Maintenance Trastuzumab Research Articles

A randomized phase III double-blind placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105)

BackgroundIn 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC.Findings96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43–1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61–1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab.ConclusionsIn this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.Clinical Trial Information: NCT00520975

Investigating the Efficacy and Safety of a Dose-Dense Paclitaxel, Cyclophosphamide With Trastuzumab in Stage I-II Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer

BackgroundThe evolution of systemic therapies has improved outcomes for patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Nonetheless, the tolerability and safety profile of systemic therapies represent an area for further improvement. Here we report the results of a phase 2 trial evaluating a nonanthracycline, nonplatinum adjuvant treatment regimen for patients following initial surgical resection. MethodsWe enrolled patients with stage I or II HER2+ breast cancer who underwent upfront surgery to receive adjuvant treatment with 6 cycles of dose-dense Paclitaxel, cyclophosphamide and Trastuzumab (PC-H) every 2 weeks, followed by 13 cycles of maintenance trastuzumab every 3 weeks to complete 52 weeks of treatment (compromising 19 cycles). The primary objective was to determine the safety and feasibility of adjuvant PC-H, measured by the completion rate frequency and the grade of adverse events, using National Cancer Institute Common Terminology Criteria. The secondary objective was to estimate relapse-free survival and overall survival. ResultsBetween 2010 and 2019, a total of 39 patients were enrolled. Of those, 34 patients (87.18%) completed the planned treatment. Severe adverse events of grade 3 or 4 occurred in 27 patients (69.23%), including 3 patients (7.69%) with grade 3-4 decrease in ejection fraction. At median follow up of 5.6 years, all 39 patients were alive. The 5-year relapse-free survival was 94.30% (95% CI: 75.3-100). ConclusionsPC-H demonstrated overall safety and efficacy, yielding high rates of relapse-free survival among patients with early stage (HER2+) breast cancer.

Outcome with pertuzumab, docetaxel, and trastuzumab (PTH) regimen in patients with HER2 positive metastatic breast cancer: Real-world data from a single center in India.

e13037 Background: Pertuzumab, Docetaxel and Trastuzumab (PTH) regimen constitutes one of the standard treatment regimens in human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC). The real-world outcomes of its use from the Indian sub-continent are lacking. Methods: We retrospectively reviewed the medical records of HER2-positive MBC treated with an upfront PTH regimen at the All India Institute of Medical Sciences, New Delhi, India, between Aug 2016 to July 2023. A total of six cycles of PTH [pertuzumab (840 mg loading followed by 420 mg), docetaxel (75 mg/m2), trastuzumab (8 mg/kg loading followed by 6 mg/kg) q21 days] were planned along with granulocyte-colony stimulating factor (GCSF) prophylaxis. Patients were continued on maintenance trastuzumab after 6 cycles (till disease progression) and hormonal agent if indicated. The primary outcome was progression-free survival (PFS). The secondary outcome was overall survival (OS), overall response rate (ORR) rates, and toxicity. Results: Eighty-seven were included with a median age of 48 years (range, 25-73). Overall, 38 (43.6%) patients had hormone-positive (estrogen receptor and or progesterone receptor) disease and 48 (55.17%) were premenopausal. Thirty-five (40.2%) patients had received prior adjuvant and neoadjuvant treatment. Eighty patients (91.5%) had visceral metastasis and the most common site was the liver followed by the lung. After a median follow-up of 36 months, the median PFS was 15 months and OS was 42 months. The ORR was 85.3% and complete response (CR) was observed in 14(16.09%) patients. The survival outcomes were significantly better among those with hormone-negative disease and among those who achieved CR after 6 cycles of PTH. Grade 3/4 toxicity was seen in 12% of patients which led to dose modification, interruption, and change in chemotherapy. Two patients developed reversible left asymptomatic ventricular systolic dysfunction. None of the patients developed congestive heart failure. The most common grade 3/4 toxicities were diarrhea in 8 (9.1%) patients, cutaneous rash in 2 (2.2%) patients and thrombocytopenia in 2 (2.2%) patients. There were two cases of febrile neutropenia. Conclusions: In a real-world context, PTH is an effective and well-tolerated regimen for in patients with HER2-positive MBC in India. Hormone-positive disease has poor survival compared with hormone negative disease.

Phase II/III study of paclitaxel/carboplatin alone or combined with either trastuzumab and hyaluronidase-oysk or pertuzumab, trastuzumab, and hyaluronidase-zzxf in HER2 positive, stage I-IV endometrial serous carcinoma or carcinosarcoma (NRG-GY026).

