0-∞ (mcg·h/mL) 0.94 88.25%-99.69% EU-PERT/US-PERT AUC 0-∞ (mcg·h/mL) 0.96 90.74%-102.55% PERT-IJS/EU-PERT AUC 0-t (mcg·h/mL) 0.97 91.39%-103.32% PERT-IJS/US-PERT AUC 0-t (mcg·h/mL) 0.94 88.06%-99.56% EU-PERT/US-PERT AUC 0-t (mcg·h/mL) 0.96 90.61%-102.47% PERT-IJS/EU-PERT C max (mcg/mL) 1.00 94.28%-106.01% PERT-IJS/US-PERT C max (mcg/mL) 0.97 91.70%-103.12% EU-PERT/US-PERT C max (mcg/mL) 0.97 91.71%-103.16%

Trastuzumab (TRA) is a key drug in human epidermal growth factor receptor type 2 (HER2)-positive breast cancer treatment. Infusion reactions (IR) with TRA are frequently observed in practice. Although the efficacy of premedication has been previously reported, it remains uncommon. The probability of severe IR due to TRA is low; however, when it does occur, it is associated with patient discomfort and expenditure of medical resources. This study aimed to analyze the factors associated with the occurrence of IR in patients with breast cancer who received TRA. We retrospectively studied 204 patients who underwent TRA for breast cancer treatment between September 2008 and June 2023, identifying factors influencing the occurrence of IR at the time of TRA administration. A total of 182 patients were included in this study, and the incidence of IR was 25.8% (47/182 patients). Multiple logistic regression analysis showed that pertuzumab (PER) use, high alkaline phosphatase (ALP), and low high-density lipoprotein (HDL) cholesterol levels were associated with IR. IR should be considered when PER is combined with TRA. ALP and HDL cholesterol levels may be predictive markers of TRA-induced IR in patients with breast cancer.

Trastuzumab (TRZ) fue el primer anticuerpo monoclonal (AcM) IgG humanizado aprobado para el tratamiento del cáncer de mama (CM). Desde su aprobación en 1998, se estima que se ha administrado a más de 2,5 millones de mujeres en todo el mundo y se encuentra en la lista de medicamentos esenciales de la OMS. TRZ ha revolucionado la terapia del CM HER2+. Tanto los mecanismos no inmunológicos como los inmunomediados explican la actividad clínica de TRZ. La asociación entre el polimorfismo del FcƴRIIIa y la eficacia terapéutica de los AcMs se ha comprobado en varios modelos. Los pacientes con los genotipos F/V y V/F presentan una mejor respuesta clínica cuando son tratados con diferentes anticuerpos. Sin embargo, existen datos controvertidos sobre la asociación con el polimorfismo FcƴRIIIa y la actividad del TRZ En este trabajo evaluamos las variantes del polimorfismo FcƴRIIIa en pacientes con CM HER2+ en terapia neoadyuvante (NA) compuesta de quimioterapia (QT) basada en taxanos y platino en combinación con TRZ y pertuzumab (PER). Si bien nuestro estudio no logo identificar ninguna asociación genética de los distintos alelos del FcgRIIIa con la respuesta al tratamiento neoadyuvante de quimioterapia en combinación con TRZ, quizás debido al bajo número de pacientes que no presentaron respuesta patológica completa (RPC), estos resultados no excluyen un papel para los FcγR.

