Endpoint Of Progression-free Survival Research Articles

Cisplatin- or Carboplatin-Based Chemotherapy Plus Pembrolizumab in Advanced Urothelial Cancer: Exploratory Analysis From the Phase 3 KEYNOTE-361 Study

IntroductionKEYNOTE-361 evaluated first-line pembrolizumab with and without platinum-based chemotherapy versus chemotherapy alone in advanced or metastatic urothelial carcinoma. The primary end points of progression-free survival (PFS) or overall survival (OS) were not met. Exploratory analysis of efficacy by platinum agent (cisplatin or carboplatin) is reported. Patients and MethodsEligible patients were randomly assigned 1:1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles with or without chemotherapy (gemcitabine with investigator's choice of either cisplatin or carboplatin) or chemotherapy alone. This exploratory subset analysis evaluated PFS and objective response rate (ORR) per RECIST v1.1 by blinded independent central review and OS for cisplatin- or carboplatin-based chemotherapy with versus without pembrolizumab for patients assigned to chemotherapy-containing arms of KEYNOTE-361. ResultsOf 1010 patients enrolled, 703 were assigned to receive a chemotherapy-containing regimen (n = 312 cisplatin based; n = 391 carboplatin based). Median follow-up was 31.3 months. For cisplatin-based arms, with versus without pembrolizumab, median OS was 20.1 versus 16.4 months (HR 0.88, 95% CI 0.67-1.15) and median PFS was 8.5 versus 7.1 months (HR 0.67, 0.51-0.89). ORR was 64.1% versus 48.7%, respectively. For carboplatin-based arms, with versus without pembrolizumab, median OS was 15.5 versus 12.3 months (HR 0.84, 95% CI 0.67-1.06) and median PFS was 8.0 versus 6.7 months (HR 0.86, 0.68-1.09). ORR was 47.2% versus 41.8%, respectively. Among patients in the cisplatin-based versus carboplatin-based chemotherapy alone arms, 55.8% versus 41.8% received a subsequent anti–programmed cell death protein 1/ligand 1 therapy. The addition of pembrolizumab did not significantly increase the incidence of adverse events reported. ConclusionResults suggest trends towards OS and PFS improvements with the addition of pembrolizumab to gemcitabine-platinum doublet over gemcitabine-platinum alone regardless of whether cisplatin or carboplatin was the chosen platinum agent. OS may have been influenced by active subsequent therapies. MicroAbstractUntil recently, the standard first-line treatment for advanced urothelial carcinoma included platinum-based chemotherapy containing either cisplatin or carboplatin. This exploratory analysis from the KEYNOTE-361 study describes efficacy outcomes with the addition of pembrolizumab to cisplatin- or carboplatin-based chemotherapy to determine if there are differences in clinical benefit between patients who received cisplatin-based versus carboplatin-based combination therapy.

Body composition derangements in lung cancer patients treated with first-line pembrolizumab: A multicentre observational study.

While immune checkpoint inhibitors (ICIs) are increasingly reshaping the therapeutic landscape of non-small-cell lung cancer (NSCLC), only a limited proportion of patients achieve a relevant and long-lasting benefit with these treatments, calling for the identification of clinical and, ideally modifiable, predictors of efficacy. Body composition phenotypes may reflect aspects of patients' immunology and thereby their ability to respond to ICIs. This study aims to explore the possible association between pre-treatment body composition phenotypes, tumour response, and clinical outcomes in patients receiving first-line pembrolizumab monotherapy for advanced NSCLC. A retrospective review of consecutive patients with treatment-naïve NSCLC and PD-L1 expression ≥50% undergoing pembrolizumab at three academic institutions was performed. Pre-treatment body composition parameters were measured at the third lumbar vertebra level by computed tomography, defined using pre-established cut-offs. Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival and overall survival (PFS and OS), compared through the log-rank test and the Cox proportional hazards model. Data from 134 patients (93 males [69.4%] and 41 females [30.6%]) were collected. Median age was 69years (range 36-85), with a median follow-up of 12months (range 1-131). The median body mass index (BMI) was 24.5 (IQR 21.5; 26.1) kg/m2. Overall, 59.0% and 51.5% of patients met established radiographic criteria for evidence of sarcopenia and myosteatosis, respectively, which occur across the BMI spectrum. Multivariate regression analysis, adjusted for co-morbidities, revealed that sarcopenia (aOR 5.56, 95% CI. 2.46-12.6, P<0.0001) and low intermuscular adipose tissue (IMAT) area (aOR 1.83, 95% CI. 1.22-2.83, P=0.001) were associated with a lower rate of ORR (30.4% vs. 70.5%, P<0.0001 and 30.7% vs. 73.2%, P<0.0001, respectively). Moreover, both in univariate and multivariate analysis, adjusted for co-morbidities, low performance status according to the Eastern Cooperative Oncology Group scale (ECOG PS), sarcopenia and low IMAT were significantly related to short PFS (ECOG PS: aHR 2.73, 95% CI 1.60-4.66, P<0.0001; sarcopenia: aHR 2.24, 95% CI 1.37-3.67, P=0.001; IMAT depot: aHR 2.26, 95% 1.40-3.63, P=0.002) and OS (ECOG PS: aHR 3.44, 95% CI 1.96-6.01, P<0.0001; sarcopenia: aHR 4.68, 95% CI 2.44-8.99, P<0.0001; IMAT depot: aHR 3.18, 95% 1.72-5.88, P<0.0001). Skeletal muscle abnormalities, apparently frequent in NSCLC, potentially represent intriguing predictive markers of response to ICIs and survival outcomes. Large prospective trials are needed to validate ICIs responders' clinical biomarkers.

GOG-3097/ENGOT-ov81/GTG-UK/RAMP 301: a phase 3, randomized trial evaluating avutometinib plus defactinib compared with investigator’s choice of treatment in patients with recurrent low grade serous ovarian cancer

BackgroundThere are no approved treatments specifically for low grade serous ovarian cancer; current standard of care treatment options are limited in efficacy and tolerability. The combination of avutometinib with defactinib...

