BACKGROUND:We assessed long-term safety, efficacy, and health-related quality of life during the continuation phase after 3 years' follow-up in PHranceSCa (NCT03674112). PATIENTS AND METHODS:This was a randomized, open-label, international, multicenter, crossover, Phase II study in adjuvant HER2-positive early breast cancer. One hundred fifty nine patients received 3 cycles of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC), then 3 of intravenous pertuzumab and trastuzumab (P + H IV), or vice versa. Postcrossover, patients continued preferred treatment (≤ 18 cycles total). RESULTS:Most adverse events, including all cardiac events (n = 2) and anaphylaxis/hypersensitivity (n = 3) were grade 1/2. None were grade 4/5. Grade 1/2 local injection-site reactions occurred in 13 patients (9.4%) receiving PH FDC SC. Other events occurred at comparable rates between arms. The overall event-free rate for invasive disease-free survival was 94.17% (95% confidence interval, 90.47-97.87) at 3 years; overall survival was 98.71% (96.92-100). Meaningful changes from baseline in health-related quality of life included improvements in role and social functioning, and reductions in financial difficulty. CONCLUSION:PH FDC SC was well tolerated, with safety consistent with that of P + H IV (except local injection-site reactions) and no grade ≥ 3 anaphylaxis/hypersensitivity or new safety signals in the continuation period. Immature efficacy data showed high event-free rates, consistent with the known clinical benefit of pertuzumab and trastuzumab (although follow-up was relatively short at 3 years). PHranceSCa adds to the totality of evidence reinforcing the long-term clinical benefit and safety of pertuzumab and trastuzumab.

3087 Background: Tumor-targeted drug delivery technologies are urgently needed to overcome conventional chemotherapy’s lack of tumor selectivity. Alphalex conjugates, which contain a pH-low insertion peptide (pHLIP), a linker and a payload, are designed to overcome this lack of selectivity. Unlike antibody drug conjugates, alphalex PDCs target tumors in an antigen-agnostic manner. At pH ≥7.0, the peptide is unstructured. In the low-pH tumor microenvironment the peptide forms an alpha helix and inserts directionally into the tumor cell membrane delivering the linker and payload intracellularly where the linker is cleaved releasing the payload in the cytosol. CBX-12 consists of the pH-sensitive peptide, a self-immolating linker, and the topoisomerase 1 (TOP1) inhibitor exatecan. Methods: In this Phase 1 trial, cohorts of pts were treated with escalating doses of CBX-12 in a 3 + 3 design on three dosing schedules: daily x 5 every 3 weeks, daily x 3 every 3 weeks or once weekly. The primary objectives are safety, tolerability and to determine the MTD and/or RP2D. Secondary and exploratory objectives include evaluation of plasma PK of CBX-12 and exatecan, anti-tumor activity per RECIST v1.1, and measurement of anti-drug antibodies. Results: As of 26 Jan 2023, 42 pts have been treated on three schedules. The most frequent treatment-related AEs (TRAEs) were anaemia (42.9%), nausea (38.1%), fatigue (33.3%), ANC and WBC decreased (33.3% each), vomiting (26.2%), diarrhoea (23.8%) and thrombocytopenia (19.0%). The most frequent Gr3/4 TRAEs were ANC decreased (28.6%), anemia (23.8%), WBC decrease (16.7%), thrombocytopenia (14.3%). Dose limiting toxicity was observed in 6 pts: myelosuppression (6 pts) febrile neutropenia (2 pts), and sepsis (2 pts). Responses were observed in 2 of 9 pts with ovarian cancer and 2 of 8 with breast cancer. The MTD on the daily x 3 schedule is 45mg/m 2 . Dose evaluation continues on the weekly schedule. Conclusions: In this FIH study of a pH-targeting alphalex PDC, CBX-12 demonstrated single-agent antitumor activity including 4 responses with the dominant toxicity of myelosuppression. Phase 2 expansion cohorts are planned in pts with platinum-resistant ovarian cancer and hormone-receptor positive, HER2 negative breast cancer. Clinical trial information: NCT04902872 .

