Prior Trastuzumab Research Articles

Real-world efficacy and safety of inetetamab-based therapy in patients with HER2-positive metastatic breast cancer with prior trastuzumab exposure: A multi-center retrospective study.

Real-world efficacy and safety of inetetamab-based therapy in patients with HER2-positive metastatic breast cancer with prior trastuzumab exposure: A multi-center retrospective study.

Real world experience of trastuzumab deruxtecan for the treatment of metastatic breast cancer in the UK.

1024 Background: Trastuzumab deruxtecan (TDXd), an antibody drug conjugate, was first approved in the UK for the treatment of human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer (mBC) in 2021. We aimed to review the efficacy and tolerability of TDXd in a real-world UK setting. Methods: We collected clinical and demographic data from medical records on HER2+ mBC patients treated with TDXd in the UK from Jan 2021 to Dec 2023 inclusive. This included: radiological response, the frequency of dose reductions and treatment delays, and reasons for discontinuation. Clinical trial patients were excluded. Descriptive statistical techniques were applied. Results: Data was collected from 26 UK cancer centres on 280 patients. The median age at TDXd initiation was 56 years (range 29-85). Median treatment duration was 9 cycles (range 1-40). 239 patients (85%) had visceral disease. 257 and 196 patients (92% and 70%, respectively) had received prior Trastuzumab and Pertuzumab, respectively. 233 patients (83%) had received prior TDM1. The median number of lines of treatment prior to TDXd was 3 (range 1 to 9). 20 patients (7%) were initiated on a reduced dose and 115 further patients (41%) required at least one dose reduction. 151 patients (54%) had at least one dose interruption due to: infection or neutropenia (n=61), other toxicity (n=85), interstitial lung disease (ILD) investigation (n=39), patient request (n=81), other concurrent illness (n=10), and cardiac investigation (n=6). Of these, 55 patients had more than one treatment break. 157 patients (56%) had discontinued TDXd treatment due to: disease progression or death (n=100), drug toxicity (n=39) of which 22 were due to ILD, and patient choice (n=8). 123 patients remained treatment at the time of analysis. The overall response rate of TDXd was 63% overall: stable disease 23%, partial response 56%, complete response 7%. Conclusions: The real-world data set is not directly comparable to either the DB02 or DB03 trials, as it included patients who had received TDXd in both the second line and later line settings. However, the majority (80%) of these patients were treated in the third line and beyond. The rates of drug interruption and reduction were higher in the real-world data set than in DB02, which may impact on efficacy in the real-world setting. Overall response rate is similar between trial data and our real-world data, although the latter was not measured by RECIST. Data collection is ongoing, including an analysis of real-world progression free survival. [Table: see text]

Abstract PO4-17-02: A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND

Abstract Background: Approximately 20% of breast cancer (BC) cases are human epidermal growth factor receptor 2-positive (HER2+; immunohistochemistry [IHC] 3+, IHC 2+/in-situ hybridization [ISH]+), and up to ~50% of patients with primary or metastatic BC (mBC) have HER2-low tumors (IHC 1+, IHC 2+/ISH−), a new therapeutically targetable subset of BC. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved in the USA, EU, and other countries for the treatment of adult patients with unresectable or metastatic HER2+ BC who have received a prior anti-HER2-based regimen, or with unresectable or metastatic HER2-low BC who have received a prior chemotherapy (CTx) in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant CTx. Approvals followed positive results from the DESTINY-Breast03 and DESTINY-Breast04 clinical trials. In DESTINY-Breast03, T-DXd improved median progression-free survival (mPFS) compared with trastuzumab emtansine (28.8 vs 6.8 months, respectively; P< 0.0001) in previously treated (prior trastuzumab and taxane) patients with HER2+ mBC. In DESTINY-Breast04, T-DXd significantly improved mPFS vs physician’s choice of CTx (9.9 vs 5.1 months, respectively; P< 0.001) in all randomized patients with HER2-low mBC who were previously treated with one or two lines of CTx. Alongside these efficacy benefits, T-DXd has demonstrated an acceptable and generally manageable safety profile. To optimize care and maximize treatment benefit, insights into real-world T-DXd use and safety events of interest, including patient management and experience, are needed. This study aims to describe the effectiveness and tolerability of T-DXd in patients with HER2+ or HER2-low unresectable and/or mBC in a real-world setting. Trial design: DESTINY-Breast-RESPOND (NCT05592483) is a multicenter (120 sites planned as of June 2023), multi-country (HER2+ cohort: several regions globally; HER2-low cohort: North America only), prospective, observational study characterizing real-world clinical use, effectiveness, tolerability, and patient experience among adults who initiated T-DXd monotherapy, per standard of care, for HER2+ (second line or earlier) and HER2-low unresectable and/or mBC (T-DXd not provided by study sponsor). The decision to initiate T-DXd will be made by the physician prior to, and independent from, participation in this study. Approximately 750 patients with HER2+ and 250 patients with HER2-low disease will be enrolled. Patients must have received prior treatment with a trastuzumab-containing regimen in the metastatic setting or have evidence of disease progression within 6 months of neoadjuvant or adjuvant treatment (HER2+ cohort), or prior CTx in the metastatic setting or have evidence of disease progression within 6 months of adjuvant CTx (HER2-low cohort). Data will be collected via chart abstraction, patient-reported outcome questionnaires on tolerability and safety (PGI-TT, NCI PRO-CTCAE, and EORTC IL19), and a daily patient nausea/vomiting symptom diary. Endpoints will be analyzed separately for HER2+ and HER2-low cohorts. The primary endpoint of interest is time to next treatment from T-DXd initiation, a measure of real-world effectiveness. Other important endpoints include treatment patterns, safety events of interest (nausea/vomiting, fatigue, alopecia, interstitial lung disease/pneumonitis, left ventricular ejection fraction decrease) and their management, time to T-DXd discontinuation, and patient-reported tolerability. Patients will be observed until end of study (~60% of patients receive subsequent treatment or have died), withdrawal from study, or loss to follow up, whichever occurs first. Citation Format: Joyce O'Shaughnessy, Reva Basho, Maryam Lustberg, Gary H Lyman, Manoj Prahladan, Gareth D. James, Della Varghese, Flavia Lujan, Hans Tesch. A multicenter, prospective, observational study of patients receiving trastuzumab deruxtecan for the treatment of HER2-positive and HER2-low unresectable and/or metastatic breast cancer: DESTINY-Breast-RESPOND [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 PO4-17-02.

Abstract PO1-04-01: Phase 1 dose escalation study of ARX788, a next-generation anti-HER2 antibody drug conjugate, in heavily pretreated breast cancer patients

