Trastuzumab-based Therapy Research Articles

The AGAMENON-SEOM model for prediction of survival in patients with advanced HER2-positive oesophagogastric adenocarcinoma receiving first-line trastuzumab-based therapy.

Trastuzumab and chemotherapy is the standard first-line treatment in human epidermal growth factor receptor 2 (HER2)-positive advanced gastro-oesophageal cancer. The objective was to develop a predictive model for overall survival (OS) and progression-free survival (PFS) in patients treated with trastuzumab. Patients with HER2-positive advanced gastro-oesophageal adenocarcinoma (AGA) from the Spanish Society of Medical Oncology (SEOM)-AGAMENON registry and treated first line with trastuzumab and chemotherapy between 2008 and 2021 were included. The model was externally validated in an independent series (The Christie NHS Foundation Trust, Manchester, UK). In all, 737 patients were recruited (AGAMENON-SEOM, n = 654; Manchester, n = 83). Median PFS and OS in the training cohort were 7.76 [95% confidence interval (CI), 7.13-8.25] and 14.0 months (95% CI, 13.0-14.9), respectively. Six covariates were significantly associated with OS: neutrophil-to-lymphocyte ratio, Eastern Cooperative Oncology Group performance status, Lauren subtype, HER2 expression, histological grade and tumour burden. The AGAMENON-HER2 model demonstrated adequate calibration and fair discriminatory ability with a c-index for corrected PFS/OS of 0.606 (95% CI, 0.578-0.636) and 0.623 (95% CI, 0.594-0.655), respectively. In the validation cohort, the model is well calibrated, with a c-index of 0.650 and 0.683 for PFS and OS, respectively. The AGAMENON-HER2 prognostic tool stratifies HER2-positive AGA patients receiving trastuzumab and chemotherapy according to their estimated survival endpoints.

Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer

BackgroundNeratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies. MethodsPatients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L. Results563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed. ConclusionsThese complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective. ClinicalTrials.gov registration numberNCT02400476.

HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial.

In JACOB trial, pertuzumab added to trastuzumab-chemotherapy did not significantly improve survival of patients with HER2-positive metastatic gastric cancer, despite 3.3 months increase versus placebo. HER2 copy-number variation (CNV) and AMNESIA panel encompassing primary resistance alterations (KRAS/PIK3CA/MET mutations, KRAS/EGFR/MET amplifications) may improve patients' selection for HER2 inhibition. In a post hoc analysis of JACOB on 327 samples successfully sequenced by next-generation sequencing (NGS; Oncomine Focus DNA), HER2 CNV, HER2 expression by IHC, and AMNESIA were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) by univariable/multivariable models. Median HER2 CNV was 4.7 (interquartile range, 2.2-16.9). HER2 CNV-high versus low using the median as cutoff was associated with longer median PFS (10.5 vs. 6.4 months; HR = 0.48; 95% confidence interval: 0.38-0.62; P < 0.001) and OS (20.3 vs. 13.0 months; HR = 0.54; 0.42-0.72; P < 0.001). Combining HER2 CNV and IHC improved discriminative ability, with better outcomes restricted to HER2-high/HER2 3+ subgroup. AMNESIA positivity was found in 51 (16%), with unadjusted HR = 1.35 (0.98-1.86) for PFS; 1.43 (1.00-2.03) for OS.In multivariable models, only HER2 CNV status remained significant for PFS (P < 0.001) and OS (P = 0.004). Higher ORR was significantly associated with IHC 3+ [61% vs. 34% in 2+; OR = 3.11 (1.89-5.17)] and HER2-high [59% vs. 43% in HER2-low; OR = 1.84 (1.16-2.94)], with highest OR in the top CNV quartile. These biomarkers were not associated with treatment effect of pertuzumab. HER2 CNV-high assessed by NGS may be associated with better ORR, PFS, and OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation.

Trastuzumab-based regimens beyond progression: A crucial treatment option for HER2+ advanced/metastatic breast cancer

Upon its establishment for the treatment of metastatic breast cancer (mBC), continuing trastuzumab beyond disease progression was an important paradigm shift that became the recommendation by major guidelines. However, data supporting continuation of human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab beyond the second-line setting are limited, resulting in a lack of approval of, or access to, this therapeutic strategy in many countries. This study aimed to provide additional data on the continued use of trastuzumab and trastuzumab-based therapies in combination with chemotherapy (CT) as third-line treatment for patients with mBC. This open-cohort, retrospective, observational study used deidentified patient-level data from an electronic health record–derived database that included patients with mBC who initiated third-line treatment with trastuzumab-based therapy combined with CT (Tras + CT; n = 288) or CT alone (CT; n = 49). Patients who received Tras + CT had a longer weighted median overall survival vs those who received CT only: 20.6 months (95% CI, 18.3–26.4 months) vs 10.1 months (95% CI, 7.8–12.3 months), respectively (hazard ratio [HR], 0.29; 95% CI, 0.16–0.53). This study provides additional support for maintaining trastuzumab-based therapies for patients with HER2+ mBC beyond second-line treatment. This treatment option should be available for all patients with mBC worldwide.

