Prior Therapy For Metastatic Disease Research Articles

Abstract CT286: TILVANCE-301, a phase 3 study of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab vs pembrolizumab alone in treatment-naive unresectable or metastatic melanoma

Abstract Introduction: Novel early-line therapies for advanced (unresectable or metastatic) melanoma are needed to improve the rate of deep and durable responses and increase the proportion of patients with long-term benefit. TILVANCE-301 will evaluate the efficacy and safety of lifileucel autologous TIL cell therapy plus pembrolizumab in patients with untreated advanced melanoma. Methods: TILVANCE-301 (NCT05727904) is a phase 3, multicenter, randomized, open-label, parallel group study that will randomize ~670 patients (1:1; Day 0) to Arm A: lifileucel plus pembrolizumab (Day 3: tumor tissue resection for TIL manufacturing; Day 5: pembrolizumab 200 mg; Day 26: pembrolizumab 400 mg; Day 28-29: cyclophosphamide 60 mg/kg; Day 28-32: fludarabine 25 mg/m2; Day 33: lifileucel; Day 34-37: ≤6 doses of high-dose IL-2; Week 10: pembrolizumab 400 mg Q6W) or Arm B: pembrolizumab alone (same pembrolizumab dosing as Arm A). Patients in Arm B with confirmed progressive disease verified by blinded independent review committee (BIRC) have the option to receive lifileucel monotherapy as immediate next treatment and may continue pembrolizumab until start of nonmyeloablative lymphodepletion. Eligible adults have histologically confirmed advanced melanoma, Eastern Cooperative Oncology Group performance status of 0-1, estimated life expectancy >6 months, ≥1 resectable lesion to generate lifileucel, and ≥1 remaining measurable lesion. Prior neoadjuvant or adjuvant treatment including immune checkpoint inhibitors may be allowed. Prior therapy for metastatic disease, symptomatic untreated brain metastases, organ allograft or prior cell therapy, uveal/ocular melanoma, and chronic systemic steroid therapy are not permitted. The dual primary efficacy endpoints are BIRC-assessed (RECIST v1.1) objective response rate (ORR) and progression-free survival (PFS). Key secondary efficacy endpoint is overall survival. Additional secondary efficacy endpoints include BIRC-assessed complete response (CR) rate, duration of response (DOR), and event-free survival (EFS); investigator-assessed ORR, PFS, CR rate, DOR, EFS, and PFS2; and safety as characterized by severity and seriousness of treatment-emergent adverse events and relationship to study drug. Exploratory endpoints include in vivo T-cell persistence (unique CDR3 sequences in peripheral blood mononuclear cell [PBMC] over time) and correlative biomarkers (eg, lifileucel phenotypic and functional characteristics; lifileucel, tumor, and PBMC gene expression profiles; tumor mutational landscape). The study will enroll globally, with initial sites in Europe, North America, and Australia. Trial registration: NCT05727904 Citation Format: Sajeve Thomas, Young Ki Hong, Yazan Samhouri, James Larkin, David J. Olson, Gino K. In, Victoria Atkinson, Philip Lammers, Andrew J. Furness, Juan Martin-Liberal, Patrick Terheyden, Andrew S. Poklepovic, Ryan H. Nguyen, Idit Peretz, Marcus Butler, Adnan Khattak, Lavinia Spain, E.M. Gaughan, Melissa Wilson, John W. Dubay, Anja Williams, Stephanie Goff, Gary C. Doolittle, Jason Chesney, Friedrich Graf Finckenstein, Jeffrey Chou, Xiao Wu, Giri Sulur, Wen Shi, John Haanen. TILVANCE-301, a phase 3 study of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab vs pembrolizumab alone in treatment-naive unresectable or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT286.

AdvanTIG-105: Phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with stage IV gastric/gastroesophageal adenocarcinoma (GC/GEJC).

31 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n=27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP <5% (n=28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

EE276 Economic Evaluation of Trifluridine and Tipiracil Hydrochloride in the Treatment of Metastatic Gastric Cancer in the Brazilian Private Health Care Sector

The Brazilian Private Health Care Sector has first-line and second-line metastatic gastric cancer (mGC) treatment options using traditional chemotherapy and targeted therapy. Recently, trifluridine and tipiracil hydrochloride (FTD/TPI) was approved in the third-line treatment and is the only treatment option to this subgroup of patients. Our objective was to evaluate the cost-effectiveness of FTD/TPI in mGC patients, including gastroesophageal junction adenocarcinoma, who have received at least two prior therapies for metastatic disease and are eligible for third-line treatment, from the perspective of private health care sector in Brazil.

A phase 3 study (TILVANCE-301) to assess the efficacy and safety of lifileucel, an autologous tumor-infiltrating lymphocyte cell therapy, in combination with pembrolizumab compared with pembrolizumab alone in patients with untreated unresectable or metastatic melanoma.

