HER2-positive Advanced Breast Cancer Research Articles

Real-life experience of trastuzumab deruxtecan (T-DXd) in patients with heavily pretreated HER2 positive advanced breast cancer: A retrospective single institution study.

e13035 Background: T-DXd is a HER2 antibody–drug conjugate. It improves patient outcomes and is FDA approved for the treatment of patients with Her-2 positive and Her-2 low metastatic breast cancer. However, the impact of T-DXd use in real life compared with the findings reported in clinical trials with strict inclusion criteria has rarely been assessed. We performed a real-world study to evaluate the outcomes of patients with advanced HER2+ and HER2-low expression breast cancer. Methods: We conducted a retrospective single institution study and collected the clinical and pathologic data of patients with metastatic breast cancer who were treated with T-DXd from 2019 to 2022. The primary end point, time to treatment failure (TTF) was defined as the interval from T-DXd initiation to discontinuation. We compared the TTF of T-DXd with previous lines of treatment and also report its safety and tolerability. Results: Thirty-one patients were included in this study, seventeen with HER2-low expression and fourteen with HER2 positive. Patients had received a mean of three prior lines of therapy (ranging from 1 to 13). 32.2% of patients had ≥ 5 lines of therapy prior to T-DXd. TTF was 104 days, 95% CI [58,162] in T-DXd compared with 151 days, 95% CI [119,217] in the previous line of therapy. 2 patients (6.4%) had treatment discontinuation due to adverse events (AEs) (1 patient due to grade 3 fatigue and 1 patient due to concern for ILD). 3 patients (9.6%) had treatment delay or dose reduction due to AEs. A total of 67.7% of patients (21/31) developed AEs on T-DXd. 4 (12.9%) had grade 3 or 4 AEs. Fatigue was the most common AE followed by nausea/vomiting and thrombocytopenia. A total of 17 patients had T-DXd discontinued-15 patients discontinued due to progression or death, 2 discontinued due to AEs. 9 out of 31 patients had brain metastasis. Amongst patients with brain metastases, 7 showed stable disease while on T-DXd (1 had previously progressed on tucatinib, trastuzumab, and capecitabine). In the subgroup analysis, in patients with HER2-low expression, TTF was 98 days 95% CI [41-153] with T-DXd compared with 192 days, 95% CI [84,363] in the previous line of therapy. 2 out of 14 patients developed grade 3 or 4 AEs. Fatigue was the most common AE. In HER2+ subgroups, TTF was 126 days, 95% CI [58,353] in T-DXd vs 125 days, 95% CI [106,217] in the previous line of therapy. 2 out of 17 patients developed grade 3 or 4 AEs. Conclusions: To the best of our knowledge this is the first real life retrospective study evaluating the efficacy and tolerability of T-DXd. Overall, T-DXd had acceptable efficacy and tolerable toxicity in heavily pretreated patients. T-DXd showed a good response rate in patients with active brain metastasis. Our findings are consistent with published data on T-Dxd but is limited by virtue of retrospective series.

De-escalating therapy dilemma in small HER2 positive node negative breast cancer.

e12626 Background: Neoadjuvant therapy (NAT) is the standard of care for locally advanced HER2 positive breast cancer (BC) and provides pathologic complete response (pCR), a key prognostic factor and indicator to decide whether to escalate to adjuvant T-DM1 in case of residual disease, as per the KRISTINE trial. However, optimal sequencing of treatment (NAT vs. surgery first) is less clear in T1cN0 (stage I) HER2 positive BC. Moreover, the long-term follow-up of the Adjuvant Paclitaxel and Trastuzumab (APT) trial showed that deescalating chemotherapy is a possible strategy for small HER2-positive node negative breast cancers when tumor size is 3 cm or less. In clinical practice, there is a recurrent debate in multidisciplinary boards to decide the adequate strategy in small HER2 positive node negative BC. Although these tumors are considered of good prognosis, recent results by An et al. 2022 fuels the debate. They showed in a large observational cohort that T1N0 HER2 positive BC APT eligible treated with NAT and not achieving pCR have similar survival to patients with T2N0 tumors with residual disease, suggesting a higher risk group among small tumors.The aim of the study was to analyze the profile and outcome of APT eligible patients treated with NAT using a detailed tumor size breakdown. Methods: APT eligible patients treated with NAT were identified among a real-world cohort of 340 early HER2 positive BC patients receiving NAT at Oscar Lambret Cancer Center (Lille, France). The outcome of the APT eligible patients (n = 115) was analyzed according to tumor size ( < 15mm, 15-20mm, 21-30mm). Results: All patients were female with a median age of 54 years and received neoadjuvant anthracyclines followed by taxanes and trastuzumab. The ratio of hormone receptor (HR) positive / HR negative tumors was 72% / 28%. A similar distribution of grade 2 / grade 3 tumors was observed. Up to 75% of the patients did not have a complete pathologic response to NAT. In HR positive, the pCR rate was 43% in HER2 positive tumor of less than 15mm, 26% in tumors of 15-20mm, 25% in tumors of 21-30mm, and 32% in tumors of 31-50mm. In HR negative tumors, pCR rate was 81% in tumors of 15-20mm, 56% in tumors of 21-30mm, and 67% in tumors of 31-50mm. Conclusions: These results showed that APT eligible small HER2 positive and HR positive tumors had low chemosensitivity leading to adjuvant treatment escalation as per standard of care. It raises questions about the appropriate selection of patients for de-escalation in this population subset.