Molecular Subtypes Are Associated With Clinical Benefit in Cisplatin-Treated Metastatic Urothelial Cancer Patients.

Cisplatin-based combination chemotherapy (CHT) is standard of care in metastatic urothelial cancer (mUC); however, no predictive molecular biomarkers are available for clinical use. The aim of this study was to investigate the impact of molecular subtypes in relation to treatment response and survival in patients with mUC treated with first-line CHT. Molecular subtype classification according to the Lund Taxonomy (LundTax) was performed by tumor transcriptomic profiling and immunostaining in a retrospective cohort. Molecular subtypes were investigated in relation to the primary end point overall response rate (ORR) and secondary end points progression-free survival (PFS) and overall survival (OS). Differential gene expression and association to treatment response were explored. Ninety-five patients with mUC were classified into urothelial-like (Uro, 43%), genomically unstable (GU, 26%), basal squamous-like (Ba/Sq, 20%), mesenchymal-like (Mes-like, 8%), and small cell neuroendocrine-like (Sc/NE, 3%) subtypes. Patients with Mes-like tumors had lower ORR (14%) compared with Uro (70%), GU (77%), Ba/Sq (75%), and Sc/NE (67%; odds ratio, 0.06 [95% CI, 0.01 to 0.54], P = .012). Furthermore, patients with Mes-like tumors had significantly shorter PFS (hazard ratio [HR], 5.18 [95% CI, 2.28 to 11.76], P < .001) and OS (HR, 3.19 [95% CI, 1.45 to 7.03], P = .004). Patients with Uro and GU showed the longest survival. In responders, an enrichment of downregulated stromal- and immune-related genes was seen. Downregulation of interferon-induced transmembrane protein 2 was associated with increased ORR and improved OS. This study identifies different CHT responses by LundTax molecular subtypes in patients with mUC, where the Mes-like subtype was associated with lower response rate and shorter survival.

Pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer and brain metastases (PERMEATE trial): overall survival results from a multicenter, single-arm, two-cohort, phase 2 trial

The phase 2 PERMEATE study has shown the antitumor activity and safety of pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases. In this report, survival results were updated with extended follow-up. Between January 29, 2019 and July 10, 2020, adult patients with HER2-positive metastatic breast cancer who had radiotherapy-naïve brain metastases (cohort A, n=59) or progressive disease after radiotherapy (cohort B, n=19) were enrolled and received pyrotinib (400mg once daily) and capecitabine (1000mg/m2 twice daily on days 1-14 of each 21-day cycle) until disease progression or unacceptable toxicity. Secondary endpoints progression-free survival (PFS) and overall survival (OS) were updated, and post-hoc central nervous system (CNS)-PFS was analyzed. This study is registered with ClinicalTrials.gov (NCT03691051). As of February 2, 2023, the median follow-up duration was 30.9 months (interquartile range, 16.1-39.8). Median PFS was 10.9 months (95% confidence interval [CI], 7.6-14.6) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 35.9 months (95% CI, 24.4-not reached) in cohort A and 30.6 months (95% CI, 12.6-33.3) in cohort B. Median CNS-PFS was 13.6 months (95% CI, 9.0-15.8) in cohort A and 5.7 months (95% CI, 3.4-11.5) in cohort B. Median OS was 34.1 months (95% CI, 21.7-not reached) for 14 patients with intracranial progression only in cohort A who restarted pyrotinib plus capecitabine after local radiotherapy. These data support further validation in a randomized controlled trial for the assessment of pyrotinib in combination with capecitabine as systemic therapy for patients with HER2-positive breast cancer and brain metastases. National Cancer Center Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals.

OPERA-01: A randomized, open-label, phase 3 study of palazestrant (OP-1250) vs standard-of-care for patients with ER+, HER2- advanced or metastatic breast cancer after endocrine therapy and CDK4/6 inhibitors.

TPS22 Background: In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC), endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard-of-care (SOC) treatment in the first-line setting. However, patients develop resistance, most commonly due to acquired mutations in ESR1. Efficacy of available ET post CDK4/6i treatment is limited. Therefore, a significant unmet need exists for patients with ET-CDKi-resistant ER+, HER2– MBC to improve outcomes and delay time to chemotherapy. Palazestrant is an oral small molecule complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds ER and completely blocks ER-driven transcriptional activity, irrespective of ESR1 mutation status. In a phase 1/2 monotherapy study in heavily pretreated patients with ER+, HER2– advanced or MBC (NCT04505826), palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in patients with and without ESR1 mutation at the recommended Phase 2 dose of 120 mg once a day (qd) (Lin et al. ESMO 2023 MO382). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patietns with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Eligible patients are adults who have a confirmed diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1-2 prior lines of ET, last ET duration for ≥6 months; must have received CDK4/6i with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC. No prior chemotherapy in the metastatic setting is permitted. In the dose selection part of the study, 120 patients are randomized to 90 mg qd or 120 mg qd palazestrant or SOC monotherapy. The dose selection will be conducted when 80 patients in both palazestrant arms have had an opportunity to be on treatment for 16 weeks. Overall, 510 patients, including patients from the dose selection part, will be randomized to palazestrant or SOC ET. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1 mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in patients with and without ESR1 mutations. The study started recruitment in November 2023. Clinical trial information: NCT06016738 .