Background Tumor-associated macrophages (TAMs) are a major component of the immune infiltrate in most cancers and play a key role in establishing the immunosuppressive tumor microenvironment (TME) that enables tumor progression. However, TAMs are phenotypically plastic and have the potential to be reprogrammed into immunostimulatory cells that enhance innate and adaptive anti-tumor immunity. BDC-3042 is a novel agonistic antibody targeting an immune-activating receptor expressed on TAMs known as Dectin-2 (CLEC6A).1 Dectin-2 is a C-type lectin receptor best known for its role in pathogen recognition and induction of protective immune responses against fungi and other microbes. We have previously demonstrated that Dectin-2 agonism stimulates pro-inflammatory cytokine secretion and antigen presentation by TAMs, resulting in robust CD8+ T cell-mediated anti-tumor immunity in syngeneic mouse models.2 Differential gene expression of Dectin-2 has been found in a wide range of solid tumor-associated macrophages compared to non-malignant tissues. Nonclinical studies with BDC-3042 have demonstrated its potential to reprogram TAMs and elicit anti-tumor activity as a novel immunotherapeutic approach for diverse human cancers.2 A phase 1/2, four-part, first-in-human, dose-escalation and dose-expansion study of BDC-3042 as a single agent and in combination with pembrolizumab in subjects with advanced malignancies has been initiated. Methods This dose-escalation and dose-expansion study is enrolling approximately 185 subjects with advanced malignancies, including triple-negative breast cancer, renal cell carcinoma, colon cancer, head and neck cancer, non-small cell lung cancer, and ovarian cancer. Primary objectives of the dose-escalation phase are to define safety and tolerability and to determine the recommended phase 2 dose (RP2D) of BDC-3042 as a monotherapy (Part 1) and in combination with pembrolizumab (Part 2). Part 2 is planned to start once single agent BDC-3042 safety data are available. Part 1 will be the dose escalation. The dose-expansion phase of the study will evaluate preliminary anti-tumor activity of BDC-3042 monotherapy (Part 3) and in combination with pembrolizumab (Part 4). Secondary objectives will evaluate pharmacokinetic parameters and pharmacodynamic biomarkers in tumor tissue and in peripheral blood associated with drug exposure. Exploratory analyses will also be conducted to assess BDC-3042's ability to reprogram TAMs and identify biomarkers associated with BDC-3042 biological activity with and without pembrolizumab. This study is being conducted in the US and is currently recruiting patients. References Kenkel JA, F Xiao, PY Ho, JL Nolin, et al. 'Abstract 2964: Targeting tumor-associated macrophages to enhance anti-tumor immunity with the Dectin-2 agonistic antibody BDC-3042.' Cancer Research 2023;83(7_Supplement):2964. Kenkel J, P Ho, S Kongara, K Henning, et al. '862 Dectin-2, a novel target for tumor macrophage reprogramming in cancer immunotherapy.' Journal for ImmunoTherapy of Cancer 2021;9(Suppl 2):A903-A903. Ethics Approval Protocols, protocol amendments, and informed consents are approved by Institutional review boards or independent ethics committees of participating sites. The study will be conducted in compliance with the Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice. All patients will provide written informed consent.

Background Fibronectin (FN) is a ubiquitously expressed, high-molecular weight, extracellular matrix glycoprotein. The extra domain B splice variant of FN (EDB+FN) is a novel therapeutic target that is upregulated in the tumor microenvironment (TME) of multiple solid tumor types with restricted expression in normal tissues. PYX-201 is an investigational antibody drug conjugate consisting of a site-specific engineered EDB+FN-targeting monoclonal antibody conjugated to vc0101, which shows improved linker-payload stability and bystander activity in preclinical studies. The linker-payload vc0101 is completely synthetic and delivers auristatin PF-06380101 (Aur0101), a microtubule depolymerizing agent with potent anti-mitotic and cytotoxic properties. PYX-201 may have multiple mechanisms of action: promoting cell destruction by directly binding to EDB+FN, releasing payload into the TME and into nearby cancer cells, and potentiating immune cell infiltration upon release of the payload. PYX-201 has been shown to induce tumor regression in xenograft mouse models of non-small cell lung cancer (NSCLC) and pancreatic cancer. In a syngeneic model of breast cancer, a mouse analogue of PYX-201 induced upregulation of PD-L1 and infiltration of CD3+ T cells in tumors.1 Methods PYX-201 is being evaluated in a first-in-human, open-label, non-randomized, Phase 1 dose-escalation (Part 1) study in participants with advanced solid tumors. Part 1 utilizes a Bayesian optimal interval design to explore ascending doses of PYX-201 administered as an intravenous infusion to evaluate safety and efficacy and to identify the recommended Part 2 dose(s). The study is designed to characterize safety and pharmacokinetics and will incorporate a robust translational biomarker plan. Upon completion of Part 1 and depending upon data obtained, a Part 2 dose expansion part of the study may be initiated. The PYX-201–101 study began enrolling participants in February 2023 and will be conducted in the US and Europe. Adverse events are assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 and protocol-specific ophthalmic complications table. Tumor response is determined according to Response Evaluation Criteria in Solid Tumors 1.1 criteria and safety findings are reviewed by the dose escalation steering committee, which will monitor safety and recommends dose(s) for Part 2. The study population will include participants with NSCLC, hormone receptor positive breast cancer, triple negative breast cancer, head and neck squamous cell carcinoma, ovarian cancer, thyroid cancer, pancreatic ductal adenocarcinoma, soft tissue sarcoma, hepatocellular carcinoma, and kidney cancer. Trial Registration NCT05720117 Reference Hooper AT, Marquette K, Chang CP, Golas J, Jain S, Lam MH, Guffroy M, Leal M, Falahatpisheh H, Mathur D, Chen T. Anti-Extra Domain B Splice Variant of Fibronectin Antibody-Drug Conjugate Eliminates Tumors with Enhanced Efficacy When Combined with Checkpoint Blockade. Molecular Cancer Therapeutics. 2022 Sep 6;21(9):1462–72.