Preliminary analysis of pyrotinib and dalpiciclib-based therapy in HER2-positive advanced breast cancer (ABC).

e13027 Background: The efficacy of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) and HER2 target agents combined with endocrine treatment (ET) has been demonstrated in hormone receptor (HR)-positive and HER2+ ABC, while little was known about the role of CDK4/6i in HR-/HER2+ ABC. In this prospective, multi-center, multi-cohort, phase 2 study (NCT04095390), we assessed the efficacy and safety of pyrotinib (P) and a CDK4/6i, dalpiciclib (D)-based therapy in HER2+ ABC with disparate HR statuses. Methods: HER2+ ABC females with known HR status were eligible if previously treated with trastuzumab (T). No more than one prior systemic regimen in advanced setting was allowed. Cohort A: HR+ pts received P (320 mg QD) and D (125 mg QD, 21 days on and 7 days off) combined with letrozole (2.5 mg QD). Cohort B or C: HR- pts were randomized to receive P and D combined with or without capecitabine (500 mg TID). Pts were treated until progression or unaccepted toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: As of Jan. 16, 2023, 33 pts were enrolled. We describe pts' distribution and characteristics. 26 pts had at least one efficacy assessment, and 17 (65.4%) achieved confirmed objective responses. ORR was 66.7% (10/15), 80% (4/5), and 50% (3/6) in cohort A, B, and C, respectively. Among the ITT population, the estimated median PFS was 24.9 mo. (24.9 mo., NR, and 20.2 mo. in cohort A, B, and C, respectively). 32 (97.0%) pts experienced treatment-related adverse events (TRAEs). Grade (G) 3-4 TRAEs occurred in 81.8% of pts, and the most frequent (≥ 10%) ones were neutropenia (72.7%), leukopenia (57.6%), diarrhea (21.2%), and mucositis (12.1%). Safety profiles were similar among cohorts, except more G3-4 mucositis, hand-foot syndrome and thrombocytopenia in cohort B. Two in cohort B discontinued due to toxicity (1 rash, and 1 neutropenia). One death was reported after withdrawal and unrelated to the study. Median OS was not reached. Conclusions: Our study shows P and D combined with ET is effective in HR+/HER2+ ABC, providing a chemo-free option to these pts. In HR-/HER2+ ABC, we preliminarily observed that the addition of chemotherapy could improve effectiveness of P and D, but also increase toxicities. Due to the limited sample, the findings need further confirmation. Clinical trial information: NCT04095390 . [Table: see text]

Identifying the optimal therapeutics for patients with hormone receptor-positive, HER2-positive advanced breast cancer: A systematic review and network meta-analysis.

e13023 Background: Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer is a distinct subtype with different prognosis and response to treatment. HER2-targeted therapy is currently recommended for patients with HR+/HER2+ advanced breast cancer. However, there is debate over which drugs to add on the basis of HER2 blockade yields the optimal efficacy. Moreover, the research on replacing chemotherapy with endocrine therapy in the regimens are under way. This systematic review and network meta-analysis was conducted to find the optimal treatment for this subtype. Methods: Eligible randomized controlled trials (RCTs) comparing different interventions in metastatic HR+/HER2+ breast cancer were included by comprehensively searching PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences before September 5th, 2022. The outcomes of interest included progression free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs). Pooled hazard ratios (HRs) or odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate the predefined outcomes based on the data type. The optimal therapeutics were identified by utilizing the cumulative ranking curves (SUCRA). Results: In total, 23 pieces of literature of 20 RCTs were included. Regarding PFS, significant differences were detected between dual HER2 blockade plus endocrine therapy versus endocrine therapy alone (HR 0.45, 95% CrI 0.25-0.83; HR 0.47, 95% CrI 0.27-0.87), and trastuzumab, pertuzumab plus chemotherapy versus trastuzumab plus chemotherapy (HR 0.69, 95% CrI 0.47-0.96). The SUCRA values suggested the relatively better efficacy of dual HER2-targeted therapy plus endocrine therapy (86% to 91%) or chemotherapy (62% to 81%) in prolonging PFS and OS. The HER2 blockade-containing regimens showed similar safety profiles in eight documented TRAEs. Conclusions: Prominent status of dual-targeted therapy for patients with HR+/HER2+ metastatic breast cancer was revealed. Compared with chemotherapy-containing regimens, the endocrine therapy-containing regimens showed better efficacy and similar safety profile, which could be recommended in practice.