TPS9607 Background: Most patients (pts) with advanced (unresectable or metastatic) melanoma receiving front-line immune checkpoint inhibitor (ICI) therapy progress within a year (Robert Lancet Oncol 2019; Larkin NEJM 2019; Tawbi NEJM 2022). Early-line therapies are needed to improve the rate of deep and durable responses and increase the proportion of pts with long-term benefit. Lifileucel demonstrated an ORR of 31.4% and median DOR not reached (median 36.5 mo follow-up) in pts with post-ICI advanced melanoma (Sarnaik SITC 2022). Earlier-line treatment with lifileucel plus pembrolizumab (pembro) in pts with ICI-naïve advanced melanoma demonstrated an ORR of 67%, including a CR rate of 25% (Iovance Press Release, April 5, 2022; O’Malley JITC 2021). TILVANCE-301 will evaluate the efficacy and safety of lifileucel plus pembro compared with pembro alone in pts with untreated advanced melanoma. Methods: TILVANCE-301 (NCT05727904) is a phase 3, multicenter, randomized, open-label, parallel group, treatment study that will randomize ~670 pts (1:1) to either Arm A: lifileucel plus pembro (study intervention includes tumor tissue resection, pembro, nonmyeloablative lymphodepletion [NMA-LD], lifileucel infusion, an abbreviated course of high-dose IL-2, and thereafter, continued pembro) or Arm B: pembro alone. Pts in Arm B who receive pembro and experience confirmed progressive disease verified by blinded independent review committee (BIRC) have the option to receive lifileucel as the immediate next line of treatment. Eligible adults have histologically confirmed advanced melanoma (Stage IIIC, IIID, or IV); ECOG PS of 0 or 1; estimated life expectancy > 6 mo; ≥1 resectable lesion ~1.5 cm in diameter postresection to generate lifileucel and ≥1 measurable lesion (RECIST v1.1); and adequate hematologic parameters and organ function. Neoadjuvant or adjuvant treatment including ICI meeting protocol-specified criteria may be allowed. Exclusion criteria include prior therapy for metastatic disease; symptomatic untreated brain metastases; organ allograft or prior cell transfer therapy; uveal/ocular melanoma; chronic systemic steroid therapy; active systemic infections; cardiovascular, respiratory, or immune system illnesses; primary/acquired immunodeficiency; or other primary malignancy in the last 3 y. The dual primary efficacy endpoints are BIRC-assessed (RECIST v1.1) ORR and PFS. Key secondary efficacy endpoint is OS. Additional secondary efficacy endpoints include BIRC-assessed CR rate, DOR, and EFS; investigator-assessed ORR, PFS, CR rate, DOR, EFS, and PFS2; and safety as characterized by severity and seriousness of TEAEs, and relationship to study drug. The study will enroll globally. Clinical trial information: NCT05727904 .

AdvanTIG-105: A phase 1b dose-expansion study of ociperlimab (OCI) + tislelizumab (TIS) with chemotherapy (chemo) in patients (pts) with stage IV gastric/gastroesophageal adenocarcinoma (GC/GEJC).

4028 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 4.6 months (95% CI: 3.9, 7.1). Median PFS was 8.2 months (95% CI: 5.8, not evaluable). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n = 27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP < 5% (n = 28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

Abstract OT1-03-02: Efficacy and safety of SKB264 for previously treated metastatic triple negative breast cancer in Phase 2 study

Abstract Background: The therapeutic options for patients (pts) with previously treated metastatic TNBC are limited compared with other breast cancer subtypes. SKB264 is an antibody drug conjugate (ADC) composed of an anti-TROP2 antibody coupled to the cytotoxic belotecan-derivative via a novel linker. Here, we present results from a Phase 2 expansion cohort for pts with mTNBC (NCT04152499). Methods: Pts with previously treated mTNBC were enrolled to receive SKB264 4 mg/kg Q2W or 5 mg/kg Q2W in a non-randomized fashion until disease progression/unacceptable toxicity. The assessment for tumor response was performed every 8 weeks per RECIST v1.1 assessed by investigator. The TROP2 expression was scored using the semi-quantitative H-score method, and cut off point was set to 200. TROP2 expression and its association with anti-tumor activity was retrospectively analyzed. Results: At data cut-off date (May 15, 2022), 59 pts were enrolled (23 in 4 mg/kg, 36 in 5 mg/kg), 88% of them (52 pts) had received ≥3 prior therapies for metastatic disease. Among 53 patients with tissue available for TROP2 testing, 29 patients (55%) had TROP2 high (H-score >200-300) tumors. The median follow up was 9.6 months. Of 55 pts (21 in 4 mg/kg and 34 in 5 mg/kg) evaluable for response assessment (≥1 on-study scan), the confirmed ORR (cORR) was 40% (22/55) and disease control rate (PR+CR+SD) was 80% (44/55). The cORR was 55% (16/29) in the subset of patients with high TROP2 expression. The median duration of response (DoR) was not reached with range from 1.0+ to 11.0+ months and the 6-month DoR rate was 82%. Median PFS was 5.7 months (95% Cl: 3.9, 7.6). Treatment-related adverse events (TRAEs) of ≥ Grade 3 were reported in 55.9% (33/59) of pts. The most common ≥ Grade 3 TRAEs (≥ 10%) were neutrophil count decreased (23.7%), anemia (20.3%) and platelet count decreased (16.9%). TRAEs led to dose reduction in 15.2% (9/59) of pts and to discontinuation in 6.8% (4/59) of pts. No treatment-related AEs leading to death or interstitial lung disease (ILD) were reported. Safety and anti-tumor activities of SKB264 by dose level will be presented. Conclusions: SKB264 demonstrates a manageable safety profile and promising antitumor activity in pts with heavily pretreated mTNBC. SKB264 toxicity was mainly hematologic. A Phase 3 study of SKB264 vs investigator selected chemo alone in pts with locally advanced inoperable or metastatic TNBC was initiated (NCT05347134). Citation Format: Yongmei Yin, Xinhong Wu, Quchang Ouyang, Min Yan, Lihua Song, YunPeng Liu, Zhongsheng Tong, Cuizhi Geng, Ying Wang, Guohua Yu, Xiang Wang, Ying Cheng, Weihong Zhao, Qun Li, Yina Diao, Gesha Liu, Junyou Ge, Jin Li. Efficacy and safety of SKB264 for previously treated metastatic triple negative breast cancer in Phase 2 study [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 OT1-03-02.

