Trastuzumab and Pertuzumab in HER2-Positive Metastatic Breast Cancer in West Africa: A Retrospective Cohort Study from Côte d’Ivoire

Background: MYL-1401O, a biosimilar of trastuzumab, has demonstrated efficacy and safety equivalent to reference trastuzumab (RTZ) in clinical trials for treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). This study presents a real-world analysis comparing MYL-1401O with RTZ, focusing on single and dual anti-HER2 blockade therapies. The analysis encompasses neoadjuvant and first-line palliative treatments for HER2-positive early breast cancer (EBC) and MBC patients within a single hospital in Taiwan. Methods: A retrospective analysis was conducted using medical records from Kaohsiung Veterans General Hospital. Patients treated with RTZ from January 2010 to December 2022 and MYL-1401O from January 2020 to December 2022 were included. The study focused on HER2-positive EBC patients who received neoadjuvant chemotherapy with RTZ or MYL-1401O ± pertuzumab (n = 140) and untreated stage IV MBC patients who received first-line palliative treatment with RTZ or MYL-1401O ± pertuzumab (n = 150). Primary endpoints included achieving pathological complete response (pCR) in the EBC group and progression-free survival (PFS) in the MBC group. Secondary endpoints were objective response rate (ORR), disease control rate (DCR), and cardiac safety. Subgroup analyses included patients receiving dual anti-HER2 blockade. Results: Comparable pCR rates were observed between MYL-1401O and RTZ in the neoadjuvant chemotherapy group: 42.2% (19/45) for MYL-1401O and 51.6% (49/95) for RTZ (p = 0.301). Median PFS in MBC patients was similar between groups without statistically significant difference: not reached for MYL-1401O and 14.1 months for RTZ (95% CI, 9.0-19.1, p = 0.061). ORR, DCR, and cardiac safety profiles did not significantly differ between MYL-1401O and RTZ. Conclusions: This real-world study demonstrates that MYL-1401O is as effective and safe as RTZ in Asian patients with HER2-positive EBC or MBC, supporting its clinical utility in these populations. Citation Format: Ming-Chang Tsai. Real-World Assessment of biosimilar Trastuzumab MYL-1401O vs. reference Trastuzumab in HER2-Positive Breast Cancer: Utilization, Efficacy, and Safety in Asian patients [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-12-15.

Background: Ado-trastuzumab emtansine (T-DM1), a HER2-targeted antibody drug conjugate (ADC), is approved for patients with HER2-positive metastatic breast cancer (BC) after disease progression on a trastuzumab-based regimen. Approval of T-DM1 was based on the EMILIA trial in which T-DM1 demonstrated an objective response rate (ORR) of 43.6%, a median progression-free survival (PFS) of 9.6 months, and an overall survival (OS) of 30.9 months (Verma S, et al. NEJM. 2012). DS-8201a is a novel HER2-targeted ADC with a humanized HER2 antibody attached to a topoisomerase I inhibitor payload by a cleavable peptide-based linker, and with a high drug-to-antibody ratio of 7 to 8. In an ongoing phase 1 trial, DS-8201a showed a manageable safety profile and promising antitumor activity in HER2-positive BC previously treated with T-DM1 (confirmed ORR of 54.5%; April 2018 data cutoff) (Iwata et al, ASCO 2018). The pivotal, phase 2 DESTINY-BREAST01 trial in this population with HER2-positive BC who received prior T-DM1 is ongoing (Baselga et al, ASCO 2018). Study Description: This multicenter, open-label, phase 3 trial will assess the efficacy and safety of DS-8201a vs T-DM1 in subjects with HER2-positive (IHC 3+ or IHC 2+/ISH+; confirmed by centralized testing) unresectable and/or metastatic BC previously treated with trastuzumab and a taxane (NCT03529110, DESTINY-BREAST03). Subjects who previously received a HER2-targeted ADC are excluded. Approximately 500 eligible subjects will be randomized (1:1) to receive DS-8201a (5.4 mg/kg) or T-DM1 (3.6 mg/kg) IV once every 3 weeks. Randomization will be stratified by hormone receptor status, prior pertuzumab treatment, and history of visceral disease. For subjects randomized to T-DM1, the treatment will be in accordance with the approved label. The primary efficacy endpoint is PFS based on blinded, independent central review using RECIST v1.1 criteria. Secondary efficacy endpoints include OS, ORR, duration of response, clinical benefit rate, and PFS based on investigator assessment. Safety assessments include serious and treatment-emergent adverse events, physical examinations, vital signs, and clinical laboratory parameters. Health related quality of life will also be measured. The primary analysis for PFS will be performed when approximately 331 PFS events have been observed. This will provide 90% power to detect a hazard ratio of 0.70 for PFS with a 1-sided alpha of 0.025, assuming a median PFS with T-DM1 of 9.6 months and that PFS follows an exponential distribution. Long-term follow-up will continue after the primary analysis every 3 months until death, withdrawal of consent, loss to follow-up, or study closure. Efficacy analyses will include all randomized subjects, and safety analyses will include all randomized subjects who received ≥1 dose of study treatment. The study will enroll subjects from approximately 150 sites851468 including in North America, Europe, and Asia. Citation Format: Verma S, Shahidi J, Lee C, Wang K, Cortes J. Trastuzumab deruxtecan (DS-8201a) vs ado-trastuzumab emtansine (T-DM1) for subjects with HER2-positive, unresectable and/or metastatic breast cancer who previously received trastuzumab and a taxane: A phase 3, randomized study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-03.