Zanidatamab (zani), a HER2-targeted bispecific antibody, in combination with docetaxel as first-line therapy (1L) for patients (pts) with advanced HER2-positive breast cancer (BC): Updated results from a phase 1b/2 study.

1044 Background: Despite HER2-targeted agents improving outcomes in HER2-positive (+) BC, some pts develop resistance, relapse, or do not respond to current 1L therapies. Zani, also known as ZW25, is a novel HER2-targeted bispecific antibody that binds to two distinct extracellular domains of HER2. Preliminary results from this phase 1b/2 trial (NCT04276493) showed that zani plus docetaxel had a manageable safety profile and demonstrated promising antitumor activity in pts with advanced HER2+ BC; here we present the updated data following enrollment completion. Methods: Cohort 1 of this open-label study is evaluating zani in combination with docetaxel as a 1L therapy in adult females with advanced HER2+ BC who may have received prior neoadjuvant/adjuvant therapy. Cohort 1a pts received zani 30 mg/kg intravenously (IV), Cohort 1b pts received zani 1800 mg IV, both with docetaxel 75 mg/m2 IV every 3 weeks. The primary endpoints were safety and investigator (INV)-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints included INV-assessed duration of response (DoR) and disease control rate (DCR). Results: As of Nov 22, 2022, 37 pts (median age 55.0 years [range: 33-80]) were assigned to Cohort 1a (n=10) or 1b (n=27). Median study follow-up was 15.5 months (range: 1.1-29.3); patients received a median of 13 treatment cycles (range 1-37) and 18 (48.6%) pts remained on treatment. Of the 33 efficacy evaluable (EE) pts, confirmed ORR was 90.9% (95% confidence interval [CI]: 75.7, 98.1). Efficacy data are summarized in Table. In total, 36 (97.3%) pts experienced ≥1 treatment-related adverse event (TRAE); 25 (67.6%) pts experienced ≥grade 3 TRAEs. The most common ≥grade 3 TRAEs were decreased neutrophil count, experienced by 18 (48.6%) pts, and decreased white blood cell count, experienced by 7 (18.9%) pts. Serious TRAEs occurred in 6 (16.2%) pts; no TRAEs led to death. Conclusions: Zani combined with docetaxel demonstrated promising antitumor activity as 1L therapy for advanced HER2+ BC, with a manageable safety profile. Clinical trial information: NCT04276493 . [Table: see text]

Neoadjuvant inetetamab combined with pertuzumab, paclitaxel, and carboplatin (TCbIP) for locally advanced HER2-positive breast cancer: Primary analysis of a phase II study.

e12597 Background: Inetetamab (Cipterbin) is a neotype HER2-targeted monoclonal antibody with amino acids modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity (ADCC) effect. Unfortunately, no robust evidence evaluating the combination of inetetamab combined with pertuzumab, paclitaxel and carboplatin (TCbIP) exists for neoadjuvant therapy. This study aimed to evaluate the efficacy and safety of TCbIP as a neoadjuvant therapy of patients with locally advanced (LA) HER2-positive breast cancer. Methods: This phase II trial included patients with histologically confirmed stage IIA to IIIC HER2-positive primary invasive breast cancer. Eligible patients receive TCbIP treatment every 3 weeks for a maximum of 6 cycles, followed by surgery. The primary endpoint was pathologic complete response (pCR, ypT0/is ypN0) rate. Key secondary endpoints included near pCR (npCR, residual breast disease < 1cm) rate, objective response rate (ORR) and safety. Efficacy was analyzed in the intention-to-treat (ITT) and per-protocol (PP) populations. The ITT population included patients who received at least 2 cycles of TCbIP treatment but excluded those who were lost to follow-up without surgery and those who received other targeted therapy. The PP population included patients who met all the trial criterias, complianted with the protocol, and did not violate any major protocol. The safety population included all patients who received at least one dose of the study drugs and had available safety data. Results: A total of 24 patients were enrolled from November 2021 to February 2023. Of 24 patients, 1 patient received 1 cycle of study treatment and was lost to follow-up without surgery, and 4 patients received 1 cycle of study treatment and were still in treatment, leaving 19 patients in the ITT population. Among 19 patients in the ITT population (median age, 50 years; 78.9% in stage III), 12 patients completed the study treatment and surgery (PP population) and 7 patients were still in neoadjuvant treatment. ORR was achieved 78.9% in the ITT population (15 of 19 patients) and 91.7% in the PP population (11 of 12 patients). Among 12 patients of PP population, 8 patients (66.7%) achieved pCR and 10 patients (83.3%) achieved npCR. For patients with hormone receptor negative and positive tumors, the pCR rates were 71.4% (5/7) and 60.0% (3/5) ( P = 0.771), and the npCR rates were 85.7% (6/7) and 80.0% (4/5) ( P = 0.793), respectively. The most common grade ³3 adverse events were hair loss (41.7%) and neutropenia (12.5%). No significant reduction in the left ventricular ejection fraction was observed in any patient. No patients withdrew from the treatment due to adverse drug reactions. Conclusions: TCbIP displays a promising efficacy (pCR rate of 66.7%) and manageable toxicity in patients with HER2-positive LA breast cancer in the neoadjuvant setting. Clinical trial information: NCT05749016 .