2531 Background: TST005 is a novel bi-functional fusion protein combining a high affinity PD-L1 mAb and a differentiated TGF-β trap with improved stability. In pre-clinical study, TST005 showed no antibody-dependent dependent cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) activity. Methods: This is a Phase 1, dose escalation study with classic 3+3 design to evaluate the safety, tolerability, PK and pharmacodynamic and preliminary anti-tumor activity of TST005 and determine the maximum tolerated dose and/or the Recommended Phase 2 Dose (RP2D). Eligible solid tumor patients who have failed prior standard therapy(ies) and have received no more than one prior immune checkpoint inhibitor (ICI) treatment will be enrolled to receive TST005 intravenous (IV) infusion every 3 weeks until disease progression assessed by the Investigator per RECIST v1.1 and/or immune RECIST, or unacceptable toxicity. Results: The study is ongoing at 4 clinical centers in US and China. As of 31 Jan 2023, 18 eligible subjects have been enrolled into different TST005 dose levels: 2 at dose of 1mg/kg, 4 at 3 mg/kg, 4 at 10 mg/kg, 3 at 20 mg/kg, and 5 at the last dose level of 30 mg/kg. The enrollment is still ongoing. No DLT was observed so far. The most common treatment-emergent adverse events (TEAEs) ( > 10%) included: fatigue (38.9%), rash (22.2%), anemia (16.7%), myalgia (16.7%), and arthralgia, dehydration diarrhea, dry skin, hematuria, hypokalemia, pruritus, lymphocyte count decreased were 11.1%. 7 patients (38.9%) experienced ≥Grade 3 (G3) TEAEs according to CTCAE V5.0, 1 of whom were considered as related to TST005: it was an infusion related reaction (G3), and caused discontinuation of treatment. Two subjects experienced IRRs (G2 and G3 respectively), both at the dose of 3mg/kg cohort. One subject of 30mg/kg dose cohort presented a squamous cell carcinoma of skin, which is known as a classic side effect of TGF-β directed therapies. The subject was discontinued from study and to receive resection. No treatment-related deaths occurred. TST005 demonstrated a nonlinear PK profile between 1 to 20 mg/kg with calculated t1/2 of 4-9 days. ADA was observed in most ADA evaluable subjects, PK at doses ≥ 10mg/kg were not impacted by ADA. At 20mg/kg, the receptor occupancy increased to > 90% immediately after infusion and remain at this level up to C2D1. Start from 1mg/kg, serum TGF-β1 was depleted immediately after dosing, sustained to next dose of TST005. 11 subjects had at least one post treatment tumor assessment per RECIST 1.1. 7 subjects (63.6%) had best overall response of SD. No PR or CR had been observed. Conclusions: TST005 monotherapy demonstrated a good safety and tolerability, nonlinear PK characteristics and significant target engagement in patients with advanced solid tumors. Continue investigation of TST005 as monotherapy or in combination with other therapies are warranted. Clinical trial information: NCT04958434 .

