2569 Background: Immune activation is important for survival in cancer. Eftilagimod alfa (E), an antigen-presenting cell (APC) activator, binds to a subset of MHC class II molecules on APCs to mediate lymphocyte, e.g. T cell (CD4/CD8), recruitment/activation. Clinical studies of E in combination with a PD-1 antagonist (P) or chemotherapy (C) have shown promising results in phase 2 studies, and E is currently investigated in a phase 3 study in combination with P and C in first-line NSCLC (NCT06726265). We present cumulative correlation studies of immune activation in blood after administration of E with clinical efficacy in late-stage cancer patients (pts). Methods: Five (5) studies with 569 pts were evaluated. 30 mg E in combination with either P (pembrolizumab IV at 200 mg q3w or 400 mg q6w or 2 mg/kg q3w) or C (paclitaxel 80 mg/m 2 day 1, 8, 15, q4w) was administered SC biweekly for 6 months (mo), then every 2-4 weeks for 6-18 mo in pts with late-stage metastatic NSCLC, HNSCC, melanoma, or breast cancer. Absolute lymphocyte count (ALC) was taken before dosing (day 1 per cycle). ALC response was pre-defined as a change ≥0.2 x 10 9 /L in ≤3 mo on study. Samples for gene expression profile (GEP) were taken pre-dose / 3 mo in a subset (N=111). IFN-g and CXCL10 were assessed pre-dose / after 1 st E admin in a subset (N=79). Clinical efficacy was assessed by iRECIST and survival. Results: Treatment with E led to a rapid (3 mo) and sustained (~12 mo) stat. sign. (p=0.03) ALC gain versus control arm. 54.4% of all pts treated with E were ALC responders (53.6% for E+P; 55.1% for E+C). In ALC responders with E, overall survival (OS) was significantly improved (see Table 1) compared to non ALC responders. Effects were observed irrespective of the combination partner, P or C, with a median increase of 6.8 or 5.2 mo, respectively. In pts treated with P or C alone (control), 40.4% were ALC responders but with no sign. median OS gain. Clinical responders (iPR or iCR as BOR) exhibited consistent upregulation of immune pathways associated with T-cell functions, NK cell functions and cytotoxicity during treatment in GEP analysis. These functions were not upregulated in non-responders. IFN-g and CXCL10 concentrations increased quickly (~8h) and significantly post-first E dosing compared to baseline and levels remained elevated until next E dosing. This effect with E was consistent with P or C. Conclusions: E leads to immediate and sustained ALC increase and TH1 type reaction, which is associated with clinical efficacy in combination with P or C. Treatment Effects Results E (N=408) ALC Responder with E 54.4% (N=222/408) Impact on survival: ALC responder vs. ALC non-responder Median OS+ 7.7 mo(23.4 vs.15.7 mo)HR=0.69; p=0.002 Control arm (N=161) ALC Responder in control arm 40.4% (N= 65/161) Impact on survival: ALC responder vs. ALC non-responder Median OS+2.9 mo(20.4 vs. 17.4 mo)HR=0.98; p=0.93