Identifying HER2 from serum-derived exosomes in advanced gastric cancer as a promising biomarker for assessing tissue HER2 status and predicting the efficacy of trastuzumab-based therapy.

This study aimed to evaluate the clinical relevance of exosomal HER2 (Exo HER2) level in assessing the tissue HER2 status and predicting the efficacy of trastuzumab treatment. In this prospective study, patients with advanced gastric cancer (AGC) from three hospitals between August 2016 to November 2020 were enrolled. The Exo HER2 level was detected by enzyme-linked immunosorbent assay. Receiver operating characteristic curve (ROC) was drawn referring to the HER2 tissue status to assess the diagnostic value of Exo HER2. Cox proportional hazards regression and logistic regression were used to evaluate the association between Exo HER2 and progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) in patients who received trastuzumab-based first-line therapy. In this study, 242 patients with advanced or metastatic gastric adenocarcinoma were registered. Of these, 238 AGC patients were eligible for evaluating serum-derived exosome HER2 diagnostic value, including 114 HER2-positive. Finally, 64 were eligible for efficacy analysis. The area under the ROC curve was 0.746. The optimal cutoff value for diagnosing tissue HER2-positive status was 729.95 ng/ml, with a sensitivity of 66.7% and a specificity of 74.2%. In 64 patients treated with trastuzumab, higher baseline Exo HER2 level indicated better prognosis. 844 ng/ml and 723 ng/ml were the right cutoffs for distinguishing the population with superior PFS (hazard ratio [HR]=0.41, P= 0.017) and OS (HR=0.30, P< 0.001), respectively. Serum exosomal HER2 level might serve as an effective biomarker for assessing tissue HER2 status in AGC and screening the potential patients who might benefit from anti-HER2 therapy.

1205MO Updated analysis of DESTINY-Gastric02: A phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable/metastatic gastric/gastroesophageal junction (GEJ) cancer who progressed on or after trastuzumab-containing regimen

Primary results of DESTINY-Gastric02 (NCT04014075; data cutoff [DCO] April 9, 2021), a single-arm, phase II trial of T-DXd in Western pts with HER2+ gastric/GEJ cancer, demonstrated a confirmed objective response rate (cORR) of 38.0% (95% CI, 27.3-49.6), and safety consistent with the established T-DXd safety profile. We report OS and updated efficacy and safety. Pts with centrally confirmed HER2+ (IHC3+ or IHC2+/ISH+ biopsy after progression on trastuzumab-based therapy) unresectable/metastatic gastric/GEJ cancer who progressed on or after 1L therapy received T-DXd 6.4 mg/kg Q3W. The primary endpoint was cORR per RECIST v1.1 by independent central review (ICR). Progression-free survival (PFS) by ICR, duration of response (DOR) by ICR, OS, and patient-reported outcomes based on the European Organization for Research and Treatment of Cancer 5-dimension 5-levels (EQ-5D-5L) quality-of-life (QoL) and Functional Assessment of Cancer Therapy-Gastric (FACT-GA) questionnaires were secondary endpoints. At DCO (November 8, 2021), 79 pts from the US/EU had received T-DXd. 76 pts (96.2%) had received 1 prior line of therapy and 3 (3.8%) had received 2 lines. With a median duration of follow up of 10.2 mo, 10 pts (12.7%) remained on treatment. Median OS was 12.1 mo (95% CI, 9.4-15.4); landmark 12-mo OS rate was 50.6%. cORR was 41.8% (33/79; 4 complete and 29 partial responses). Median DOR was 8.1 mo (95% CI, 5.9-NE). Median PFS was 5.6 mo (95% CI, 4.2-8.3). All pts experienced ≥1 treatment-emergent adverse event (TEAE); 55.7% experienced grade ≥3 TEAEs. The most common TEAEs were nausea (67.1%), vomiting (44.3%) and fatigue (57.0%). Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 8 pts (10.1%); 6 (7.6%) had grade 1-2 and 2 (2.5%) had grade 5. At DCO (April 9, 2021), QoL assessed by EQ-5D-5L and FACT-GA had been maintained over the treatment course. T-DXd continues to demonstrate substantial clinical benefit and a tolerable safety profile in 2L+ Western pts with HER2+ unresectable/metastatic gastric/GEJ cancer.