Supplementary Data from Trilaciclib Prior to Chemotherapy in Patients with Metastatic Triple-Negative Breast Cancer: Final Efficacy and Subgroup Analysis from a Randomized Phase II Study

TPS1114 Background: Targeted protein degradation (TPD) molecules have expanded the therapeutic options through their catalytic mechanism of action (MOA) and ability to degrade “undruggable” proteins. To increase the efficacy versus tolerability window of protein degradation and improve drug delivery, ORM-5029 uses a Dual-Precision TPD (TPD2) approach combining the catalytic mechanism of TPDs with the precision of tumor-targeting therapeutic antibodies. ORM-5029 is a first-in-class human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) comprised of SMol006, a highly potent GSPT1 degrader, conjugated to pertuzumab, a clinically validated antibody. HER2 is overexpressed in cancers such as breast, ovarian and gastric, and associated with early-onset aggressive disease. ORM-5029 is in development for treatment of HER2-expressing solid tumors. The MOA is mediated by targeted uptake of the ADC, release of the TPD payload, and cell death by GSPT1 degradation. ORM-5029 showed robust in vitro and in vivo efficacy in multiple HER2-expressing models with comparable activity to trastuzumab deruxtecan and strong activity in trastuzumab emtansine-refractory models. Methods: This phase 1 first-in-human study evaluates the safety, tolerability, and efficacy of ORM-5029 administered by intravenous infusion in patients (pts) with HER2-expressing advanced solid tumors (NCT05511844). The escalation, guided by the Bayesian Optimal Interval design, explores cohorts of ORM-5029 to identify the maximum tolerated dose (MTD) and/or expansion dose level (EDL). Each cohort will enroll ≥3 breast cancer pts with at least HER2 1+ (HER2 low) or greater by immunohistochemistry or positive by in situ hybridization. Expansion cohort A (HER2+ breast cancer) may enroll in parallel to escalation evaluating doses showing pharmacodynamic activity or efficacy. Up to 10 pts may be enrolled at each dose explored in cohort A. Enrollment into expansion cohort B (up to 21 pts) and cohort C (up to 22 pts) will begin once the EDL has been determined to further assess the safety, tolerability and efficacy of ORM-5029 using a Simon’s optimal 2-stage design. Cohort B will enroll pts with HER2+ breast cancer refractory or intolerant to standard treatment after ≥2 HER2 therapies in the metastatic setting. Cohort C will enroll pts with advanced solid tumors that are refractory or intolerable to standard treatment or for which no standard treatment is available, including HER2+ gastric or gastroesophageal junction adenocarcinoma or tumors with HER2 expression, amplification or mutations (e.g., colorectal, bile duct, ovarian, bladder, non-small cell lung). Study enrollment began in October 2022 in the United States. Escalation cohort 1 was completed without DLT; enrollment in cohort 2 began as of December 2022. Clinical trial information: NCT05511844 .

Abstract Purpose: We report final antitumor efficacy results from a phase II study of trilaciclib, an intravenous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, administered prior to gemcitabine plus carboplatin (GCb) in patients with metastatic triple-negative breast cancer (NCT02978716). Patients and Methods: Patients were randomized (1:1:1) to group 1 [GCb (days 1, 8); n = 34], group 2 [trilaciclib prior to GCb (days 1, 8); n = 33], or group 3 [trilaciclib (days 1, 8) and trilaciclib prior to GCb (days 2, 9); n = 35]. Subgroup analyses were performed according to CDK4/6 dependence, level of programmed death-ligand 1 (PD-L1) expression, and RNA-based immune signatures using proportional hazards regression. T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify, quantify, and compare the abundance of each unique TCRβ CDR3 at baseline and on treatment. Results: Median overall survival (OS) was 12.6 months in group 1, not reached in group 2 (HR = 0.31; P = 0.0016), 17.8 months in group 3 (HR = 0.40; P = 0.0004), and 19.8 months in groups 2 and 3 combined (HR = 0.37; P < 0.0001). Efficacy outcomes were comparable regardless of cancer CDK4/6 dependence status and immune signatures. Administering trilaciclib prior to GCb prolonged OS irrespective of PD-L1 status but had greater benefit in the PD-L1–positive population. T-cell activation was enhanced in patients receiving trilaciclib. Conclusions: Administering trilaciclib prior to GCb enhanced antitumor efficacy, with significant improvements in OS. Efficacy outcomes in immunologic subgroups and enhancements in T-cell activation suggest these improvements may be mediated via immunologic mechanisms.