FS-1502 in HER2-positive advanced breast cancer: Results from an open-label, phase 1 study.

3044 Background: FS-1502 is an anti-HER2 antibody-drug conjugate that was well tolerated and showed good antitumor activity in patients (pts) with advanced HER2 -expressing solid tumors in the dose-escalation stage of the current Phase 1 study. The results were presented at SABCS 2022. The recommend Phase 2 dose (RP2D) was 2.3 mg/kg IV once every 3 weeks. Here, we report the efficacy and safety of HER2-positive breast cancer (BC) pts treated with FS-1502 at the RP2D. Methods: This open-label Phase 1 trial was conducted at 9 hospitals in China. Heavily pretreated HER2-positive (IHC 3+ or 2+/FISH+) BC pts who had failed prior anti-HER2 therapy were recruited in the dose-expansion stage. All HER2-positive BC pts treated at the RP2D were pooled for analysis. Efficacy endpoints included objective response rate (ORR) and disease control rate (DCR) per RECIST v1.1. Safety endpoints included treatment-emergent adverse events (TEAEs) and the laboratory data. Results: As of cutoff date, December 24, 2022, the median study follow-up duration was 5.2 months. A total of 70 female HER2-positive BC pts, with a median age of 51.8 (range: 31-76) years, were enrolled and received at least one dose of FS-1502. The median prior therapy line was 3 (range: 1-16), and 91.4% (64/70) of pts had previously received at least 2 therapy lines. The most common metastasis organs were lung 55.7% (39/70), lymph node 54.3% (38/70) and bone 50% (35/70). 81.4% (57/70) of pts had at least 3 metastatic lesions. All pts had previously received anti-HER2 therapy, among which trastuzumab ± pertuzumab (n = 67, 96%) and pyrotinib (n = 52, 74%) were the most common. Among 68 efficacy-evaluable pts, the best ORR of 52.9% (36/68) (95% CI, 40.45-65.17) was achieved with 2 complete responses and 34 partial responses. DCR was 88.2% (60/68), median progression-free survival was 15.5 months (95% CI, 4.57,-), and median duration of response was 12.9 months (95% CI, 5.72,-). FS-1502 was well tolerated. No related interstitial lung disease occurred in any grade. Eye toxicity was mostly Grade 1 or 2 of dry eye and keratitis. Grade ≥ 3 study-related TEAEs were reported in 27 (38.6%) pts, in which the most common events (≥ 5%) were hypokalemia (18.6%), platelet count decreased (7.1%), and neutrophil count decreased (5.7%). One (1.4%) patient experienced adverse events leading to drug discontinuation (hemoptysis). Adverse events leading to death were reported in 2 (2.9%) pts (bacterial pneumonia and hemoptysis, respectively). Bacterial pneumonia was not related to FS-1502, while hemoptysis was possibly related to the drug. Conclusions: FS-1502 demonstrated very promising antitumor activity and was well tolerated in heavily pretreated HER2-positive BC, with mild eye toxicity and no related interstitial lung disease reported. A Phase 3 clinical trial is under planning to further confirm efficacy and safety of FS-1502 in pts with advanced HER2-positive BC. Clinical trial information: NCT03944499 .

Combination of eribulin with trastuzumab and pertuzumab for HER2 positive advanced or recurrent breast cancer: JBCRGM03.

e13031 Background: Pertuzumab (P) was an effective first-line treatment for HER2 positive metastatic breast cancer (MBC) in the CLEOPATRA study, improving both overall and progression-free survival (PFS). However, it is challenging to provide intravenous docetaxel to MBC patients over long term at a dosage of 75 mg/m2 every three weeks. Eribulin (E) is a well tolerated cytotoxic agent. In a multicenter, open-label phase II research (UMIN000012232), we have shown the effectiveness and safety of E combined with trastuzumab (T) with P as first- and second-line treatment for metastatic or advanced BC. Methods: The study included HER2 positive MBC patients with no or one previous treatment, including advanced or recurrent chemotherapy. All patients were administered with T and taxane as perioperative or first-line chemotherapy. E (1.4 mg/m2) along with T (8 mg/kg loading dosage > 6 mg/kg), and P (840 mg loading dose > 420 mg) was administered intravenously on days 1 and 8 of a 21-day cycle, once every three weeks. The primary end point was PFS and the secondary endpoints were the response rate (RR) based on RECIST ver1.1. Overall patient survival effectiveness following P administration, E compliance, and success of follow-up therapies were observed. Results: A total of 50 patients were enrolled, with 49 of them qualifying for the safety analysis. However, the full analysis set (FAS) consisted of 46 individuals. The average patient age was 56 years old (range 23–70), and 9 (18%) and 40 (82%) patients received care in first- and second-line settings, respectively. The median PFS for patients who received main therapy was 20.5 months, whereas the median PFS for patients who received subsequent treatment was 8.6 months. Thirty-five patients (76.1%) were able to receive concomitant E until the end of protocol treatment. The overall RR was 56.5% among the 46 patients in the FAS. Nine patients (19.5%) responded completely, whereas 17 patients (37.0%) responded partially. There were 13 cases of stable disease (28.2%), six cases of progressing disease (13.0%), and one case was not evaluable (1.2%). The median survival of the primary treatment population was not reached; however, the median survival of the secondary treatment population was 42.4 months. Twenty three patients received T-DM1 as a follow-up treatment, 13 patients received TP plus chemotherapy, and five patients received additional therapies. The average duration of treatment with T-DM1 as a consequent therapy was approximately four months, whereas the average duration of treatment with HP plus chemotherapy was 11 months. Conclusions: For HER2positive MBC, E in combination with T plus P was well tolerated and may be an alternative to docetaxel-based combination therapy. Results from the JBCRG M06 trial research, which compares taxanes combination with T plus P with E combined with T plus P in first-line therapy, are still pending. Clinical trial information: UMIN000012232 .