BACKGROUND:Modulating tumor-mediated immunosuppression with immunotherapies is an effective therapeutic approach for solid tumors. INCAGN01876 is a humanized IgG1 anti-glucocorticoid-induced tumor necrosis factor receptor (GITR) monoclonal antibody. This phase 1/2 trial evaluated INCAGN01876 plus nivolumab and/or ipilimumab for advanced malignancies. METHODS:In phase 1 (dose escalation), patients received various INCAGN01876 plus nivolumab and/or ipilimumab regimens. In phase 2 (dose expansion), patients with select tumors received INCAGN01876 plus ipilimumab (treatment group [TG] C2) or INCAGN01876 plus nivolumab (TGF). Primary endpoints: safety (phase 1), objective response rate (ORR; phase 2). RESULTS:Overall, 145 patients were enrolled: 51 and 94 in phases 1 and 2, respectively (TGC2, n = 8; TGF, n = 86 [squamous cell carcinoma of the head and neck, SCCHN, n = 46]). Four patients had dose-limiting toxicities; maximum tolerated dose was not reached; INCAGN01876 300 mg Q2W was selected as the recommended phase 2 dose based on safety with nivolumab and/or ipilimumab and safety and pharmacokinetic/pharmacodynamic monotherapy data from the INCAGN 1876-101 phase 1 study. INCAGN01876-related treatment-emergent adverse events (TEAEs) occurred in 62.8% of patients (most commonly pruritus, 16.6%); grade ≥3, 13.8%. Immune-related TEAEs occurred in 31.0% of patients (most frequently pruritus, 11.7%) most were (75.6%) grade 1/2 events. Antitumor activity was observed in TGF cohorts with SCCHN or cervical cancer (ORR 23.9% and 16.7%, respectively). CONCLUSION:INCAGN01876 plus nivolumab and/or ipilimumab was generally well tolerated, with a safety profile consistent with previous reports. This observation, along with encouraging antitumor activity in SCCHN and cervical cancer, supports development of INCAGN01876 combined with immune checkpoint inhibitors.

PURPOSE:This phase III (ClinicalTrials.gov identifier: NCT03665441) study evaluated eryaspase in combination with chemotherapy as second-line treatment in advanced pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS:TRYBECA-1 enrolled patients 18 years and older whose disease progressed on or after 1L chemotherapy. Patients were randomly assigned to eryaspase plus chemotherapy (gemcitabine/nab-paclitaxel or fluorouracil [5-FU], leucovorin [LV], and irinotecan/nanoliposomal irinotecan) or chemotherapy. Treatment was administered in a 4-week cycle for each of the following drugs until disease progression or unacceptable toxicity: eryaspase 100 U/kg intravenously on days 1 and 15; gemcitabine 1,000 mg/m2 and nab-paclitaxel 125 mg/m2 intravenously on days 1, 8 and 15; irinotecan 180 mg/m2 (or nanoliposomal irinotecan 70 mg/m2) intravenously on days 1 and 15; 5-FU 2,400 mg/m2 as one 46-hour infusion (with a bolus of 400 mg/m2); and LV 400 mg/m2 intravenously on days 1 and 15. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS:A total of 512 patients were randomly assigned (n = 255 for eryaspase and n = 257 for chemotherapy alone). Baseline characteristics were balanced between the two groups. There were 420 deaths, with a median OS of 7.5 months for eryaspase and chemotherapy versus 6.7 months for chemotherapy (hazard ratio [HR], 0.92 [95% CI, 0.76 to 1.11]; P = .374); the median PFS was 3.7 months versus 3.4 months (HR, 0.88 [95% CI, 0.73 to 1.07]; P = .196), and the ORR was 16.1% versus 12.5% (odds ratio, 1.35; [95% CI, 0.81 to 2.24]), respectively. Grade ≥3 adverse events (AEs) included neutropenia (25.4% v 20.3%), asthenia (16.9% v 13.8%), and anemia (17.3% v 12.2%) in the experimental versus control arms, respectively. CONCLUSION:The addition of eryaspase to chemotherapy did not improve OS, PFS, or ORR. AEs were generally consistent with previous reports of chemotherapy. These results do not support additional development of eryaspase in PDAC.