Aim: The aim of the study was to assess patient preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in patients with HER2-positive early breast cancer in PHranceSCa (NCT03674112). Materials and methods: Patients who completed neoadjuvant P + H + chemotherapy + surgery were randomised 1:1 to three intravenous (IV) P + H cycles followed by three cycles of PH FDC SC or vice versa (crossover) and then chose subcutaneous (SC) injection or IV infusion to continue up to 18 cycles (continuation). Assessments were via patient and healthcare professional (HCP) questionnaires. Results: One hundred and sixty patients were randomised (cut-off: 24 February 2020); 136 (85.0%, 95% confidence interval: 78.5-90.2%) preferred SC; 22 (13.8% ) preferred IV; 2 (1.3 %) had no preference. The main reasons for SC preference were reduced clinic time (n = 119) and comfort during administration (n = 73). One hundred and forty-one patients (88.1%) were very satisfied/satisfied with SC injection versus 108 (67.5%) with IV infusion; 86.9% chose PH FDC SC continuation. HCP perceptions of median patient treatment room time ranged from 33.0-50.0 min with SC and 130.0-300.0 min with IV. Most adverse events (AEs) were grade 1/2 (no 4/5s); serious AE rates were low. AE rates before and after switching were similar (cycles 1-3 IV-> cycles 4-6 SC: 77.5%-> 72.5%; cycles 1-3 SC-> cycles 4-6 IV: 77.5%-> 63.8%). Conclusion: Most patients strongly preferred PH FDC SC over P + H IV. PH FDC SC was generally well tolerated, with no new safety signals (even when switching), and offers a quicker alternative to IV infusion. 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Question What is the effect of alisertib when added to paclitaxel in the treatment of patients with estrogen receptor-positive, ERBB2-negative or triple-negative metastatic breast cancer? Findings In this randomized clinical trial including 139 patients, the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved progression-free survival compared with paclitaxel alone, and toxic effects with paclitaxel plus alisertib were manageable with alisertib dose reduction. Meaning These findings suggest that in patients with estrogen receptor-positive, ERBB2-negative metastatic breast cancer, the addition of alisertib to paclitaxel is promising and worthy of further study. This randomized clinical trial compares paclitaxel alone vs paclitaxel plus alisertib for patients with estrogen receptor-positive, ERBB2-negative or triple-negative metastatic breast cancer. Importance Elevated expression of AURKA adversely affects prognosis in estrogen receptor (ER)-positive and ERBB2 (formerly HER2)-negative and triple-negative breast cancer and is associated with resistance to taxanes. Objective To compare paclitaxel alone vs paclitaxel plus alisertib in patients with ER-positive and ERBB2-negative or triple-negative metastatic breast cancer (MBC). Design, Setting, and Participants In this randomized clinical trial conducted with the US Oncology Network, participants were randomized to intravenous (IV) paclitaxel 90 mg/m(2) on days 1, 8, and 15 on a 28-day cycle or IV paclitaxel 60 mg/m(2) on days 1, 8, and 15 plus oral alisertib 40 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 on a 28-day cycle. Stratification was by prior neo or adjuvant taxane and by line of metastatic therapy. Eligible patients were those who had undergone endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, more than 12 months treatment-free interval from neo or adjuvant taxane therapy, and with measurable or evaluable lytic bone-disease. Data were analyzed from March 2019 through May 2019. Main Outcomes and Measures The main outcome was progression-free survival (PFS) with secondary end points of overall survival (OS), overall response rate, clinical benefit rate, safety, and analysis of archival breast cancer tissues for molecular markers associated with benefit from alisertib. Results A total of 174 patients were randomized, including with 86 randomized to paclitaxel and 88 patients randomized to paclitaxel plus alisertib, and 169 patients received study treatment. The final cohort included 139 patients with a median (interquartile range [IQR]) age of 62 (27-84) years with ER-positive and ERBB2-negative MBC, with 70 randomized to paclitaxel and 69 randomized to paclitaxel plus alisertib. The TNBC cohort closed with only 35 patients enrolled due to slow accrual and were not included in efficacy analyses. The median (IQR) follow-up was 22 (10.6-25.1) months, and median (IQR) PFS was 10.2 (3.8-15.7) months with paclitaxel plus alisertib vs 7.1 (3.8-10.6) months with paclitaxel alone (HR, 0.56; 95% CI, 0.37-0.84; P = .005). Median (IQR) OS was 26.3 (12.4-37.2) months for patients who received paclitaxel plus alisertib vs 25.1 (11.0-31.4) months for paclitaxel alone (HR, 0.89; 95% CI, 0.58-1.38; P = .61). Grade 3 or 4 adverse events occurred in 56 patients (84.8%) receiving paclitaxel plus alisertib vs 34 patients (48.6%) receiving paclitaxel alone. The main grade 3 or 4 adverse events with paclitaxel plus alisertib vs paclitaxel alone were neutropenia (50 patients [59.5%] vs 14 patients [16.4%]), anemia (8 patients [9.5%] vs 1 patient [1.2%]), diarrhea (9 patients [10.7%] vs 0 patients), and stomatitis or oral mucositis (13 patients [15.5%] vs 0 patients). One patient receiving paclitaxel plus alisertib died of sepsis. Conclusions and Relevance This randomized clinical trial found that the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved PFS compared with paclitaxel alone, and toxic effects with paclitaxel plus alisertib were manageable with alisertib dose reduction. These data support further evaluation of alisertib in patients with ER-positive, ERBB2-negative MBC.