Trastuzumab Beyond Progression in Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: UK Practice now and in the Future

Background: Dual anti-HER2 blockade with trastuzumab and pertuzumab (HP) plus chemotherapy is an effective therapy (Rx) in the 1st-line setting for HER2-positive metastatic breast cancer (MBC). Our single arm phase II study included patients (pts) treated with HP plus paclitaxel in the 2nd-line setting with progression-free survival (PFS) benefit. Recently, we reported results from a retrospective study of pts treated at our institution, suggesting a longer PFS for those who received HP-based Rxs when compared to any other anti-HER2 based Rxs in the 2nd-line setting. To further assess the activity of this combination in later Rx lines, we conducted a retrospective analysis of pts with HER2-positive MBC who had progressive disease after 2nd-line and were treated with HP-based Rxs in the 3rd and later lines at MSKCC. Historically, the median (med) PFS in this setting with trastuzumab-based Rx is about 3-4 months. Methods: Pts diagnosed with HER2-positive MBC and treated with HP-based Rxs at MSKCC between 1-1-2011 and 03-30-2015 and who progressed on 2nd-line Rx were identified through an institutional database. Primary endpoint was PFS in 3rd and later treatment lines. Results: 70 pts who received any HP-based Rx in the 3rd or later lines of treatment were eligible. The med number of prior anti-HER2 Rx was 3. The baseline characteristics and Rxs are summarized in Table 1. The med PFS for the entire cohort was 5.7 months (95% CI, 4.8-6.5). Conclusions: In this retrospective analysis involving heavly pretreated patients, HP-based Rx appears to be an active regimen and compares favorably to historical data. This supports the NCCN endorsement of HP-based Rx in later lines if HP has not been delivered previously. Baseline Characteristics and treatments (n=70)Characteristic(n)(%)Age Median56 Range27-83 Gender Female70100.0Male00.0Race Black1014.3White5477.1Other68.6Ethnicity Non Hispanic6694.3Hispanic45.7ER/PR status ER and PR negative2738.6ER and/or PR positive4361.4Type of disease Non visceral1622.9Visceral5477.1Visceral CNS2130.0Anti-HER2 in early stage Yes2941.4No4158.6Line of therapy 3rd line1927.14th line1521.45th line912.96th line912.97th line811.48th line and beyond1014.3HP-based regimens Chemotherapy + HP5477.1Endocrine therapy + HP57.1HP alone912.9Other22.9 Citation Format: Argolo D, Friedman M, Smyth L, Iyengar N, Singh J, Patil S, Norton L, Baselga J, Hudis C, Dang C. Activity of HP-based therapies as third and later lines for the treatment of HER2-positive metastatic breast cancer: A retrospective study from a single institution. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-20.

Background: Although huge progresses have been achieved in treating HER2-positive BC, HER2-positive metastatic breast cancer (MBC) remains incurable, nearly 70% to 75% MBC patients will progression after first-line treatment with trastuzumab, posing a disproportionate health burden on patients and presenting a substantial unmet medical need. Breast cancer metastasizes to the brain is a late event, which will happen to approximately 50% of patients with HER2+ breast cancer, with a median survival of 7 to 18 months after diagnosis. In recent years, a growing number of small-molecule TKIs produce an antitumor effect on the brain. However, whether monoclonal antibodies plus small-molecule TKIs can exactly enhance the treatment efficiency of breast cancer with brain metastasis patients requires further verification. Inetetamab is a Chinese-origin recombinant anti-HER2 monoclonal antibody with aminoamides modified Fc segment which optimizes the antibody-dependent cellular cytotoxicity (ADCC) effect. Herein, we assessed the efficacy and safety of inetetamab-containing regimens in patients with HER2-positive metastatic breast cancer (MBC), particularly focused on the benefits by patients with brain metastases. Methods: We retrospectively reviewed the medical records of patients with HER2-positive MBC who received inetetamab-containing regimens as a salvage treatment at any line setting from December 2020 and April 2024.The primary end point was progression-free survival (PFS) in the total population (TP). Secondary end points included PFS in the subgroup with brain metastases, objective response rate (ORR), disease control rate (DCR), and safety. The study is ongoing, but recruitment is complete. Results: At the data cutoff date of June 1,2024, a total of 90 patients were enrolled in this analysis. Median follow-up duration was 7.2 months (IQR 3.6–13.1). The median PFS reached 12 months (95% confidence interval [CI] 7.3 to 17 months) in the TP. The ORR was 46.7 % (42/90), and the DCR was 92.2 % (83/90). The median PFS of first-line, second-line, third-line or above were not reach,15.9 months (95% CI 11.9 to NA months),5.9 months (95% CI 4.4 to 12.2 months), respectively. Cox univariate and multivariate analyses demonstrated that first- and second-line was the significant favorable prognostic factor for PFS (treated as first- and second-line vs third-line or above: 15.9 vs 5.9 months, p=0.0021). 30 out of 90 patients had brain metastases, the median PFS in the subgroup with brain metastases reached 12 months (95% CI 4.7 to 19.3 months). Notably, in this subgroup, the median PFS had no significant differences with overall patients (p=0.568), ORR was 53.3% (16/30), DCR was 96.7% (29/30). Furthermore, subgroup analysis revealed a median PFS of 12 months (95% CI 5.5 to 18.5 months) in patients with brain metastases radiotherapy (N=22). The most frequently combine target regimen was pyrotinib or apatinib (29/30, 96.7%). The most common treatment-related adverse events (frequency ≥ 10%) were diarrhoea (52.2%), vomiting/ nausea (20%), fatigue (20%), and leukopenia (18.9%). Grade≥ 3 treatment-related adverse events mainly were diarrhea (12.2%). No grade 4 diarrhea or cardiac-related events were reported. Conclusion: Inetetamab offers a promising option and a manageable safety profile for HER2-positive MBC who pretreated with multiple-line therapies. Meanwhile, Inetetamab plus small-molecule TKIs regimens show the activity in brain metastases population, which deserve further validation in a larger group trial. Citation Format: Liping Chen. Inetetamab-base regimens for patients with HER2-positive metastatic breast cancer and brain metastases: a real-world retrospective study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-05-08.