Abstract Introduction: ARX788 is a next-generation anti-HER2 antibody-drug conjugate (ADC) conjugated to amberstatin269 (AS269), a potent cytotoxic tubulin inhibitor. ARX788 is highly stable with nearly identical PK profiles for the total ADC and the total antibody due to proprietary site-specific oxime conjugation chemistry. The stability of ARX788 results in limited systemic toxicity and increased targeted delivery of payload to tumor cells. Clinical benefit of ARX788 has been observed in patients (pts) with HER2-positive (HER2-pos) breast cancer (BC) in multiple clinical trials and recently in a randomized, controlled, phase 3 registrational trial conducted in China. Methods: ARX788-1711 (NCT03255070)was a phase 1 dose-escalation study of ARX788 monotherapy in pts with advanced solid tumors with HER2 expression. There was no limit to the number of prior therapies. An objective of the trial was investigating the safety and tolerability of ARX788 in pts with BC. Results: Between August 2020 and June 2023, 42 pts with HER2-pos and HER2-low BC with a median of 6 prior lines of therapy received intravenous ARX788 at either 1.5, 1.6, or 1.7 mg/kg every 21 days (Q3W) or every 28 days (Q4W). Treatment regimens were combined for these analyses. ARX788 was generally well tolerated. Most adverse events (AEs) were grade (Gr) 1 or 2, the most common being ocular, alopecia, nausea, and fatigue. Gr3 treatment-related AEs (TRAEs) occurred in 23.8% of pts and included nausea, ocular, AST and ALP increase (4.8% each); one pt (2.4%) had Gr3 pneumonitis/interstitial lung disease. A Gr3 ocular SAE occurred 48 days after the pt’s last study dose and was resolving 9 days after onset. There were no Gr4 or Gr5 events. Treatment discontinuation due to drug-related AEs occurred in 7.1% of pts. Overall response rate (ORR) per RECIST v1.1 was analyzed in groups by HER2-low or HER2-pos tumor status. In pts with HER2-pos BC (n=11) the ORR was 54.5% (4 confirmed, 2 unconfirmed); in pts with HER2-low BC (n=30) the ORR was 23.3% (5 confirmed, 2 unconfirmed). The disease control rate (confirmed complete or partial response + stable disease) was 81.8% and 76.7%, for HER2-pos and HER2-low BC, respectively. Six of 9 pts with confirmed responses had a duration of response greater than 5 months. Six of eight pts with prior trastuzumab deruxtecan (T-DXd) exposure also had prior trastuzumab emtansine (T-DM1). Two pts with prior T-DM1 and T-DXd had significant target lesion reductions of 55% and 32%; these were a HER2-low pt with 6 prior cancer therapy regimens and a HER2-pos pt with 9 prior cancer therapy regimens, respectively. Both pts came off treatment before response confirmation. As of the data cut-off (19 Jun 2023), 4 of 9 confirmed responders remain on treatment and continue to experience clinical benefit including one pt with prior T-DM1 exposure with a durable response of 15.8 months. Importantly, significant target lesion reductions were observed in heavily pretreated pts who also received prior T-DXd and T-DM1. Discussion: Based on the promising safety and antitumor activity of ARX788 in this heavily pretreated pt population, a phase 2 study is open (NCT04829604) and enrolling pts with HER2-pos BC who have been previously treated with T-DXd. Citation Format: Sophia Frentzas, Haesong Park, George Budd, Vinod Ganju, Catherine Shannon, Sara Hurvitz, Katharine Cuff, Peter Lau, Richard Eek, Joyce O'Shaughnessy, Fran Boyle, Sandra Aung, Colin Hessel, Janice Lu. Phase 1 dose escalation study of ARX788, a next-generation anti-HER2 antibody drug conjugate, in heavily pretreated breast cancer patients [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 PO1-04-01.

Abstract PO1-17-08: Post-approval treatment patterns and tolerability of neratinib in HER2+ early-stage breast cancer

Abstract Background: While the approval status for neratinib in HER2+ early-stage breast cancer (EBC) allows its use following any trastuzumab-based therapy, the phase 3 ExteNET trial (NCT00878709), which yielded an improvement in disease-free survival, was conducted when single-agent adjuvant trastuzumab was standard of care (SOC) and before approvals of adjuvant pertuzumab + trastuzumab (FDA-approved 2017) or trastuzumab emtansine (T-DM1; FDA-approved 2019). Given recent changes in SOC for HER2+ EBC, health care professionals may seek contemporary and real-world information regarding treatment patterns and tolerability of neratinib. Methods: A literature review was performed to identify studies that characterized trends in use of extended adjuvant neratinib in HER2+ EBC. Due to differences in study design (interventional, observational, claims data) and populations studied, a descriptive summary of data is presented in lieu of statistical cross-study comparisons. Results: Following FDA approval of neratinib in HER2+ EBC in 2017, five studies have reported treatment patterns of extended adjuvant neratinib in a clinical trial or real-world setting; three studies included safety data (Table 1). In the phase 2 CONTROL trial (NCT02400476; N=563; 2015–2021), approx. 82%, 17%, and 1% of neratinib-treated pts received prior adjuvant trastuzumab, pertuzumab, or T-DM1, respectively, and prior neoadjuvant/adjuvant pertuzumab did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration.1 In an interim analysis of the observational ELEANOR study (NCT04388384; N=187; 2020–ongoing), approx. 41%, 33%, and 19% of neratinib-treated pts received prior adjuvant trastuzumab (as their only anti-HER2 treatment), pertuzumab + trastuzumab, or T-DM1, respectively; corresponding rates of grade ≥3 diarrhea were 19%, 25%, and 14%, respectively, with no new safety signals reported.2 In a chart review from the US Oncology Network (N=166; 2017–2020), approx. 99%, 43%, and 2% of neratinib-treated pts received prior adjuvant trastuzumab (56% as their sole anti-HER2 treatment), pertuzumab, or T-DM1, respectively.3 Diarrhea was mainly moderate (29%; n=43/150) or mild (22%; n=33/150), with few severe cases (1%; n=2/150).3 In a retrospective analysis employing the IQVIA claims database (N=385; 2017–2021), prior use of recently approved adjuvant agents increased over time, with rates of prior pertuzumab + trastuzumab or prior T-DM1 as high as 52% and 14%, respectively, in 2020.4 In the Neat-HER virtual registry (N=46; 2018–2021), approx. 41% and 11% of neratinib-treated pts received prior adjuvant pertuzumab or T-DM1, respectively.5 Conclusions: Recent studies have observed neratinib use in clinical practice following adjuvant trastuzumab-based therapy including pertuzumab + trastuzumab or T-DM1. Preliminary data suggest a similar safety profile for pts with/without prior pertuzumab. These datasets are limited by the fact that: (1) some pts were enrolled in the CONTROL trial prior to launch of adjuvant T-DM1 and pertuzumab; (2) the interval between T-DM1 launch in Europe and start of the ELEANOR study was relatively short; and (3) not all toxicity measures were formally graded. A summary of available safety and effectiveness results is forthcoming. Additional interventional and non-interventional studies will continue to evaluate the safety and effectiveness of neratinib following current SOC adjuvant therapy in HER2+ EBC. Table 1. Treatment patterns of HER2-targeted adjuvant agents preceding neratinib use in HER2+ EBC ITT, intent-to-treat; T-DM1, ado-trastuzumab emtansine. aTherapies were recorded as used for adjuvant therapy in CONTROL, ELEANOR, US Oncology, and Neat-HER. CONTROL includes unpublished data. In the IQVIA claims analysis, HER2-targeted agent(s) used within 12 months prior to neratinib initiation were assumed to be adjuvant therapies. Pertuzumab use was generally taken in combination with trastuzumab as dual HER2 blockade and some pts received more than one anti-HER2 adjuvant treatment, for example T-DM1 in addition to pertuzumab plus trastuzumab. bAdjuvant trastuzumab monotherapy or in combination with chemotherapy unless noted otherwise. cThe proportion of patients who took at least one tablet of neratinib for ≥75% of the prescribed treatment days and did not take neratinib on days when neratinib was not prescribed. dData forthcoming. eIncludes prior trastuzumab monotherapy and trastuzumab used in combination with pertuzumab; 93/166 pts (56%) received trastuzumab as their only anti-HER2 agent (monotherapy or in combination with chemotherapy; unpublished data). fIncludes prior trastuzumab monotherapy as well as trastuzumab used in combination with pertuzumab. References Citation Format: Kelly McCann, Nadia Harbeck, Debu Tripathy, Arlene Chan, Jay Andersen, Joyce O'Shaughnessy, Gregory Vidal. Post-approval treatment patterns and tolerability of neratinib in HER2+ early-stage 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 PO1-17-08.