Abstract Purpose: As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings. Patients and Methods: In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1–2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination. Results: The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8–38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2–31.1) for stratum 2 (n = 101). Patients with PD-L1–positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1–negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9–54.3) vs 16.1% (95% CI: 5.5–33.7); stratum 2, 24.4% (95% CI: 12.9–39.5) vs 18.2% (95% CI: 8.2–32.7)]. Conclusions: Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

PURPOSE This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer, including those with estrogen receptor gene alpha ( ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor–positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

Abstract Background: Targeting the estrogen receptor (ER) has proven to be one of the most successful strategies in treating HR+ (ER+ and PR+) and HER2- breast cancer. Selective estrogen receptor degraders (SERD) can be used as single agents or in combination with CDK4/6 inhibitors such as palbociclib. Fulvestrant is currently the only approved agent in its class and is limited by poor oral bioavailability necessitating monthly intramuscular injections. D-0502 is an orally bioavailable SERD with potent activity in various HR+ and HER2- breast cancer cell lines and xenograft models. Its combination with palbociclib in both MCF-7 xenograft models and ESR-1 mutated (Y537S) patient derived breast cancer xenograft models resulted in further tumor growth inhibition or regression. Drug metabolism and pharmacokinetic studies both in vitro and in vivo demonstrated that D-0502 exhibits favorable PK profiles suitable for clinical development. Methods: A first-in-human phase 1 study was conducted to evaluate D-0502 in women with advanced or metastatic HR+, HER2- breast cancer (MBC) (NCT03471663). The primary objective is to characterize the safety and tolerability of D-0502 and D-0502 in combination with palbociclib, to identify an MTD and/or RP2D. The secondary objectives are to evaluate the PK properties and the preliminary anti-tumor activities. Patients received D-0502 orally once daily in 28-day cycles. The study has completed dose escalation (phase 1a), and dose expansion and combination studies (phase 1b) are ongoing. In phase Ia, patients were enrolled and evaluated using conventional 3+3 dose-escalation to identify the MTD of D-0502 as a single agent. The phase 1b was divided into 2 stages. In Stage 1, D-0502 was evaluated with palbociclib at a dose below the MTD first before escalating to the MTD. Stage 1 also included patients in China treated at a dose below and at the MTD as single agent as well as in combination with palbociclib. Stage 2 will further evaluate the MTD for both single agent and combination of D-0502 with palbociclib. Results: At the time of this abstract submission, phase 1a dose escalation is completed, R2PD has been identified, and no DLTs were observed. PK analysis of D-0502 indicates a dose proportional increase in exposure as the dose increases, and the exposure has exceeded the potential therapeutic exposure level based on preclinical studies. The Phase Ib Stage 1 portion has also completed enrollment and the study is currently enrolling patients into phase Ib Stage 2. D-0502 as a single agent or in combination has been well tolerated with radiological tumor response and clinical benefit response (CBR) observed. Safety, PK and preliminary efficacy data will be reported at the meeting presentation. Conclusion: A first-in-human phase 1 study of D-0502 has been initiated in women with advanced or metastatic HR-positive and HER2-negative breast cancer. D-0502 has been well tolerated and achieved significant exposure and preliminary clinical activity in patients. Further results will be presented at the meeting. Citation Format: Cynthia Osborne, Donald A Richards, Sharon T Wilks, Sami Diab, Dejan Juric, Kate Lathrop, Andrea Silber, William Edenfield, Amardeep Aulakh, Ben Cho, Binghe Xu, Tao Sun, Quchang Ouyang, Yanxia Shi, Kathryn Stazzone, Zhe Shi, Ling Zhang, Yaolin Wang, Erika P Hamilton. A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer [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 PS11-26.