Potential role of CXCR4 in trastuzumab resistance in breast cancer patients

Despite the efficacy of trastuzumab in treating HER2-positive breast cancer patients, a significant proportion of patients relapse after treatment. The role of C-X-C chemokine receptor type 4 (CXCR4) in trastuzumab resistance was studied only in cell lines and the underlying mechanisms remain largely unclear. This study investigated the role of CXCR4 in trastuzumab resistance in breast cancer patients and explored the possible underlying mechanisms. The study was performed retrospectively on tissue samples from 62 breast cancer patients including 42 who were treated with trastuzumab and chemotherapy and 20 who received chemotherapy alone in adjuvant setting. Expression levels of CXCR4 and its regulators hypoxia-inducible factor 1-alpha (HIF-1α), tristetraprolin (TTP), human antigen R (HuR), itchy E3 ubiquitin protein ligase (ITCH), miR-302a and miR-494 were determined and their associations with tumor recurrence and disease-free survival were analyzed. In trastuzumab-treated patients, high CXCR4 expression was associated with recurrence and was an independent predictor of progression risk after therapy. CXCR4 correlated positively with its transcriptional regulator, HIF-1α, and negatively with its post-translational regulator, ITCH. HIF-1α, HuR and ITCH were significantly associated with clinical outcome. In chemotherapy-treated patients, neither CXCR4 nor any of its regulators were associated with recurrence or predicted disease progression risk after chemotherapy. In conclusion, this study suggests a potential role for CXCR4 in recurrence after trastuzumab-based therapy in human breast cancer that could be mediated, at least in part, by hypoxia and/or decreased ubiquitination. These findings highlight the potential utility of CXCR4 as a promising target for enhancing trastuzumab therapeutic outcome.

Left ventricular ejection fraction and cardiac biomarkers for dynamic prediction of cardiotoxicity in early breast cancer.

Background/PurposeThis study aims to quantify the utility of monitoring LVEF, hs-cTnT, and NT-proBNP for dynamic cardiotoxicity risk assessment in women with HER2+ early breast cancer undergoing neoadjuvant/adjuvant trastuzumab-based therapy.Materials and methodsWe used joint models of longitudinal and time-to-event data to analyze 1,136 echocardiography reports and 326 hs-cTnT and NT-proBNP measurements from 185 women. Cardiotoxicity was defined as a 10% decline in LVEF below 50% and/or clinically overt heart failure.ResultsMedian pre-treatment LVEF was 64%, and 19 patients (10%) experienced cardiotoxicity (asymptomatic n = 12, during treatment n = 19). The pre-treatment LVEF strongly predicted for cardiotoxicity (subdistribution hazard ratio per 5% increase in pre-treatment LVEF = 0.68, 95%CI: 0.48–0.95, p = 0.026). In contrast, pre-treatment hs-cTnT and NT-proBNP were not consistently associated with cardiotoxicity. During treatment, the longitudinal LVEF trajectory dynamically identified women at high risk of developing cardiotoxicity (hazard ratio per 5% LVEF increase at any time of follow-up = 0.36, 95% CI: 0.2–0.65, p = 0.005). Thirty-four patients (18%) developed an LVEF decline ≥ 5% from pre-treatment to first follow-up (“early LVEF decline”). One-year cardiotoxicity risk was 6.8% in those without early LVEF decline and pre-treatment LVEF ≥ 60% (n = 117), 15.9% in those with early LVEF decline or pre-treatment LVEF < 60% (n = 65), and 66.7% in those with early LVEF decline and pre-treatment LVEF < 60% (n = 3), (Gray’s test p < 0.0001).ConclusionCardiotoxicity risk is low in two thirds of women with HER2+ early breast cancer who have pre-treatment LVEF ≥ 60% and no early LVEF decline > 5% during trastuzumab-based therapy. The longitudinal LVEF trajectory but not hs-cTnT or NT-proBNP allows for a dynamic assessment of cardiotoxicity risk in this setting.

Moderately hypofractionated radiation therapy for breast cancer: A Brazilian cohort study