During the last decade, the introduction of agents that target the human epidermal growth factor receptor 2 (HER2), such as the monoclonal antibody trastuzumab (Herceptin; Roche, Basel, Switzerland) or the tyrosine kinase inhibitor lapatinib (Tykerb; GlaxoSmithKline, Research Triangle Park, NC), in combination with chemotherapy, has changed the course of HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to taxanes increases progression-free survival (PFS) and overall survival (OS), whereas the addition of lapatinib to capecitabine increases PFS after treatment with regimens that include an anthracycline, a taxane, and trastuzumab. In the adjuvant setting, trastuzumab increases diseasefree survival and OS. In addition to these impressive advances, clinical research to improve the outcome in HER2-positive breast cancer is as vibrant as it has ever been. A number of important questions are being addressed at this time, including the delineation of the role of neoadjuvant (presurgical) therapy, theconceptofdualHER2receptorblockade, theidentificationof markers of sensitivity or resistance to therapy, and, finally, the study of new agents. As reported in the article that accompanies this editorial, the timely Neoadjuvant Translational Breast Cancer Research Consortium 006 (TBCRC 006) trial by Rimawi et al has addressed three of these questionsandhas identifiedonemorepiece in thepuzzle: the importance ofaddinghormonal therapyinthesubsetofpatientswithHER2-positive/ hormone receptor (HR) –positive tumors. To place this study in context, let us look at what we know today. In the neoadjuvant setting, the addition of trastuzumab to chemotherapy and maintenance for 1 year increases pathologic complete response (pCR) rates and 3-year event-free survival (EFS). And there is increasing evidence that there is a good correlation between pCR and EFS in HER2-positive disease, which has led to the acceptance of pCR as the primary end point in a number of neoadjuvant studies. If some of these studies, such as the Neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Organisation (NeoALTTO) study, further confirm that pCR is a surrogate marker of EFS, improved pCR in HER2-positive breast cancer could lead to regulatory approval of novel agents in this disease. In terms of dual HER2 blockade, laboratory studies have shown that a more complete blockage of the HER2 and/or the HER signaling pathway by combining two or three inhibitors with nonoverlapping mechanisms of action improves cell death and tumor shrinkage in HER2-positive models. These preclinical findings have now been confirmed in the clinical setting. Trastuzumab and lapatinib (or trastuzumab and pertuzumab [Perjeta; Genentech, South San Francisco, CA], a humanized monoclonal antibody binding to the HER2 dimerization domain), in combination with chemotherapy, results in pCR rates of 45.8% to 51.3% compared with pCR rates of 24.0% to 29.5% with a single anti-HER2 agent combined with the same chemotherapy schedule. Moreover, the addition of pertuzumab to trastuzumab and docetaxel increases PFS and OS in first-line metastatic HER2-positive disease. These results have led to regulatory approval of pertuzumab and have placed the dual HER2 blockade with pertuzumab and trastuzumab in combination with chemotherapy as the standard of care in first-line metastatic disease. Furthermore, dual HER2 blockade strategies could also become standard of care in other settings. For example, the ongoing Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) phase III trial is evaluating the adjuvant dual HER2 blockade with trastuzumab and lapatinib afterchemotherapy,andAStudyofPertuzumabinAdditiontoChemotherapy and Herceptin (Trastuzumab) As Adjuvant Therapy in Patients With HER2-Positive Primary Breast Cancer (APHINITY), a phase III trial, is also currently evaluating adjuvant trastuzumab and pertuzumab with chemotherapy. Given that the dual HER2 blockade is more efficacious that single-agent HER2 therapy, a question that arises is whether the dual blockade may eliminate the need for chemotherapy in a subset of patients. In support of this proposal, the dual HER2 blockade without chemotherapy has shown high activity in a group of patients with metastatic and primary HER2-positive breast cancer. In HER2-positive metastatic breast cancer that was previously treated with trastuzumab, the addition of pertuzumab or lapatinib to trastuzumab showed higher clinical benefit than either pertuzumab or lapatinib alone. In treatment-naive JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 14 MAY 1