Abstract Background Trilaciclib is an intravenous (IV) cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Preliminary data showed that adding trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly increased overall survival (OS) compared with GCb alone among patients with metastatic triple-negative breast cancer (mTNBC) (Tan et al., Lancet Oncol. 2019;20:1587-1601). Here, final antitumor efficacy results (objective response rate [ORR], progression-free survival [PFS], and OS) are reported for the whole study population, and in cohorts according to CDK4/6 dependence and level of programmed death ligand-1 (PD-L1) expression. Methods This was a randomized, open-label, phase 2 study of patients with mTNBC who had received ≤2 previous lines of chemotherapy in the recurrent/metastatic setting (NCT02978716). Patients were randomized (1:1:1) to receive GCb on days 1 and 8 (group 1, n=34), trilaciclib prior to GCb on days 1 and 8 (group 2, n=33), or trilaciclib alone on days 1 and 8 and prior to GCb on days 2 and 9 (group 3, n=35), in 21-day cycles. PFS and OS (prespecified secondary endpoints) were assessed in the intention-to-treat (ITT) population, and ORR in response-evaluable patients. Patient tumors were characterized as CDK4/6 independent (basal-like) or indeterminate (HER2-enriched, normal-like, luminal A/B) according to the established PAM50 signature, or CDK4/6 dependent (luminal androgen receptor) or indeterminate (basal-like 1/2, mesenchymal) according to the established Lehmann signature. PD-L1 expression was scored as negative or positive if <1% or ≥1% of the total tumor area contained PD-L1-labelled immune cells, respectively, using the Ventana SP142 assay. Association of CDK4/6 dependence and PD-L1 expression with antitumor efficacy was assessed using proportional hazards regression. Results Median follow-up was 8.4 months (range: 0.1-25.7) for group 1, 14.0 months (1.3-33.6) for group 2, and 15.3 months (3.5-33.7) for group 3. The ORR among response-evaluable patients was 7/24 (29.2%) in group 1, 15/30 (50.0%) in group 2, and 12/31 (38.7%) in group 3. Median PFS (95% confidence interval [CI]) in the ITT population was 5.7 (3.3, 9.9) months in group 1, 9.4 (6.1, 11.9) months in group 2, and 7.3 (6.2, 13.9) months in group 3, with hazard ratios (HRs) of 0.62 (P = 0.2099) and 0.63 (P = 0.1816), for groups 2 and 3 versus group 1, respectively. Overall, 73.5%, 39.4%, and 57.1% of patients in groups 1, 2, and 3 had died. Median OS (95% CI) was 12.6 (6.3, 15.6) months in group 1, not reached (NR) (10.2, NR) in group 2 (HR = 0.31, P = 0.0016), and 17.8 (12.9, 32.7) months in group 3 (HR = 0.40, P = 0.0004). For groups 2 and 3 combined, median OS was 19.8 (14.0, NR) months (HR = 0.37, P <0.0001 vs group 1). ORR, PFS, and OS were comparable in tumors categorized as CDK4/6 dependent, independent, or indeterminate. Antitumor efficacy by PD-L1 status is provided in the Table. Conclusions Mature data from this study confirm that administering trilaciclib prior to GCb enhances antitumor efficacy compared with GCb alone, with statistically significant improvements in OS. Subgroup analyses suggest that adding trilaciclib prior to GCb benefits patients regardless of CDK4/6 dependence status and PD-L1 expression. Additional immune subtyping analyses are ongoing and will be presented. Group 1Group 2Group 3PD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePatients, n171016101616ORR, n (%)4 (23.5)3 (30.0)8 (50.0)4 (40.0)7 (43.8)4 (25.0)Median PFS, months (95% CI)3.5 (2.2, NR)9.5 (5.2, NR)7.9 (4.3, NR)11.9 (8.8, NR)9.0 (6.2, NR)6.9 (6.4, NR)P value (Wald Test)––0.3470.6040.0690.766HR (95% CI)––0.70 (0.3, 1.5)0.76 (0.3, 2.2)0.46 (0.2, 1.1)1.16 (0.4, 3.1)Median OS, months (95% CI)10.5 (6.3, 18.8)13.9 (12.6, NR)20.1 (10.2, NR)NR (9.4, NR)32.7 (15.3, NR)17.8 (12.9, NR)P value (Wald Test)––0.0280.0830.020.239HR (95% CI)––0.35 (0.1, 0.9)0.34 (0.1, 1.2)0.33 (0.1, 0.8)0.57 (0.2, 1.5)HR and P values are for comparisons between group 2 versus group 1, and group 3 versus group 1.+ve, positive; –ve, negative; CI, confidence interval; HR, hazard ratio; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression-free survival. Citation Format: Joyce O'Shaughnessy, Gail S Wright, Anu R Thummala, Michael A Danso, Lazar Popovic, Timothy J Pluard, Hyo S Han, Željko Vojnović, Nikola Vasev, Ling Ma, Donald A Richards, Sharon T Wilks, Dušan Milenković, Jie Xiao, Jessica A Sorrentino, Janet Horton, Antoinette R Tan. Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: Final analysis of a randomized phase 2 trial [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 PD1-06.