Results from numerous clinical trials have led to a consensus that moderately hypofractionated radiation therapy is the ideal postoperative irradiation treatment plan in patients with breast cancer (BC). However, there are specific situations such as chest wall (with or without breast reconstruction) and regional node irradiation that still face obstacles in its widespread use. There is a lack of evidence supporting the use of moderately hypofractionated irradiation from the Latin American context. This study aims to describe the profile and clinical outcomes of patients treated with moderate hypofractionation for both early-stage (Stage I and II) and locally advanced BC (Stage III) regardless of the type of surgery in a Brazilian Oncology Center. All patients with non-metastatic BC who were treated with moderately hypofractionated schedules of 40Gy in 15 fractions or 42.4Gy in 16 fractions between 2010 to 2019 at Hospital Sírio-Libanês, Brazil were retrospectively analyzed. The rates of local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), distance recurrence-free survival (DRFS) and overall survival (OS) were estimated. Acute and late toxicity profiles were accessed for the entire cohort. A total of 670 patients were included. The median age was 57 years and the median follow-up time was 31 months. Most of the patients had stage I and II breast cancer, and 81.6% underwent breast-conserving surgery. Of the 123 women who underwent mastectomy treatment, 29% (n=37) had immediate reconstruction with implants and 28% (n=35) with autologous tissue. Seventy-one per cent of the patients presented luminal subtype tumour and 84.3% received adjuvant hormonal therapy. Chemotherapy was administered to almost half of the patients and all 80 patients with Her-2 positive disease received trastuzumab-based systemic therapy. One-third of patients received regional node irradiation; boost was performed in 41.1% of treatments. The 5-year LRFS, RRFS, DRFS and OS was 95.6%, 97.6%,92.2% and 95.9%, respectively. Acute and late side effects profile were mild and only 2.9% of patients developed grade 3 dermatitis. Among patients with breast implants, 11.4% had capsular contracture. In this Brazilian institution experience, moderately hypofractionated irradiation to the breast, chest wall (with or without breast reconstruction), and regional lymph nodes was safe and with an acceptable toxicity profile. None.

Predictive Role of CD36 Expression in HER2-Positive Breast Cancer Patients Receiving Neoadjuvant Trastuzumab.

Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage HER2-positive breast cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models. Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival in 180 patients enrolled in the phase III trial Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO), which randomly assigned stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pretreatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase II trial NeoSphere. In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse event-free survival in patients treated with trastuzumab-based therapy (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.20 to 2.46), but not with lapatinib-based (HR = 1.02, 95% CI = 0.68 to 1.53) or trastuzumab-lapatinib-based (HR = 1.08, 95% CI = 0.60 to 1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient disease-free survival in both the whole study cohort (HR = 1.197, 95% CI = 1.002 to 1.428) and patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI = 1.049 to 1.568). High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy.

SA33 Real-World Cardiac Safety of Anti-HER2 Therapies in Elderly Patients with HER2+/HR-Metastatic Breast Cancer: A Retrospective Cohort Study Using SEER-Medicare DATA 2012-2016

Anti-HER2 therapies have significantly improved survival in human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (mBC). However, clinical trials have identified increased cardiac risk with trastuzumab-based therapies. The purpose of our study was to assess the incidence of cardiac safety events after trastuzumab initiation among elderly HER2+ mBC patients in the real-world setting.

Abstract CT232: A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01

Abstract Background: GP2 is a biologic nine amino acid peptide of the HER2/neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient received the 6 primary intradermal GLSI-100 injections (p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events were observed considered related to the immunotherapy. Trial Design: This Phase 3 trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status, prior pertuzumab therapy and region. Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. Eligibility Criteria: The patient population is defined by these key eligibility criteria: 1. HER2/neu positive and HLA-A*02 2. Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy 3. Exclude Stage IV 4. Completed at least 90% of planned trastuzumab-based therapy Trial Objectives: 1. To determine if GP2 therapy increases IBCFS 2. To assess the safety profile of GP2 3. To monitor immunologic responses to treatment and assess relationship to efficacy and safety Accrual: Site selection and study start-up is in progress at multiple sites. Target enrollment is 598 subjects. Contact information: Snehal Patel Greenwich LifeSciences, Inc. Stafford, TX Email: snehal.patel@greenwichlifesciences.com Website: greenwichlifesciences.com Funding: This trial is supported by Greenwich LifeSciences. Citation Format: Snehal S. Patel, Jaye Thompson, Mira S. Patel, F. Joseph Daugherty, C. Kent Osborne, Mothaffar F. Rimawi. A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT232.

Abstract 5079: Comparative proteome analysis for predicting the prognosis of trastuzumab-based therapy