Abstract RF02-06: AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658)

Abstract Background: Chemotherapy (chemo) + H is standard of care therapy for pts with refractory HER2+ MBC. It is unknown whether the addition of immune checkpoint inhibitor (ICI) or a 4-1BB agonist (U) improves efficacy of standard chemo + H for this population. Methods: Eligible pts had HER2+ MBC previously treated with H, pertuzumab (P), and T-DM1. Pts previously treated with N or ICI were excluded. 100 pts were randomized 1:2:2 to tx with NH, NHA, or NHAU. ER status and presence of liver metastases were stratification factors. The original co-primary objectives were to compare progression-free survival (PFS) of (1) NHA vs NH; and (2) NHAU vs NHA. In 2021, due to discontinuation of clinical development of U, an unplanned interim futility analysis reviewed by IDMC led to closure of NHAU and randomization of the final 13 pts to NH or NHA. For the comparison of NH vs NHA, with 60 pts randomized (20 vs 40) there was 88% power for a log-rank test to detect improvement in median PFS (mPFS) from 2 to 4 mos with one-sided alpha of 0.1. Corresponding 2-sided 80% confidence intervals (CI) were reported for the stratified Cox model hazard ratios (HR), along with stratified one-sided log-rank p-value. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and safety/tolerability. Results: 100 pts were randomized from 7/2018-3/2023, and 97 pts started tx on trial: 18 NH, 45 NHA, and 34 NHAU (prior to its closure). Pts were 99% female, with median age 54 yrs (range 26-78 yrs); 70% White, 14% Black, and 8% Asian; 7% were Hispanic. 66% of pts had hormone receptor-positive tumors, and 76% had visceral metastases. All pts were previously treated with H, P, and T-DM1, and 17% had prior trastuzumab deruxtecan. 63% of pts had received ≥3 lines of HER2 tx for MBC (range 1-13 lines), and median interval from MBC diagnosis to randomization was 32 mos (interquartile range 22-61 mos). mPFS and ORR results are shown in the Table. One patient remained progression-free on tx at analysis. NHA was associated with a statistically significant improvement in PFS compared to NH (HR=0.56 (80% CI 0.37-0.86, p=0.04)). No difference in PFS was observed between NHAU vs NHA (HR=1.20 (80% CI 0.84-1.73) as final estimate after closure of NHAU for futility). Of 9 pts with confirmed responses in NHA arm, 3 pts had DOR >12 mos. Grade 3-4 treatment-emergent adverse events (AEs) were similar by tx: 61% NH, 62% NHA, and 67% NHAU. There were no grade 5 treatment-related AEs. Immune-related all grade AEs in the A-containing arms (n=79 safety-evaluable pts treated with A) included: AST increase (n=15), ALT increase (n=9), hyper/hypothyroidism (n=8), adrenal insufficiency (n=2), and pneumonitis (n=1), of which two events were grade 3 (adrenal insufficiency and AST increase) and none were grade 4. Only 3 pts (1 in NHA; 2 in NHAU) stopped trial tx for unacceptable AEs. Required baseline and on-tx biopsies were performed; PD-L1 and TIL data will be presented. Conclusions: This trial demonstrated significant improvement in PFS with addition of avelumab to NH among pts with heavily pre-treated HER2+ MBC. 4-1BB agonist did not improve PFS. To our knowledge, this is the first randomized trial to report results of chemo/H +/- ICI in HER2+ MBC. Further investigation of ICI with chemo/H for pts with refractory HER2+ MBC is warranted, and the potential predictive value of immune biomarkers should be explored. *one-sided stratified log rank test p-value Citation Format: Adrienne Waks, Ruichao Shi, Meredith Regan, Chau Dang, Cesar Santa-Maria, Kelly Westbrook, Vandana Abramson, Rashmi Murthy, Rita Nanda, Hope Rugo, Amy Clark, Candace Mainor, Claire Dees, Valentina Hoyos, Kathy Miller, Erica Stringer-Reasor, Natasha Hunter, Sun Young Oh, Michelle DeMeo, Amanda Okpoebo, Erin Elias, Busem Kurt, Nancy Lin, Mothaffar Rimawi, Antonio Wolff, Elizabeth Mittendorf, Shom Goel, Sara Tolaney, Sherene Loi, Ian Krop. AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658) [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 RF02-06.

Abstract PO3-04-06: A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone

Abstract Background Trastuzumab deruxtecan (T-DXd) has demonstrated efficacy in patients with brain metastasis (BM), a group historically with poor outcomes. The prevalence of BMs in patients commencing T-DXd is currently unknown. To date, no direct comparisons have been made of the activity of T-DXd in patients with active BM versus those with extracranial progression alone. This real-world study explored the prevalence of BMs at commencement of T-DXd, the efficacy of T-DXd in active BM versus extracranial progression alone and the safety of T-DXd. Methods Patients with HER2-positive advanced breast cancer treated with T-DXd between June 2021 and February 2023 at our specialist cancer hospital were identified and notes reviewed. Clinico-pathological information, prior treatment, the presence or absence of CNS disease, outcomes and treatment-emergent adverse events (TEAE) were recorded. Data cut-off was 28th February 2023. Results 29 female patients: 16 extracranial disease alone, 12 BM and 1 LMD were identified. Prevalence of BM at commencement of T-DXd was 41% (12 of 29). Median age was 52 (IQR 44-62), with a median 2 (range 2-6) prior lines of HER2 directed and chemotherapy:86% (25 of 29) had received prior trastuzumab and pertuzumab, 100% (29 of 29) T-DM1 and 3% (1 of 29) patient trastuzumab duocarmazine. At a median follow-up of 13.8 months, median progression free survival (PFS) for overall population was 13.9 months (95% CI: 12.4-NE), 16.1 months (95% CI: 15.1-NE) for active BMs, and 12.4 months (95% CI: 8.3-NE) for progressive extracranial disease alone (P=0.106). 12-month OS rate was 74% (95% CI: 59-95) in the overall population, 83% (95% CI: 58-100) and 66% (95% CI: 45-96) for active BMs, and extracranial only disease respectively (P=0.678). Objective response rates: overall population was 69% (95% CI: 52-86), active BMs was 60% (95% CI: 30-90), and progressive extracranial disease alone was 69% (95% CI: 46-91). 6% (1 of 16) with extracranial disease alone developed BM during treatment with T-DXd. Reasons for treatment discontinuation: 67% (10 of 15) disease progression or death; 33% (5 of 15) toxicity. 48% (14 of 29) remain on treatment. Most common TEAEs were fatigue (97%; 28 of 29), alopecia (76%; 22 of 29), and constipation (72%; 21 of 29). Pneumonitis occurred in 9 patients (31%, included 2 deaths). 1 pathologically confirmed case of radionecrosis was documented. An updated analysis with an additional 9 patients who commenced T-DXd since February 2023 will be presented. Conclusion In this real-world study a significant number of patients had BM at the commencement of T-DXd. We demonstrate that in advanced HER2 positive breast cancer that T-DXd is as effective, in terms of PFS and OS, in active BMs as it is in progressive extracranial disease alone. These data provide the first evidence that in contrast to the historical data that active BM may no longer be a detriment to survival as compared to progressive extracranial disease alone when treated with T-Dxd. These observations warrant further investigations in larger series. The high rate of pneumonitis warrants further consideration. Citation Format: James Pearson, Adeel Khan, Talvinder Bhogal, Helen Wong, Andrea Law, Samantha Mills, Nuria Santamaria, Joanne Cliff, Douglas Errington, Allison Hall, Clare Hart, Zafar Malik, Raj Sripadam, Helen Innes, Helen Flint, Gabriella Langton, Eliyaz Ahmed, Jill Bishop, Richard Jackson, Carlo Palmieri. A comparison of the efficacy of trastuzumab deruxtecan in advanced HER2-positive breast cancer: active brain metastasis versus progressive extracranial disease alone [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 PO3-04-06.