4501 Background: In the JAVELIN Bladder 100 phase 3 trial, avelumab 1L maintenance + best supportive care (BSC) significantly prolonged overall survival (OS) and progression-free survival (PFS) vs BSC alone in pts with aUC without progression following 1L platinum-based chemotherapy (PBC). The JAVELIN Bladder Medley phase 2 trial is investigating the combination of avelumab with other antitumor agents in this pt population to assess efficacy and safety vs avelumab maintenance monotherapy. SG is a Trop-2–directed antibody and topoisomerase inhibitor drug conjugate being investigated in solid tumors. Here we report an interim analysis of avelumab + SG vs avelumab monotherapy. Methods: Eligible pts had unresectable locally advanced or metastatic UC, ECOG performance status (PS) 0-1, and no disease progression after 4-6 cycles of 1L PBC. Pts were randomized 2:1 to avelumab + SG or avelumab monotherapy, stratified by presence of visceral metastases at start of 1L PBC. Primary endpoints were investigator-assessed PFS and safety; OS was a secondary endpoint. For PFS and OS analyses, data in the avelumab monotherapy arm were extended per protocol using propensity score-weighted JAVELIN Bladder 100 data. Results: At data cutoff (Sep 16, 2024), 38 of 74 pts (51.4%) in the avelumab + SG arm and 10 of 37 pts (27.0%) in the avelumab monotherapy arm were still receiving study treatment. In the avelumab + SG and avelumab monotherapy arms, respectively, median age was 70 and 67 years, 50.0% and 51.4% had visceral metastases at start of 1L PBC, and a lower proportion of pts in the avelumab + SG arm had ECOG PS of 1 (31.1% vs 54.1%). Median PFS was 11.17 months (95% CI, 7.43-not estimable [NE]) with avelumab + SG vs 3.75 months (95% CI, 3.32-6.77) with avelumab monotherapy (hazard ratio [HR], 0.49 [95% CI, 0.31-0.76]). OS data were immature at cutoff; median OS was not reached (95% CI, 15.51-NE) in the avelumab + SG arm vs 23.75 months (95% CI, 18.79-30.82) in the avelumab monotherapy arm (HR, 0.79 [95% CI, 0.42-1.50]). In the avelumab + SG and avelumab monotherapy arms, respectively, treatment-related adverse events (TRAEs) of any grade occurred in 71 (97.3%) vs 23 pts (63.9%), and were grade ≥3 in 51 (69.9%) vs 0 pts. TRAEs led to discontinuation of both avelumab + SG in 4.1% (SG only in 12.3%) vs avelumab monotherapy in 2.8%. One pt in the avelumab + SG arm had a SG-related AE that led to death (acute subarachnoid hemorrhage in the setting of sepsis and pancytopenia). Conclusions: In pts with aUC without progression after 1L PBC, avelumab + SG as maintenance treatment improved PFS vs avelumab monotherapy. TRAEs were more frequent in the combination arm and were consistent with the known safety profile of SG and avelumab. Further investigation of avelumab in combination with anti–Trop-2 antibody-drug conjugates in aUC is warranted. Clinical trial information: NCT05327530 .

Background Second-line treatment options for persistent, recurrent or metastatic (r/m) cervical cancer are limited. We investigated the safety, efficacy, and immunogenicity of the therapeutic DNA-based vaccine VB10.16 combined with the immune checkpoint inhibitor atezolizumab in patients with human papillomavirus (HPV)16-positive r/m cervical cancer.Patients and methods This multicenter, single-arm, phase 2a study (NCT04405349, registered 26 May 2020) enrolled adult patients with persistent, r/m HPV16-positive cervical cancer. Patients received 3 mg VB10.16 (every 3 weeks (Q3W) for 12 weeks, hereafter every 6 weeks) combined with 1,200 mg atezolizumab (Q3W) for 48 weeks in total with a 12-month follow-up. The primary endpoints were incidence and severity of adverse events (AEs) and objective response rate (ORR; Response Evaluation Criteria in Solid Tumor V.1.1). ORR was assessed in the efficacy population, being all response-evaluable patients who received any administration of VB10.16 and atezolizumab and had at least one post-baseline imaging assessment.Results Between June 16, 2020, and January 25, 2022, 52 patients received at least one administration of study treatment. Of these, 47 patients had a minimum of one post-baseline tumor assessment. The median follow-up time for survival was 11.7 months. AEs related to VB10.16 were non-serious and mainly mild injection site reactions (9 of 52 patients). There were no signs of new toxicities other than what was already described with atezolizumab. ORR was 19.1% (95% CI 9.1% to 33.3%). Median duration of response was not reached (n.r.) (95% CI 2.2 to n.r.), median progression-free survival was 4.1 months (95% CI 2.1 to 6.2), and median overall survival was 21.3 months (95% CI 8.5 to n.r.). In programmed death-ligand 1 (PD-L1)-positive patients (n=24), ORR was 29.2% (95% CI 12.6 to 51.1). HPV16-specific T-cell responses were analyzed in 36 of 47 patients with an increase observed in 22/36 (61%).Conclusions The therapeutic DNA-based vaccine VB10.16 combined with atezolizumab was safe and well tolerated showing a promising clinically meaningful efficacy with durable responses in patients with persistent, r/m HPV16-positive cervical cancer, especially if PD-L1-positive.