To use population physiologically based pharmacokinetic (PopPBPK) modelling to optimize target expression, kinetics and clearance of HER1/2 directed therapeutic monoclonal antibodies (mAbs). Thus, to propose a general workflow of PopPBPK modelling and its application in clinical pharmacology. Full PBPK model of pertuzumab (PTZ) was developed in patient population using Simcyp V21R1 incorporating mechanistic targeted-mediated drug disposition process by fitting known clinical PK and sparse receptor proteomics data to optimize target expression and kinetics of HER2 receptor. Trastuzumab (TTZ) PBPK modelling was used to validate the optimized HER2 target. Additionally, the simulator was also used to develop a full PBPK model for the HER1-directed mAb cetuximab (CTX) to assess the underlying targeted-mediated drug disposition-independent elimination mechanisms. HER2 final parameterisation coming from the PBPK modelling of PTZ was successfully cross validated through PBPK modelling of TTZ with average fold error (AFE), absolute AFE and percent prediction error values for area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax ) of 1.13, 1.16 and 16, and 1.01, 1.07 and 7, respectively. CTX PBPK model performance was validated after the incorporation of an additional systemic clearance of 0.033 L/h as AFE and absolute AFE showed an acceptable predictive power of AUC and Cmax with percent prediction error of 13% for AUC and 10% for Cmax . Optimisation of both system and drug related parameters were performed through PBPK modelling to improve model performance of therapeutic mAbs (PTZ, TTZ and CTX). General workflow was proposed to develop and apply PopPBPK to support clinical development of mAbs targeting same receptor.

Background: The number of elderly patients with breast cancer has increased in recent years, many of whom reside alone. This makes choosing their treatment difficult because of domestic considerations and declining physical and cognitive functions. Chemotherapy is often omitted owing to age, and treatment can subsequently be inadequate. Case presentation: Our patient was an 82-year-old woman presenting with the chief complaint of an enlarged left breast mass. The mass had undergone self-destruction with hemorrhage and enlarged left axillary and supraclavicular lymph nodes. She lived alone; therefore, initial chemotherapy of trastuzumab (HER)+pertuzumab (PER)+weekly paclitaxel (wPTX) two-step dose reduction was performed in the hospital. A subcutaneous mass appeared, which disappeared after irradiation. Subsequently, tri-weekly HER+PER administration was continued. Conclusion: A multidisciplinary approach to therapy may offer elderly patients living alone with inoperable breast cancer patients the ability to continue treatment and control their disease following careful consideration of their comorbidities and decline in physical and cognitive functions. Such multidisciplinary treatment options minimize the occurrence of side effects, allowing for long-term continuation of therapy, helping to maintain quality of life and potentially prolonging overall survival.

HER2-positive breast cancer (BC) is an aggressive subtype that affects 20–25% of BC patients. For these patients, neoadjuvant therapy is a good option that targets a pathological complete response (pCR) and more breast-conserving surgery. In effect, the outcomes of patients with HER2-positive BC have dramatically improved since the introduction of anti-HER2 antibodies such as trastuzumab (TZ) and/or pertuzumab (PZ) added to chemotherapy. This study sought to examine whether correlation exists between copy number variations (CNVs) in several genes related to the PI3K/AKT pathway (HER2, FGFR1, PIK3CA, AKT3 and MDM2) and the efficacy of anti-HER2 neoadjuvant treatment in patients with early HER2-positive BC. Forty-nine patients received TZ or PZ/TZ and chemotherapy as neoadjuvant treatment. Gene CNVs were determined by quantitative polymerase chain reaction on paraffin-embedded biopsy specimens. The response to 6 months of therapy was assessed by Miller–Payne grading of the tumor on surgical resection; grades 4 and 5, indicating >90% tumor reduction, were defined as a good response. A good response was shown by 64.5% and a pCR by 31.2% of patients. When stratified by anti-HER2 antibody received and gene CNV, it was found that patients with FGFR1 gene amplification or those with FGFR1 amplification treated with TZ alone showed a poor response (p = 0.024 and p = 0.037, respectively). In the subset of patients treated with TZ/PZ combined, the pCR rate was significantly lower among those showing FGFR1 amplification (p = 0.021). Although based on a small sample size, our findings suggest that patients with FGFR1 amplification might benefit less from anti-HER2 antibody therapy.