Abstract OT1-02-01: Phase III postneoadjuvant study evaluating sacituzumab govitecan (SG), an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment - SASCIA

Abstract Background: Women with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NACT) or hormone-receptor (HR)-positive/HER2-negative breast cancer (BC) with a CPS (clinical and post treatment pathological stage) +EG (estrogen receptor status and grade) score ≥3 or score 2 and nodal involvement after NACT (ypN+) are at high risk of recurrence. SG is approved by the Food and Drug Administration for the treatment of patients with metastatic TNBC who received at least two prior therapies for metastatic disease and has shown activity in heavily pretreated patients with metastatic HR-positive/HER2-negative BC. SG may represent a new option against residual disease after NACT. Trial Design: SASCIA is a phase III, prospective, international, multicenter, randomized, open label, parallel group study (NCT04595565) of the GBG in collaboration with the AGO-B. Eligible patients must have received taxane-based NACT for 16 weeks, including 6 weeks of a taxane. Patients should have centrally confirmed HER2-negative BC (IHC score 0-1 or FISH negative) and either HR-negative (<1%), with any residual invasive disease > ypT1mi or HR-positive (≥1%), with a CPS+EG score ≥3 or CPS+EG score 2 and ypN+ using local ER and grade assessed on core biopsies taken before NACT. Radiotherapy should be delivered before study treatment start. Patients are randomized 1:1 to receive either SG 10 mg/kg body weight (days 1, 8 q3w for eight cycles) or treatment of physician´s choice (capecitabine 2000 mg/m² day 1-14 q21 or platinum-based chemotherapy i.e. carboplatin AUC 5 q3w or AUC 1.5 weekly for eight 3 weekly cycles or observation). Randomization is stratified by HR status (positive, negative) and nodal involvement after NACT (ypN+, ypN0). Endocrine-based therapy will be administered according to local guidelines in patients with HR-positive BC. The primary endpoint is invasive disease-free survival (iDFS). Secondary endpoints include comparison of overall survival (OS, key secondary endpoint), distant disease-free survival, locoregional recurrences-free interval, safety, compliance, iDFS and OS according to stratified and - predefined subgroups, patient reported outcome, and quality of life between treatment arms. As of 21st June 2021, 57/1200 patients have been randomized in Germany. Citation Format: Frederik Marmé, Marcus Schmidt, Jenny Furlanetto, Carsten Denkert, Anthony Goncalves, Elmar Stickeler, Mattea Reinisch, Silvia Antolín, Toralf Reimer, Wolfgang Janni, Philippe Aftimos, Michael Untch, Laura Michel, Marija Balic, Bruno Sinn, Volker Möbus, Patrick Morris, Laura Schöllhorn, Sabine Schmatloch, Julia Rey, Sibylle Loibl. Phase III postneoadjuvant study evaluating sacituzumab govitecan (SG), an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment - SASCIA [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-02-01.

Abstract P2-14-17: A phase 1b study of PVX-410 vaccine in combination with pembrolizumab in metastatic triple negative breast cancer (mTNBC)