5538 Background: Therapeutic cancer vaccines combined with immune checkpoint inhibitors offer a promising strategy to enhance anti-tumor responses. We recently demonstrated the safety and clinical efficacy of VB10.16, a DNA-based therapeutic cancer vaccine encoding HPV16 E6/E7 oncoproteins fused to CCL3L1 for antigen-presenting cell targeting, in HPV16-positive persistent, recurrent or metastatic cervical cancer 1 . This analysis explores the association between HPV16-specific T cell responses, tumor microenvironment (TME) characteristics, and clinical outcomes in the phase 2a trial. Methods: In this multicenter, open-label trial, 52 patients with advanced HPV16-positive cervical cancer received VB10.16 (3 mg intramuscularly) combined with atezolizumab (1200 mg intravenously) for up to 48 weeks. Primary endpoints were safety and objective response rate per RECIST v1.1. Secondary endpoints included overall survival (OS) and HPV16-specific T cell responses via IFN-γ ELISpot (n=36). Predefined exploratory endpoints included systemic immunosuppression and TME inflammatory status in baseline tumors, assessed via myeloid cell counts (baseline to ~week 9, n=47), flow cytometry (T cell/myeloid-derived suppressor cells [MDSC] ratio, n=21), and gene expression analyses (n=29). Results: Patients with reduced on-treatment systemic immunosuppression demonstrated stronger HPV16-specific T cell responses than patients without (myeloid cell counts decreased in 17/47 patients; T cell/MDSC ratio increased in 12/21 patients). On-treatment reduction in systemic immunosuppression was associated with a higher clinical benefit rate (complete response [CR]/partial response [PR]/stable disease [SD] in 17/28 vs 4/19 patients by myeloid counts and 10/12 vs 2/9 by T cell/MDSC ratio), suggesting associations between T cell response, systemic immunosuppression and effect of immunotherapies. Among the 9 responders in the efficacy population (n=47; 3 CR; 6.4% and 6 PR; 12.8%), 5 patients had available gene expression data from baseline tumors. Patients with pro-inflammatory/proliferative TME signatures demonstrated higher CR/PR rates (4/14 vs. 1/15) and longer OS compared to patients with stromal/immunosuppressive signaling (mOS not reached vs 8.3 months). Clinical benefit was also observed in stromal/immunosuppressive TMEs (1/15 CR, 6/15 SD), highlighting VB10.16’s potential to overcome local immunosuppression. Conclusions: VB10.16 combined with atezolizumab induces durable responses, mitigates local and systemic immunosuppression, and demonstrates synergy between biomarkers and clinical outcomes. High CR/PR rates with favorable immune and TME characteristics highlight the promise of this combination therapy, warranting further exploration. 1 Hillemanns P et al , 2025 doi:10.1136/jitc-2024-010827. Clinical trial information: NCT04405349 .