Background:The PI3K/Akt/mTOR pathway is a critical regulator of cell growth, survival, and metabolism in cancer. Its activation plays an important role in resistance to chemotherapy and HER2 targeted therapy. PIK3CA activating mutations and PTEN loss were reported in 30% and 16% of BOLERO-1 and 32% and 12% of BOLERO-3 patients, respectively. Exploratory analyses suggested that the addition of everolimus to trastuzumab and chemotherapy improved progression free survival (PFS) in patients with PIK3CA mutations and PTEN loss. In the phase III CLEOPATRA trial, while the combination of pertuzumab (P) plus trastuzumab (H) plus docetaxel (T) as compared with trastuzumab (H) plus docetaxel (T), significantly prolonged PFS (18.5 vs 12.4 months) for first-line treatment for HER2-positive (+ve) metastatic breast cancer (MBC), longer median PFS was observed in patients with wildtype versus mutated PIK3CA in both the control (13.8 v 8.6 months) and pertuzumab groups (21.8 v 12.5 months). Copanlisib is a highly selective, class 1 pan-PI3K inhibitor with predominant activity against both the δ and α isoforms. It is currently FDA approved for the treatment of adults with relapsed follicular lymphoma. This study hypothesizes that the addition of copanlisib to dual HER2 targeted therapy after first line induction treatment will improve clinical outcomes in HER2 positive MBC patients with PIK3CA or PTEN genomic alterations. Trial Design: This is a randomized, two- arm, open label, phase-2 study to evaluate the clinical activity of copanlisib added to HP maintenance after induction with THP in HER2 +ve MBC patients with PIK3CA mutations or PTEN loss. A safety run-in cohort (phase 1B) will be performed. Copanlisib will be administered weekly on D1, D8 of a 21-day cycle. Eligibility criteriaHER2 +ve MBC based on ASCO-CAP criteria (HER2 status based on metastatic tissue)• Activating mutations in PIK3CA, or PTEN loss• ECOG performance status ≤1• Normal organ and marrow function• Within 8 weeks of completion of first-line induction therapy with THP (Phase-2). Any prior treatment provided eligible to receive THP induction (Phase-1B) Specific aimsTo assess the benefit of adding copanlisib to HP in HER2+ve MBC patients with PIK3CA mutations or PTEN loss after induction treatment (Phase-2)• To determine safety and recommended phase 2 dose (RP2D) of copanlisib, HP combination in HER2 MBC patients (Phase-1B)• To correlate PFS and OS with the triplet combination with the number of induction cycles, hormone receptor status, and PTEN loss by IHC• To identify potential predictive and prognostic biomarkers for copanlisib activity Statistical methodsThe primary objective of the phase-1B portion is to determine the RP2D for the combination of copanlisib, trastuzumab, and pertuzumab. Phase 1 portion will use a 3+3 dose de-escalation design. The primary objective of the phase 2 portion is to determine a difference in PFS with the addition of copanlisib to HP maintenance after induction. Projected median PFS in control group is 8 months and 16 months in the experimental arm. We aim to detect a HR of 0.50 with power of 0.90 with 1-sided alpha of 0.1. With a sample size of 82, 12 months post-accrual follow-up, and accrual rate of 5 patients per month, the study duration is 30 months. To have 82 evaluable patients with a 15% drop-out rate, we would need to enroll 96 patients. A Wieand rule futility interim analysis will be conducted when half of the total of 54 required PFS events are observed. Citation Format: Senthil Damodaran, Rashmi K Murthy, Maliha Nusrat, Babita Saigal, Samantha C Trager, Debu Tripathy, Funda Meric-Bernstam. Phase Ib/II trial of copanlisib in combination with trastuzumab and pertuzumab after induction treatment of HER2 positive metastatic breast cancer with PIK3CA mutation or PTEN mutation [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-34-01.

Background The continuum of anti-HER2 agents is regarded as a standard strategy for HER2 positive metastatic breast cancer patients who had progressed disease with anti-HER2 agent- containing treatments. However, there has been lack of data on which agents should be continued and how long continuous anti-HER2 therapies would be effective. This study was aimed to evaluate the efficacy of lapatinib plus vinorelbine in HER2 positive metastatic breast cancer patients who had progressed on both trastuzumab and lapatinib treatments. Methods A total of 149 patients were randomly assigned to lapatinib with vinorelbine (LV) (n=75; laptinib, 1000mg daily ; vinorelbine 20mg/m2 D1,D8 q3w) or vinorelbine alone (V) (n=74; 30mg/m2 D1,D8 q3w). The stratification factors were followings; 1) visceral metastasis, 2) previous response to lapatinib treatment, CR+PR vs. SD ≥ 12 weeks. The primary endpoint was progression free survival (PFS) rate at 18 weeks. The secondary endpoints were objective response rate (ORR), PFS, and overall survival (OS). Results : Both arms were well balanced in various clinical factors. The median number of previous anti-HER2 therapies were 2 (range 2-5). There was no significant difference in PFS rate at 18 weeks between LV and V arms (44.0% vs 36.5%, p=0.44). ORR was 19.7% in LV arm and 16.9% in V arm (p=0.881). PFS and OS did not differ between two arms (LV vs V; median PFS, 16weeks vs 12 weeks, HR= 0.86, 95% CI 0.61-1.22, p=0.41; median OS, 15.0 months vs 18.9 months, HR= 1.07, 95% CI 0.72-1.58, p=0.72). In subgroup analysis, there was no difference in PFS and OS between two arms according to previous response to lapatinib (median PFS, CR+PR vs. SD ≥ 12 weeks, 12.1weeks vs.17.4 weeks; HR= 1.242, 95% CI 0.881-1.751, p=0.215; median OS, 14.9 months vs. 19.4 months; HR= 1.179, 95% CI 0.797-1.744, p=0.41). Most common adverse events in both arms were neutropenia which was more often observed in V arm (55% vs 73%, p=0.03). Overall, the profiles of adverse events were similar in both arms and all were manageable. Conclusion Lapatinib plus vinorelbine treatment was tolerable, however, it did not demonstrate the clinical benefits compared to vinorelbine alone in HER2 positive metastatic breast cancer patients after progression on both trastuzumab and lapatinib. Citation Format: Sim SH, Park IH, Jung KH, Kim S-B, Ahn J-H, Lee K-H, Im S-A, Im Y-H, Park YH, Sohn JH, Kim YJ, Lee S, Kim H-J, Chae YS, Park K-H, Nam B-H, Lee KS, Ro J. Randomized phase II study of lapatinib plus vinorelbine versus vinorelbine in patients with HER2 positive metastatic breast cancer progressed after lapatinib and trastuzumab treatment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-23.