Integrated clinical and genomic models using machine-learning methods to predict the efficacy of paclitaxel-based chemotherapy in patients with advanced gastric cancer

BackgroundPaclitaxel is commonly used as a second-line therapy for advanced gastric cancer (AGC). The decision to proceed with second-line chemotherapy and select an appropriate regimen is critical for vulnerable patients with AGC progressing after first-line chemotherapy. However, no predictive biomarkers exist to identify patients with AGC who would benefit from paclitaxel-based chemotherapy.MethodsThis study included 288 patients with AGC receiving second-line paclitaxel-based chemotherapy between 2017 and 2022 as part of the K-MASTER project, a nationwide government-funded precision medicine initiative. The data included clinical (age [young-onset vs. others], sex, histology [intestinal vs. diffuse type], prior trastuzumab use, duration of first-line chemotherapy), and genomic factors (pathogenic or likely pathogenic variants). Data were randomly divided into training and validation sets (0.8:0.2). Four machine learning (ML) methods, namely random forest (RF), logistic regression (LR), artificial neural network (ANN), and ANN with genetic embedding (ANN with GE), were used to develop the prediction model and validated in the validation sets.ResultsThe median patient age was 64 years (range 25–91), and 65.6% of those were male. A total of 288 patients were divided into the training (n = 230) and validation (n = 58) sets. No significant differences existed in baseline characteristics between the training and validation sets. In the training set, the areas under the ROC curves (AUROC) for predicting better progression-free survival (PFS) with paclitaxel-based chemotherapy were 0.499, 0.679, 0.618, and 0.732 in the RF, LR, ANN, and ANN with GE models, respectively. The ANN with the GE model that achieved the highest AUROC recorded accuracy, sensitivity, specificity, and F1-score performance of 0.458, 0.912, 0.724, and 0.579, respectively. In the validation set, the ANN with GE model predicted that paclitaxel-sensitive patients had significantly longer PFS (median PFS 7.59 vs. 2.07 months, P = 0.020) and overall survival (OS) (median OS 14.70 vs. 7.50 months, P = 0.008). The LR model predicted that paclitaxel-sensitive patients showed a trend for longer PFS (median PFS 6.48 vs. 2.33 months, P = 0.078) and OS (median OS 12.20 vs. 8.61 months, P = 0.099).ConclusionsThese ML models, integrated with clinical and genomic factors, offer the possibility to help identify patients with AGC who may benefit from paclitaxel chemotherapy.

453P Clinical outcomes of pyrotinib-based therapy after prior trastuzumab and pertuzumab in HER2-positive metastatic breast cancer

453P Clinical outcomes of pyrotinib-based therapy after prior trastuzumab and pertuzumab in HER2-positive metastatic breast cancer

Radiotherapy combined with pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and brain metastases: A single-arm, exploratory trial.

e13024 Background: Previous researches indicated the enhanced radiosensitivity in HER2-positive cancer cells by pyrotinib. For patients with treatment-naive brain metastases and central nervous system (CNS) symptoms, whether radiotherapy (current mainstay treatment) combined with pyrotinib-based systemic regimen is more beneficial remains unclear. This study explored radiotherapy combined with pyrotinib plus capecitabine in this population. Methods: In this exploratory trial (NCT04767828), patients aged 18-75 years who had HER2-positive metastatic breast cancer and untreated symptomatic brain metastases with an Eastern Cooperative Oncology Group performance status of 0-2 were included. Patients with meningeal metastases or without measurable CNS lesions were excluded. Eligible patients received whole-brain radiotherapy (WBRT) or stereotactic radiotherapy (SRT). The irradiation sites, total radiation dose, and fractions were decided by investigator based on the number of CNS lesions and size. Pyrotinib (400 mg, once a day) and capecitabine (1000 mg/m2, twice a day, on days 1-14 of each 21-day cycle) were given since the start of radiotherapy until disease progression or intolerable toxicity. The primary endpoint was CNS progression-free survival (PFS), assessed by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Extracranial lesions were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Between May 5, 2020 and November 25, 2022, a total of 19 patients were enrolled. Thirteen (68%) patients had other visceral metastases, and 18 (95%) had prior trastuzumab treatment (5 for early breast cancer, 12 for advanced breast cancer, and 1 for both). Fifteen (79%) patients received WBRT and 4 (21%) received SRT. By the data cutoff date on January 16, 2023, the median follow-up duration was 15.0 months (range, 1.7-24.8). Median CNS PFS was 10.0 months (95% CI, 5.3-14.7). CNS objective response rate was 100%, including two (11%) patients with CNS complete response. Median overall PFS was 8.5 months (95% CI, 4.8-12.2). Median overall survival was 19.0 months (95% CI, 13.1-24.9). The most common grade 3 or 4 adverse events were vomiting (16%) and nausea (11%). For 11 patients with available results of Mini-Mental State Examination (MMSE), 10 (91%) had normal cognitive function during study period or recovered to normal level within 6 months after radiotherapy. Conclusions: Radiotherapy combined with pyrotinib plus capecitabine shows favorable CNS response and promising survival outcomes in patients with HER2-positive metastatic breast cancer and untreated symptomatic brain metastases, with an acceptable safety profile. This combination strategy warrants further validation in large samples. Clinical trial information: NCT04767828 .

PLEASURABLE: Results and biomarkers analysis from the phase II study of dalpiciclib combined with pyrotinib and endocrine therapy (ET) in women with dual-receptor positive (ER+/HER2+) metastatic breast cancer (MBC).

1046 Background: In the front-line setting, our previous work demonstrated an impressive median progression-free survival (PFS) of 11.3 months with 66.7% response rate, and concluded a recommended phase 2 dose of pyrotinib 320mg/d, dalpiciclib (SHR6390, a novel CDK4/6i) 125mg/d, and letrozole 2.5mg/d for HR+/HER2+ MBC patients (pts) (Xichun Hu, FRONT ONCOL 2022). Results and biomarkers analysis from phase II dose expansion study are presented. Methods: ER+/HER2+ MBC Pts eligible for first- or second-line treatment were enrolled to receive dalpiciclib combined with pyrotinib and ET (letrozole or fulvestrant determined by physician’s choice). The primary endpoint was objective response rate (ORR). For biomarkers analysis, 68Ga-HER2 affibody, pre-treatment tissue-derived DNA and circulating tumor DNA (ctDNA) were assessed by PET/CT, and next-generation sequencing (NGS), respectively. Results: As of January 19, 2023, 48 pts were enrolled. 17 pts (35.4%) were treatment naïve, and 31 pts (64.6%) had received prior trastuzumab. The ORR was 68.1% (32/47) and disease control rate was 100% (47/47). In trastuzumab-naïve and trastuzumab-pretreated patients, ORR was 81.3% (13/16) and 61.3% (19/31), respectively. PFS and OS data were not mature by cut-off date. No new safety signals were observed. The most frequent treatment-related adverse events were neutropenia (95.8%; G3:60.4%, G4:6.3%), leukopenia (91.7%; G3:45.8%), diarrhea (87.5%; G3:2.1%), anemia (79.2%; G3:4.2%), oral mucositis (68.8%, G3:2.1%) and platelet count decreased (41.7%; G3:2.1%, G4:2.1%). The heterogeneity of 68Ga-HER2 affibody uptake was observed among patients, both at baseline (N=16，median SUV max 7.5, range, 2.3-34.9) and after 2 cycles of therapy (N=12，median SUV max 4.0, range, 0-14.9). All patients with a decline in 68Ga-HER2 affibody uptake (N=8) achieved partial response, while the uptake in non-responders was elevated (N=2). NGS was conducted to detect somatic and germline mutations in baseline tissue (n=10) and ctDNA (n=10) samples. Two patients with BRCA mutation (one had somatic BRCA1/ 2 mutation and another with germline BRCA2 mutation) had no tumor response. Conclusions: The chemotherapy-sparing regimens showed significant anti-tumor activity for ER+/HER2+ MBC pts in the front-line setting. The 68Ga-HER2 affibody PET/CT may be a potential predictive biomarker of therapy response. Additional analysis including correlation of biomarkers with long-term outcomes is underway. Clinical trial information: NCT03772353 .