TPS1125 Background: Eftilagimod alpha (efti), a soluble LAG-3 protein, acts as an MHC class II agonist that enhances immunity by mediating antigen presenting cell and CD8 T-cell activation. Data from a randomized, phase 2b trial of efti plus paclitaxel compared to placebo plus paclitaxel in patients (pts) with HR+ HER2– metastatic breast cancer (MBC) (AIPAC; NCT02614833) showed sustained pharmacodynamic activity that was linked to improved overall survival (OS) in the efti arm. AIPAC-003 is a randomized, double-blind, placebo-controlled phase 3 trial testing efti plus paclitaxel in HER2-neg/low MBC pts, following an initial open-label dose optimization lead-in (DOL) component to determine the optimal biological dose (OBD) of efti in this combination. Methods: The DOL phase will determine the OBD of efti prior to start of the P3 part of the study. Enrolment for the DOL began in November 2023 with the aim to recruit 66 pts. Primary objectives in the DOL are: safety and tolerability of 90 mg vs 30 mg efti and defining the OBD of efti in combination with weekly paclitaxel. Determination of the OBD will be based on the totality of safety and tolerability data together with overall response rate (ORR) and pharmacodynamic marker (CD8+ T cells, absolute lymphocyte count) data. Secondary objectives in the DOL include efficacy, QoL and PK profile always of 30 mg efti vs. 90 mg on top of weekly paclitaxel. In the Phase 3 component pts will be randomized to receive either paclitaxel + efti or paclitaxel + placebo in a double-blinded fashion. The primary endpoint (EP) for the proposed Phase 3 is OS and the exact patient population will be defined after determination of the OBD. Key secondary EPs include progression free survival and ORR by RECIST 1.1, quality of life and safety. Pts will receive paclitaxel (80 mg/m2 I.V. on D1, 8 and 15 in a 4-week cycle), followed by efti or placebo (DOL: 30 or 90 mg efti; Phase 3: OBD of efti or placebo) S.C. on D1 and 15 in a 4-week cycle for up to 12 months. Imaging is done every 8 weeks and assessed by the investigator. in the DOL blood samples are taken from 0 to 96 hours in cycle 1 and 4 to determine PK / PD profiles. PK / PD parameters are assessed by a central lab. Key inclusion criteria: Pts with either a) HR+ and HER2-neg/low and endocrine therapy-resistant MBC or b) TNBC not eligible for anti-PD-1-based therapy. Pts must have measurable disease, ECOG PS 0-1 and no prior chemotherapy for metastatic disease. Key exclusion criteria: Pts if HR+ who are not considered endocrine resistant and/or have received < 1 line of therapy in the metastatic setting. Pts who are considered TNBC and are eligible for anti-PD-(L)1 containing therapy. Clinical trial information: NCT05747794 .

Background Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. Methods SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing. Findings Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 166 months (IQR 129-194) for the camizestrant 75 mg group, 163 months (129-183) for the camizestrant 150 mg group, and 147 months (127-201) for the fulvestrant 500 mg group. Median progression-free survival was 72 months (90% CI 37-109) with camizestrant 75 mg, 77 months (55-129) with camizestrant 150 mg, and 37 months (20-60) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 059 (90% CI 042-082; p=0017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 064 (046-089; p=00090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred. Interpretation Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor- positive, HER2-negative breast cancer.

PDF file - 1418K, Forest plot of the treatment effect of rilotumumab compared with placebo on OS by covariate subgroups in the intention-to-treat analysis set. ECOG, Eastern Cooperative Oncology Group; PD, progressive disease.

PDF file - 31K, Waterfall plot of the maximum change of PSA levels from baseline in patients who received rilotumumab (A) or placebo (B) in the intention-to-treat analysis set. A PSA response was defined as ≥50% decline in two consecutive PSA levels ≥3 weeks apart. Six patients in the rilotumumab group were omitted because post-baseline data were not available.

PDF file - 1076K, Kaplan-Meier plot of PFS by tumor MET subgroups in the combined rilotumumab and control arms (A) and forest plot of the biomarker effect of high versus low tumor MET expression on PFS within the combined rilotumumab and control arms (B). MP, mitoxantrone and prednisone; NA, not applicable.

PDF file - 28K, Kaplan-Meier plot of OS (A) and PFS (B) by tumor MET expression in all treatment arms combined.