Abstract Trastuzumab, a HER2-targeting antibody, has markedly altered the clinical course of the disease in HER2 + gastric cancer, which is 10-15% of metastatic GC. However, the majority of patients develop resistance within one year of treatment. Therefore, understanding the mechanisms of trastuzumab resistance is urgently needed to overcome trastuzumab resistance. This study explored the characteristics of trastuzumab resistant cell lines through comparative proteome analysis. We previously reported establishment of four trastuzumab resistant cell lines from HER2 amplified GC cell lines by trastuzumab dose-escalation treatment; YCC-33TR, YCC-38TR, NCI-N87TR, and SNU-216TR. Formalin-fixed paraffin-embedded tissue samples were obtained 10 GC patients prior to trastuzumab therapy. The patients were first stratified into poor and good responders based on whether their tumors had or had not progressed. For analysis of differentially expressed proteins (DEPs), label-free quantitative proteomic profiling was performed using high-resolution LC-MS system. Gene ontology (GO) and KEGG pathway enrichment analyses were conducted using DAVID database. Consistent with the previous results, we found that HER2 expression in TR cell lines remained as high as parental cell lines, also in proteomic profiling. As a result of proteomic analysis, total 5285 proteins were identified in 4 parental and 4 TR cell lines; 4854 common proteins, while 55 proteins unique to parental cell lines and 58 proteins unique to TR cell lines. Then, we did the hierarchical clustering with these DEPs to identify protein expression patterns. We observed that 129 and 62 proteins were upregulated in parental and TR cell lines, respectively (p&amp;lt;0.05). We identified C5orf51 and CENP-E, poor prognostic factors, were upregulated 200-fold in TR cell lines. Interestingly, we found that HLA-B, ITM2C, and PPP1R3D were highly expressed in TR cell lines and trastuzumab poor responders. In conclusion, we performed comparative proteome analysis in parental and TR cell lines and investigated the corresponding expression change. It may gain further novel insights into the mechanisms of trastuzuamb resistance. Citation Format: Juin Park, Woo Sun Kwon, Sun Kyoung Kang, Tae Soo Kim, Jihyun Hwang, Sang Woo Cho, Kyunggon Kim, Hyun Cheol Chung, Sun Young Rha. Comparative proteome analysis for predicting the prognosis of trastuzumab-based therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5079.

Characterization of ERBB2 (HER2) Alterations in Metastatic Non-small Cell Lung Cancer and Comparison of Outcomes of Different Trastuzumab-based Regimens

IntroductionAbout 3%-5% of mNSCLC have ERBB2 (HER2) alterations, but currently, there are no FDA-approved targeted therapies for this indication. We compared treatment response between trastuzumab-based and non–targeted regimens in ERBB2-mutant mNSCLC. MethodsThis retrospective, single-institution study included patients with mNSCLC with ERBB2 alterations identified by next-generation sequencing. Best overall response was determined using Response Evaluation Criteria in Solid Tumors 1.1. ResultsWe identified 3 groups of patients: ERBB2-mutant/EGFR-wildtype mNSCLC (n = 33), ERBB2-amplified/EGFR-wildtype mNSCLC without concurrent ERBB2 mutations (n = 6), and ERBB2-altered/EGFR-mutant mNSCLC (n = 8). Observed mutations included A775_G776insYVMA (n = 23), Gly778_Pro780dup (n = 4), Ser310Phe (n = 3), and others (n = 5). Among the 33 with ERBB2-mutant/EGFR-wildtype mNSCLC, those with and without A775_G776insYVMA had significantly different median overall survival (OS) of 17.7 and 52.9 months, respectively (Cox regression multivariable HR: 5.03, 95% CI: 1.37-18.51, P = .02). In those with mNSCLC with A775_G776insYVMA, trastuzumab-based therapies were associated with greater OS (20.3 vs. 9.8 months; multivariable HR: 0.19, 95% CI: 0.04-0.87, P = .032). Objective response and disease control rates (median tumor size change) in the 33 patients with ERBB2-mutant/EGFR-wildtype mNSCLC were 40.0% and 80.0% (-35.8%), respectively, for patients treated with trastuzumab deruxtecan; 0% and 30.0% (-5.2%) for trastuzumab emtansine; and 7.1% and 50.0% (-13.0%) for trastuzumab/chemotherapy combinations. ConclusionIn ERBB2-mutant/EGFR-wildtype mNSCLC, while most trastuzumab-based regimens had modest activity in this real-world analysis, trastuzumab deruxtecan had highest response rates and best tumor size reduction. Receipt of any trastuzumab-based regimen was associated with greater OS with A775_G776insYVMA. There remains an unmet need for approved targeted therapies for ERBB2-mutant/EGFR-wildtype NSCLC.

A randomized, multicenter, placebo-controlled, phase III study to evaluate the efficacy and safety of HER2/neu peptide GLSI-100 (GP2 + GM-CSF) in patients with residual disease or high-risk PCR after both neo-adjuvant and postoperative adjuvant anti-HER2 therapy, Flamingo-01.