P4-21-14: A randomized phase II trial of trastuzumab + capecitabine versus lapatinib + capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes: WJOG6110B/ELTOP

Objective: Breast Cancer is one of the most common malignant tumors in women. HER-2 is a driver gene for poor prognosis in breast cancer. Anti-HER-2 drugs have significantly improved the prognosis of patients with HER-2 positive metastatic breast cancer. There is still a lack of exploration of first-line anti-HER2 treatment options and translational studies only for patients with metastases after adjuvant and/or neoadjuvant trastuzumab therapy. This study is based on our previous clinical trial of pyrotinib in combination with albumin-bound paclitaxel in first line for patients with HER-2-positive metastatic breast cancer after adjuvant and/or neoadjuvant trastuzumab therapy, with the aim of exploring the efficacy and adverse events in the enrolled patients. And to explore the markers associated with Progression Free Survival (PFS) by using Olink technique to detect blood samples from patients. To provide a better screening of the benefit population and provide guidance for the treatment of HER-2 positive metastatic breast cancer. Methods: From December 2019 to July 2023, our previous clinical trial prospectively enrolls 27 patients with HER-2-positive metastatic breast cancer after adjuvant and/or neoadjuvant trastuzumab therapy. Pyrotinib (400 mg, po, qd) combined with albumin-bound paclitaxel (200 mg, ivdrip, d1, d8, q21d) was used as the first-line treatment regimen. Patients were evaluated for efficacy. Survival analysis was performed by using the Kaplan-Meier method. Blood samples were collected during treatment. We selected 21 blood samples from patients, and dynamically detected plasma protein changes by Olink technique. Differential protein analysis between groups according to hormone receptor status, trastuzumab primary/secondary resistance, and the presence of visceral metastases. And the proteins associated with PFS were analyzed. Results: Among the 27 patients whose efficacy had been evaluated, 7 patients were evaluated as CR, 18 patients as PR, and 2 patients as SD. The objective response rate was 92.6%, and the disease control rate was 100%. The median follow-up was 17.8 months and the median PFS has not yet been reached. Diarrhea is the most common adverse event. Grade 3 or higher adverse events include diarrhea, leukocytopenia, neutropenia, and hand-foot syndrome. The progression free survival was significantly worse in patients with visceral metastases (P=0.01). Results of Olink protein dynamic assay showed a significant downregulation of CEACAM5, TXLNA, PVRL4and ERBB2. Differential proteins between groups showed that there were no significant differential proteins between the hormone receptor-positive and negative groups at the baseline node, but 7 proteins were upregulated in the hormone receptor-positive group compared with the negative group at the progression node, with EMS-1, WIF-1, and hK14 being the most significant. Compared to primary resistance, trastuzumab secondary resistance appeared 4 proteins upregulated at the baseline node, with hK14 and CYR61 being the most significantly; and 33 proteins were upregulated at the progression node, with CYR61, CXL17, FURIN, and ABL1 being the most significantly. Patients with high expression of TLR3 and low expression of RET at the baseline node had longer PFS. Conclusions: This study demonstrates that pyrotinib in combination with albumin-bound paclitaxel as a first-line treatment regimen shows good efficacy and a manageable safety for patients with HER-2-positive metastatic breast cancer after adjuvant and/or neoadjuvant trastuzumab therapy. PFS was shorter in patients with visceral metastases. TLR3 and RET were the proteins that significantly associated with PFS in patients. Citation Format: Huihui Li, Xiaochu Man, Sha Yin, Dongdong Zhou, Baoxuan Zhang, Shu Fang, Fangchao Zheng, Chao Li, Xinzhao Wang, Wei Huang, Linlin Wang, Qingqing He, Hui Fu, Yan Zhang, Changrui Liu, Lin Dong, Xianguang Zhao, Liang Xu, Xiao Sun, Bingjie Fan, Lihua Song, Zhengbo Zhou, Qiaorui Tan, Jinming Yu. Efficacy, safety and translational study of pyrotinib combined with albumin-bound paclitaxel as firstline treatment of HER-2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-07.