TPS5641 Background: Uterine serous carcinoma and uterine carcinosarcoma are rare, high-risk uterine cancer subtypes that overexpress HER2 in up to 40% and 10% of cases, respectively. Phase II data demonstrated a benefit in adding trastuzumab in HER2 positive advanced and recurrent uterine serous carcinoma. Dual anti-HER2 therapy has the potential for further improvement in survival. Methods: This is a non-blinded, three-arm randomized phase II/III study. The primary objective is to evaluate the efficacy of trastuzumab and hyaluronidase-oysk (HERCEPTIN HYLECTA) or a fixed dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) in combination with paclitaxel/carboplatin in patients with HER2 positive uterine serous carcinoma or carcinosarcoma. The primary outcome of the phase II component is PFS. Depending on the phase II results, the study will progress to a phase III study of either two or three study arms. Patients in the control arm (Arm 1) receive carboplatin and paclitaxel every 3 weeks for 6 cycles. Patients on Arm 2 receive carboplatin and paclitaxel with trastuzumab and hyaluronidase-oysk every 3 weeks for 6 cycles plus one year of maintenance trastuzumab and hyaluronidase-oysk. Patients enrolled on Arm 3 receive carboplatin and paclitaxel with trastuzumab, pertuzumab, and hyaluronidase-zzxf every 3 weeks for 6 cycles plus one year of maintenance trastuzumab, pertuzumab, and hyaluronidase-zzxf . Those with an ongoing partial response may continue maintenance therapy for up to three years. Patients are eligible if they are diagnosed with chemo-naïve, non-recurrent stage IA-IVB myoinvasive uterine serous or carcinosarcoma. All tumors must be HER2 positive as defined by the ASCO/CAP Breast Cancer 2018 guidelines (testing performed locally). Tumors may also be HER2 positive based on next generation sequencing testing. Patients may have measurable, non-measurable, or no measurable disease and may have a plan for vaginal brachytherapy . Key exclusion criteria include severe heart disease or interstitial lung disease. The phase II portion of this study is open and enrolling. Clinical trial information: NCT05256225 .

Abstract PO5-21-01: Carcinoma en cuirasse- a rare, but striking, cutaneous manifestation of metastatic breast cancer

Abstract Introduction: Carcinoma en cuirasse is a rare cutaneous metastatic presentation most commonly arising from primary breast cancers, typically after mastectomy. It appears like cellulitis and later develops into thickened rough patches of skin and even nodules. Carcinoma en cuirasse holds a poor prognosis, and treatment is difficult. Chemotherapeutic agents are unable to reach the tumor cells necessary, and radiation is ineffective because of skin curvature. Case Presentation: We report a female in her 70s with prior history of left breast ductal carcinoma in situ status post-radiation and lumpectomy, who presented with skin thickening of the left breast and solid masses in bilateral breasts 10 years later. Biopsy showed invasive ductal carcinoma of left breast (estrogen receptor [ER]/progesterone receptor positive [PR], human epidermal growth factor receptor-2 [HER2] negative) and ductal carcinoma in situ of right breast (ER/PR positive). She underwent right breast lumpectomy; however, the left breast mastectomy was aborted due to worsening of her skin findings on preoperative examination. An excisional skin biopsy revealed poorly differentiated invasive ductal carcinoma involving the dermis, deep dermis and focally involving the epidermis. Her diagnosis changed to stage 4 breast cancer, specifically carcinoma en cuirasse. Systemic treatment was initiated with palbociclib and letrozole and subsequently, she underwent left breast mastectomy given an excellent response to initial therapy. Surgical biopsy interestingly was HER2 positive and therefore her regimen was changed to taxotere, trastuzumab and pertuzumab. She completed adjuvant treatment and has been on maintenance trastuzumab along with letrozole currently and is doing well 5 years later with negative PET scans. Discussion: Our case is unique due to diagnosis of carcinoma en cuirasse before mastectomy, change in HER2 receptor status during treatment and excellent response to therapy with ongoing response to date. We think that an early diagnosis as well as targeted treatment could be the possible reasons for prolonged survival of more than 5 years. Conclusion: Any unexplained skin findings in breast cancer patients should prompt consideration of carcinoma en cuirasse. With ongoing treatment advances, many newer therapy options are available for metastatic breast cancer. Based on our case, we think that patients with this disease can have better outcomes. Citation Format: Manasi Godbole, Kashmira Wani, Shereen Zia, Vrushali Dabak. Carcinoma en cuirasse- a rare, but striking, cutaneous manifestation of metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-21-01.

Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer

In ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC), combining trastuzumab and pertuzumab with taxane-based chemotherapy is the first line of standard care. Given that trastuzumab plus pertuzumab was proven effective in ERBB2-positive MBC, even without chemotherapy, whether the optimal first-line strategy could be trastuzumab plus pertuzumab alone instead of with chemotherapy is unresolved. To assess overall survival (OS) at 2 years and progression-free survival (PFS) for patients randomly assigned to receive first-line pertuzumab plus trastuzumab alone or with chemotherapy followed by trastuzumab and emtansine at progression; PFS of second-line trastuzumab and emtansine treatment following trastuzumab plus pertuzumab; and OS and PFS in the ERBB2-enriched and ERBB2-nonenriched subtypes. This was a secondary analysis of a multicenter, open-label, phase 2 randomized clinical trial conducted at 27 sites in France, 20 sites in Switzerland, 9 sites in the Netherlands, and 1 site in Germany. Overall, 210 patients with centrally confirmed ERBB2-positive MBC were randomized between May 3, 2013, and January 4, 2016, with termination of the trial May 26, 2020. Data were analyzed from December 18, 2020, to May 10, 2022. Patients randomly received pertuzumab (840 mg intravenously [IV], then 420 mg IV every 3 weeks) plus trastuzumab (8 mg/kg IV, then 6 mg/kg IV every 3 weeks) without chemotherapy (group A) or pertuzumab plus trastuzumab (same doses) with either paclitaxel (90 mg/m2 for days 1, 8, and 15, then every 4 weeks for ≥4 months) or vinorelbine tartrate (25 mg/m2 for first administration followed by 30 mg/m2 on days 1 and 8 and every 3 weeks for ≥4 months) followed by pertuzumab plus trastuzumab maintenance after chemotherapy discontinuation (group B). Overall survival at 24 months by treatment group, PFS for first-line treatment, PFS for second-line treatment, and patient-reported quality of life (QOL). A total of 210 patients were included in the analysis, with a median age of 58 (range, 26-85) years. For group A, 24-month OS was 79.0% (90% CI, 71.4%-85.4%); for group B, 78.1% (90% CI, 70.4%-84.5%). Median PFS with first-line treatment was 8.4 (95% CI, 7.9-12.0) months in group A and 23.3 (95% CI, 18.9-33.1) months in group B. Unlike expectations, OS and PFS did not markedly differ between populations with ERBB2-enriched and ERBB2-nonenriched cancer. Adverse events were less common without chemotherapy, with small QOL improvements from baseline in group A and stable QOL in group B. The findings of this secondary analysis of a randomized clinical trial suggest that the chemotherapy-free anti-ERBB2 strategy is feasible without being detrimental in terms of OS. The 50-gene prediction analysis of microarray signature could not help to identify the most appropriate patient population for this approach. ClinicalTrials.gov Identifier: NCT01835236.

Comprehensive biomarker analysis of long-term response to trastuzumab in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma

BackgroundA subgroup of patients with HER2-positive metastatic gastric and gastroesophageal junction cancers shows long-term response under trastuzumab maintenance monotherapy. Obviously, HER2 status alone is not able to identify these patients. We performed this study to identify potential new prognostic biomarkers for this long-term responding patient group. Patients and methodsTumour samples of 19 patients with HER2-positive metastatic gastric and gastroesophageal junction cancer who underwent trastuzumab treatment were retrospectively collected from multiple centres. Patients were divided into long-term responding (n = 7) or short-term responding group (n = 12) according to progression-free survival (PFS≥12 months vs. PFS < 12 months). Next-generation sequencing and microarray-based gene expression analysis were performed along with HER2 and PD-L1 immunohistochemistry. ResultsLong-term responding patients had significantly higher PD-L1 combined positive scores (CPS) and CPS correlated with longer progression-free survival. PD-L1 positivity (CPS ≥ 1) was further associated with an increased CD4+ memory T-cell score. The ERBB2 copy number as well as the tumour mutational burden could not discriminate between short-term and long-term responding patients. Genetic alterations and coamplifications in HER2 pathway associated genes such as EGFR, which were connected to trastuzumab resistance, were present in 10% of the patients and equally distributed between the groups. ConclusionThe study highlights the clinical relevance of PD-L1 testing also in the context of trastuzumab treatment and offers a biological rational by demonstrating elevated CD4+ memory T-cells scores in the PD-L1-positive group.

MicroRNAs (miRs) as biomarkers of resistance to trastuzumab in HER2-positive oesophago-gastric cancer: Sub-study within the Planning Treatment for Oesophago-Gastric Cancer—A Randomised Maintenance Therapy Trial (PLATFORM).