TPS1110 Background: GP2 is a biologic nine amino acid peptide of the HER2/ neu protein delivered in combination with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) that stimulates an immune response targeting HER2/neu expressing cancers, the combination known as GLSI-100. In a prospective, randomized, single-blinded, placebo-controlled, multicenter Phase IIb study, no recurrences were observed in the HER2+ population after 5 years of follow-up, if the patient was treated with GLSI-100, survived and was followed from more than 6 months ( p = 0.0338). Immunotherapy elicited a potent response measured by skin tests and immunological assays. Of the 146 patients that have been treated with GLSI-100 over 4 clinical trials, GLSI-100 was well-tolerated and no serious adverse events were observed considered related to the immunotherapy. Methods: This Phase 3 trial is a prospective, randomized, double-blinded, multi-center study. After 1 year of trastuzumab-based therapy, 6 intradermal injections of GLSI-100 or placebo will be administered over the first 6 months and 5 subsequent boosters will be administered over the next 2.5 years for a total of 11 injections over 3 years. The participant duration of the trial will be 3 years treatment plus 1 additional year follow-up for a total of 4 years following the first year of treatment with trastuzumab-based therapy. Patients will be stratified based on residual disease status at surgery, hormone receptor status and region. Approximately 498 patients will be enrolled. To detect a hazard ratio of 0.3 in invasive breast cancer free survival (IBCFS), 28 events will be required. An interim analysis for superiority and futility will be conducted when at least 14 events have occurred. This sample size provides 80% power if the annual rate of events in placebo patients is 2.4% or greater. Up to 100 non-HLA-A*02 subjects will be enrolled in an open-label arm. Eligibility Criteria: The patient population is defined by these key eligibility criteria: HER2/neu positive and HLA-A*02; Residual disease or High risk pCR (Stage III at presentation) post neo-adjuvant therapy; Exclude Stage IV; Completed at least 90% of planned trastuzumab-based therapy. Trial Objectives: To determine if GP2 therapy increases IBCFS; To assess the safety profile of GP2; To monitor immunologic responses to treatment and assess relationship to efficacy and safety. Accrual: Site selection and study start-up is in progress at multiple sites. Target enrollment is 598 subjects. Clinical trial information: 05232916.

Prognostic factors influencing progression-free survival in HER2 positive metastatic breast cancer patients who treated with lapatinib and capecitabine combination.

e13031 Background: Her2 positivity is detected in about 20% of breast cancer patients. After trastuzumab-based therapy, lapatinib and capecitabine combination is a treatment option in HER2-positive metastatic patients. The study aimed to evaluate the prognostic factors in HER2 positive metastatic breast cancer patients treated lapatinib and capecitabine combination. Methods: We evaluated data of the HER2 positive metastatic breast cancer patients who were treated with lapatinib and capecitabine retrospectively. The patients' clinical, pathological, and treatment features were recorded from the hospital database. Kaplan Meier and Cox regression analysis were used for survival analysis. Results: 102 patients were included in the study. The median age was 47 (range, 24-87), and 99 (97.1%) patients were female. The number of de-novo metastatic patients was 44 (43.1%). The most common metastatic sites were bone (62.4%), brain (58.6%), liver (35.6%), and lung (34.7%), respectively. All patients were previously treated with trastuzumab-based chemotherapy. 44 (44.1%) patients received hormonotherapy (tamoxifen or aromatase inhibitor), and 23 (22.5%) patients palliative radiotherapy. Complete response was 8.2%, partial response 32%, and stable disease 25.8% with lapatinib and capecitabine combinations. At a median follow of 11.6 months, progression-free survival was 8 (95% CI, 5.1-10.8) months. In multivariate analysis, age (p = 0.020), de-novo metastatic disease (p = 0.028), and endocrine therapy (p = 0.020) were statistically significant prognostic factors for progression-free survival. However, history of breast surgery (p = 0.060), number of chemotherapy used with trastuzumab (p = 0.338), number of metastatic sites (p = 0.257), and palliative radiotherapy (p = 0.394) were not significant. Conclusions: We showed real-life outcomes of the lapatinib and capecitabine combination in metastatic HER2-positive breast cancer patients. Also, we detect that being under age 50 years, de-novo metastatic disease, and hormone-negative tumor were poor prognostic factors of progression-free survival.

P-159 Trastuzumab deruxtecan (T-DXd) in patients with HER2-positive gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma who have progressed on or after a trastuzumab-containing regimen (DESTINY-Gastric04): A randomized phase 3 study