1832P Cardiotoxicity of the HER2 dimerisation inhibitor pertuzumab in patients with breast cancer HER2+: A systematic review

Abstract Background: trastuzumab (TZB) is approved for the treatment of HER2-positive (HER2+) breast cancer in different indications and schemes. The association of pertuzumab (PTZ) in some regimens has shown to improve the clinical benefit. Recently, biosimilars (BS) of trastuzumab were approved after extensive exercises of comparison with the originator, proving that these new biologicals are highly similar in structure and biological activity, and inherent microheterogeneity is not clinically relevant, since efficacy, safety and immunogenicity were found to be equivalent in pivotal phase 3 trials. In this study, we aimed to compare binding and biological activities of biosimilar trastuzumab (BS-TZB) or trastuzumab originator in association with PTZ in cell culture-based assays. Methods: two cancer cell lines were used to perform all the tests: BT474 (HER2+/ progesterone (PR) and estrogen receptor (ER)- positive) and HCC1954 (HER2+/PR and ER-negative); fluorescent labeling of trastuzumab originator (Herceptin®- Produtos Roche Químicos e Farmacêuticos S.A.) with Alexa 488, biosimilar of trastuzumab (trastuzumab-dkst, Biocon Limited/ Zedora- Libbs Farmacêutica Ltda.) with Alexa 488 and pertuzumab (Perjeta®- Produtos Roche Químicos e Farmacêuticos S.A.) with Alexa 647; FACS-based antigen binding evaluations and live cell imaging were performed (TZB or BS-TZB, and PTZ at concentrations of: 0; 10; 100; 1,000 ng/mL in every combinations. Predefined acceptance criteria for ligand-binding assay (LBA) was ±20% (25% at lower limit of quantification - LLOQ). Proliferation and CDC (complement-dependent cytotoxicity) assays: TZB or BS-TZB were tested at concentrations of: 0.01; 0.03; 0.1; 0.3; 1; 3; 10; 30; 100 μg/mL combined with PTZ at concentrations 1; 10; 100 μg/mL; the number of viable cells were estimated by quantitation of the ATP present using the CellTiter-Glo® kit. Equivalence was stablished with 95% confidence if 90% confidence interval (CI) of difference between means (DBM) lies within the zone of indifference (±20%). Results: tests were done using different concentrations and combinations of antibodies. For LBA, results are shown with concentrations in which the effect was neither minimal nor maximal (for both cell lines: 100 ng/mL for PTZ; 1,000 ng/mL for TZB or BS-TZB) (Table 1). For proliferation and CDC analysis, results at concentrations 100 μg/mL for PTZ, and TZB or BS-TZB (for both cell lines) are shown as a ratio to control. Table 1: Ligand-binding, proliferation and CDC assays. SD: standard deviation.Cell lineAnti-bodiesLBA (% cells) mean ± SDDBM 90% CIProliferation (ratio) mean ±SDDBM 90% CICDC (% cells) mean ± SDDBM 90% CIBT474BS-TZB + PTZ69.6 ±0.3-4.5 to -3.465.3 ±2.5-7.2 to -0.358.2 ±0.1-5.8 to -3.2TZB + PTZ73.5 ±0.369.6 ±1.262.8 ±1.1HCC1954BS-TZB + PTZ94.2 ±0.35.8 to 6.480.5 ±1.9-14.3 to -0.349.8 ±0.1-4.3 to -1.9TZB + PTZ88.1 ±0.187.8 ±5.452.9 ±1.0 Conclusions: trastuzumab and pertuzumab bind to HER2 receptor at different subdomains acting synergistically and, ultimately, improving the clinical benefit. In this study we comparatively evaluated the ligand and biological activities of the biosimilar BS-TZB and the TZB originator in the presence of PTZ. In addition to the previous findings of highly similar structure and biological activities of biosimilar to its originator, this study showed that not only PTZ binding to HER2 domain II but also biological activity showed the same pattern in the presence of BS-TZB as well as in the presence of TZB. Herein, in evaluated mechanisms, we have showed that the combination of BS-TZB and PTZ are highly similar to the combination of TZB and PTZ. Citation Format: Franklin F Pimentel, Juliano S Toledo, João Gonçalves, Leandro L Alves, Mayara I de Paula, Jurandyr M de Andrade, Daniel G Tiezzi, Roger Chammas. Comparative evaluation of a trastuzumab biosimilar or originator trastuzumab in association with pertuzumab: Binding and biological activities in cell culture-based assays [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-05-08.