419 Background: A predictive biomarker for resistance to trastuzumab in HER2 positive oesophago-gastric cancer would refine patient selection. Our preclinical studies suggest that patients with HIGH baseline plasma miR-148a-3p levels will experience shorter Overall Survival (OS), Progression Free Survival (PFS), and worse Progression Free Rates (PFR) than those with LOW plasma miR-148a-3p levels. Methods: This sub-study is a prospective biomarker analysis of baseline plasma samples for HER2 positive advanced oesophago-gastric cancer patients registered within Arm B1 of the Phase 2 open label, multicentre, randomised PLATFORM trial (NCT02678182). All HER2 positive patients assessable for clinical response and miR signatures were included. Copies of miR-148a-3p and miR-16 per ml of plasma were quantified using Digital Droplet Polymerase Chain Reaction (ddPCR). OS as primary endpoint for miR-148a-3p LOW (≤median) versus HIGH (&gt;median) was analysed using Kaplan-Meier curves and Cox model regression. Secondary endpoints were PFS and PFR. OS and PFS are from start of 1st line therapy; PFR are from start of maintenance trastuzumab. Sensitivity analysis normalised miR-148a-3p to miR-16. Results: Of 63 patients with analysable lab samples and available survival data, normalisation was possible for 41 patients. Median follow-up was 38 months. There was no statistically significant relationship between OS and miR-148-3p copies/μl of ddPCR reaction LOW versus HIGH (n= 62, Hazard Ratio (HR) 0.98, p=0.933), PFS (n=62, HR 1.08, p=0.759) or PFR (n=31, Odds Radio (OR) 0.67, p=0.577). Normalised miR-148a-3p (NmiR-148a-3p) LOW versus HIGH demonstrated a statistically significant difference in PFR at 3 months (n=23, OR=0.11, p=0.027) but no difference in OS or PFS. A model adjusting for primary tumour site, metastatic disease and number of sites demonstrated a statistically significant difference in PFR at 3 months (aOR=0.03, p=0.029). Conclusions: Patients with HIGH NmiR-148-3p have 0.03 times the odds of being progression-free at 3 months than patients with LOW NmiR-148a-3p in this population, when adjusted for key factors. Limitations include small sample size and normalisation. Clinical trial information: NCT02678182 . [Table: see text]

A real-world experience of TCH (docetaxel/carboplatin/trastuzumab) regimen in early, locally advanced and oligometastatic HER2 positive breast cancer from tertiary care center in North India.

e12505 Background: In HER2 positive breast cancer, TCH is a safe and efficacious anthracycline free regimen used as both adjuvant and neoadjuvant modality. Three is scarcity of data regarding its long term safety and efficacy from India. Methods: This retrospective study comprised of 210HER2 positive breast cancer female patients treated with TCH [docetaxel (75mg/m2), carboplatin (AUC=6) and trastuzumab (8mg/kg loading followed by 6mg/kg) q 21 days with GSF prophylaxis] protocol for 6 cycles at our centre between Jan 2014 and Dec 2021. All eligible patients received maintenance trastuzumab, hormonal therapy and radiotherapy as per institutional protocol. The information regarding baseline clinico-demographic characteristics, treatment details, outcomes and toxicities were collected and evaluated. Results: The median age was 49 years (23-72), 113 (53.8%) were post-menopausal and 100 (47.6%) were Estrogen receptor/Progesterone receptor positive. Sixty-eight (32.4%) patients were stage I and II, 112 (53.3%) stage III and 30 (14.3%) were oligometastatic. TCH regimen was given as neoadjuvant chemotherapy (NACT) in 130 (61.9%) patients and as adjuvant chemotherapy in 80 (38.1%) patients. Of the patients receiving NACT, 114 (87.6%) patients underwent surgery. Twenty-two (19.3%) patients underwent breast conservation surgery and 92 (80.7%) underwent modified radical mastectomy. Over the study period, 62 (29.5%) patients had progression of the disease and 22 (10.5%) patients died. With a median follow up of 31.9 months, 3-year disease free survival (DFS) was 63.5% and overall survival (OS) was 90.8%. Median DFS was 31 months in patients with node positive disease and was not reached in patients with node positive disease. Of the patients who received NACT, pathologic complete response (pCR) was recorded in 42 (36.8%) patients. Three-year DFS was 59.1% in patients who achieved pCR and 44.8% in those who did not achieve pCR. Any grade 3/4 toxicity was seen in 26.7% patients which caused dose modification in 13.9% patients. The most common grade 3/4 hematological toxicity was anemia (15.1%) and thrombocytopenia (10.4%), while non-hematological toxicity was diarrhea (11.6%). Febrile neutropenia was seen in 4 (1.9%) patients. Four patients (1.9%) had reversible decrease in cardiac left ventricular ejection fraction. Conclusions: Anthracycline free TCH regimen is an effective and safe regimen for use in curative (adjuvant and neoadjuvant) setting for HER2 positive breast cancer in Indian women with outcomes comparable to the anthracycline based regimens reported in literature.

First-line treatment of patients with HER2-positive metastatic gastric and gastroesophageal carcinoma