Concerning Safety and Efficacy of Concurrent and Consolidative Durvalumab With Thoracic Radiation Therapy in PDL1-Unselected Stage III Non-Small Cell Lung Cancer: Brief Report

IntroductionConsolidative durvalumab, an anti-programmed death ligand 1 (PDL1) immune checkpoint inhibitor, administered after concurrent chemoradiation improves outcomes of patients with locally advanced non-small cell lung cancer (NSCLC) without substantially increasing toxicities. We studied a chemotherapy-free regimen of thoracic radiotherapy (RT) with concurrent and consolidative durvalumab. MethodsThis single-arm phase II trial enrolled patients with stage III NSCLC (regardless of tumor PDL1 expression), performance status ECOG 0-1, adequate pulmonary function, and RT fields meeting standard organ constraints. Participants received two cycles of durvalumab (1500 mg every 4 weeks) concurrently with thoracic RT (60 Gy in 30 fractions), followed by up to 13 cycles of consolidative durvalumab. ResultsAfter 10 patients were enrolled, the trial was closed due to poor clinical outcomes. With a median follow-up of 12 months, five patients had disease progression and eight patients died. Six patients experienced 15 treatment-related, grade ≥3 events, including one grade 4 acute kidney injury during consolidation and two fatal pulmonary events. One fatal pulmonary event occurred during the concurrent phase in an active smoker; the other occurred after the first cycle of consolidative durvalumab. The primary endpoint of progression-free survival (PFS) at 12 months was 20% (50% for PDL1≥1% versus 0% for PDL1 unavailable or <1%). Median overall survival (OS) was not reached, 10.5 months, and 7 months, for PDL1 ≥1%, <1%, and unavailable, respectively. ConclusionsIn PDL1 unselected stage III NSCLC, thoracic RT plus concurrent and consolidative durvalumab is associated with high-grade toxicity and early disease progression.

Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial

Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting. Deutsche Krebshilfe.

Progression-free survival end points in prostate cancer: are we truly making progress.

Progression-free survival end points in prostate cancer: are we truly making progress.

Factors influencing the clinical added value (CAV) in France over more than a decade.

e23102 Background: The rise of cancer drug prices has raised alarm over the need to base pricing decisions on the clinical added value (CAV). The French National Authority for Health (HAS) is responsible for health technology assessment (HTA) in France. For each indication retained for reimbursement, the HAS assesses the CAV on a 5-point scale ranging from I (Major) to V (absence of clinical added value). This assessment is primarily based on medical evidence. The CAV score is one of the factors contributing to price negotiations between the French ministry and pharmaceutical companies. Methods: A retrospective and descriptive study analysis of all indications in oncology (hematology and solid tumors), excluding accelerated approvals for innovative treatments, was conducted by the HAS comparing the 2010-2015 and 2016-2022 periods. For each assessment, information relative to the level of evidence and the clinical effect of the drug from the HAS opinion were collected and focused on the study’s conclusive endpoints and design. Results: The global distribution of CAV score between the two studied periods (2010-2015 and 2016-2022) was similar. However, the distribution of CAV score based on study design differed between the two periods. Regarding non comparative studies, the proportion of indications that were attributed a CAV score V increased 1.7 times between 2010-2015 and 2016-2022 and those with a CAV score I-III was nearly divided by 3. Differences were equally observed for the distribution of CAV score between the two periods based on the conclusive endpoints in the pivotal study. For the studies with a conclusive endpoint on overall survival, the rate of CAV I-III was multiplied by 1.68 (an increase from 6 to 36 cases). Concerning the cases with a progression-free survival endpoint, an observed increase of 1.3 times was noted for the CAV I-III. Lastly, studies with a conclusive overall response rate (ORR) saw an increase of 1.4 times for the CAV V as well as a decrease of 0.76 times for the CAV I-III. Over the most recent period (2016-2022), the conclusive endpoints identified in the evaluated studies were predominantly the overall response rate (93%, n = 42/45) for phase II studies. For phase III studies, progression-free survival and overall survival were respectively identified in 45% and 30% of the cases. Conclusions: Thisstudy shows that the number of indications evaluated has increased and that the assessment of the CAV is closely correlated with the choices of the study design (comparative or not) and the primary endpoint (clinically relevant or not). However, other elements underpin and qualify its valuation such as the medical need. These elements are reviewed in the HAS Guidance which emphasises overall survival as a primary endpoint and comparative data.

A randomised phase 2 study of liposomal irinotecan in combination with 5-fluorouracil/leucovorin and oxalipalatin versus nab-paclitaxel plus gemcitabine in unresectable locally advanced or metastatic pancreatic cancer.

4141 Background: FOLFIRINOX remained as first-line standard of care. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery. Liposomal irinotecan (HE072) is a liposomal formulation that encapsulates irinotecan in a lipid bilayer vesicle, as a generic drug, had been approved for marketing in China on September 15, 2022, and was used in combination with 5-fluorouracil (5-FU) and leucovorin for patients with metastatic pancreatic cancer who progressed after receiving gemcitabine treatment. This study aims to compare with nab-paclitaxel+gemcitabine (AG), which is another first-line stand of care, through substitute HE072 for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective delivery. Methods: HE072-CSP-004 was a randomised, open-label, multi-center, phase 2 study. Patients with unresectable locally advanced or metastatic pancreatic cancer were randomly assigned (2:1) to receive NALIRIFOX (HE072 50 mg/m², oxaliplatin 60 mg/m², leucovorin 400 mg/m², and fluorouracil 2400 mg/m², administered sequentially as a continuous intravenous infusion over 46 h) on days 1 and 15 of a 28-day cycle or AG (nab-paclitaxel 125 mg/m² and gemcitabine 1000 mg/m²), administered intravenously, on days 1, 8, and 15 of a 28-day cycle. Other key eligibility criteria include ECOG performance status of 0 to 1, untreated with systematic anti-tumor regimens; Primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), disease control rate (DCR), and duration of response (DOR). Results: As of Dec 12, 2023, 117 patients were randomly assigned (NALIRIFOX, 78; AG, 39). The two groups were comparable on baseline characteristics. The median PFS differences was statistically significant as 7.6 months (95%CI 5.49-9.17) with NALIRIFOX versus 3.7 months (95%CI 3.15-5.06) with AG (hazard ratio 0.55; 95% CI 0.34-0.87; p=0.0104). Median OS was 13.4 months (95%CI 9.89-NE) with NALIRIFOX versus 8.8 months (95%CI 6.87-12.16) with AG (hazard ratio 0.66; 95% CI 0.39-1.11; p=0.1125). Grade 3 or higher treatment-emergent adverse events (TRAE) occurred in 52 (66.7%) of 78 patients receiving NALIRIFOX and 30 (76.9%) of 39 patients receiving AG. No new safety signal was observed. Conclusions: The study met the primary endpoint of PFS demonstrating statistically significant and clinically meaningful improvements in PFS and with a trend of OS benefit for NALIRIFOX over AG. The safety profile was consistent with the known risks of the individual toxicity. This study is consistent with the existing NAPOLI 3 study. Clinical trial information: NCT05047991 .