TPS658 Background: Dual blockade of HER2 with the combination of trastuzumab (T) and lapatinib (L) enhances antitumor activity in HER2-positive breast cancer (BC) preclinical models due to the complementary mechanisms of action of the 2 agents. In patients (pts) with T-treated HER2-positive metastatic BC (MBC), treatment with the combination was associated with longer progression-free (PFS) and overall survival (OS) compared with L alone. In pts with stage II/III BC, preoperative treatment with the combination plus paclitaxel (P) resulted in significantly higher pathologic complete response rates compared with P combined with either agent alone. This evidence supports the concept of dual HER2 blockade as a treatment strategy for HER2-positive MBC. The present study is designed to evaluate whether the addition of L improves PFS among women with HER2-positive MBC receiving T as maintenance therapy. Methods: In this open-label, Phase III study, 280 pts will be stratified by line of treatment (first/second) and hormone receptor status (positive/negative), then randomized 1:1 to receive maintenance treatment with either L (1000 mg qd, continuously) in combination with T (6 mg/kg once every 3 weeks [q3w]) or T (6 mg/kg q3w) alone. Pts will receive study treatment until disease progression, death, discontinuation due to adverse events, or other reasons. The primary endpoint is PFS; secondary endpoints are OS, clinical benefit rate, and safety. Key eligibility criteria include pts with HER2-positive MBC who have completed 12 to 24 weeks of first- or second-line treatment with T plus chemotherapy with an objective response or stable disease at time of chemotherapy discontinuation. Pts with stable brain metastases are eligible if entering the study on second-line treatment. Efficacy endpoints will be analyzed in the ITT population. A total of 193 PFS events is required to detect a 50% increase in median PFS (hazard ratio=0.67) for L plus T compared with T alone (median PFS 27 vs 18 weeks, respectively). The hypothesis will be tested using a 1-sided test with 80% power and a type I error of 0.025. The trial is currently open for accrual in the United States and Canada.

Background HER2-targeted therapies have substantially improved survival in patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization-positive) advanced or metastatic breast cancer. Despite significant advancements, patients ultimately develop resistance to standard-of-care HER2-targeted therapies. Therefore, a need remains for regimens that prolong disease control and survival in these patients. T-DXd is a HER2-targeted antibody-drug conjugate containing a linker selectively cleaved in tumor cells and a topoisomerase I inhibitor payload with high cell-membrane permeability. T-DXd has been approved by the FDA for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received ≥ 2 prior anti-HER2-based regimens in the metastatic setting and by Japan’s Ministry of Health, Labour and Welfare for use in patients with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy (use limited to patients refractory to or intolerant of standard treatments). Results from the phase 2 DESTINY-Breast01 trial demonstrated an objective response rate (ORR) of 60.9% per independent central review and a median progression-free survival (PFS) of 16.4 months in a heavily pretreated population (median of 6 prior lines of therapy) of patients with HER2-positive advanced or metastatic breast cancer treated with T-DXd (Modi S, et al. N Engl J Med. 2020;382:610-621). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd combinations in patients with HER2-positive advanced or metastatic breast cancer. Study Description DESTINY-Breast07 is a global, multicenter, open-label, phase 1b/2 dose-finding and dose-expansion trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd in combination with other therapies in patients with HER2-positive advanced or metastatic breast cancer. Patients will be enrolled globally at ≈ 110 sites in ≈ 10 countries. The study will initially consist of 4 combination modules, each with 2 parts: dose finding (part 1) and dose expansion (part 2), and a T-DXd monotherapy module (part 2 only). The 4 combination modules will enroll patients for treatment with (1) T-DXd + durvalumab, (2) T-DXd + pertuzumab, (3) T-DXd + paclitaxel, or (4) T-DXd + durvalumab + paclitaxel. New combination treatment modules may be added via protocol amendment. Part 1 of each combination module will enroll patients who have had disease progression on ≥ 1 prior line of therapy in the metastatic setting. In part 2, patients who have received no prior therapy for metastatic disease will be randomized to receive a combination regimen or T-DXd monotherapy. Antitumor activity will be evaluated based on investigator assessment according to RECIST 1.1. The primary endpoint is to assess the safety and tolerability of T-DXd combinations and determine the recommended phase 2 doses. Secondary endpoints include ORR, PFS, duration of response, overall survival, pharmacokinetics, and immunogenicity. Citation Format: Fabrice Andre, Erika Hamilton, Sherene Loi, Peter Schmid, Tinghui Yu, Shiyao Lu, Sarice Boston, Celina D'Cruz, Pia Herbolsheimer, Komal Jhaveri. Trastuzumab deruxtecan (T-DXd; DS-8201) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2 open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-04.