Multi-omic subtyping and molecular determinants of neoadjuvant therapeutic regimen for locally advanced HER2-positive and triple-negative breast cancer: Implications of novel therapy.

e12600 Background: Neoadjuvant chemotherapy is the backbone treatment modalities for BC patients for locally advanced breast cancer (BC) improves R0 resection rate. Determinants of differentially therapeutic response to anthracycline or platinum-based neoadjuvant therapy were largely unknown but were urgently needed to maximize patients’ benefit. Methods: A total of 149 local advanced (cT2-3, cN0-2, cM0-1) BC patients (HER2 positive BC, n = 54 and TNBC, n = 95) were retrospectively enrolled in the study, whole-exon sequencing (WES), mRNA sequencing and (phosphor-)proteomics were systematically conducted and comprehensively analyzed. The primary end point of the study was the pathological complete response (pCR) rate. The Cancer Genome Atlas (TCGA) BC dataset and GSE130787 set were used to validate our analysis. Cancer cell line encyclopedia (CCLE) dataset was utilized to screen putative small molecular inhibitors to BC cells with molecular features of resistance. Results: Through integrated analysis of multi-omics data, three subtypes with distinct molecular features were identified: immune-activated (IA) subtype, vesicular transport pathways activation (VTs) subtype, and kinase activation (KA) subtype. Same scenario of molecular subtypes can be repeated in TCGA dataset and prognosis of these subtypes can be differentiate ( p= 0.02). Patients with IA subtype majorly favored cisplatin-based treatment ( p= 0.005). And this phenomenon was confirmed in external dataset (GSE130787, n = 26, HER2-positive BC receiving TCbH treatment). Patients with VTs subtype, with significant enrichment of vesicular transport-related pathways, displayed anthracycline sensitivity. Anthracycline transporter, ABCB1 expression was significantly reduced in VTs subtype at both mRNA ( p < 0.001) and protein ( p < 0.05) levels. CCLE breast cancer cells with the characteristics of VTs subtype and lower ABCB1 expression also displayed the sensitivity of epirubicin ( p = 0.0037). Patient with KA subtype was insensitive to both platinum and anthracycline-based therapy. Multiple kinase pathways, especially, non-canonical TGF-β signaling pathway-related genes were overexpressed (p < 0.05), and significantly correlated with non-pCR ( p= 0.002). Phosphor-proteomic analysis indicated TGFβ1-mediated RhoA/ROCK pathway (Cofilin, RhoA kinase, MYH14 proteins) were highly activated. Eleven drugs were found in CCLE inhibiting growth of BC cell lines with upregulated non-canonical TGF-β pathway genes ( p < 0.05). Conclusions: Three multi-omic subtypes with distinct response to anthracycline or platinum-based therapy were identified. Moreover, activated non-canonical TGF-β pathway may mediate therapeutic resistance, but also indicated therapeutic vulnerabilities of several kinase inhibitors.

HER2 persistence after treatment with T-DXd in breast and gastrointestinal cancers.