Abstract Background: Immunotherapy with checkpoint inhibition is active in mTNBC. Both pembrolizumab and atezolizumab are FDA approved for programmed cell death ligand 1 positive (PDL1+) mTNBC. Vaccines may further induce host immune response and enhance therapeutic activity of checkpoint inhibitors. PVX-410 (PVX) (OncoPep, Inc.) is a novel, HLA-A2 restricted, tetra-peptide vaccine, with 3 of its 4 antigens (XBP1[2 splice variants] and CD138) commonly overexpressed in TNBC. We present results from a phase 1b study evaluating the immune response, safety and tolerability, and clinical activity of PVX and pembrolizumab (PEM) in mTNBC. Methods: Eligibility for this phase 1b multi-center, single-arm study included HLA-A2+, PD-L1 unselected female patients (pts) ≥18 years with metastatic or inoperable locally advanced TNBC, measurable disease, and any number of prior therapies, including prior checkpoint inhibitor therapy. Pts received 6 doses of 800µg PVX emulsified in Montanide ISA 720 VG by subcutaneous injection co-administered with intramuscular Hiltonol weekly for 6 weeks (wks) followed by booster vaccine doses at wks 10 and 28, with concurrent intravenous 200 mg PEM every 3 wks starting with the second PVX dose. Therapy was given until progressive disease, unacceptable toxicity or a maximum of 24 months. Blood samples were scheduled for immune response assessment at baseline and at weeks 2, 5, 10, 28, and 52 post-treatment initiation. The primary objective was PVX- specific immune response at week 10. Immune response was defined as a ≥2-fold change over baseline in the proportion of CD3+CD8+ T cells that expressed IFNγ and the proportion of CD3+CD8+ T cells positive for PVX tetramers following an in vitro stimulation of PBMC with PVX peptides using a flow cytometric assay. Secondary objectives were immune response at wk 28, safety and tolerability, and clinical endpoints (RR, CBR, DCR, DoR, PFS, and OS). Results: Between 3/2018 and 8/2020, 19 pts enrolled. Median age was 62 yrs (range 46-79), with median 2 (range 0-9) lines of prior therapy for metastatic disease. Median disease-free interval among 16 pts with prior early TNBC was 3.3 years. Among 19 enrolled patients, 16 were available for analysis at the time of abstract submission. Among the 16, 10 pts were evaluable at week 10 and 7(70%) demonstrated a PVX specific immune response. There were 6 patients who progressed before week 10, of whom 3 (50%) had a positive immune response at the EOT visit. Immune response persisted in all evaluable pts assessed at week 28 (n=4). Immune response data for all evaluable patients will be updated at the presentation. Among 19 patients evaluable for safety analysis, the most common adverse events (AEs) attributable to PVX (grade ≥2) included: fatigue (21%), arthralgia (11%) injection site reaction (5 %) pain (5%) lymphocyte count decreased (5%), maculopapular rash (5%) and skin infection (5%) . There were two grade 3 AEs attributed to PEM (AST elevation, hyponatremia) and one grade 4 AE (ALT elevation). There were no grade 5 AEs. The clinical benefit rate (CR+PR+SD for ≥16 weeks) was 31.6% with no confirmed partial or complete responses. Best overall response was SD in 9 (47%) patients. Analysis of additional clinical endpoints including PFS and OS is ongoing and will be presented at the meeting. Conclusions: PVX plus PEM is safe with manageable toxicity in pts with mTNBC. No new unexpected adverse events were identified. Immune response data show PVX induces antigen-specific T cell expansion as observed by increases in PVX tetramer and IFN positive T cells. Clinical disease control was observed with a CBR of 31.6%. Based on these promising immune response results in this pretreated population, a phase 2 study with PVX+PEM in combination with standard chemotherapy in treatment naïve, PD-L1+ mTNBC is underway (NCT04634747). Citation Format: Steven J Isakoff, Nadine M. Tung, Jun Yin, Nabihah Tayob, Joanne Parker, Julie Rosenberg, Aditya Bardia, Laura Spring, Hannah Park, Maya Collins, William T. Barry, Mariano Severgnini, Doris Peterkin, Sara M. Tolaney. A phase 1b study of PVX-410 vaccine in combination with pembrolizumab in metastatic triple negative breast cancer (mTNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-14-17.

Phase II study of PEGPH20 plus pembrolizumab for patients (pts) with hyaluronan (HA)-high refractory metastatic pancreatic adenocarcinoma (mPC): PCRT16-001.

576 Background: Stromal HA poses a physical barrier and protects tumor cells from immune surveillance. PEGPH20 is a pegylated, human recombinant PH20 hyaluronidase that remodels tumor stroma. Preclinical studies of PEGPH20 showed improved infiltration of cytotoxic T-lymphocytes and delivery of chemotherapy and PD1/PD-L1 antibodies. This study aimed to evaluate the efficacy, safety, and translational biomarkers of PEGPH20 plus pembrolizumab in pts with HA-high refractory mPC. Methods: mPC pts with HA-high expression, ECOG PS 0-1, ≤ 2 prior therapies for metastatic disease, life expectancy ≥ 12 weeks were treated with PEGPH20 3 µg/kg iv on D1, D8, D15 and pembrolizumab 200 mg iv on D1 in 21-day cycles. Primary endpoint was progression-free survival (PFS). Secondary endpoints were safety, overall survival (OS), and objective response rate (ORR). Blood and tumor biopsies were collected at baseline and on-study. Translational endpoints included flow cytometry and IHC for immune subsets, T-cell receptor sequencing, immune transcriptome, circulating cytokines, and plasma and tumor HA levels. Assuming a one-sided α-level of 0.05 and power of 80%, 31 evaluable pts were needed to detect an improvement of median PFS from 3 to 6 months. Results: Between May 2019 to Nov 2019, 38 pts were screened for HA expression, and 8 pts were enrolled, with median age 68 years (range 60-73), 7 males, and median 2 prior therapies (range 1-4). The accrual was stopped early by Halozyme Pharmaceuticals due to lack of benefit from PEGPH20 added to chemotherapy in the HALO-301 study. Treatment exposure median was 2 cycles (range 1-6). Reasons for study discontinuation were disease progression (n = 4), termination by sponsor (n = 3), patient withdrawal to enroll in hospice (n = 1). Treatment related toxicities were musculoskeletal (n = 6, grade 1/2), edema (n = 2, grade 1), fatigue (n = 1, grade 3), dyspnea (n = 1, grade 2), hypothyroidism (n = 1, grade 2). Median OS was 7.2 months (95% CI 1.2-11.8), and median PFS was 1.5 months (95% CI 0.9-4.4). Best response was stable disease (n = 2, 25%) lasting 2.2 and 9 months, respectively, and no responses were noted. Patients with available molecular sequencing data had MSS tumors. Translational biomarkers will be presented. Conclusions: Pembrolizumab and PEGPH20 did not increase PFS compared to historical data among heavily pretreated mPC pts, but the median OS of 7.2 months is encouraging. Translational analyses will provide insights into immune modulatory effects from PEGPH20 that could inform future studies with stroma targeted therapies and immune checkpoint blockade in mPC. Clinical trial information: NCT03634332.