Fluoropyrimidine+cisplatin/oxaliplatin+trastuzumab therapy is recommended for the first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric adenocarcinoma. However, there is no comprehensive study on which platinum-based treatment should be preferred. This study aimed to compare the treatment response and survival characteristics of patients with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer who received fluorouracil, oxaliplatin, and leucovorin (mFOLFOX)+trastuzumab or cisplatin and fluorouracil (CF)+trastuzumab as first-line therapy. It was a multicenter, retrospective study of the Turkish Oncology Group, which included 243 patients from 21 oncology centers. There were 113 patients in the mFOLFOX+trastuzumab arm and 130 patients in the CF+trastuzumab arm. The median age was 62 years in the mFOLFOX+trastuzumab arm and 61 years in the CF+trastuzumab arm (p = 0.495). About 81.4% of patients in the mFOLFOX+trastuzumab arm and 83.1% in the CF+trastuzumab arm had gastric tumor localization (p = 0.735). The median progression-free survival (PFS) was significantly higher in the mFOLFOX+trastuzumab arm (9.4 months vs. 7.3 months, p = 0.024). The median overall survival (OS) was similar in both groups (18.4 months vs. 15.1 months, p = 0.640). Maintenance trastuzumab was continued after chemotherapy in 101 patients. In this subgroup, the median OS was 23.3 months and the median PFS was 13.3 months. In conclusion, mFOLFOX+trastuzumab is similar to CF+trastuzumab in terms of the median OS, but it is more effective in terms of the median PFS in the first-line treatment of HER2-positive metastatic gastric and GEJ cancer. The choice of treatment should be made by considering the prominent toxicity findings of the chemotherapy regimens.

Alternative trastuzumab dosing strategies in HER2-positive early breast cancer are associated with patient out-of-pocket savings

Patients with breast cancer frequently experience financial hardship, often due to the high costs of anti-cancer drugs. We sought to develop alternative trastuzumab dosing strategies, compare their pharmacokinetic effectiveness to standard dosing, and assess the expected financial implications of transitioning to them. We extracted clinical data from the records of 135 retrospectively identified patients with HER2-positive early breast cancer at a single, urban comprehensive cancer center who were treated with trastuzumab between 2017 and 2019. We performed pharmacokinetic simulations on a range of trastuzumab dose levels and frequencies, assessing efficacy by trough trastuzumab concentration (Ctrough) and population and individual likelihoods of Ctrough exceeding trastuzumab minimum effective concentration (MEC). We performed deterministic financial modeling to estimate the treatment-associated financial savings from alternative dosing strategies. Trastuzumab maintenance doses of 4 mg/kg every 3 weeks (Q3W) and 6 mg/kg every 4 weeks (Q4W) had nearly identical probabilities of Ctrough being above MEC as standard of care 6 mg/kg every 3 weeks. In the primary financial analysis, both trastuzumab 4 mg/kg Q3W and 6 mg/kg Q4W were associated with significant drug- and administration-related out-of-pocket cost savings over the duration of therapy, ranging from $765 (neoadjuvant, Q4W) to $2791 (adjuvant, Q4W). In particular, Q4W trastuzumab increased savings related to lost wages and travel cost avoidance. Low-dose and reduced frequency trastuzumab in appropriately selected patients may significantly reduce total drug utilization and meaningfully reduce patient financial toxicity. Prospective clinical trials evaluating low-dose or reduced-frequency administration of therapeutic monoclonal antibodies are warranted and needed.

Trastuzumab tolerability in the treatment of advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress HER2/neu

ObjectiveDue to previously reported trastuzumab safety concerns and the scant data available in endometrial cancer patients, we sought to assess the safety, tolerability and toxicity profile of trastuzumab in patients with advanced/recurrent uterine serous carcinoma (USC) that overexpress HER2/neu in our multicenter randomized phase II trial. MethodsPatients were randomized 1:1 to receive carboplatin/paclitaxel (C/P) for 6 cycles ± trastuzumab (T) with the experimental arm continuing to receive single agent trastuzumab maintenance treatment until disease progression/toxicity. Progression-free-survival was the primary endpoint; overall-survival and toxicity were secondary endpoints. Adverse events (AEs) were compared between treatment arms. ResultsThere were 28 patients in the C/P arm and 32 patients in the experimental (C/P + T) arm. Fifty-eight patients (97%) experienced 977 treatment-related AEs of which 875 (89.6%) were low-grade (grade 1–2) and 102 (10.4%) were high-grade (grade 3–5). The mean ± standard deviation of AEs per patient was 15.5 ± 16.3 in the C/P arm and 17.0 ± 16.0 in the C/P + T arm. Gastrointestinal AEs were the most common in both arms (n = 155, 15.7%) of which 94.2% were low-grade (n = 146). Importantly, no significant difference between treatment arms was detected in any system-organ class of AE including cardiac AE. Five (17%) of 29 patients who received prolonged trastuzumab maintenance therapy had no sign of cumulative toxicity after an average (range) of 5.1 (4.2–6.3) years. ConclusionsTrastuzumab appears to be safe and has a manageable toxicity profile both when used in combination with chemotherapy and when used for single agent maintenance in patients with HER2/neu positive USC. This safety profile is reassuring given the proven efficacy of trastuzumab in advanced/recurrent HER2/neu positive USC.

Efficacy of trastuzumab and potential risk factors on survival inpatients with HER2-positive metastatic gastric cancer.