1052 Background: T-DXd is a HER2-targeted antibody drug conjugate approved for treatment of advanced HER2-positive breast and gastroesophageal cancers and HER2-low breast cancers. The prevalence of HER2 loss after exposure to T-DXd is unknown and has implications for treatment strategies in refractory patients. Methods: We investigated clinically reported HER2 immunohistochemistry (IHC) scoring on post-treatment tissue biopsies from patients who received at least 2 cycles of T-DXd as of 2/2023. IHC was performed using mAB clone 4B5 (Ventana) and scored by ASCO/CAP guidelines on a scale of 0 to 3+. MSK-IMPACT next generation sequencing (NGS) was performed on paired pre- and post-treatment samples when available. Statistics are descriptive. Results: A total of 62 patients with breast, gastroesophageal, or colon cancer had available post-treatment biopsies. The majority (n = 51) had breast cancer, including 32 with HER2-positive and 19 with HER2-low disease. Median time on therapy was 30 weeks in HER2-positive and 21 weeks in HER2-low breast cancer. All 32 patients with HER2-positive breast cancer had detectable HER2 expression by IHC on post-treatment biopsies (median IHC score 2+; range 1+ to 3+). Of those with HER2-low breast cancer, 12 (63.1%) patients had detectible IHC after treatment. Of the 7 with IHC scores of zero, 3 also had scores of zero on the most proximal pre-treatment biopsies. Seven patients with gastroesophageal and 3 with colorectal cancer were included, with a median time on therapy of 12 and 9 weeks respectively, of which 1 (9%) exhibited HER2-loss after treatment. Among all patients with HER2-positive cancers, the rate of complete HER2-loss by IHC after exposure to T-DXd was 2.3%. Thirty-two patients had paired genomic analysis, including 25 breast and 7 gastrointestinal cancers. No change was observed in the fraction of genome altered (p = 0.0736, q = .327) or tumor mutational burden (p = 0.139, q = .487) with T-DXd exposure. Changes in ERBB2 copy number did not show clear directionality, with 15 patients (46.7%) exhibiting ERBB2 amplification pre-treatment and 12 (37.5%) post-treatment, the sum of 3 temporal gains and 6 losses of ERBB2 amplification across the threshold of 1.8. Conclusions: HER2 remained detectable by IHC in the majority of patients treated with T-DXd in this cohort, especially those with HER2-positive cancers. These findings suggest that resistance to T-DXd may occur via target-independent factors, and that HER2 could still be exploited therapeutically in these populations. Further prospective studies using quantitative assays are needed to confirm these hypotheses. [Table: see text]

INSIGHT-HER2BC: Real-world evidence of TCHP regimen to describe the best patient profile and open up questions—The interim results.

e12607 Background: Neoadjuvant therapy (NAT) of TCHP regimen is approved for standard therapy for early and locally advanced HER2-positive breast cancer (eHER2+ BC) based on encourage TRYPHAENA and KRISTINE trials results. There are limited data regarding patients (pts) treatment outcomes after NAT TCHP in the routine clinical practice. Here we presented the 1st results of ambispective observational program to assess the efficacy and safety of cancer therapy in patients with solid tumors. Early HER2+ breast cancer group: INSIGHT-HER2BC. Methods: We ambispectively reviewed medical records of pts with eHER2+ BC who underwent NAT 6xTCHP (6 docetaxel/carboplatin + trastuzumab/pertuzumab) at three Moscow oncology centers since Jan’2017. This ongoing trial has launched in Feb’22. Here is presented descriptive analyses of pCR (ypT0/is, ypN0) rate for pts who completed NAT and 1-3 yrs. disease-free survival (DFS). Results: At the data cut-off (Jan’2023) 934 pts with HER2+ eBC underwent ≥ 1 cycle of NAТ. The median age is 54.3 y.o. (range: 22-78) where 36% pts were older 60 y.o.; 14% pts - younger than 40 y.o. 75% (571) pts had surgery results. pCR rate is related to KRISTINE trial: 58% (330) pts in the ITT (intention-to-treat) population vs 56% pts, respectively. pCR rate for pts with locally advanced BC is 55% vs 59% for operable BC (114/208 and 215/363 pts, respectively). There is difference in pCR rate achievement according to hormone status (HR+ vs HR-) and HER2 status (3+ vs 2+/ISH +). 1-yr. DFS for pCR group is 97% vs 94% for non-pCR; 2-yr. DFS is 83% vs 83%, respectively, and 3-yr. DFS 64% for pCR group vs 58% for non-pCR. In HR-HER2+ BC the biggest drop between pCR and non-pCR is registered at the 3-yr. DFS: 56% vs 22% while in HR+HER2+ there is almost equal decrease was observed every yr.: 97% vs 93% - 1st yr.; 90% vs 85% - 2nd yr.; 72% vs 68% - 3d yr. Conclusions: NAT TCHP is the effective regimen for HER2+ eBC in the real-world population. The efficiency is observed regardless of disease stage and age. However, there is clear unmet need to find new therapeutic options for HER2 (2+/ISH+) BC. Preliminary results of DFS is markedly lower than in TRYPHAENA and KRISTINE trials but in conjunction with another real-world evidence data. DFS in HR+HER2+ and HR-HER2+ pts likely reflects distinct tumor biology. The mature data for long-term outcomes are awaited. [Table: see text]

Construction of a prognostic hierarchical model for patients with HER2 positive breast cancer with brain metastases.