Sacituzumab tirumotecan (SKB264/MK-2870) in patients (pts) with previously treated locally recurrent or metastatic triple-negative breast cancer (TNBC): Results from the phase III OptiTROP-Breast01 study.

104 Background: TROP2 (trophoblast cell surface antigen 2) is highly expressed in TNBC and is associated with worse survival. Sacituzumab tirumotecan (SKB264/MK-2870) is a TROP2 ADC developed with a novel linker to conjugate the payload, a belotecan-derivative topoisomerase I inhibitor with a drug-to-antibody-ratio (DAR) of 7.4. The hydrolytically linker permits both extracellular pH-sensitive cleavage and intracellular enzymatic cleavage to release the membrane permeable payload enabling the “bystander effect”. Here, we report the results from a phase Ⅲ study of sacituzumab tirumotecan in pts with advanced TNBC (OptiTROP-Breast01, NCT05347134). Methods: In this randomized phase Ⅲ trial, SKB264 was compared with physician's choice of chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in pts with locally recurrent or metastatic TNBC who had received two or more prior therapies including at least one for metastatic setting. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). The TROP2 expression was determined by immunohistochemistry (IHC) using the semi-quantitative H-score method. Results: Pts were randomly assigned to receive SKB264 (n = 130) or chemotherapy (n = 133). The median age was 51 years; 87% had visceral metastases; 26% received prior PD-1/PD-L1 inhibitors; 48% received three or more prior lines of chemotherapy for advanced disease. The primary endpoint of PFS was met based on interim analysis (data cutoff: Jun 21, 2023) with a 69% reduction in risk of progression or death (HR 0.31; 95% CI, 0.22 to 0.45; P &lt;0.00001). The median PFS assessed by BICR was 5.7 months (95% CI, 4.3 to 7.2) with SKB264 and 2.3 months (95% CI, 1.6 to 2.7) with chemotherapy; PFS at 6 months was 43.4% vs 11.1%. In the subset of pts with TROP2 H-score &gt; 200, the median PFS was 5.8 months with SKB264 and 1.9 months with chemotherapy (HR 0.28; 95% CI, 0.17 to 0.48). At the first planned interim analysis for overall survival (OS) (data cutoff: Nov 30, 2023) with median follow-up of 10.4 months, OS was statistically significant in favor of SKB264 (HR 0.53; 95% CI, 0.36 to 0.78; P =0.0005); the median OS was not reached (95% CI, 11.2 to NE) with SKB264 and 9.4 months (95% CI, 8.5 to 11.7) with chemotherapy. The objective response rate assessed by BICR was 43.8% with SKB264 and 12.8% with chemotherapy. Most common grade ≥ 3 treatment-related adverse events (SKB264 vs chemotherapy) were neutrophil count decreased (32.3% vs 47.0%), anemia (27.7% vs 6.1%) and white blood cell count decreased (25.4% vs 36.4%). Conclusions: Sacituzumab tirumotecan monotherapy demonstrated statistically significant and clinically meaningful PFS and OS benefit over chemotherapy, with a manageable safety profile in pts with heavily pretreated advanced TNBC and limited treatment options. Clinical trial information: NCT05347134 .

A phase 2, single arm, European multi-center trial evaluating the efficacy of afatinib as first line or later line treatment in advanced chordoma.

11517 Background: EGFR and Her2 overexpression in chordoma is well known, and chordoma cell-lines and mouse models were proven to be sensitive to EGFR inhibitor afatinib. This phase 2, single arm, European multi-center trial was designed to evaluate the efficacy of afatinib as first- or later-line tyrosine kinase inhibitor (TKI) treatment in advanced chordoma. Here we report efficacy and safety data. Methods: Eligible patients (pts) had locally advanced or metastatic, pathologically proven, EGFR expressing chordoma, not amenable for local therapies, with confirmed measurable and progressive lesions according to RECIST1.1. Pts were treated with afatinib 40mg/day in a 4 week cycle until disease progression (PD), unacceptable toxicity or withdrawal. Radiological tumor response assessment was performed every 3 cycles. The primary endpoint was response defined as progression free survival (PFS) rate ≥12 months (mos) for first-line cohort 1 and ≥ 9 mos for further-line treatment cohort 2, and change from baseline in EORTC QLQ- C30 and Brief pain inventory (BPI) questionnaires. Pts were enrolled using a Simon’s two-stage design, enrolling 13 patients in stage one, ≥3 patients with a PFS ≥ 12 or 9 mos were needed to enter stage two, where 43 pts total were to be enrolled, and ≥13 free from progression at 9 or 12 mos were required to meet the primary endpoint for success. Results: From Jun 2018 to Oct 2022, 47 pts were included. Four were ineligible for efficacy analysis (1 withdrawal, 3 stopped due to toxicity before first radiological evaluation). 34 entered cohort 1, 13 cohort 2. 31 (66.0%) were men, median age was 53 (range 28-85) years. 16 (34.0%) pts received prior systemic therapy (3 chemotherapy, 13 TKI, 2 immunotherapy, 2 other). The PFS rate at 12 mos was 40.0% in cohort 1 (12/30 pts), and 38.5% in cohort 2 (5/13 pts). Overall median PFS was 8.6 mos (95% CI 5.6-13.6); 9.1 mos (95% CI 5.8-16.6) in cohort 1 and 7.1 mos (95% CI 2.8-16.5) in cohort 2. Two pts remained on treatment at time of analysis. Best objective response by RECIST 1.1 was partial response in 4 pts (9.3%), stable disease in 33 (76.7%), PD in 5 pts (11.6%) and 1 (2.3%) unknown due to clinical progression. Median follow-up time was 23.7 mos (interquartile range 11.0-21.2). 16/47 pts (30.4%) experienced grade ≥3 adverse events (AEs). No grade 5 AEs related to afatinib were reported. Most common grade 3-4 afatinib-related AEs were skin toxicity (10.6% of pts), diarrhea (10.6%), mucositis (6.4%), hypertension (4.3%). Dose reduction was needed in 20/47 (42.6%) pts, and at least one dose interruption was needed in 31/47 (66.0%) pts. Conclusions: With a PFS rate at 12 mos of 40.0% in the first-line cohort and 38.5% at 9 mos in the further-line cohort, this phase 2 study met the PFS endpoint. QoLQ data will be provided at the conference . Partial response by RECIST was seen in 4/43 pts. Toxicity and dose reductions were relevant but manageable in most pts. Clinical trial information: NCT03083678 .