T-DXd is an antibody–drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. T-DXd is approved globally to treat HER2-positive (HER2+) metastatic breast cancer, and to treat HER2+ GC after trastuzumab-based therapy (United States and Israel) or GC that has progressed after chemotherapy (Japan). In the primary analysis of DESTINY-Gastric01 (DS8201-A-J202; NCT03329690), an open-label, multicenter, randomized, phase 2 trial in patients with HER2+ advanced GC or GEJ adenocarcinoma, T-DXd demonstrated clinically relevant improvement compared with standard of care in objective response rate (ORR; 51% versus 14%; P P = 0.01) in the third-line or later (Shitara, N Engl J Med 2020). The DESTINY-Gastric04 study aims to evaluate the efficacy and safety of T-DXd compared with the combination of ramucirumab and paclitaxel in patients with HER2+ GC or GEJ adenocarcinoma in the second-line setting. DESTINY-Gastric04 (NCT04704934) is a global, multicenter, open-label, 2-arm, randomized, phase 3 study in patients with HER2+ metastatic and/or unresectable GC or GEJ adenocarcinoma. Eligible patients must be adults (according to local regulations), with an ECOG performance status of 0 or 1 at screening, with documented GC or GEJ adenocarcinoma that has been previously treated in the metastatic first-line setting (including neoadjuvant or adjuvant therapy if progression on or within 6 months of completing therapy) with a trastuzumab-containing regimen. HER2-positivity (IHC 3+ or IHC 2+/ISH+) must be centrally confirmed on tumor biopsies obtained after progression on or after trastuzumab. Patients must not have received anticancer therapy after a first-line trastuzumab-containing regimen. Patients will be randomized 1:1 to receive T-DXd (6.4 mg/kg every 3 weeks) or ramucirumab (8 mg/kg on days 1 and 15 of a 28-day cycle) in combination with paclitaxel (80 mg/m2 on days 1, 8, and 15 of a 28-day cycle). This study is actively enrolling from 24 different countries across Europe and Asia with approximately 490 participants planned. The primary endpoint is OS. Secondary endpoints include progression-free survival, ORR, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity of T-DXd. NCT04704934. Under the guidance of authors, assistance in medical writing and editorial support was provided by Laura Halvorson, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc. This study was funded by Daiichi Sankyo, Inc., and AstraZeneca.

Maintenance endocrine therapy prolonged progression-free survival of first-line chemotherapy with trastuzumab in advanced HR-positive, HER2-positive breast cancer patients.

e13023 Background: Human epidermal growth factor receptor-2 (HER2) positive breast cancer is a growing concern due to the boom in anti-HER2 therapy. Trastuzumab as the most classic anti-HER2 therapy drug, combined with chemotherapy has become the standard first-line treatment for advanced HER2-positive (HER2+) patients. Although some real-world studies of trastuzumab have been reported, less is known about the role of hormone receptors (HR) in first-line combined therapy. For maintenance therapy after chemotherapy combined with anti-HER2 therapy, the guidance given by clinical trials is the maintenance of targeted therapy. However, for those with HER2+/HR-positive (HR+) breast cancer, whether adding endocrine maintenance therapy can benefit progression-free survival (PFS) in addition to anti-HER2 therapy still needs more research. Thus, the purpose of this study was to retrospectively analyze real-world data, determine the factors that influence the trastuzumab-based therapy in advanced HER2-positive breast cancer patients. Methods: We retrospectively collected the treatment information of advanced breast cancer patients underwent first-line chemotherapy with trastuzumab from 2012 to 2021 in Zhejiang Cancer Hospital. Kaplan–Meier analysis and Cox regression methods were used to calculate and compare the PFS. Results: The study finally enrolled 285 patients meeting the requirement, including 150 HER2+/HR-negative (HR-) and 135 HER2+/HR+ (triple-positive) patients. The median chemotherapy treatment cycles and trastuzumab cycles were 7 (6-8) and 12 (7-17) cycles, respectively. For triple-positive breast cancer, maintenance endocrine therapy was aslo given concurrently with trastusumab in 75 patients after chemotherapy and trastusumab. Overally, the median PFS of first-line treatment was 11.73 (10.16-13.30) months, which was consistent with literature reports. Multivariate analysis revealed that HR positive [hazard ratio, 0.69; 95% confidence interval (CI), 0.52–0.92; P= 0.010], and non-brain metastasis (hazard ratio, 0.54; 95% CI, 0.29–0.99; P= 0.048) were independent prognostic factors. Further Kaplan–Meier analysis demonstrated triple-positive patients with maintenance endocrine therapy significantly had longer PFS than triple-positive patients without maintenance endocrine therapy and HER2+/HR- patients (21.33m vs. 10.13m vs. 9.53m, respectively, P &lt; 0.001). Conclusions: HR-positive was an independent prognostic factor for HER2-positive advanced breast cancer patients receiving first-line chemotherapy with trastuzumab. And endocrine therapy combined trastuzumab as Maintenance after chemotherapy prolonged PFS in HR-positive subgroup patients.

Pyrotinib in combination with metronomic oral vinorelbine in patients with HER2-positive advanced breast cancer who had failed prior trastuzumab-based therapy: A single-center, single-arm, prospective phase 2 study.