Abstract PD18-08: Efficacy and safety results of KN026, a HER2-targeted bispecific antibody combined with docetaxel in first-line treatment of HER2-positive recurrent/metastatic breast cancer

Abstract Background: 1. The 3-drug combination therapy, trastuzumab, pertuzumab, and taxane chemotherapy is one of the standard treatment options for the first-line treatment of HER2-positive recurrent/metastatic breast cancer. 2. KN026 is a novel bispecific HER2-targeted antibody : Fully humanized, IgG1-like antibody binds to two distinct HER2 epitopes, the same domains as trastuzumab (ECD4) and pertuzumab (ECD2). IgG1 Fc fragment of KN026 binding FcγRIIIa mediates potent ADCC 3. Preliminary safety and efficacy results from Phase 1 study data (data as of January 22, 2020) of KN026 monotherapy in HER2-positive advanced breast cancer were presented at ASCO 2020, showed promising efficacy and well tolerated safety. Herein, we present the results from the phase 2 trial. Methods:  Eligible subjects with HER2-positive and first-line systemic treatment-naïve (relapse ≥12 months after the end of neoadjuvant/adjuvant therapy) recurrent or metastatic breast cancer were enrolled in this study.  Subjects received KN026 30 mg/kg combined with docetaxel 75 mg/m2 Q3W until disease progression, unacceptable toxicity, withdrawal of informed consent from subjects, or other circumstances that require drug discontinuation.  The primary endpoints were ORR and duration of response (DoR). The secondary endpoints included safety, PFS and OS. Results:  At data cut-off date (Mar 26, 2022), the median follow-up was 13.8 months (Interquartile Range [IQR] 12.22, 14.00). 57 subjects were enrolled, the median age was 52 years, 100% were female, and 89.5 % (51/57) were stage IV.  Of the 55 subjects evaluable for efficacy, 21 had received prior taxane, 4 had received prior trastuzumab in combination with taxane, 30 without any prior trastuzumab and taxane. Nearly half of the subjects (25/55) had previously received trastuzumab and/or taxane chemotherapy.  The confirmed ORR within 55 evaluable subjects was 76.4% (95% CI: 62.98, 86.77) and DoR was 18.1 months (95% CI: 12.45, NE).  Median PFS was 19.3 months (95% CI: 13.86, NE) and median OS was not reached. Median PFS is not yet mature. The 12-, and 18-month OS rates were 93.5% (95% CI: 80.79, 97.89), and 88.3 % (95% CI: 68.93, 95.92), respectively.  The confirmed ORR was 80% in 30 trastuzumab-and taxane-naïve subjects. Among these subjects, OS rates at 12, and 18 months were 100% (95% CI: 100,100), and 90.0% (95% CI: 47.30, 98.53), and the median PFS was 19.3 months (95% CI:13.77, NE).  Treatment emergent adverse events with incidence rate ≥20% and TEAE≥Grade 3 were neutropenia (n=23, 40.4%) and leucopenia (n=16, 28.1%), respectively.  The incidence of serious adverse events was 15.8%(9/57), including 5.3% (3/57) for febrile neutropenia, 3.5% (2/57) for leucopenia, and less than 2% for other SAEs  There were no deaths due to KN026 drug-related AEs in this study. Conclusions: KN026 in combination with docetaxel is well tolerated and has shown promising clinical benefit as a 1L treatment for HER2-positive advanced breast cancer. At data cut-off date (Mar 26, 2022), median PFS was 19.3 months while 18-month OS rate was 88.3%, which is very encouraging. Efficacy and safety require large-scale phase III studies to verify. Citation Format: Qingyuan Zhang, Jingxuan Wang, Quchang Ouyang, Xiaojia Wang, Jingfen Wang, Lu Gan, Daren Lin, Zhong Ouyang, Ting Xu, Yilan Liu, Summer Xia. Efficacy and safety results of KN026, a HER2-targeted bispecific antibody combined with docetaxel in first-line treatment of HER2-positive recurrent/metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-08.

Abstract PD18-09: ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1

Abstract Background: Amplification of the human epidermal growth factor receptor 2 (HER2) gene with consequent HER2 protein overexpression occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. The HER2-targeted ADC trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive metastatic BC (mBC) after prior trastuzumab and taxane therapy. However, disease progression occurs in all patients requiring additional therapeutic options. The use of second-generation anti-HER2 ADCs using alternative molecules is being investigated to overcome drug resistance. ARX788 is a next-generation ADC using a technology platform whereby a HER2-specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 lead to its slow release and prolongation of the peak serum pAF-AS269 concentration, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Here, early evidence of activity of ARX788 in patients previously treated with T-DM1 is shown. Methods: ACE-Breast-03 (NCT04829604) is an ongoing global, phase 2, single-arm study evaluating ARX788 in patients with HER2+ mBC whose disease has progressed following T-DM1, T-DXd, and/or tucatinib-containing regimens. The ARX788 is administered with an initial dose of 1.5 mg/kg Q4W and subsequent doses of 1.3 mg/kg Q4W. Eligibility criteria included central laboratory confirmed HER2+ mBC per ASCO/CAP guidelines, measurable disease, and adequate organ function. Stable treated brain metastases are allowed. Patients with interstitial lung disease (ILD) or pneumonitis in prior 12 months; active ocular infections or any chronic corneal disorder; are excluded. The primary endpoint is overall response rate (ORR). Results: At the data cutoff of 11-Jul-2022, 7 patients were enrolled in ACE-Breast-03 (v1.0) who previously experienced disease progression on T-DM1 and had response-evaluable disease. Pts had a median age of 59 years and had received a median of 5 lines of prior anti-HER2 cancer therapy (range: 2-8). None of the pts in this subset had received T-DXd or tucatinib. 5 pts were previously treated with HER2-targeted TKIs (neratinib and lapatinib), as well as an investigational HER2 ADC and responded to ARX788 (3 PR; 2 SD). Two patients had hormone receptor (HR)-positive disease and 5 had HR-negative mBC. Treatment with ARX788 remains ongoing with the median time of ARX788 therapy of 4.5 months. The confirmed ORR was 57.1% (4/7 pts) and an unconfirmed ORR of 71.4% (5/7 pts) as one pt experienced an unconfirmed response with PR after 2 cycles. The disease control rate (DCR) was 100% (7/7 pts). No drug-related grade ≥3 AEs were reported; 57.1% (4/7 pts) reported ocular AEs including grade 1 events in 3 pts (i.e., dry eye, blurred vision) and a grade 2 event in one pt (lagophthalmos). No pneumonitis or ILD was observed. ARX788 was well-tolerated, and AEs were manageable. Conclusion: In this small cohort of patients previously treated with T-DM1, ARX788 had a manageable AE profile and demonstrated promising clinical activity (confirmed ORR 57%; DCR 100%). Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 ARX788 demonstrated promising clinical activity in patients previously treated with T-DM1. Citation Format: Sara Hurvitz, Kevin Kalinsky, Vinod Ganju, Kashif Ali, Laila Agrawal, William Gradishar, George Sledge, Anu Thummala, Arlene Chan, Sophia Frentzas, Joo Hyuk Sohn, Kyong-Hwa Park, Keon Uk Park, Catherine Shannon, Joshua Drago, Sara Tolaney, Hope Rugo, Michael F. Press, Alex Alika, Dong Xu, Janice Lu, Debu Tripathy. ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-09.