Enfortumab vedotin (EV) with pembrolizumab (P) versus chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Analysis of cisplatin (cis)-eligible population from EV-302/KEYNOTE-A39.

4562 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, randomized, open-label, global study comparing EV+P with platinum-based chemo (PBC) for first-line (1L) treatment (tx) of patients (pts) with la/mUC regardless of cis eligibility. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with PBC for the dual primary endpoints of progression-free survival (PFS) (hazard ratio [HR]: 0.45; P&lt;0.00001) and overall survival (OS) (HR: 0.47; P&lt;0.00001) in the overall pt population (Powles ESMO 2023), reducing the risk of progression and/or death by more than 50%. EV+P was FDA-approved in Dec 2023 for tx of adults with la/mUC. As cis eligibility status has long defined 1L tx, here we present results for pts who were eligible for cis at randomization. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg IV; Days 1 and 8) and P (200 mg IV; Day 1) or PBC (gemcitabine with cis or carboplatin). Select secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and safety. Pts were deemed eligible/ineligible for cis by protocol-defined criteria and were stratified accordingly. Results: 478 pts (EV+P: 244, PBC: 234) were cis-eligible at randomization. 220 (94.0%) pts in the PBC arm received cis at Cycle 1. mPFS was 14.6 mo for EV+P; 6.5 mo for PBC (HR: 0.48, 95% CI, 0.38, 0.62). mOS was 31.5 mo for EV+P; 18.4 mo for PBC (HR: 0.53, 95% CI, 0.39, 0.72). ORR for EV+P was 70.8% with 32.5% complete response (CR) rate; mDOR (95% CI) was not reached (18.2 mo, NR). ORR for PBC was 53.0% with 15.5% CR rate; mDOR (95% CI) was 8.3 mo (5.9, 10.9). In EV+P arm, 82 pts (33.6%) remained on tx at data cutoff (DCO). 85 pts (34.8%) received subsequent therapy. 72 pts (29.5%) received any platinum-based therapy as first subsequent therapy; 43 pts (17.6%) received cis. In PBC arm, all pts were off study tx at DCO. 146 pts (62.4%) received any PD-1/L1 therapy following PBC. 83 pts received maintenance avelumab; 59 pts received PD-1/L1 therapy as 2L tx. Grade ≥3 TRAEs occurred in 53.9% of pts with EV+P and 62.7% of pts with PBC. Most common grade ≥3 TRAEs of special interest for EV were skin reactions (14.8%), hyperglycemia (7.8%), and peripheral neuropathy (5.8%). Most common grade ≥3 tx-emergent AEs of special interest for P were severe skin reactions (9.5%), pneumonitis (4.9%), and colitis (2.9%). Conclusions: EV+P improved clinical outcomes in pts who were eligible for cis with previously untreated la/mUC, reducing the risk of death by 47% compared with PBC. Results were consistent with the overall population. The AE profile of EV+P was generally manageable with no new safety signals. The results of EV-302 support EV+P as a new SOC for la/mUC, including pts who are eligible for cis. Clinical trial information: NCT04223856 .

OPERA-01: A randomized, open-label, phase 3 study of palazestrant (OP-1250) vs standard-of-care for ER+, HER2- advanced or metastatic breast cancer patients after endocrine therapy and CDK4/6 inhibitors.

TPS1135 Background: In estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC), endocrine therapy (ET) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard-of-care (SOC) treatment in the first-line setting. However, patients develop resistance, most commonly due to acquired mutations in ESR1. Efficacy of available ET post CDK4/6i treatment is limited. Therefore, a significant unmet need exists for patients with ET-CDKi-resistant ER+, HER2– MBC to improve outcomes and delay time to chemotherapy. Palazestrant is an oral small molecule complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds ER and completely blocks ER-driven transcriptional activity, irrespective of ESR1 mutation status. In a phase 1/2 monotherapy study in heavily pretreated patients with ER+, HER2– advanced or MBC (NCT04505826), palazestrant showed a tolerable safety profile, favorable pharmacokinetics and encouraging antitumor efficacy in patients with and without ESR1 mutation at the recommended Phase 2 dose of 120 mg once a day (qd) (1). Methods: OPERA-01 (NCT06016738) is a multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to SOC ET (fulvestrant, anastrozole, letrozole, or exemestane) in patients with ER+, HER2– MBC that relapsed or progressed on 1-2 prior lines of ET, including a CDK4/6i. Eligible patients are adults who have a confirmed diagnosis of evaluable ER+, HER2– inoperable locally advanced or MBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior treatments must include 1-2 prior lines of ET, last ET duration for ≥6 months; must have received CDK4/6i with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC. No prior chemotherapy in the metastatic setting is permitted. In the dose selection part of the study, 120 patients are randomized to 90 mg qd or 120 mg qd palazestrant or SOC monotherapy. The dose selection will be conducted when 80 patients in both palazestrant arms have had an opportunity to be on treatment for16 weeks. Overall, 510 patients, including patients from the dose selection part, will be randomized to palazestrant or SOC ET. The primary endpoint of progression-free survival will be assessed by blinded independent central review in patients with and without ESR1mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in patients with and without ESR1mutations. The study started recruitment in November 2023. 1. Lin et al. ESMO 2023 MO382. Clinical trial information: NCT06016738 .