e13030 Background: Brain metastasis occurs in about 50% of advanced HER2-positive breast cancer patients. In clinical practice, we need accurate model to predict the patients’ survival time. According to survival time, we can arrange reasonable treatment strategy for HER2 positive breast cancer with brain metastases. Methods: The study recruited HER2-positive breast cancer brain metastasis (BCBM) patients who attended the Fifth Medical Center of PLA General Hospital from June 2003 to June 2022.All statistics were performed using SPSS version 22.0 and R version 3.4.3 software. Results: This study included 300 patients with HER2-positive BCBM. The median age at Brain Metastases diagnosis was 48.5 years, and the median Brain Metastases Overall Survival time (BMOS) was 18.0 months (95% CI: 14.6-21.4). A single-factor analysis of BMOS revealed that age, number of brain metastasis lesions, number of extracranial lesions during BCBM, radiotherapy after BCBM, anti-HER2 therapy after BCBM, and survival prognosis after BCBM were associated with survival prognosis after diagnosis of BCBM. According to a multi-factor analysis, the age, the number of brain metastases, radiotherapy after BCBM, and anti-HER2 therapy after BCBM were all independent factors influencing survival after diagnosis of BCBM. Different independent prognostic factors comprised the patient hierarchical evaluation model. Patients' warning scores range from 0 to 7. We divided the patients into three groups with obvious differences in prognosis： Low- intermediate-risk (score≥1), stroke group (score≥3) and high-risk group (score≥6). The patient prognosis was worse when the warning score was high. The results of Kaplan-Meier survival curve analysis showed significant prognosis differences between the three groups of patients (P < 0.0001). The mean Area Under Curve of the receiver operating characteristic curve for 1-yeasr, 2-year, and 3-year prognosis prediction was 0.69,0.71, and 0.67, respectively. For low-risk patients, the prognosis was significantly improved by using any anti-HER2 medications (P<0.05). Trastuzumab + Pertuzumab can significantly improve the prognosis of patients at intermediate risk (P<0.001, HR=0.24,95%CI: 0.13-0.43). Patients in the intermediate-risk group received both anti-HER2 medication and combined radiotherapy significantly prolonged BMOS in patients who received only drug therapy or radiotherapy (P=0.0132). Conclusions: A survival and prognostic stratification model was constructed based on the clinicopathological characteristics and treatment pattern of a large cohort of HER2-positive breast cancer patients with brain metastases, and the patients were divided into the low-risk group, intermediate-risk group and high-risk group. The optimal individualized treatment strategy was recommended according to different groups.

Drug-drug interaction potentials of tucatinib inhibition of human UDP-glucuronosyltransferases

Tucatinib is known as a tyrosine kinase inhibitor (TKI), which has been commonly approved for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer. However, there haven't been systematic study about the inhibition of tucatinib on UDP-Glucuronosyltransferases (UGTs) and the potential risk of drug-drug interactions (DDIs). In present study, we aimed to systematically investigate the inhibition of tucatinib on recombinant human UGTs and pooled human liver microsomes (HLMs), and to quantitatively evaluate its potential risk of DDIs by in vitro-in vivo extrapolation (IVIVE). Our data indicated that tucatinib exhibited extensive inhibition on recombinant UGTs. Tucatinib was a weak inhibitor of UGT1A4, 2B4 and 2B7; tucatinib possessed a strong inhibitory effect on UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17, with IC50 values of 0.53 μM–15.50 μM. Especially, it also potently inhibited estradiol and SN-38 glucuronidation in HLMs with IC50 values of 46.83 μM and 1.33 μM. The quantitative prediction of DDIs risk indicated that the co-administration of tucatinib with drugs mainly metabolized by hepatic or intestinal UGTs (UGT1A1, UGT1A3, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2B15 and UGT2B17) might result in potential DDIs risk through inhibition of glucuronidation. More attention should be paid to the influence of tucatinib on UGTs in liver and intestine to avoid unnecessary clinical DDIs risk.

Tucatinib promotes immune activation and synergizes with programmed cell death-1 and programmed cell death-ligand 1 inhibition in HER2-positive breast cancer.

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy. We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors. In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone. Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.

Ado-tratuzumab emtansine beyond breast cancer: therapeutic role of targeting other HER2-positive cancers.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved by the FDA in 2013 for advanced HER2-positive breast cancer treatment exhibiting promising clinical benefits. However, HER2 overexpression and gene amplification have also been reported in other cancers like gastric cancer, non-small cell lung cancer (NSCLC), and colorectal cancer. Numerous preclinical studies have also revealed the significant antitumor effect of T-DM1 on HER2-positive tumors. With the advancement in research, several clinical trials have been conducted to investigate the antitumor effect of T-DM1. In this review, we briefly introduced the pharmacological effects of T-DM1. We reviewed its preclinical and clinical studies, especially on other HER2-positive cancers, establishing what has been encountered between its preclinical and clinical studies. In clinical studies, we found that T-DM1 has a therapeutic value on other cancers. An insignificant effect was observed on gastric cancer and NSCLC, inconsistent with the preclinical studies.