Palbociclib plus letrozole as treatment for postmenopausal women with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer for whom letrozole therapy is deemed appropriate: An expanded access study in Australia and India.

Palbociclib was approved in the United States in 2015 to treat estrogen receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This study evaluated outcomes and safety in patients treated with palbociclib in Australia and India with hormone receptor-positive (HR+)/HER2- ABC before palbociclib became commercially available. Postmenopausal women (≥18 years) with HR+/HER2- ABC who were appropriate candidates for letrozole therapy received palbociclib 125mg once daily for 21 days followed by 7 days off, and letrozole 2.5mg once daily (continuous). Safety, tumor response, and patient-reported outcomes (Australian cohort) were evaluated. In total, 252 patients received palbociclib plus letrozole (Australia, n=152; India, n=100). More patients in the Australian versus Indian cohort had received prior chemotherapy (advanced/metastatic setting: 45.9%vs. 32.0%), endocrine therapy (advanced/metastatic setting: 63.2%vs. 54.3%), and advanced/metastatic therapies (61.8%vs. 31.0%). The most frequently reported all-grade palbociclib-related treatment-emergent adverse events were neutropenia (66.7%), fatigue (35.3%), and stomatitis (26.6%); grade 3/4 neutropenia was reported as palbociclib-related in 62.7% of patients. Febrile neutropenia was reported in six patients (2.4%). Eight patients (3.2%) discontinued because of an adverse event. The objective response rate was 19.4% (95% CI, 14.7%-24.9%) overall and 2.3% in Australian patients with ≥2 lines of prior therapy for metastatic disease. Patient-reported quality of life scores were maintained throughout the study. In an expanded access setting in Australia and India, palbociclib plus letrozole was well tolerated in patients with HR+/HER2- ABC, with a safety profile consistent with previous reports.

Sacituzumab Govitecan for Treatment of Refractory Triple-Negative Metastatic Breast Cancer.

Sacituzumab govitecan was initially approved in April 2020 under accelerated approval for the treatment of patients with metastatic triplenegative breast cancer who received at least two prior therapies for metastatic disease. A confirmatory phase III trial evaluating sacituzumab govitecan vs. chemotherapy of the provider's choice was published in April 2021. Based on this trial, the FDA granted sacituzumab govitecan full regulatory approval. This antibody-drug conjugate is composed of a monoclonal antibody targeted at Trop-2 and contains the active metabolite of irinotecan, SN-38, as a cytotoxic side moiety. In a phase III clinical trial, sacituzumab govitecan demonstrated a median progression-free survival of 5.7 months vs. 1.7 months with chemotherapy. It is now an additional option for patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received two or more prior systemic therapies, at least one of them for metastatic disease.

199TiP Phase III post-neoadjuvant study evaluating sacituzumab govitecan (SG), an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment: SASCIA

Women with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NACT) or hormone-receptor (HR)-positive/HER2-negative breast cancer (BC) with a CPS (clinical and post treatment pathological stage) +EG (estrogen receptor status and grade) score ≥3 or score 2 and nodal involvement after NACT (ypN+) are at high risk of recurrence. SG is approved by the Food and Drug Administration for the treatment of patients with metastatic TNBC who received at least two prior therapies for metastatic disease and has shown activity in heavily pretreated patients with metastatic HR-positive/HER2-negative BC.

Phase I/II study of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.