1033 Background: In 15% to 30% of breast cancers, human epidermal growth factor receptor 2 (HER2) is overexpressed, this is related to aggressive disease and poor prognosis. Although important clinical benefits for patients have been achieved by the use of the HER2 antibody trastuzumab, 50% to 74% of patients with metastatic disease have no response to treatment, and approximately 75% progress within one year. The purpose of this study was to evaluate the efficacy and safety of oral pyrotinib in combination with oral metronomic vinorelbine in patients with HER2-positive advanced breast cancer who had failed prior trastuzumab-based therapy. Methods: This prospective phase 2 study enrolled patients aged 18-75 years with HER2-positive advanced breast cancer who had failed prior trastuzumab-based therapy, and had an Eastern Cooperative Oncology Group performance score of 0-2. Patients received pyrotinib 400 mg once daily and vinorelbine 40 mg once on Monday, Wednesday, Friday of each week until disease progression or unacceptable toxicity. Both pyrotinib and vinorelbine were orally administered 30 min after meals. The primary endpoint was progression-free survival (PFS). The secondary endpoints were objective response rate (ORR), disease remission rate (DCR), overall survival (OS), quality of life (QoL) and safety (CTCAE 5.0). The follow-up of this study is ongoing, but enrolment is closed. This study is registered on Clinical Trials.gov, number NCT04903652. Results: Between Oct 21, 2019, and Jan 21, 2022, 36 patients were enrolled and all of them were included in the intent-to-treat (ITT) population. 20 of 36 patients had disease progress or death. Median follow-up was 16.23 months. The median PFS (mPFS) was 14.23 months (95% CI 8.13-20.33). The ORR and DCR were 38.9% and 83.3%, respectively. The median OS was not reached. Grade 3 adverse events (AEs) occurred in 17 of 36 patients, the most common were diarrhea 27.8% and stomachache 5.6%. No grade 4 AEs were observed. Conclusions: Pyrotinib combined with metronomic oral vinorelbine showed promising efficacy and manageable safety in patients with HER2-positive advanced breast cancer who had failed prior trastuzumab-based therapy. This study might represent a potential treatment option for these patients. Clinical trial information: NCT04903652..

BERENICE Final Analysis: Cardiac Safety Study of Neoadjuvant Pertuzumab, Trastuzumab, and Chemotherapy Followed by Adjuvant Pertuzumab and Trastuzumab in HER2-Positive Early Breast Cancer.

Simple SummaryA combination of pertuzumab, trastuzumab, and chemotherapy is a standard treatment for patients with a type of breast cancer called HER2-positive. Before the BERENICE study, little was known about the safety and effectiveness of pertuzumab with trastuzumab after surgery. Cardiac safety was a particular concern, especially when the chemotherapy given before surgery included drugs called anthracyclines. BERENICE was designed to assess the cardiac safety of pertuzumab with trastuzumab before surgery in combination with two different types of anthracycline-based chemotherapies. This paper describes additional safety and effectiveness data from BERENICE after patients had undergone surgery and when they had finished treatment. The incidence of cardiac side effects was low regardless of anthracycline use. The cardiac safety of pertuzumab and trastuzumab is now well characterized based on our study and others. Available information supports the use of pertuzumab–trastuzumab-based therapies as a standard treatment in HER2-positive early breast cancer.BERENICE (NCT02132949) assessed the cardiac safety of the neoadjuvant–adjuvant pertuzumab–trastuzumab-based therapy for high-risk, HER2-positive early breast cancer (EBC). We describe key secondary objectives at final analysis. Eligible patients received dose-dense doxorubicin and cyclophosphamide q2w × 4 ➝ paclitaxel qw × 12 (Cohort A) or 5-fluorouracil, epirubicin, cyclophosphamide q3w × 4 ➝ docetaxel q3w × 4 (B) as per physician’s choice. Pertuzumab–trastuzumab (q3w) was initiated from the taxane start and continued post-surgery to complete 1 year. Median follow-up: 64.5 months. There were no new cardiac issues and a low incidence of Class III/IV heart failure (Cohort B only: one patient (0.5%) in the adjuvant and treatment-free follow-up (TFFU) periods). Fourteen patients (7.7%) had LVEF declines of ≥10% points from baseline to <50% in Cohort A, as did 20 (10.5%) in B during the adjuvant period (12 (6.2%) in A and 7 (3.6%) in B during TFFU). The five-year event-free survival rates in Cohorts A and B were 90.8% (95% CI: 86.5, 95.2) and 89.2% (84.8, 93.6), respectively. The five-year overall survival rates were 96.1% (95% CI: 93.3, 98.9) and 93.8% (90.3, 97.2), respectively. The final analysis of BERENICE further supports pertuzumab–trastuzumab-based therapies as standard of care for high-risk, HER2-positive EBC.