Abstract PO1-05-12: Pooled clinical trial data analyses comparing the biology of HER2-low vs HER2-0 breast cancer in patients with metastatic breast cancer following treatment with standard single agent chemotherapy

Abstract Background: Prior analyses of observational data suggest that for patients with metastatic breast cancer (MBC), tumor biology does not vary by HER2-low vs. HER2-0 expression given similar overall survival (OS) times after accounting for patients’ clinicopathologic features including hormone receptor (HR) status. We sought to evaluate potential differential biology by HER2-low status by (1) studying data pertaining to patients treated in historic clinical trials (i.e., data collected to measure associations between protocol defined treatments and outcomes) and (2) evaluating the endpoint of progression-free survival (PFS) in addition to OS following treatment with standard single agent chemotherapy for MBC. Methods: Pooling anonymized clinical trial data from studies within the Medidata Enterprise Data Store, we identified 142 women with HER2-negative MBC who received treatment with an NCCN recommended single agent chemotherapy in the context of a clinical trial. Using patient-level immunohistochemistry (IHC) results, we categorized patients as either HER2-low (IHC 1+/2+ and not amplified by in situ hybridization) or HER2-0 (IHC 0). We compared patients’ baseline demographic and clinicopathologic features according to HER2-low vs HER2-0 status. We used Cox proportional-hazard models stratified by HR status to estimate OS and PFS according to HER2-low vs HER2-0 classification while adjusting for patients' baseline demographic and clinicopathologic attributes. Results: Patients with HER2-low disease represented 20% (28/142) of the HER2-negative cohort. Twenty-five percent (7/28) of HER2-low patients had tumors that expressed hormone receptors compared with 17% (19/114) of HER2-0 patients (p=0.31). In this cohort, the maximum follow up time was 38.4 months. For HER2-low patients vs HER2-0 patients, the median OS was 10.7 vs. 12.7 months (p=0.37), and the median PFS was 3.5 vs. 2.9 months (log rank test, p=0.53) respectively. In Cox proportional-hazard models that adjusted for patient demographic and clinicopathologic features and were stratified by HR status, patients with HER2-low tumors had an 16% elevated (non-significant) hazard of death compared with patients with HER2-0 tumors (HR 1.16, 95% CI: 0.69-1.95) and a 22% reduced (non-significant) hazard of progression or death (HR 0.78, 95% CI: 0.45-1.35). Conclusions: Analyses of pooled historic clinical trial data pertaining to women with HER2-negative MBC who were treated with single agent chemotherapy revealed no meaningful clinical differences in either OS or PFS endpoints according to HER2-negative subtypes (i.e., HER2-low vs. HER2-0) after accounting for patient demographic and clinicopathologic features. These results support prior findings from observational research suggesting that there are no biological differences associated with HER2-negative subtypes. Table. Multivariable Cox Proportional Hazards Models for OS and PFS Stratified by Hormone Receptor Status, (N=134) Variable OS PFS HR* 95% CI HR* 95% CI Age (decade) 0.84 0.70-1.01 0.86 0.72-1.01 Race White 1.00 (referent) 1.00 (referent) Black 1.75 0.84-3.63 1.57 0.66-3.73 Asian 0.93 0.47-1.80 1.33 0.71-2.51 Other 1.69 0.45-6.38 2.10 0.62-7.15 Ethnicity Non-Hispanic or Latino 1.00 (referent) 1.00 (referent) Hispanic or Latino 2.10 0.95-4.64 1.02 0.44-2.35 HER2 Characterization HER2-0 1.00 (referent) 1.00 (referent) HER2-1+/2+ 1.16 0.69-1.95 0.78 0.45-1.35 Prior Lines of Chemotherapy for Metastatic Disease 0 1.00 (referent) 1.00 (referent) 1 0.82 0.46-1.46 1.13 0.65-1.95 2 0.69 0.35-1.36 1.00 0.52-1.93 3 0.59 0.10-3.42 2.18 0.45-10.50 ECOG Performance Status 0 1.00 (referent) 1.00 (referent) 1 1.65 1.07-2.54 1.57 1.02-2.43 Legend: OS=overall survival; PFS=progression-free survival; HR=hazard ratio; HER2=human epidermal group factor receptor 2; ECOG=Eastern Cooperative Oncology Group. *Analyses adjusted for clinical trial membership (coefficients not reported) Citation Format: Elizabeth Lamont, Emily Stein, Paolo Tarantino, Sara Tolaney, Corinne Ahlberg, Krishna Chinnathambu, Jiezhi Qi, Kala Tummagunta, Jackie Bilan, Ruthanna Davi, Lisa Ensign. Pooled clinical trial data analyses comparing the biology of HER2-low vs HER2-0 breast cancer in patients with metastatic breast cancer following treatment with standard single agent chemotherapy [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 PO1-05-12.

Abstract PO4-27-06: Design of Active Phase 3 ENABLAR-2 Study Evaluating Enobosarm +/- Abemaciclib in Patients with AR+ER+HER2- 2nd-Line Metastatic Breast Cancer Following Tumor Progression on an Estrogen Blocking Agent Plus Palbociclib or Ribociclib