1018 Background: H3B-6545, a selective, small molecule covalent antagonist of ERα demonstrated preclinical and preliminary clinical activity against ER+ breast cancer (Hamilton EP, SABCS, 2020). This study evaluated the activity and tolerability of H3B-6545 in patients (pts) with metastatic ER+, HER2-, breast cancer refractory to endocrine therapy. Methods: Patients received H3B-6545 once daily at the recommended phase II dose of 450 mg. The primary objective of the phase II is to estimate the objective response rate (ORR), progression-free survival (PFS), clinical benefit rate (CBR) and secondary objectives include safety. Results: 83 pts were treated with 450 mg in the phase II part of the trial. Additionally, 11 pts were treated with 450 mg in the phase I part of the trial and are included in this analysis. Median age was 62 years (range: 38 to 87 years), 81% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 8). Prior CDK4/6 inhibitors, aromatase inhibitors, fulvestrant, and chemotherapy were received by 85%, 80%, 72%, and 50% of the pts, respectively. 58 pts (62%) had detectable ESR1 mutations in liquid biopsies, including 10 (11%) and 19 pts (20%) who had clonal Y537S and clonal D538G mutation, respectively. As of January 29, 2021, grade (gr) 2 or higher adverse events (AE) reported in ≥10% were anemia (19%), fatigue (16%), nausea (17%), and diarrhea (12%). Laboratory gr 2 or higher abnormalities reported in ≥10% pts were creatinine clearance decrease (38%), hemoglobin decrease (37%), bilirubin increase (12%), ALT increase (14%), AST increase (13%), and creatinine increase (11%). AE of gr 1 sinus bradycardia (asymptomatic) was reported in 34% and gr 2 (symptomatic, no intervention needed) was reported in 5%. Gr 2 and 3 QTcF prolongation were reported in 2 and 3 pts, respectively. There were no treatment-related deaths. Efficacy estimates are presented in the table below. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, CDK4/6 inhibitor, and/or chemotherapy in the metastatic setting. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients. Clinical activity was observed in pts with ESR1 mutations. Clinical trial information: NCT03250676 .[Table: see text]

Assessment of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) cohort by agent in the phase 3 ASCENT study of patients (pts) with metastatic triple-negative breast cancer (mTNBC).

1077 Background: In pts with pretreated mTNBC, standard-of-care chemotherapy is associated with low objective response rates (ORRs) and short median progression-free survival (PFS). SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received accelerated FDA approval for treatment of pts with mTNBC who have received ≥2 prior therapies for metastatic disease. The confirmatory phase 3 ASCENT study (NCT02574455) in pts with relapsed/refractory mTNBC demonstrated a significant survival benefit of SG over TPC (median PFS: 5.6 vs 1.7 mo, HR 0.41, P< 0.0001; median overall survival [OS]: 12.1 vs 6.7 mo, HR 0.48, P< 0.0001) with a tolerable safety profile. Here we summarize efficacy results for SG vs each TPC agent in ASCENT to examine how each TPC agent performed individually. Methods: Pts had mTNBC refractory to or progressing after ≥2 prior standard chemotherapy regimens. Pts were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8, every 21 days) or single-agent TPC (eribulin, vinorelbine, capecitabine, or gemcitabine). Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Secondary endpoints were ORR per RECIST 1.1, duration of response, OS, and safety. Outcomes for each of the agents in the TPC arm were analyzed and compared with SG. Results: Of 529 pts enrolled, 468 were BMNeg. Among pts in the TPC cohort (n = 233), eribulin was the most commonly chosen chemotherapy (n = 126), followed by vinorelbine (n = 47), capecitabine (n = 31), and gemcitabine (n = 29). Treatment with eribulin, vinorelbine, capecitabine, and gemcitabine resulted in shorter median PFS vs SG (2.1, 1.6, 1.6, and 2.7 vs 5.6 mo, respectively); similar results were observed for median OS (6.9, 5.9, 5.2, and 8.4 vs 12.1 mo), ORR (5%, 4%, 6%, and 3% vs 35%), and clinical benefit rate (CBR; 8%, 6%, 10%, and 14% vs 45%). Key grade ≥3 treatment-related adverse events (TRAEs) with TPC overall vs SG included neutropenia (33% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), and anemia (5% vs 8%). Key grade ≥3 TRAEs with eribulin vs SG included neutropenia (30% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), anemia (2% vs 8%), and peripheral neuropathy (2% vs none), respectively. The safety profiles of vinorelbine, capecitabine, and gemcitabine combined were consistent with that of TPC overall and with eribulin. One treatment-related death was reported for the TPC arm (eribulin) and none with SG. Conclusions: The efficacy benefit observed with SG vs TPC in pts with mTNBC was retained when evaluating each TPC chemotherapy agent individually. These results confirm that SG should be considered as a new standard of care in pts with pretreated mTNBC. Clinical trial information: NCT02574455 .

Phase III postneoadjuvant study evaluating sacituzumab govitecan, an antibody drug conjugate in primary HER2-negative breast cancer patients with high relapse risk after standard neoadjuvant treatment: SASCIA.