Aim: To evaluate the efficacy of trastuzumab and potential risk factors on survival in patients with HER2-positive metastatic gastric cancer. Methods: We retrospectively included138 patients who were given trastuzumab-based chemotherapy as first-line treatment and analyzed the relationship between clinical response rates and maintenance treatment status and survival outcomes. Results: In the whole group, the median progression-free survivaland overall survivalwere 10.2 and 16months, respectively. Clinical response was obtained in 79% of patients. The median overall survival was 16.9months in follow-up group and 19.0months in the maintenance group in patients with clinical response. Continuation of maintenance trastuzumab created a significant survival advantage (p=0.021). Eastern Cooperative Oncology Group performance status2 (hazard ratio [HR]: 2.02), grade 3 (HR: 1.78) and more than four metastatic lesions (HR: 1.67) were determined as risk factors for death. Conclusion: We recommend the continuation of maintenance trastuzumab in patients with clinical response, but those with identified risk factors may not benefit from treatment because life expectancy may be low.

Patient out-of-pocket savings with lower-dose trastuzumab.

e18828 Background: Trastuzumab-related costs of human epidermal growth factor receptor 2 (HER2) positive breast cancer treatment are significant, approaching $70,000 per patient in the adjuvant setting alone. Recently developed population pharmacokinetic models demonstrate that therapeutic levels of trastuzumab are maintained despite decreased maintenance dose or dose frequency, potentially improving trastuzumab’s value proposition. In this observational study, we evaluate the potential patient- and health system-level financial implications of low-dose trastuzumab. Methods: We identified 196 individuals who received treatment for HER2-positive breast cancer with trastuzumab or its biosimilars at a single urban comprehensive cancer center between January 1, 2017 and October 31, 2019. We estimate, using publicly available information, patient-experienced out-of-pocket costs using deterministic modeling under different conditions corresponding to changes in dosing practices, geographic site of trastuzumab administration, patient employment status, intent of treatment, and billing procedures, as well as Medicare cost-savings estimates. Results: Both reducing the maintenance dose of trastuzumab from the FDA-labeled dose of 6 mg/kg to 4 mg/kg Q3W and reducing maintenance dose frequency of trastuzumab from 6 mg/kg Q3W to Q4W were each associated with significant patient savings on drug- and administration-related out-of-pocket costs. Depending on billing practice and clinical scenario, patient savings as a percentage of total costs were 9-20% (neoadjuvant), 17-22% (adjuvant), and 14-19% (metastatic) with 6 mg/kg Q4W dosing. Similarly, 4 mg/kg Q3W dosing had savings of 15-25% (neoadjuvant), 19-28% (adjuvant), and 13-28% (metastatic). Utilization of off-label dosing regimens could result in $2.69 billion USD in annual Medicare spending on trastuzumab, an estimated savings of $670-810 million USD. Conclusions: Meaningful patient-level and system-level financial savings in the treatment of HER2-positive breast cancer can be achieved using pharmacokinetically near-equivalent low-dose or reduced frequency maintenance trastuzumab dosing. Given the significant potential savings, further prospective studies aimed at reducing dose or frequency of monoclonal antibodies in the treatment of cancer are warranted.

Trastuzumab ± Capecitabine Maintenance After the First-Line Treatment of HER2-Positive Advanced Gastric Cancer: Retrospective Observational Real-Life Data of Turkish Oncology Group.

In the ToGA trial for HER2-positive advanced gastric cancer, cisplatin plus fluoropyrimidine was given for 6 cycles; trastuzumab was given until disease progression. However, there is a lack of real-life data about trastuzumab maintenance after 6 cycle chemotherapy. This study aims to present real-life data of trastuzumab ± capecitabine maintenance after 6 cycles of platinum, fluoropyrimidine, and trastuzumab in non-progressive patients. This is a retrospective multicenter study of the Turkish Oncology Group. A total of 35 HER2-positive, inoperable locally advanced, recurrent, or metastatic gastric adenocarcinoma patients being non-progressive at the end of 6 cycle chemotherapy and being given trastuzumab ± capecitabine as maintenance treatment were included from sixteen oncology centers. Baseline characteristics, objective tumor responses, progression free and overall survival data, and toxicities were determined. About 68% of the patients were given CF, and 32% were given FOLFOX with trastuzumab as the first-line treatment. The best response in 6 cycle chemotherapy was complete 8 (22%), partial 24 (68%), and stable disease 3 (8%). All patients had trastuzumab maintenance (median cycle 13; range 7-51), and 49% of the patients had capecitabine with trastuzumab (median capecitabine cycle 6; range 2-30). The median PFS of the patients was 12.0months (95% CI 10.3-13.7), and median OS was 17.4months (95% CI 15.2-19.5). There were 2 patients with grade 1 cardiotoxicity. Trastuzumab maintenance ± capecitabine after 6 cycles of trastuzumab plus combined chemotherapy treatment revealed efficacy and safety in non-progressive HER2-positive advanced gastric cancer.