Abstract Background: Targeting the androgen receptor (AR) with an oral selective agonist, enobosarm, is a novel approach to overcome ER and CDK4/6 resistance to suppress metastatic breast cancer (mBC). Preclinical studies in CDK4/6 inhibitor and estrogen blocking agent resistant PDX mBC models demonstrated that enobosarm alone or in combination with another CDK 4/6 inhibitor suppressed PDX mBC growth. In a subgroup analysis from a Phase 2 study, enobosarm demonstrated efficacy in the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who had tumor progression on estrogen blocking agent and a CDK 4/6 inhibitor with a best overall response rate of 30% (2CRs and 1 PR). A Phase 3 ENABLAR-2 multi-center, open label, study evaluating enobosarm +/- abemaciclib is open and active for the treatment of HR+HER2- mBC. Methods: The two-staged Phase 3 ENABLAR-2, open-label, randomized, multicenter study is being conducted in AR+ER+ HER2- 2nd-line mBC who have progressed on estrogen blocking agent plus palbociclib or ribociclib. In the Stage 1 of the study (160 patients), five treatment arms will be assessed with the primary efficacy endpoint of ORR: enobosarm 9 mg QD, enobosarm 1 mg QD + abemaciclib, enobosarm 3 mg QD + abemaciclib, enobosarm 9 mg QD + abemaciclib, and an estrogen blocking agent, active control (a nonsteroidal AI, exemestane +/- everolimus, or SERD). Secondary efficacy endpoints include progression-free survival (PFS). In Stage 2 of the study, patients will be randomized to receive enobosarm +/- abemaciclib (based on outcome of ORR in Stage 1) or estrogen blocking agent, active control, with the primary endpoint of PFS and secondary efficacy endpoints including, ORR, CBR, OS, as well as changes in quality-of-life measurements (SPPB, EORTC-QLQ, body composition measured by DEXA). Randomization will be stratified by AR% nuclei staining and by line of treatment for metastatic disease. Subjects will receive study drug until disease progression is observed. Preliminary Results: To date, 3 patients have been treated with enobosarm 9 mg in combination with abemaciclib. The combination therapy was well tolerated with no new safety findings. There were no drug-drug interactions between enobosarm and abemaciclib. Two patients have achieved BOR of a partial response with up to 79% and 56% reduction in their target lesion recorded by local reads on day 224 post-treatment initiation (PTI). The third patient has achieved a stable disease and continues to receive treatment (on study 10+ months). Conclusions: Preliminary data of efficacy and safety of enobosarm in combination with abemaciclib are encouraging. The Phase 3 ENABLAR-2 study is underway to further evaluate enobosarm monotherapy or in abemaciclib combination therapy in 2nd-line metastatic breast cancer population. Clinical trial information: NCT05065411. Research Sponsor: Veru Inc Citation Format: Kristine Rinn, Hannah Linden, Lee Schwartzberg, Gary Barnette, Domingo Rodriguez, Itay Shalev, Mitchell Steiner, Adam Brufsky, Joyce O'Shaughnessy. Design of Active Phase 3 ENABLAR-2 Study Evaluating Enobosarm +/- Abemaciclib in Patients with AR+ER+HER2- 2nd-Line Metastatic Breast Cancer Following Tumor Progression on an Estrogen Blocking Agent Plus Palbociclib or Ribociclib [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 PO4-27-06.

Abstract PO2-06-11: A phase II randomized trial of gemcitabine plus cisplatin(GP) vs gemcitabine plus carboplatin (GC) as the first-line treatment for patients with metastatic triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive disease with limited treatment options and poor prognosis. Gemcitabine plus carboplatin (GC) is one of the classic chemotherapeutic regimens for patients with metastatic triple-negative breast cancer(mTNBC) and also a backbone regimen for chemoimmunotherapy, with a median progression-free survival (PFS) of 4.6 months in the first-line (O'Shaughnessy J, et al. J Clin Oncol 2014). Gemcitabine plus cisplatin (GP) has also demonstrated promising efficacy and safety in the first-line phase III trial of mTNBC, with a median PFS of 7.7 months (Hu XC, et al. Lancet Oncol 2015). To further investigate the superiority between carboplatin and cisplatin when combined with gemcitabine, a prospective phase II study was conducted to directly compare the efficacy and safety of GP with GC in the first-line treatment for patients with mTNBC (NCT02341911). Methods: Patients with untreated mTNBC were randomized 1:1 to receive gemcitabine (1250 mg/m2, D1,8) plus cisplatin (75 mg/m2, D1) or gemcitabine (1000mg/m2, D1,8) plus carboplatin (area under the curve 2 mg × min/mL, D1,8) every 21 days until disease progression or intolerable toxicity. The stratification factors included visceral metastasis (yes or no) and the number of metastatic sites (1, 2, or ≥3). The primary endpoint was PFS and secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. Results A total of 150 mTNBC patients were enrolled. After a median follow-up of 49.1 months (IQR 31.3-70.7), PFS events had been recorded in 55 (73.3%) of 75 patients in the GP group and 59 (78.7%) of 75 patients in the GC group. PFS was numerically longer in the GP group than in the GC group, though not significantly (median, 7.8 months [95% CI 7.2–8.4] vs. 6.9 months [95% CI 6.4–7.4]; HR, 0.93; 95% CI 0.64–1.34; P = 0.689; stratified HR, 0.84; 95% CI 0.58–1.23; P = 0.375). Median OS was 20.7 months (95%CI 17.9-23.5) in GP group and 20.9 months (95%CI 15.3-26.5) in GC group, HR, 1.13; 95% CI 0.77–1.67; P = 0.537; stratified HR, 1.03; 95% CI 0.70–1.52; P = 0.886). The ORR of GP and GC was 49.3% and 41.3% in the intent-to-treat population. Dose reduction occurred in 30(40.0%) patients in the GP group and 38 (50.7%) patients in the GC group. Grade 3 and 4 hematological AEs, including leucopenia, neutropenia, anemia, and thrombocytopenia were slightly higher in the GC group. Grade 3 and 4 non-hematological AEs, including nausea, vomiting, and hearing toxicity, were more common in the GP group. No treatment-related deaths were reported. Conclusions Cisplatin was not associated with a survival advantage over carboplatin when combined with gemcitabine as a first-line treatment for patients with mTNBC, though numerically longer PFS and higher ORR was observed. The safety profiles of the two combinations were different but the adverse events were manageable. Citation Format: Chengcheng Gong, Yannan Zhao, Leiping Wang, Jun Cao, Zhonghua Tao, Ting Li, Mingchuan Zhao, Haitao Miao, Juan Jin, Xichun Hu, Biyun Wang. A phase II randomized trial of gemcitabine plus cisplatin(GP) vs gemcitabine plus carboplatin (GC) as the first-line treatment for patients with metastatic triple-negative 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 PO2-06-11.