Background POLARIS is an ongoing, prospective, real-world (RW) study of palbociclib (PAL) in patients (pts) with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (HR+/HER2- ABC). A biomarker goal of this study was to evaluate serial changes in circulating tumor DNA (ctDNA) dynamics among pts with long-term clinical response to PAL plus endocrine therapy (ie, received ≥18 cycles). Methods The data set included pts who received PAL combination therapy, gave consent for blood collection to obtain ctDNA, and had long-term clinical response. The Guardant360 Next-Generation Sequencing platform, which analyzed approximately 73 genes, was used to sequence ctDNA for somatic single-nucleotide variants, including copy number variants. Longitudinal ctDNA changes (at baseline and various time points) and the RW clinical response to PAL are described. Results As of December 17, 2020, 35 pts of 1280 enrolled received ≥18 cycles of PAL combination therapy, with blood samples collected over a minimum of a 24-month period. Pts received PAL plus an aromatase inhibitor (n=16) or fulvestrant (n=19). Median age was 64 years. Thirty pts (85.7%) were white, 29 (82.9%) were postmenopausal, 31 (88.6%) had an Eastern Cooperative Oncology Group score of 0 or 1, 12 (34.3%) had visceral disease, 9 (25.7%) had de novo disease, and 24 (68.6%) had recurrent disease. Six pts (17.1%) had a RW best overall response (BOR) of complete response (CR), 9 (25.7%) had partial response (PR), and 20 (57.1%) had stable disease (SD). Two pts had disease progression resulting in change of therapy at cycles 25 and 38, respectively. Biomarker samples were collected from a median (range) total number of 9 (3-12) visits. The median (range) number of somatic variants detected was 4 (0-11) and included the most prevalent somatic mutations (eg, PIK3CA, TP53, BRCA1/2, FGFR2, GATA3). No ctDNA mutations were detected in 6 pts (17%) post baseline up to 24 months. Among 15 pts who achieved CR/PR, 12 (80%) either had no detectable or sustained very low ctDNA burden or had corresponding ctDNA decrease. Among 16 pts who remained with SD, 12 (75%) either had no detectable or sustained very low ctDNA burden or had ctDNA decrease. Among 8 pts whose disease progressed, 5 (63%) had an increasing trend in ctDNA mutation frequency. Conclusions This study is among the first to provide serial blood-based tumor genotyping data from routine clinical practice. Interim data indicate that even pts with ongoing detectable ctDNA have a BOR of CR, PR, or SD with PAL for HR+/HER2- ABC, suggesting certain mutations might not be drivers of PAL resistance. Dynamic changes of ctDNA mutations may be predictive for treatment response, and may have clinical utility in disease surveillance monitoring. Additional longitudinal data will be presented. Pfizer; NCT03280303 Citation Format: Joanne L. Blum, Aditya Bardia, Sharon Wilks, Steven L. McCune, Carrie L. Dul, John J. Migas, Derrick W. Spell, Zhe Zhang, Yuan Liu, Yao Wang, Debu Tripathy. Longitudinal ctDNA changes in patients with long-term response to palbociclib combination therapy for advanced breast cancer: A preliminary analysis from the real-world POLARIS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB033.

TPS1104 Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Clinical trial information: NCT01969643 .

Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Citation Format: Heather C Beckwith, Diana C Medgyesy, Jame Abraham, Rita Nanda, Katherine HR Tkaczuk, Ian E Krop, Lajos Pusztai, Shanu Modi, Monica M Mita, Jennifer M Specht, Sara A Hurvitz, Hyo S Han, Kevin Kalinsky, Sharon Wilks, Joyce O’Shaughnessy, Lowell L Hart, Hope S Rugo, Zahi I Mitri, Phillip M Garfin, Howard A Burris III. SGNLVA-001: A phase 1 open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer [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-03-03.