Re-administration of Docetaxel for relapse after Pertuzumab and Trastuzumab maintenance therapy

Neoadjuvant combination treatment with chemotherapy (CTX), trastuzumab (TZM), and pertuzumab (PTZ) has been shown to result in higher pathological complete response rates (pCR) in comparison with treatment with chemotherapy and trastuzumab (CTX/TZM). This analysis was aimed at real-world validation of these results from prospective randomized trials. In a retrospective analysis conducted in the PRAEGNANT network, patients were eligible for inclusion if they had either received neoadjuvant therapy with CTX/TZM or chemotherapy, trastuzumab, and pertuzumab (CTX/TZM/PTZ) and subsequently underwent surgery for their primary breast cancer. The effect of the two neoadjuvant regimens on pCR in addition to commonly applicable predictors of pCR was analyzed in 300 patients from three study sites, using logistic regression analyses with treatment arm, age, clinical tumor stage, grading, and hormone receptor status as predictors. pCR with complete disappearance of all tumor cells was seen in 30.2% (n = 58) of patients treated with CTX/TZM and in 52.8% (n = 57) of those treated with CTX/TZM/PTZ. CTX/TZM/PTZ was positively associated with pCR (adjusted odds ratio 2.44; 95% CI 1.49-4.02). Mastectomy rates were not influenced by the therapy. The results of clinical trials were confirmed in this dataset of patients who were treated outside of clinical trials in everyday routine work. pCR rates can be improved by 20% with pertuzumab in routine clinical use.

Complete response after pertuzumab + trastuzumab + docetaxel in metastatic Her2-positive breast cancer patients: review of four cases

Complete response after docetaxel+pertuzumab+trastuzumab chemotherapy for multimetastatic positive Her-2 breast cancer

PCN237 - Risk-Sharing Agreement: A Model For Her2 (+) Breast Cancer Suitable For The Chilean Context

336 (PB-131) - Adjuvant pertuzumab (PER) for HER2-positive early stage breast cancer (eBC): A Swiss experience

The outcomes of human epidermal growth factor receptor 2 (HER2)-positive breast cancer was dramatically changed by the introduction of targeted therapies against the HER2 receptor (1).The monoclonal antibody trastuzumab was the first HER2-directed treatment that demonstrated, together with chemotherapy, a significant improvement in treatment outcomes of this subgroup of patients, both in the metastatic (2) and neo-/adjuvant (3-7) settings, thus becoming the mainstay of treatment in HER2 positive breast cancer. The remarkable results achieved led to the development of additional HER2-targeted drugs, raising the hypothesis of a double-HER2 blockade against breast cancer.

The results of the APHINITY trial were recently reported in the New England Journal of Medicine by von Minckwitz et al ., wherein adjuvant pertuzumab was combined with trastuzumab plus chemotherapy in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (1). The addition of pertuzumab produced a 0.9% lower recurrence rate and death at 3 years (1). However, the absolute benefit was better in patients with lymph node metastases; in these patients, the rate of invasive disease-free survival (DFS) was 1.8% higher in the pertuzumab group than in the placebo group (1). Pertuzumab might have a position in adjuvant treatment for patients with multiple lymph node involvement or those willing to allow considerable adverse side effects in return for questionable benefit (1). Real-world clinical significance is perhaps subtler than the rigid numbers that determine statistical significance in clinical trials. The results for pertuzumab in the APHINITY trial were statistically significant with reference to the primary endpoint of invasive DFS (1). However, compared to results of pertuzumab treatment in the context of advanced breast cancer (CLEOPATRA) and the neoadjuvant setting (NeoSphere), the results of APHINITY were a clinical and scientific disappointment (1-3).

Prior findings suggest that high levels of tumor infiltrating lymphocytes (TILs) may confer improved prognosis and predict response to therapy in patients with breast cancer. To evaluate the anti-tumor effects of TILs in patients with HER2-positive, metastatic disease, investigators have now conducted an industry-funded, retrospective analysis of the CLEOPATRA study (N Engl J Med 2015 Feb 19; 372:724), which demonstrated a survival benefit of adding pertuzumab to trastuzumab and docetaxel in 808 women with HER2-positive metastatic …

Pertuzumab recommended after price discount