Abstract PO2-04-07: Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials

Abstract Background: The numerous but conflicting first-line treatment regimens for Her-2 positive advanced breast cancer necessitate a comprehensive evaluation to inform clinical decision-making. In this study, we conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions. Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts published by ASCO, SABCS. NMA was performed using R software, STATA and Review Manager 5.4 to calculate and analyze the primary endpoint progression free survival (PFS), as well as the secondary endpoints of overall survival (OS), objective response rate (ORR) and adverse events (AE) higher than grade 3. Results: Out of the 8,603 manuscripts retrieved, we included 30 RCTs involving 12,045 patients in our analysis. Regarding PFS, the combination of trastuzumab with TKI was more favorable than dual-target therapy (hazard ratio=0.54, 95% [CI]: 0.40–0.72), and combination chemotherapy was superior to monotherapy (HR=0.66, 0.53-0.83). It is important to note that the addition of anthracycline did not result in improved PFS (HR=1.27, 0.87-1.86). For the HR+HER2+ population, dual-target plus endocrine therapy was more effective than single-target plus endocrine therapy (HR=0.65, 0.53-0.80). Monotherapy combined with dual-target therapy significantly improved OS and ORR compared to monotherapy with single-target therapy (HR=0.69, 0.56-0.84; OR=1.89, 1.34-2.65). A comprehensive analysis of both PFS and AE higher than grade 3 indicated that monotherapy plus dual-target therapy struck a balanced approach between effectiveness and toxicity compared to other regimens. Conclusions: Monotherapy plus dual-target therapy remains the optimal choice among all first-line treatment options for advanced breast cancer. The combination of trastuzumab with TKI demonstrated a significant improvement in PFS, but further data are warranted to confirm the survival benefit. Figure 1. Network diagrams of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. Figure 2. Forest plot of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. (A): PFS of HER2+ for experimental arms. (B): PFS of HR+ and HER2+ for experimental arms. (C): OS of HER2+ for experimental arms. (D): ORR of HER2+ for experimental arms. (E): Adverse events higher than grade 3 of HER2+ for experimental arms. Figure 3. Each endpoint ranking for experimental arms. (SUCRA, surface under the cumulative ranking) (A): PFS ranking for experimental arms. (B): OS ranking for experimental arms. (C): ORR ranking for experimental arms. (D): Adverse events higher than grade 3 ranking for experimental arms. (E): Experimental arms ordered by their overall probability as the best treatment in terms of both efficacy and safety Citation Format: Junxiao Wang, Yushuai Yu, Jie Zhang, Chuangui Song. Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials [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 PO2-04-07.

Abstract GS02-01: Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01

Abstract Background: The global, phase 3 TROPION-Breast01 trial (NCT05104866) assessed the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) compared with investigator’s choice of chemotherapy (ICC) in patients (pts) with inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2‒) breast cancer (BC). Primary results were presented at ESMO 2023 (Bardia A, et al. Abstract LBA11). Here we report expanded data from TROPION-Breast01. Methods: Pts aged ≥18 years who had inoperable or metastatic HR+/HER2‒ BC, had disease progression on endocrine therapy (ET) and for whom ET was unsuitable, and had received 1‒2 prior lines of systemic chemotherapy (CT), were eligible. Pts were randomized 1:1 to Dato-DXd (6 mg/kg Q3W) or ICC (eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. The dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1, and overall survival (OS). Results: In total, 732 pts were randomized: 365 to the Dato-DXd arm and 367 to ICC. At data cut-off (Jul 17, 2023), 93/39 pts in the Dato-DXd/ICC groups were ongoing treatment. Pts receiving Dato-DXd had significantly improved PFS vs ICC (HR 0.63 [95% CI 0.52‒0.76]; p&amp;lt;0.0001). Hazard ratios for PFS favored Dato-DXd over ICC across prespecified pt subgroups, including prior lines of CT in the metastatic setting (1 vs 2), prior use of CDK4/6 inhibitor (≤12 months vs &amp;gt;12 months), prior use of endocrine therapy in the metastatic setting ( &amp;lt;6 months vs ≥6 months) and brain metastases (yes vs no). OS data were not mature at this data cut-off. In the Dato-DXd vs ICC arms, 192 (53%) vs 247 (67%) pts had received a subsequent therapy after study treatment discontinuation, including 15 (4%) vs 52 (14%) who received subsequent ADC therapy, and 165 (45%) vs 186 (51%) who received subsequent CT. Median time to first subsequent therapy was 8.2 months in the Dato-DXd arm vs 5.0 months in the ICC arm (HR 0.53 [95% CI 0.45–0.64). Overall, rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was less than half that with ICC. The secondary patient-reported outcome endpoints showed that time to deterioration in physical functioning, pain, and global health status/quality of life were delayed in the Dato-DXd arm compared with ICC. Conclusions: TROPION-Breast01 met its dual primary endpoint of PFS, demonstrating statistically significant and clinically meaningful improvement in PFS with Dato-DXd compared with ICC across all subgroups. Overall, the safety profile and QoL with Dato-DXd was favorable compared with ICC. These data support Dato-DXd as a potential new therapeutic option for pts with inoperable or metastatic HR+/HER2‒ BC who have received 1‒2 prior lines of CT. Citation Format: Aditya Bardia, Komal Jhaveri, Seock-Ah Im, Michelino De Laurentiis, Binghe Xu, Sonia Pernas, Giuliano Borges, David Cescon, Masaya Hattori, Yen-Shen Lu, Noelia Martínez-Jáñez, Erika Hamilton, Shusen Wang, Junji Tsurutani, Kevin Kalinsky, Lu Xu, Sabrina Khan, Neelima Denduluri, Hope Rugo, Barbara Pistilli. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01 [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 GS02-01.