Abstract P4-02-01: Efficacy of HER2 ADCs against HER2 inhibitor resistance alterations in the PI3K and MAPK pathways in HER2-positive breast cancer

Abstract Background: HER2 positive (HER2+) breast cancers harboring downstream MAPK or PI3K pathway alterations manifest persistent downstream signaling on anti-HER2 inhibitors with metastatic patients having worse outcomes on first line trastuzumab and pertuzumab (HP) therapy. However, HER2 antibody-drug conjugates (ADCs) are not as dependent upon potent signal transduction inhibition to exert their antitumor effects. To further investigate, we sought to determine whether MAPK and/or PI3K alterations affect the biologic or clinical outcomes of patients and models receiving HER2 ADCs. Methods: We performed prospective genomic sequencing using MSK-IMPACT on patients with advanced HER2+ breast cancer who received trastuzumab emtansine (T-DM1) in the metastatic setting between March 2013 and July 2021. We collected detailed information on clinical outcomes and correlates through our institutional IRB-approved retrieval process. HER2/ER/PR status at the time of metastatic recurrence were defined as per ASCO/CAP guidelines. Cox proportional hazard models were used to determine the association between MAPK and PI3K pathways alterations and progression-free survival (PFS) on T-DM1. Common mutations associated with outcomes were modeled in HER2+ breast cancer cell lines using short hairpin RNAs and CRISPR/Cas9, and the sensitivity to HER2 ADC was evaluated via cell proliferation and xenograft assays. Results: We identified 185 HER2+ breast cancer patients treated with T-DM1 at any line (median: 5) whose primary (N=65) or metastatic (N=120) tumor samples were sequenced. Median age was 55 (range: 20-87). The majority of the patients received T-DM1 in 2nd or 3rd line (52%) and received prior trastuzumab or HER2 TKI in metastatic setting (96%). 74/185 (40%) had de novo metastatic breast cancer and 119/185 (64%) had ER/PR+/HER2+ disease. Pathogenic activating alterations involving the MAPK pathway were observed in 14% of patients with the most frequent alterations being ERBB2 activating mutations (42%) and NF1 loss (34%). PI3K pathway alterations were identified in 42% of the patients, the majority being activating mutations of PIK3CA (87%). MAPK alterations were significantly enriched in the metastatic tumors compared to the treatment-naïve primaries (20% vs 3%, p=0.001), while PI3K alterations were not (44% vs 40%, p=0.6). To reduce the possible confounding resistance mechanisms induced by prior treatment, we restricted the survival analyses to patients who received T-DM1 up to 3rd line of therapy (N=100). On multivariable analysis adjusted for ER/PR status (positive vs negative), stage at the presentation of metastatic disease (de novo metastatic vs recurrence), treatment line and type of sequenced sample (primary vs metastatic), patients with MAPK (N=14) and PI3K (N= 38) alterations had similar PFS compared to wild type (HR 1.20, 95%CI 0.62-2.30, p=0.6 and HR 1.23, 95%CI 0.77-1.95, p=0.4, respectively). Similar results were found in the combined analysis including alterations in either pathway (N=48, HR 1.28, 95%CI 0.81-2.04, p=0.3). To verify the antiproliferative effect of HER2 ADCs on breast cancer cells with MAPK pathway activation, we depleted NF1 in a panel of HER2+ breast cancer cell lines. Consistently, MAPK-altered cell lines were sensitive to FDA-approved HER2 ADCs including trastuzumab deruxtecan (T-DXd). Conclusions: In contrast to H/P therapy, T-DM1 therapy was equally effective in tumors with downstream PI3K or MAPK alterations and wild type tumors. Expanded analysis on a larger cohort, including a subgroup of patients treated with novel HER2 ADCs such as T-DXd will be presented. The characterization of PI3K and MAPK pathways status in metastatic HER2+ breast cancer may inform prioritization of treatment options. Citation Format: Emanuela Ferraro, Anton Safonov, Yuan Chen, Charlie White, Antonio Marra, Mehnaj Ahmed, Barbara Acevedo, Chau T Dang, Shanu Modi, David B. Solit, Larry Norton, Mark E. Robson, Jorge Reis-Filho, Sarat Chandarlapaty, Pedram Razavi. Efficacy of HER2 ADCs against HER2 inhibitor resistance alterations in the PI3K and MAPK pathways in HER2-positive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-01.

Abstract OT2-14-01: Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 trial

Abstract Objective: Trastuzumab-based adjuvant therapy was demonstrated to improve the prognosis of early human epidermal growth factor receptor 2 (HER-2) positive breast cancer, while about 10% of patients showed primary resistance. ExteNET study showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy significantly improved invasive disease-free survival (iDFS) in women with HER2-positive breast cancer. Besides, for patients with early hormone receptor positive breast cancer within 1 year of prior trastuzumab with residual disease after neoadjuvant therapy, extended adjuvant neratinib showed prolonged overall survival, which suggested the potential benefit of extended adjuvant therapy for high-risk patients. Pyrotinib is an oral irreversible pan-HER receptor tyrosine kinase inhibitor targeting epidermal growth factor receptor, HER2, and HER4, which showed promising efficacy and manageable safety profiles in the treatment of HER-2 positive advanced breast cancer. In this study, we aimed to evaluate the efficacy and safety of extended adjuvant pyrotinib following trastuzumab-based adjuvant therapy in patients with high-risk early HER-2 positive breast cancer. Methods: In this ongoing multicenter, open-label, phase II trial at 23 centers in China, women with operable high-risk early HER-2 positive breast cancer and known hormone receptor status, who have completed trastuzumab-based adjuvant therapy within 6 months were enrolled. High-risk patients must meet one of the following criteria: N stage ≥1; T stage ≥2; did not achieve pathological complete response (pCR) after neoadjuvant therapy; had pCR after neoadjuvant therapy but with tumor size ≥ 5cm or N stage ≥2; or tumor size less than 2cm but with high Ki67, histologic grade 3 or with lymph node micrometastasis. Eligible patients were assigned to receive 6 month or 1 year of oral pyrotinib 400mg/day. The primary endpoint was the 2-year iDFS rate. Results: Between January, 2019 and February, 2022, a total of 142 eligible women were enrolled and assigned to receive pyrotinib, with a median age of 50 (range: 25-72) years old. Ninety-seven patients had a T stage ≥2. A total of 108 patients (76.1%) had node-positive disease, and 64 (45.1%) were hormone receptor positive. Twenty-five patients used neoadjuvant therapy previously, and all of them did not receive pCR (Table 1). After a median follow-up of 20 (range: 0.25-41) months, the 2-year iDFS rate was not available. Two and four patients reported invasive disease events after 6-month and 1-year of follow-up, with the 6-month and 1-year iDFS rates of 98.6% and 97.2%, respectively. The most common adverse events reported was diarrhea (78.2%), followed by fatigue (36.6%), lymphocyte count decreased (36.6%), nausea (33.1%) and hand-foot syndrome (33.1%). Forty-three patients experienced grade 3 diarrhea, and no grade 4 or higher adverse event was reported (Table 2). Adverse event leading to treatment discontinuation occurred in 12 (8.5%) patients. Conclusion: Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy was well-tolerated and showed potential efficacy in high-risk early HER-2 positive breast cancer. The follow-up is ongoing to determine the long-term benefit of extended adjuvant pyrotinib. Table 1. Baseline characteristics of patients ER: estrogen receptor; PR: progesterone receptor. Table 2. Treatment-emergent adverse event occurring in at least 10% of the patients Citation Format: Feilin Cao, Zhaosheng Ma, Guinv Hu, Xiaotao Zhu, Shuguang Li, Shuzheng Chen, Binglie Chen, Zhanwen Li, Weizhu Wu, Xiaochun Ji, Jingde Shu, Deyou Tao, Xiaoqing Hu, Min Zheng, Ouchen Wang, Qingjing Feng, Jing Hao, Xujun Li. Pyrotinib after trastuzumab-based adjuvant therapy in high-risk early human epidermal growth factor receptor 2-positive breast cancer: a multicenter phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-14-01.