Perioperative trastuzumab, capecitabine and oxaliplatin in patients with HER2-positive resectable gastric or gastro-oesophageal junction adenocarcinoma: NEOHX phase II trial

IntroductionPerioperative chemotherapy improves overall survival (OS) and disease-free survival (DFS) compared with surgery alone in patients with resectable gastric adenocarcinoma (GA) or gastro-oesophageal junction adenocarcinoma (GEJA). The addition of trastuzumab to chemotherapy improves outcomes in patients with HER2-positive advanced gastric cancer (GC), and we aimed to explore its role in the perioperative setting. Material and methodsThis Spanish, multicentre, open-label phase II trial evaluated the efficacy and toxicity of perioperative capecitabine, oxaliplatin and trastuzumab (XELOX-T) in patients with HER2-positive resectable GA or GEJA. The primary end-point was 18-months DFS; and secondary end-points included pathological complete response (pCR) rate, R0 resection rate, OS and toxicity (NCT01130337). ResultsThirty-six patients were included. After three cycles of preoperative treatment, 14 patients (38% of the intention-to-treat population) had partial response and 18 (50%) had stable disease. Surgery was performed in 31 patients: 28 (90%) had R0 resection, three (9.6%) had a pCR and three (9.6%) died due to surgical complications. A total of 24 patients received post-operative XELOX-T, 22 of whom completed trastuzumab maintenance. Main grade III/IV toxicities included diarrhoea (33%), nausea and vomiting (8%). After a median follow-up of 24.1 months, 18-month DFS was 71% (95% confidence interval [CI], 53–83%); and an update after 102 months of follow-up showed a median OS of 79.9 months and a 60-month OS of 58% (95% CI, 40–73%). ConclusionsThese data suggest that perioperative XELOX-T in patients with HER2-positive GA and GEJA is feasible and active. Further investigation in randomised studies is warranted.

Human epidermal growth factor receptor-2 (HER2) is a potential therapeutic target in extramammary Paget’s disease of the vulva

BackgroundInvasive vulvar Paget’s disease with over-expression of the human epidermal growth factor receptor 2 (HER2) protein is potentially suitable for targeted therapy, especially in a metastatic setting where no effective...

133P HER2 transcription status of diverse solid tumours with clinical implications

Utility of HER2 mRNA expression as a potential therapeutic biomarker is unclear. We previously reported the discordant HER2 status between copy number variation (CNV), mRNA and immunohistochemistry (IHC) from a large multi-institute dataset. Herein, we investigated comprehensive HER2 status by cancer (CA) type with clinical outcome among HER2 positive patients (pts) at University of California San Diego (UCSD). By Paradigm Diagnostics (CLIA-certified laboratory), HER2 status was evaluated using IHC, qRT-PCR and NGS between 2015-2019. We evaluated pts who had all three HER2 testing available by tumor type, with UCSD outcomes included. Of 5,305 pts, 723 had CNV, mRNA and IHC evaluated (Table). Among diverse solid tumors, HER2 positivity in at least one test were seen in 76.6% (49/64) of NSCLC and 58.8% (20/34) of pancreas CA. Sole mRNA positivity (CNV-/IHC-) were found ≥35% in NSCLC, pancreatic and colorectal cancers. Among 53 UCSD pts who had all three HER2 testing, 22 pts had ≥ 1 positive HER2 test (including 24.5% [13/53] pts with mRNA+ only). We identified 7 pts that were given Anti-HER2 therapy (Tx). One pt with CNV+/mRNA+/IHC+ metastatic esophageal CA achieved complete response with chemotherapy plus trastuzumab followed by trastuzumab maintenance (progression-free survival [PFS]: 48 + months). One pt with metastatic cholangiocarcinoma mRNA+ (CNV and IHC unable to perform) achieved durable partial response with dual-anti-Her2 Tx (trastuzumab and lapatinib) (PFS: 24+ months). In contrast, 5 pts had poor outcomes despite anti-HER2 Tx, given after 3-5 previous Tx lines.Table 133PHER2 status per cancer typeCancer Type (N>10)TotalCNV + mRNA + IHC +CNV+ mRNA + IHC -CNV+ mRNA- IHC+CNV- mRNA+ IHC+CNV+ mRNA- IHC-CNV- mRNA+ IHC-CNV- mRNA- IHC+Any +NN%N%N%N%N%N%N%N%Multi-institutionBreast2603513.5––124.6–4416.983.19938.1Colon8844.5––22.3–3236.422.34045.5NSCLC6411.6––1625–3046.923.14976.6Pancreas34–––38.8–1647.112.92058.8Ovary3013.3––26.7–62013.31033.3Sarcoma27–CUP2528––141414416936Prostate21–––––14.814.829.5Hepatobiliary20210––––1515420Bladder19421.1––421.1–15.315.31052.6Gastroesophageal16212.5–16.3––16.316.3531.3H&N14–Rectal14214.317.1–––535.7–857.1Appendix11–UCSD5323.8––47.5–1324.535.72241.5 Open table in a new tab We found diverse HER2 expression patterns among solid tumors, including difficult to treat cancer of unknown primary, pancreatic CA, and hepatobiliary CA. Although it is a small cohort, patients with HER2 mRNA overexpression could respond to anti-HER2 regimen. Further clinical investigation is warranted.