A UK Real-world Evaluation of Efficacy and Toxicity of Second-line Trastuzumab Emtansine and Third-line Trastuzumab Deruxtecan in HER2-positive Advanced Breast Cancer

Purpose: Trastuzumab emtansine is routinely offered to patients in the second-line setting for advanced human epidermal growth factor receptor 2 (HER-2)-positive breast cancers. There is a paucity of UK real-world data on the progression-free survival (PFS) with trastuzumab emtansine therapy after prior pertuzumab and the risk of cardiotoxicity. Trastuzumab deruxtecan is currently approved for use after 2 or more anti-HER2 therapies based on DESTINY-Breast01 single-arm trial showing an overall response rate of 60.9% and median PFS of 16.4 [1].

A Retrospective Review of the Clinical Outcomes of Trastuzumab Deruxtecan (T-DXd) for the Treatment of Advanced HER2-positive Breast Cancer at the Mount Vernon Cancer Centre

Purpose: Trastuzumab deruxtecan (T-DXd) has been available since April 2021 via the Cancer Drugs Fund for patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more anti-HER2 therapies, following the results of the phase II DESTINY-Breast01 trial [1]. We examined our local T-DXd use and associated clinical outcomes.

209P Trastuzumab plus lapatinib or chemotherapy in patients with HER2-positive advanced breast cancer refractory to anti-HER2 therapies: A randomized, multicenter, phase II trial (GIM12-TYPHER)

Trastuzumab (T) and chemotherapy (CT) is a standard treatment in patients (pts) with HER2-positive (+) advanced breast cancer (ABC) at later lines of therapy. Lapatinib (L) and T have proven to be active in the same setting. The present study evaluated the efficacy, toxicity and quality of life (QoL) of T+L versus T + physician’s choice CT in pts with HER2+ ABC pretreated with at least two lines of anti-HER2 treatment. In this open-label, multicenter, phase II trial, pts were randomly assigned 1:1 to receive either T+L with endocrine therapy at the physician’s discretion in case of hormone receptor positive ABC (arm A) or T+CT (arm B). The primary endpoint was the clinical benefit rate (CBR) and the secondary endpoints included overall survival (OS), progression-free survival (PFS), quality of life (QoL), and safety. Between 2015 and 2020, 59 pts were randomized and evaluated for the present analyses. After a median (m) follow-up of 57.5 months (mo), the CBR was 20.7% (95% CI 9.4-39.3) vs 26.7% (95% CI 13.1-44.9; P= 0.76), the mOS was 29.9 mo (95% CI 19.6-NE) vs 31.1 mo (95% CI 26.1-NE; hazard ratio [HR] 1.07, 95% CI 0.57-2.0; P=0.82) and mPFS was 3.6 mo (95% CI 3.0-5.3) vs 6.1 mo (95% CI 4.0-14.3; HR 0.63, 95% CI 0.37-1.37; P=0.08) in arm A vs arm B, respectively. Any grade (G) adverse events (AEs) occurred in 86.2% and 66.7% of pts in arm A and B, respectively. The incidence of G3-4 AEs was 24.1% and 13.3% in arm A and B, respectively. The impact on QoL significantly favored arm A (P=0.03).Table: 209PAEsOverall (N=59)Arm A (N=29)Arm B (N=30)Patients with at least one AE45 (76.3)25 (86.2)20 (66.7)Diarrhea14 (23.7)11 (37.9)3 (10)Fatigue13 (22)7 (24.1)6 (20)Abdominal pain7 (11.9)3 (10.3)4 (13.3)Anemia7 (11.9)4 (13.8)3 (10)Neutropenia5 (8.5)0 (0)5 (16.7)Nausea5 (8.5)3 (10.3)2 (6.7)Thrombocytopenia5 (8.5)4 (13.8)1 (3.3)Paresthesia4 (6.8)0 (0)4 (13.3)Fever3 (5.1)3 (10.3)0 (0)Skin disorders3 (5.1)3 (10.3)0 (0) Open table in a new tab No difference in efficacy was observed between T+L and T+CT. QoL deterioration was less frequent in pts in T+L arm though a higher number of any AEs was observed in these patients compared with those who received T+CT. Overall, the chemotherapy-free combination of T+L may be a valid therapeutic option for pretreated pts with HER2+ ABC.

237P Real-world safety and efficacy of trastuzumab-deruxtecan (T-DXd) in HER2-positive advanced breast cancer (ABC) elderly patients (pts): The TREX-Old retrospective registry

237P Real-world safety and efficacy of trastuzumab-deruxtecan (T-DXd) in HER2-positive advanced breast cancer (ABC) elderly patients (pts): The TREX-Old retrospective registry

197P ATREZZO trial (SOLTI-1907): A phase II trial targeting estrogen receptor negative or PAM50 non-luminal disease with atezolizumab in combination with trastuzumab and vinorelbine in HER2-positive (HER2+) advanced breast cancer (ABC) - Interim analysis

197P ATREZZO trial (SOLTI-1907): A phase II trial targeting estrogen receptor negative or PAM50 non-luminal disease with atezolizumab in combination with trastuzumab and vinorelbine in HER2-positive (HER2+) advanced breast cancer (ABC) - Interim analysis