PDF file - 28K, Waterfall plot of the maximum change in the sum of the longest diameters of tumors from baseline in patients with evaluable tumor response per investigator assessment who received rilotumumab (A) or placebo (B). Fifteen patients in the rilotumumab group and five patients in the placebo group were omitted because post-baseline data were not available. PD, progressive disease; SD, stable disease; UE, unevaluable.

Background Camizestrant (C), a next-generation oral selective estrogen receptor (ER) antagonist and degrader (ngSERD) has shown promising clinical activity in ER+ breast cancer (BC) in the Phase 1 SERENA-1 study1,2 with a dose-dependent safety profile. The Phase 2 randomized SERENA-2 study (NCT04214288) initially assessed three doses of C vs fulvestrant (F) in post-menopausal women with ER+ HER2˗ BC with disease recurrence or progression after ≤1 endocrine therapy (ET) in the advanced setting. Methods SERENA-2 evaluated efficacy and safety of C 75, 150 or 300 mg monotherapy QD vs F (per label). Eligible patients were randomized 1:1:1:1. The Primary objective was to determine clinical efficacy of C vs F by investigator-assessed progression-free survival (PFS). Secondary endpoints included objective response rate, response duration, clinical benefit rate at 24 weeks, overall survival and safety. Patients had no prior F or oral SERD and ≤1 ET and ≤1 chemotherapy (CTX) in the advanced setting. To assess the impact of prior CDK4/6 inhibitor (CDK4/6i) treatment, randomization was stratified so that 50% of patients had prior CDK4/6i. Planned enrolment of 288 patients began in April 2020. The C 300 arm was closed after 20 patients were enrolled, changing target enrolment to 236. By August 2021, 240 patients had been randomized. Primary analysis was triggered when 108 progression events (75% maturity) had occurred in the best performing pair (C vs F) in August 2022. Efficacy analyses compared C 75 and 150 mg doses with F, with no formal analyses of C 300 vs F. 108 events for pairwise comparison vs F gave 86% power at the 2-sided 10% significance level. Primary analyses used a Cox proportional hazards model to compare PFS, adjusting for prior CDK4/6i and lung/liver metastases. ESR1 mutations (ESR1m) were detected in plasma samples using next-generation sequencing. Results 119/240 (49.6%) patients had had prior CDK4/6i therapy. At baseline, 88 (36.7%) patients had detectable ESR1m and 140 (58.3%) had lung/liver metastases. Prior CTX or ET rates in the advanced setting were 19.2 and 65.4%. Treatment-emergent adverse events (AEs) (grade ≥3) occurred in 77.0 (12.2), 90.4 (21.9) and 68.5 (13.7) % of patients in the C 75, C 150 and F arms. AEs leading to treatment discontinuation occurred in 2.7, 0 and 0% of patients in the C 75, C 150 and F arms. The most common AEs considered by the investigator to be causally related to study drug were photopsia (18.4%) and (sinus) bradycardia (13.6%) – all were grade 1 or 2. Hot flush (2.7%) and myalgia (2.7%) were the most common AEs related to F. Conclusions SERENA-2 is the first Phase 2 trial investigating multiple dose levels of an ngSERD vs F in post-menopausal women with advanced ER+ HER2˗ BC with disease recurrence or progression after ≤1 ET in the advanced setting. C at both 75 and 150 mg dose levels showed a statistically significant and clinically meaningful benefit in PFS vs F in the overall study population, and was well tolerated. The results of SERENA-2 support the further development of C in ER+ HER2- BC. Acknowledgements AstraZeneca sponsored this trial and funded medical writing support from Helen Heffron (InterComm International). References 1. Baird R, Oliveira M, Ciruelos Gil EM, et al. SABCS 2020 Virtual Meeting. Abstract PS11-05; 2. Oliveira M, Hamilton EP, Incorvati J et al. ASCO 2022 Annual Meeting, Chicago, IL, USA. Abstract 1032. Citation Format: Mafalda Oliveira, Denys Pominchuck, Zbigniew Nowecki, Erika Hamilton, Yaroslav Kulyaba, Timur Andabekov, Yevhen Hotko, Tamar Melkadze, Gia Nemsadze, Patrick Neven, Yuriy Semegen, Vladmir Vladmirov, Claudio Zamagni, Hannelore Denys, Frederic Forget, Zsolt Horvath, Alfiya Nesterova, Maxine Bennett, Bistra Kirova, Teresa Klinowska, Justin Lindemann, Delphine Lissa, Alastair Mathewson, Christopher Morrow, Zuzana Traugottova, Ruaan Van Zyl, Ekaterine Arkania. GS3-02 Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-02.