Real-world data of triplet combination of pyrotinib, trastuzumab, and chemotherapy in HER2-positive metastatic breast cancer: a multicenter, retrospective study.

Pyrotinib, an irreversible pan-human epidermal growth (HER) inhibitor, has proven its antitumor efficacy as a second-line treatment for HER2-positive metastatic breast cancer (HER2+ MBC) when combined with capecitabine. However, real-world data concerning the pyrotinib, trastuzumab, and chemotherapy (PyroHC) combination remains scarce. Our study is to report the treatment patterns, efficacy, and safety of the PyroHC combination in a real-world setting. This study enrolled patients with HER2+ MBC from five institutions in China, treated with PyroHC between June 2017 and January 2023 (ClinicalTrials.gov, identifier: NCT05839288). We evaluated progression-free survival (PFS), objective response rate (ORR), toxicity profile, and utilized treatment regimens. Of the 135 patients in our cohort, 91.9% had prior trastuzumab exposure and 52.2% underwent at least two systematic therapy lines before receiving PyroHC. The most prevalent chemotherapies paired with PyroH were capecitabine (36.3%). Patients receiving PyroHC achieved a median PFS of 8.67 months [95% confidence interval (CI): 6.84-10.51] and an ORR of 51.3% (95% CI: 42.1-61.5%). The first-line treatment with PyroHC led to a median PFS of 14.46 months (95% CI: 6.35-22.56). Patients with brain metastases showed a median PFS of 9.03 months (95% CI: 6.56-11.50), achieving an ORR of 52.17% (95% CI: 51.74-83.39). Longer previous trastuzumab (⩾6.37 months) or lapatinib (⩾10.05 months) therapies could indicate improved PFS, while prior pyrotinib exposure negatively influenced PFS. Notably, the most common grade 3/4 adverse events were diarrhea (37.8%), which were generally manageable. PyroHC shows promising efficacy and a satisfactory safety profile for treating HER2+ MBC, both as a first-line option and for heavily treated patients, including those with brain metastasis. Our findings suggest the duration and history of anti-HER2 therapy as potential predictors for PyroHC efficacy in advanced settings.

Cost-Effectiveness of Pyrotinib Plus Capecitabine versus Lapatinib Plus Capecitabine for the Treatment of HER2-Positive Metastatic Breast Cancer in China: A Scenario Analysis of Health Insurance Coverage.

Background: The overexpression of the human epidermal growth factor receptor-2 (HER2) gene is present in 20~25% of breast cancer (BC) patients, contributing to an inferior prognosis. Recent clinical trials showed that pyrotinib has promising antitumor activities and acceptable tolerability for those patients (ClinicalTrials.gov, NCT03080805 and NCT02422199). Therefore, this study aims to assess the cost-effectiveness of pyrotinib plus capecitabine versus lapatinib plus capecitabine for patients with HER2-positive metastatic BC after prior trastuzumab. Methods: A lifetime-partitioned survival model was established to evaluate health and economic outcomes with different treatment strategies. The primary outcome was the incremental cost-effectiveness ratio (ICER). Data were derived from the published literature, clinical trials, expert opinions, and other local charges. Sensitivity analyses were performed to assess the robustness of the findings. Scenario analyses were developed to make further evaluations. Results: The pyrotinib regimen had significant advantages over the lapatinib regimen after enrolling in the National Reimbursement Drug List (NRDL), with cost savings of USD 15,599.27 and a gain of 0.53 QALYs. Meanwhile, before enrolling in NRDL, the pyrotinib regimen afforded the same QALYs at a higher incremental cost of USD 45,400.64 versus the lapatinib regimen, producing an ICER of USD 85,944.79 per QALY. Scenario analyses yielded similar results. Sensitivity analyses suggested stability in the cost-effectiveness findings. Conclusions: Compared to lapatinib plus capecitabine, the pyrotinib plus capecitabine enrolled in NRDL is a cost-effective alternative second-line treatment for patients with HER2-positive metastatic BC in China.

A phase II study evaluating KN026 monotherapy in patients (pts) with previously treated, advanced HER2-expressing gastric or gastroesophageal junction cancers (GC/GEJC).

4040 Background: Outcomes of second or later-line treatment for pts with advanced GC/GEJC remain inferior. KN026 is a novel HER2-targeted bispecific antibody composed of VH regions of trastuzumab and pertuzumab, targeting the HER2 juxtamembrane domain (IV) and the dimerization domain (II) simultaneously. KN026 has shown promising antitumor efficacy in preclinical and phase I studies. Here we present the results of KN026 monotherapy in previously treated, advanced HER2-expressing GC/GEJC. Methods: In this multi-center, single-arm, open-label, 2-cohort phase II study, adult pts with previously treated, advanced GC/GEJC were assigned into a HER2 high-level cohort (Cohort 1: IHC3+ or IHC 2+ ISH+) or a HER2 low-level cohort (Cohort 2: IHC 1+/2+ ISH- or IHC 0/1+ISH+). KN026 was given intravenously in 10 mg/kg QW, 20 mg/kg Q2W, or 30 mg/kg Q3W. Primary endpoints were objective response rate (ORR) and duration of response (DoR) assessed by investigators per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety outcomes. This trial is registered at ClinicalTrials.gov (NCT03925974). Results: At data cut-off (Oct. 29, 2021), 45 pts were enrolled and treated with KN026; 39 were eligible for response evaluation (25 pts in Cohort 1 and 14 pts in Cohort 2). In Cohort 1, ORR was 56% (95%CI 35%-76%) with 14 PR; the median DoR was 9.7 months (mo) (95%CI 4.2-not evaluable (NE)). At a median follow-up of 14.7 mo (95%CI 9.4-16.5), the median PFS was 8.3 mo (95%CI 4.2-11.4), and median OS was 16.3 mo (95% CI 11.0- NE). In Cohort 2, ORR was 14% (95%CI 2%-43%), with median DoR being 6.2 mo (95%CI 3.2-NE). At a median follow-up of 27.5 mo (95%CI 4.1-NE), the median PFS was 1.4 mo (95%CI 1.4-4.1), and median OS was 9.6 mo (95% CI 3.5-14.9). The table shows efficacy in Cohort 1 pts who have progressed on the prior trastuzumab treatment. KN026-related adverse events (TRAEs) were observed in 37 (82%) pts; the most common TRAEs (any grade) were increased aspartate aminotransferase (12, 27%), increased alanine aminotransferase (9, 20%), rash (7,16%), anemia (7,16%), and infusion-related reaction (7,16%). Four pts reported 5 grade 3 TRAEs, including infusion-related reaction, renal hydrocele, ureteral stenosis, increased blood pressure, and abnormal hepatic function (1 each). No grade 4 or 5 TRAEs occurred. Conclusions: KN026 monotherapy yielded promising efficacy with mild to moderate toxicities in pts with previously treated, advanced GC/GEJC. Further investigation is warranted. Clinical trial information: NCT03925974. [Table: see text]

T-DM1 after Pertuzumab plus Trastuzumab: Treatment Sequence-Induced Selection Bias in HER2-Positive Metastatic Breast Cancer.