Background: Metastatic breast cancer (MBC) is still regarded as an incurable disease with improvement of survival and maintenance of quality of life (QoL) being equally important treatment goals. In patients with HER2-positive MBC, taxane-based chemotherapy in combination with dual HER2 targeted therapy with trastuzumab (T) and pertuzumab (P) is the standard of care therapy for first line patients. However, given that adverse events associated with cytostatic treatment can seriously impact the patients’ QoL, the less toxic synergistic combination of dual HER2-targeted therapy with endocrine therapy might offer a better treatment option for patients with HER2-positive and hormone-receptor (HR) positive MBC compared to cytotoxic chemotherapy-based treatment regimen. Methods:Between 9/2015 and 11/2022, the German multicenter phase III DETECT V trial randomized 271 patients with HER2-positive and HR-positive (i.e. ER positive and/or progesterone-receptor positive) MBC in the 1st-3rd line setting 1:1 to receive T and P combined with either endocrine therapy or chemotherapy followed by maintenance therapy with T, P and endocrine therapy. Chemotherapy and the endocrine agents could be chosen from a variety of available regimens according to physicians’ choice. Based on emerging data strongly suggesting an additional benefit of CDK4/6 inhibitors, an amendment came into effect in January 2019 (after 124 patients had been randomized) with the addition of ribociclib to both treatment arms. The primary objective of DETECT V is to compare tolerability between the chemotherapy-free and chemotherapy-containing treatment arm. Secondary objectives comprise the comparison of overall survival (OS), progression-free survival (PFS) and safety between chemotherapy-free and chemotherapy-containing treatment, as well as the evaluation of the effect of adding ribociclib to both treatment arms. Here we report results of the second interim efficacy analysis with data cut off April 3rd 2024 (as based on the full ITT set of 271 patients; 54 patients still in follow up). Results:Median patient age was 60 years, 209 (77.1%) of patients were in the first line setting and 139 (51.3%) patients had a metastasis-free interval exceeding 12 months. Overall survival (OS) and progression-free survival (PFS) did not differ between patients receiving chemotherapy-free and chemotherapy-containing treatment (median OS not reached vs. 46.1 months, hazard ratio 1.07, 95% CI 0.65 – 1.77, p = 0.79; median PFS 19.1 vs. 22.4 months, hazard ratio 1.19, 95% CI 0.84 – 1.69, p = 0.34). Both OS and PFS were significantly improved by the addition of ribociclib (median OS not reached vs. 46.1 months, hazard ratio 0.42, 95% CI 0.24 – 0.74, p = 0.002; median PFS 27.2 vs. 15.6 months, hazard ratio 0.52, 95% CI 0.37 – 0.75, p < 0.001). However, exploratory analyses showed that the effect of adding ribociclib seemed to be more pronounced in the chemotherapy-containing arm (OS: hazard ratio 0.25, 95% CI 0.10 – 0.62, p = 0.003; PFS: hazard ratio 0.36, 95% CI 0.21 – 0.62, p < 0.001) as compared to the chemotherapy-free arm (OS: hazard ratio 0.65, 95% CI 0.31 – 1.36, p = 0.255; PFS: hazard ratio 0.71, 95% CI 0.44 – 1.15, p = 0.159). The 2-way interactions between randomization arm and addition of ribociclib approached significance both for OS and PFS (p = 0.087 and p = 0.088, respectively). Conclusion:Our preliminary results suggest that chemotherapy-free treatment for patients with HER2-positive and HR-positive MBC might be an effective alternative, while the addition of ribociclib may further improve survival. Citation Format: Wolfgang Janni, Tanja Fehm, Volkmar Müller, Amelie De Gregorio, Thomas Decker, Andreas Hartkopf, Marianne Just, Jacqueline Sagasser, Marcus Schmidt, Pauline Wimberger, Tobias Engler, Maggie Banys-Paluchowski, Peter A. Fasching, Brigitte Rack, Andreas Schneeweiss, Jens-Uwe Blohmer, Jens Huober, Klaus Pantel, Thomas W. P. Friedl, Fabienne Schochter. Treatment de-escalation by omission of chemotherapy & the effect of adding the CDK4/6 inhibitor ribociclib in HER2-positive and hormone-receptor positive metastatic breast cancer– second interim efficacy analysis of the randomized DETECT V trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-07-28.

Since the introduction of trastuzumab in the late 1990s, the treatment landscape for patients with metastatic human epidermal growth factor receptor 2 (HER2) –positive breast cancer has changed dramatically. In addition to trastuzumab, a series of novel HER2directed therapies has gained regulatory approval, including lapatinib, pertuzumab, and ado-trastuzumab-emtansine (T-DM1). The result is that for many patients, the disease has been transformed from a rapidly lethal illness to one in which episodes of disease progression are punctuated by long periods of tumor control. Despite these advances, HER2-positive metastatic breast cancer is still not generally curable, and the vast majority of patients will eventually succumb to their disease. Furthermore, over time, up to half of patients will develop CNS metastases, and these can be a source of both substantial morbidity and mortality. The two articles that accompany this editorial directly address several related questions. First, is there a preferred anti-HER2 therapy for use in the first-line setting? Second, does the choice of anti-HER2 therapy affect the incidence of brain metastases? In addition, these studies raise important considerations regarding trial design moving forward. In the NCIC Clinical Trials Group MA.31 trial, Gelmon et al directly compared first-line trastuzumab versus lapatinib, each paired with a taxane, in patients with HER2-positive metastatic breast cancer. Among the 652 patients in the intent-to-treat population, although the objective response rates were similar, progression-free survival (PFS) was inferior in the lapatinib arm (median, 9.0 v 11.3 months; hazard ratio [HR], 1.37; P .001), and there was a trend for overall survival (OS) in favor of trastuzumab, which reached significance in the centrally confirmed HER2-positive subset (n 537; HR, 1.47; P .03). Patient-reported global quality of life, as assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (QLQ-C30), was similar between arms, although expected differences were seen that favored trastuzumab for outcomes such as diarrhea and rash. Rates of therapy discontinuation for reasons other than progression or death were similar between arms. The CEREBEL trial, as reported by Pivot et al, also compared trastuzumab versus lapatinib, this time with a capecitabine backbone. In contrast with MA.31, patients could be enrolled either in the firstline setting or in a subsequent line of therapy. Just under half of patients who were included in CEREBEL had not received any previous therapy for metastatic breast cancer. As with MA.31, although objective response rates were similar between arms, patients who were randomly assigned to the trastuzumab-containing arm experienced longer PFS and OS compared with patients who were randomly assigned to the lapatinib-containing arm (median PFS, 6.6 v 8.1 months; HR, 1.30; 95% CI, 1.04 to 1.64; median OS, 22.7 v 27.3 months; HR, 1.34, 95% CI, 0.95 to 1.90). In placing these data into context, at least two issues come to mind: the patient populations enrolled, and data regarding other anti-HER2 agents that have been developed since these trials were initiated. The patient populations in both studies were notable: in MA.31, less than 20% of patients had received previous adjuvant or neoadjuvant trastuzumab, and 43% of patients presented with de novo metastatic disease. In CEREBEL, the patient population included 18% with de novo disease; only 28% of patients had received adjuvant trastuzumab, and only 35% had previously received trastuzumab for metastatic disease. Results of the studies are generally consistent with preoperative data from several studies, including CALGB (Cancer and Leukemia Group B) study 40601, in which lapatinibtaxane was inferior to trastuzumab-taxane with respect to the primary end point of pathologic complete response in newly diagnosed, trastuzumab-naive patients with clinical stage II to III, HER2positive breast cancer. To what extent MA.31 and CEREBEL can be generalized to a population of first-line patients with metastatic disease who have relapsed despite adjuvant trastuzumab is somewhat unclear. Indeed, in a hypothesis-generating subset analysis of CEREBEL, the benefit of trastuzumab-capecitabine compared with lapatinib-capecitabine was restricted to patients without previous exposure to trastuzumab or chemotherapy. PFS did not differ by arm among patients with previous trastuzumab exposure or those treated in the second-line setting or beyond. Since these trials were initiated, two new agents have gained regulatory approval for HER2-positive metastatic breast cancer: pertuzumab and T-DM1. Given the superiority of trastuzumab-taxane compared with lapatinib-taxane in MA.31, and the superiority of pertuzumab-trastuzumab-taxane compared with trastuzumab-taxane in CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 14 MAY 1