P-350 Maintenance trastuzumab in the setting of second-line treatment in HER2 overexpressing metastatic gastric and gastroesophageal junction adenocarcinoma: Experience of our centre

Standard of care (SOC) in patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma after progression to 1st line platinum/ fluoropyrimidine-based treatment is the combination of paclitaxel and ramucirumab (P/R), based on the results of the RAINBOW trial. Trastuzumab (T) has shown clinical benefit in HER2 overexpressing cases. Nevertheless, literature published so far is scant regarding trastuzumab combination with second-line P/R. We report here our experience in the use of maintenance trastuzumab in combination with P/R in HER2 overexpressing G/GEJ adenocarcinoma patients. Correlative HER2 positive G/GEJ patients with progression of disease as per RECIST criteria after first-line treatment based on platinum, fluoropyrimidines, and trastuzumab were included in this study and treated between January 2017 and December 2019. Statistical analysis was performed according to non-parametrical tests based on the Mann-Whitney U test to compare progression-free survival (PFS) between both groups. Overall Response Rates were evaluated according to Fisher’s exact test. A total of 12 patients were included in this analysis. 8 of them (66,6%), underwent maintenance T together with P/R after confirmed progression to first-line. The remaining cases (n=4; 33,3%) were treated according to with to SOC based on P/R without T. ORR in the T+P/R group was 62.5% (n=5) reaching a disease control rate up to (DCR) of 87% (n=7) in contrast to SOC in which no response was observed showing a DCR of 50% (n=2). Statistical comparison using Fisher’s exact test did not reveal statistical significance (p=0.07) likely due to insufficient sample size. Moreover, median PFS was 5.5 months among patients receiving T+P/R and 4.5 months in the P/R group. No significant differences were found between groups (Mann Whitney U test p=0.55). In terms of toxicity, maintenance trastuzumab did not demonstrate treatment-related increased cardiotoxicity. The overall incidence of grade 3 or 4 adverse events according to the CTCAE 5.0 was 25%, 2 cases in the P/R group (1 bleeding, 1 nonfebrile neutropenia) and 1 in the combination with trastuzumab (thrombosis). Combination of trastuzumab and SOC P/R could offer benefits in terms of response and progression-free survival, although no statistical differences were seen probably as a result of our limited sample size. Nevertheless, combination therapy does neither seem to add more toxicity than that expected with the SOC based on P/R alone, nor does it appear to have remarkable cumulative cardiovascular toxicity in our series. Despite our limitations, in patients with HER2 overexpressing GEJ adenocarcinoma, maintenance trastuzumab with second-line P/R until further progression could be a feasible option in patients with good performance status who are fit for combined therapy.

Efficacy of Neoadjuvant Chemotherapy with Epirubicin and Cyclophosphamide and Weekly Paclitaxel and Trastuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Carcinoma: A Real-World Study.

Background Trastuzumab has been introduced a decade ago and demonstrated improvement in the prognosis in patients with human epidermal growth factor receptor 2- (HER2-) positive (+) breast carcinoma (BC). This study is aimed at evaluating the efficacy of epirubicin/cyclophosphamide with weekly paclitaxel-trastuzumab as neoadjuvant chemotherapies in HER2+ BC patients. Methods A total of 234 HER2+ BC patients were given neoadjuvant chemotherapy (NAC) between 2010 and 2016. The primary endpoints were pathologic complete response (pCR) and disease-free survival (DFS). Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were conducted. Results The pCR (30.4% vs. 14.8%; P = 0.004) and DFS (P = 0.036) showed significant differences between patients administered with neoadjuvant trastuzumab therapy and those who did not. Multivariate logistic regression analysis showed that neoadjuvant trastuzumab treatment was regarded as an independent predictor of pCR. Patients with pCR had prolonged DFS (P = 0.025). In patients who did not achieve pCR (non-pCR), those who received trastuzumab had more prolonged DFS (P = 0.046). The luminal B/HER2+ subtypes had prolonged DFS when compared with nonluminal B/HER2+ subtypes (P = 0.010). The luminal B/HER2+ subgroup also showed improved DFS in non-pCR patients (P = 0.010). In the subgroup of non-pCR, the luminal B/HER2+ subgroup administered with trastuzumab showed no superior DFS (P = 0.168). However, a positive result was observed in patients without trastuzumab (P = 0.039). Multivariate analysis showed cT stage (P = 0.006) and tumor grade (P = 0.041), considering them as significant prognostic factors of DFS. Conclusions HER2+ BC patients showed improvement in pCR and DFS after neoadjuvant trastuzumab treatment. Patients without pCR had prolonged DFS after trastuzumab maintenance. Although the prognosis of luminal B/HER2+ BC showed favorable outcomes in the non-pCR subgroup, those receiving trastuzumab showed no survival advantage.