PDF file - 54K, Drug exposure

Background: In patients (pts) with ER+/HER2− metastatic breast cancer (MBC) following progression on prior endocrine and CDK4/6i therapy, the EMERALD trial demonstrated significantly prolonged progression-free survival (PFS) and a manageable safety profile for elacestrant versus standard of care endocrine therapy (SoC). Benefit was observed in all pts and in pts with ESR1 mutant MBC (ESR1-mut). EMERALD is the only oral SERD monotherapy pivotal trial where all pts were pretreated with CDK4/6 inhibitor (CDK 4/6i). Here, we examine the impact of duration of prior CDK4/6i on PFS. Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled pts with ER+/HER2- MBC who previously had 1-2 lines of endocrine therapy, mandatory CDK4/6i, and ≤1 chemotherapy; prior treatment with fulvestrant was allowed. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SoC (investigator’s choice of aromatase inhibitor or fulvestrant). If randomized to the control arm, patients who received prior fulvestrant were to receive an aromatase inhibitor, and vice versa. If two CDK4/6i were used in the metastatic setting (n=40), the cumulative duration was calculated. Results: A total of 478 pts were randomized (228 with ESR1-mut) between Feb 2019 – Oct 2020 (n=239, elacestrant; n=239, SoC). Overall survival was not yet mature, as of September 2nd 2022. Updated PFS results show statistically significant results in favor of elacestrant, both in all pts and in pts with ESR1-mut. The duration of prior CDK4/6i in the metastatic setting was positively associated with PFS, the longer the duration of prior CDK4/6i in the metastatic setting (n=465), the longer the PFS on elacestrant versus SoC (Table 1). Updated safety data were consistent with previously reported results. Most of the adverse events (AEs), including nausea, were grade 1 and 2, and only 3.4% and 0.9% of the pts discontinued trial therapy because of an AE on elacestrant and SoC, respectively. A low percentage of pts received an antiemetic; 8.0%, 3.7%, and 10.3%, on elacestrant, fulvestrant, and AI, respectively. No hematological safety signal was observed and none of the patients in either of the two treatment arms had sinus bradycardia. Conclusions: EMERALD is the first phase 3 trial to demonstrate a significant PFS improvement versus SoC in all pts and in the subgroup with ESR1 mutations in pts with ER-positive/HER2-negative MBC with 1-2 prior lines of endocrine treatment ± one line of chemotherapy. Elacestrant demonstrated longer PFS versus SOC that was positively associated with the duration of prior treatment with CDK4/6i, which was more pronounced in pts with ESR1-mut MBC. In this 2nd and 3rd line setting, elacestrant was well tolerated with significantly longer PFS versus SoC, highlighting its potential role as a therapeutic option for pts with ER+/HER2- MBC. Table 1: PFS estimates in the elacestrant and SoC arms based on different cut-off points for the duration of prior CDK4/6i. Citation Format: Aditya Bardia, Francois-Clement Bidard, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frederic Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Donatienne Taylor, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, Jose Angel García-Sáenz, Emilio Bria, Marina Elena Cazzaniga, Philippe Aftimos, Javier Cortés, Giulia Tonini, Tarek Sahmoud, Nassir Habboubi, Krzysztof Grzegorzewski, Virginia Kaklamani. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-01.