Introduction: Poziotinib is a novel, pan-HER kinase inhibitor which showed potent anti-tumor activities through irreversible inhibition of HER family tyrosine kinases in preclinical and early clinical studies. Recent the open-label, multicenter phase II trial of poziotinib monotherapy evaluated that poziotinib is a new promising option for patients with HER2-positive metastatic BC who have failed more than two HER2 targeted therapy (NCT02418689). We evaluated genetic profiles of HER2-positive metastatic BC and investigated potential biomarkers of poziotinib for HER2-positive metastatic BC (MBC). Methods: All participants were diagnosed as HER2-positive BCs according to American Society of Clinical Oncology/College of American Pathologists HER2 guideline and provided tissue specimens that would be possible to extract DNA and RNA for next generation sequencing. We performed targeted deep sequencing with a customized 381 cancer gene panel (CancerSCAN™) and analyzed the relationship among the sequencing data, immunohistochemistry and clinical outcome. Results: From Apr 2015 to Feb 2016, 106 patients were enrolled in the trial from 7 institutes in Korea. Of 106 patients, biomarker data were available for 79 patients. TP53 was the most frequently mutated gene (70.8%) followed by PIK3CA (45.6%). HER2 single nucleotide variant (SNV) was detected in 13 BCs (16.5%) and HER3 SNV was in 9 (11.4%). The score of HER2 immunohistochemistry (IHC) was 3+ in 68 BCs and 2+ with positive in situ hybridization in 11 BCs. In copy number variant (CNV) analysis, HER2 amplification (86.1%) was most frequently observed and followed by CDK12 amplification (58.2%) and APOBEC3B deletion (30.4%). IHC score of HER2 was positively correlated to copy number (CN) of HER2 (P=0.001) but 11 breast cancer tissue did not have copy number amplification of HER2 (13.9%) (Six of HER2 IHC score 2+ and 5 of 3+). The median progression free survival (PFS) was 4.04 months (95% CI, 2.96 - 4.40) for patients who treated with poziotinib in this study. PIK3CA activating mutations were associated with short PFS compared to wild type (WT) and other SNVs (Median PFS of activating mutations vs. WT and others: 2.66 vs. 4.40 (months), P=0.009). HER2 CN amplification was positively correlated to duration of PFS (Median PFS of no amplification vs. 4 ≤ CN < 16 vs. 16 ≤ CN: 2.56 vs. 3.02 vs. 4.86 (months), P=0.032). HER2 SNVs prolonged duration of PFS without statistical significance (Median PFS of HER2 SNVs vs. WT: 4.24 vs. 3.19 (months), P=0.114), but 10 of 13 BCs with HER2 SNV (76.9%) had clinical benefit from poziotinib and 5 BCs (38.5%) had durable response more than 6 months. Conclusion: In this biomarker analysis, SNV of HER2 was frequently observed in HER2 positive MBCs and HER2 CN amplification was detected not in all. High CN amplification of HER2 derived longer PFS than those with low CN. To contrary to this, activating PIK3CA mutations shorten PFS compared to those with WT. In addition, HER2 SNVs might be a potential biomarker of poziotinib in HER2-positive MBC. Further functional study would be warranted. Citation Format: Kim J-Y, Lee E, Park K, Jung HH, Park W-Y, Lee K-H, Sohn JH, Lee KS, Jung KH, Kim J-H, Lee KH, Im S-A, Park YH. Molecular alterations and poziotinib, a pan-HER inhibitor efficacy in human epidermal growth factor receptor 2(HER2) positive breast cancers: Combined exploratory biomarker analysis from phase II clinical trial of poziotinib for refractory HER2 positive breast cancer(BC) patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-21.