TPS602 Background: Women with triple-negative breast cancer (TNBC) having residual disease after neoadjuvant chemotherapy (NACT) as well as HR-positive/HER2-negative breast cancer (BC) with a CPS (clinical and post treatment pathological stage) +EG (estrogen receptor status and grade) score ≥ 3 or score 2 and nodal involvement after NACT (ypN+) are at high risk of recurrence. Sacituzumab govitecan is approved for the treatment of patients with metastatic TNBC who received at least two prior therapies for metastatic disease and has shown activity in heavily pretreated patients with metastatic HR-positive/HER2-negative BC. Therefore, sacituzumab govitecan may represent a new option against the resistant residual disease after standard NACT. Methods: SASCIA is a phase III, prospective, international, multi-center, randomized, open label, parallel group study in patients with HER2-negative BC with residual disease after NACT (NCT04595565). Eligible patients must have received taxane-based NACT for 16 weeks, including at least 6 weeks of a taxane. Patients should be at high risk of recurrence after treatment, defined as having centrally confirmed HER2-negative BC (IHC score 0-1 or FISH negative according to ASCO/CAP guideline) assessed preferably on tissue from postneoadjuvant residual invasive disease of the breast and either HR-negative (<1% positive stained cells), with any residual invasive disease > ypT1mi after NACT or HR-positive (≥1% positive stained cells), with a CPS+EG score ≥ 3 or CPS+EG score 2 and ypN+ using local ER and grade assessed on core biopsies taken before NACT. Radiotherapy should be delivered before the start of study treatment. Patients are randomized 1:1 to receive either sacituzumab govitecan 10 mg/kg body weight (days 1, 8 q3w for eight cycles) or treatment of physician´s choice (capecitabine 2000 mg/m² day 1-14 q21 or platinum-based chemotherapy i.e. carboplatin AUC 5 q3w or AUC 1.5 weekly for eight 3 weekly cycles or observation). Randomization is stratified by HR status (HR-positive vs negative) and nodal involvement after NACT (ypN+ vs ypN0). In patients with HR-positive BC, endocrine-based therapy will be administered according to local guidelines. The primary endpoint is invasive disease-free survival (iDFS). Secondary endpoints include comparison of overall survival (OS, key secondary endpoint), distant disease-free survival, locoregional recurrences-free interval, safety, compliance, iDFS and OS according to stratified and - predefined subgroups, patient reported outcome, and quality of life between treatment arms. As of February 2 2021, 7/1200 patients have been randomized in Germany. International study groups will join soon. Clinical trial information: NCT04595565.

Assessment of sacituzumab govitecan (SG) in patients with prior neoadjuvant/adjuvant chemotherapy in the phase 3 ASCENT study in metastatic triple-negative breast cancer (mTNBC).

1080 Background: mTNBC is a heterogenous disease with few treatment options and poor outcomes. Pts who recur ≤ 12 mo after completing (neo)adjuvant chemotherapy may represent a subset with more aggressive disease. SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received accelerated approval for pts with mTNBC who received ≥ 2 prior therapies for metastatic disease; clinical benefit for SG over treatment of physician's choice (TPC) was confirmed in the phase 3 ASCENT study (NCT02574455) for median progression-free survival (PFS; 5.6 vs 1.7 mo), median overall survival (OS; 12.1 vs 6.7 mo), objective response rate (ORR; 35% vs 5%), clinical benefit rate (CBR; 45% vs 9%), and median duration of response (6.3 vs 3.6 mo). This ASCENT subanalysis of pts with mTNBC who recurred ≤ 12 mo after (neo)adjuvant chemotherapy and then only received 1 line of therapy in the metastatic setting assessed the benefit of SG in this subgroup vs the overall trial population. Methods: In ASCENT, pts with mTNBC refractory/relapsing after ≥ 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine). Per protocol, a pt was eligible after only 1 prior regimen in the metastatic setting if their disease recurred within 12 months of completing (neo)adjuvant therapy. Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Efficacy and safety was assessed in a subset of pts who recurred ≤ 12 mo after (neo)adjuvant chemotherapy and then received 1 line of therapy in the metastatic setting. Results: In total, 33 and 32 BMNeg pts with a median age of 49 and 51 yrs received SG and TPC in this subgroup, respectively. In this subgroup, treatment with SG (vs TPC) improved PFS (median 5.7 vs 1.5 mo; HR, 0.41; 95% CI, 0.22-0.76; P = 0.0049) and OS (median 10.9 vs 4.9 mo; HR, 0.51; 95% CI, 0.28-0.91; P = 0.0227). We also observed higher ORR (30% vs 3%) and CBR (42% vs 6%) with a median response duration of 6.7 mo with SG vs not calculable with TPC. The efficacy results from this subgroup are similar to those for SG vs TPC in the overall BMNeg population. The safety profile of SG in pts in this subgroup was consistent with prior reports. There were no treatment-related deaths with SG. Conclusions: Pts with mTNBC who recurred ≤ 12 mo after (neo)adjuvant therapy and then had 1 line of prior therapy in the metastatic setting may represent a subset with more aggressive disease. In this subgroup, pts had superior outcomes with SG vs TPC in the second-line metastatic setting, consistent with the benefit seen in the overall BMNeg population. Studies are ongoing (NeoSTAR, NCT04230109; SASCIA, NCT04595565) to evaluate SG as an earlier-line treatment option for TNBC. Clinical trial information: NCT02574455 .

A first-in-human study of AO-176, a highly differentiated anti-CD47 antibody, in patients with advanced solid tumors.