Simple SummaryReal-world data studies suggest trastuzumab emtansine (T-DM1) may be less effective following pertuzumab treatment in patients with metastatic breast cancer. However, the short time frame between pertuzumab and T-DM1 approvals may have biased these studies toward selecting pertuzumab-experienced patients with more aggressive disease. Our study assessed the impact of this selection bias on time to next treatment or death and other outcomes. Among T-DM1-treated patients, prior pertuzumab use was more frequent in the most recent years; however, no concomitant changes in outcomes were observed. The examination of pertuzumab-experienced patients over time showed that those entering the T-DM1 cohort earliest had more aggressive disease and poorer outcomes than patients entering the study in the most recent years, who had outcomes similar to those of pertuzumab-naive patients. This study demonstrates that such selection bias should be accounted for when assessing treatment sequences.Real-world studies have suggested decreased trastuzumab emtansine (T-DM1) effectiveness in patients with metastatic breast cancer (mBC) who received prior trastuzumab plus pertuzumab (H + P). However, these studies may have been biased toward pertuzumab-experienced patients with more aggressive disease. Using an electronic health record-derived database, patients diagnosed with mBC on/after 1 January 2011 who initiated T-DM1 in any treatment line (primary cohort) or who initiated second-line T-DM1 following first-line H ± P (secondary cohort) from 22 February 2013 to 31 December 2019 were included. The primary outcome was time from index date to next treatment or death (TTNT). In the primary cohort (n = 757), the percentage of patients with prior P increased from 37% to 73% across the study period, while population characteristics and treatment effectiveness measures were generally stable. Among P-experienced patients from the secondary cohort (n = 246), median time from mBC diagnosis to T-DM1 initiation increased from 10 to 14 months (2013–2019), and median TTNT increased from 4.4 to 10.2 months (2013–2018). Over time, prior H + P prevalence significantly increased with no observable impact on T-DM1 effectiveness. Drug approval timing should be considered when assessing treatment effectiveness within a sequence.

Abstract P2-13-21: Improved central nervous system outcomes in patients with early-stage HER2-positive breast cancer who receive neratinib for the recommended duration: Findings from the phase 3 ExteNET trial

Abstract Background: Non-adherence or early discontinuation from systemic adjuvant therapy is associated with an increased risk of disease recurrence and mortality. In the phase 3 ExteNET trial, neratinib (NERLYNX®), an oral irreversible pan-HER tyrosine kinase inhibitor, significantly improved invasive disease-free survival (iDFS) when given for 12 months in patients with early-stage HER2-positive (HER2+) breast cancer after trastuzumab-based therapy. Anti-diarrheal prophylaxis was not mandated by protocol and 17% of patients discontinued neratinib early because of diarrhea. Improved iDFS, distant disease-free survival, and overall survival (OS) have since been reported in patients who completed the planned duration of neratinib therapy compared with all randomized patients [ASCO 2021]. Here we assess central nervous system disease-free survival (CNS-DFS) in 3 discrete groups of patients who completed planned therapy with neratinib in ExteNET: intent-to-treat (ITT) population; patients with hormone receptor-positive disease who initiated neratinib within 1 year after prior trastuzumab (HR+/≤1 year, the population for which neratinib is approved in the EU); and HR+/≤1 year with residual disease post-neoadjuvant therapy (i.e. no pathologic complete response [pCR]). Methods: Patients with early-stage HER2+ breast cancer received oral neratinib 240 mg/day or placebo after trastuzumab-based (neo)adjuvant therapy for 12 months. Patients who completed neratinib therapy (defined as treatment duration ≥11 months or cessation of neratinib if recurrence occurred prior to 11 months) were compared with placebo (all randomized patients). CNS-DFS was defined as time from randomization to any CNS recurrence or death from any cause (exploratory endpoint). Kaplan-Meier methods were used to estimate CNS-DFS and OS rates. Hazard ratios (HR) with 95% confidence intervals (CI) for neratinib versus placebo were estimated using a Cox proportional hazards model. Data cutoffs: March 2017 (CNS-DFS); July 2019 (OS); median follow-up 8.0 (range 0-9.8) years. Results: 2840 patients were included in the ITT population (1420 per group). Among patients who completed neratinib therapy, CNS-DFS was improved versus placebo in each of the 3 patient groups (see Table). For CNS-DFS, the magnitude of effect of neratinib versus placebo was consistently greater in patients who completed neratinib therapy than in the corresponding overall randomized patient group: ITT HR, 0.70 vs 0.73; HR+/≤1 year HR, 0.27 vs 0.41; HR+/≤ 1 year no pCR HR: 0.16 vs 0.24, respectively. Conclusions: These descriptive findings suggest that, in addition to improved OS, patients who receive the recommended 12-month course of neratinib may have improved CNS outcomes. A dose-escalation strategy, which was shown to improve the tolerability of neratinib, decrease the proportion of patients who discontinue treatment due to diarrhea (3.3%), and allow more patients to stay on treatment for 11 months or longer in the CONTROL trial (NCT02400476) compared with ExteNET, may help to realize these benefits in the real-world setting. Table: CNS-DFS and OS in patients who completed planned therapy with neratinib (ITT, HR+/≤1 year and HR+/≤1 year no pCR)NCNS-DFS rate (5 years)OS rateaPopulation/group NeratinibPlaceboDifference, %bHR (95% CI)Difference, %bHR (95% CI)ITT14201420+1.10.73 (0.45-1.17)-0.10.95 (0.75-1.21)cCompleted therapyd8721420+1.20.70 (0.40-1.19)+2.00.78 (0.58-1.04)HR+/≤1 yeare670664+2.70.41 (0.18-0.85)+2.10.79 (0.55-1.13)Completed therapyd402664+3.20.27 (0.08-0.69)+5.80.49 (0.29-0.78)HR+/≤1 yearb no pCRf131164+6.40.24 (0.04-0.92)+9.10.47 (0.23-0.92)Completed therapyd92164+6.90.16 (0.01-0.81)+13.20.29 (0.10-0.68)aOS analysis after a median follow-up of 8.0 (range 0-9.8) years; bDifference (neratinib vs placebo); cStratified by randomization stratification factors; dDefined as ≥11 months of therapy or ended treatment due to disease recurrence (neratinib arm), and all randomized subjects (placebo arm); eHR+ and ≤1 year after prior trastuzumab; fResidual disease post-neoadjuvant therapy. Abbreviations: CI, confidence interval; CNS-DFS, central nervous system disease-free survival; HR, hazard ratio; HR+, hormone receptor-positive; OS, overall survival; pCR, pathologic complete response. Citation Format: Frankie Ann Holmes, Debra Patt, Yvonne Manalo, Julie C Smith, Steven W Papish, Noa Efrat, Ana Arance, Bo Zhang, Deepa Lalla, Alvin Wong, Miguel Martin. Improved central nervous system outcomes in patients with early-stage HER2-positive breast cancer who receive neratinib for the recommended duration: Findings from the phase 3 ExteNET trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-21.