2516 Background: AO-176 is a humanized IgG2 antibody that specifically targets CD47. Expressed by multiple tumor types, CD47 binds to signal regulatory protein a (SIRPa) on phagocytes, including macrophages and dendritic cells. The CD47-SIRPa complex results in a “don’t eat me” signal that allows the tumor to escape removal by the innate immune system, disabling the generation of an adaptive immune response. The differentiated mechanisms of action of AO-176 include promotion of phagocytosis, direct tumor cell killing through programmed cell death type III and induction of damage associated molecular patterns/immunogenic cell death, preferentially binding to tumor cells vs. normal cells, and enhanced binding at an acidic pH as found in tumor microenvironments. AO-176 has negligible binding to RBCs. Methods: In a phase 1/2 first-in-human study (NCT03834948) of AO-176, pts with advanced solid tumors associated with high CD47 expression and an ECOG PS of 0-1 were enrolled into escalating dose cohorts of AO-176 given IV every 7 days. Objectives included evaluation of safety, dose-limiting toxicity (DLT) and recommended phase 2 dose (RP2D), antitumor activity, pharmacokinetic (PK) parameters and exploratory biomarkers. Results: As of 4 Jan 2021, 27 pts were enrolled (median age 64 years; 67% female; 67% ECOG PS 1; median [range] of 4 [1-7] prior therapies for metastatic disease). Dose levels of 1, 3, 10, 20 and 20 (using step-up dosing) mg/kg were evaluated in >250 infusions. Most common (>10%) treatment-related adverse events (TRAEs) of any grade were thrombocytopenia and infusion-related reaction (IRR) (33% each), anemia (22%) with no evidence of hemolysis, nausea (19%), and fatigue (15%). The only G3+ TRAE occurring in >10% of pts was asymptomatic, brief thrombocytopenia (22%). No platelet transfusions were given. DLTs included IRRs in 2 pts dosed at 20 mg/kg, and asymptomatic thrombocytopenia and a cerebrovascular accident in 1 pt each in the 20 mg/kg step-up cohort. The RP2D was 10 mg/kg. Implementation of additional pre-medication and a 6-hr infusion duration in cycle 1 eliminated subsequent IRRs. Dexamethasone tapering and shortening of the infusion duration to 2 hrs was successful in all pts after cycle 1. Interim PK analysis of AO-176 demonstrated consistent exposure with linear PK. The T1/2 was ̃5 days. One pt with endometrial carcinoma who had not responded to any of 4 prior systemic regimens had a confirmed PR and remains on study for >1 year. 7 pts had SD as a best response, with 2 pts (endometrial carcinoma, gastric cancer) on study for >6 mos. Conclusions: AO-176 is a well-tolerated, differentiated anti-CD47 therapeutic. Durable anti-tumor activity was observed. Evaluations of AO-176 in combination with paclitaxel in pts with select solid tumors (NCT03834948) and as a single-agent in pts with multiple myeloma (NCT04445701) are ongoing. Clinical trial information: NCT03834948.

Cost-effectiveness of trifluridine/tipiracil as a third-line treatment of metastatic gastric cancer, including adenocarcinoma of the gastrohesophageal junction, among patients previously treated in Greece

ABSTRACT Objective: To evaluate the cost-effectiveness of trifluridine/tipiracil (FTD/TPI) compared with best supportive care (BSC) for the treatment of patients with metastatic gastric cancer(mGC), including gastroesophageal junction adenocarcinoma(GEJ), who have received at least two prior therapies for metastatic disease and are eligible for third-line treatment, in Greece. Methods: A partitioned survival model was locally adapted from a public payer perspective over a 10-year time horizon. Clinical, safety and utility data were extracted from literature. Resource consumption data obtained from a panel of local experts using a questionnaire developed for the study was combined with unit costs obtained from official sources. All costs reflect the year 2020 (€). Outcomes of the model were patients’ life years (LYs) and quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratio (ICER) per QALY and LY gained. Results: The total cost per patient was estimated to be €6,965 for FTD/TPI and €1,906 for BSC, while FTD/TPI was associated with 0.180 and 0.107 increments in LYs and QALYs, respectively, compared with BSC, resulting in an ICER of €47,144 per QALY gained and €28,112 per LY gained. Conclusion: FTD/TPI was estimated to be a cost-effective treatment option for eligible third line mGC patients, including GEJ in Greece.

Abstract OT-09-03: EMBER: A phase 1a/b trial of LY3484356, a novel, oral selective estrogen-receptor degrader (SERD), in advanced ER+ breast cancer and endometroid endometrial cancer

Abstract Background: Estrogen receptor (ER) is the key therapeutic target for the most common breast cancer (BC) subtype affecting patients worldwide. Novel degraders and antagonists of ER are under evaluation, to overcome both ER mediated resistance and the bioavailability and dosing limitations of fulvestrant (fulv), the only approved SERD. ER is also overexpressed in approximately 80% of endometroid endometrial cancers and endocrine therapy (ET) is a standard of care (SOC) option for this disease, though no ER-directed therapies are specifically approved in this setting. LY3484356 is a novel, orally bioavailable SERD with pure antagonistic properties which results in sustained inhibition of ER-dependent gene transcription and -cell growth. Preclinically, LY3484356 monotherapy shows favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1 mutants, along with enhanced antitumor efficacy when combined with abemaciclib, everolimus, or alpelisib. This trial investigates LY3484356 alone and in combination with other SOC anticancer therapies, in women with ER+ advanced BC and ER+ endometroid endometrial cancer. Trial Design: This global first-in-human phase 1a/b, study of LY3484356, includes dose escalation of LY3484356 monotherapy (n=100), followed by dose expansion (n=360) at the recommended phase 2 dose (RP2D) of LY3484356 alone and in combination with other anticancer therapies (Table). Monotherapy dose escalation will be evaluated using an interval 3+3 design. In dose expansion (Parts A-D), each combination cohort will include a safety lead-in of 3-6 patients. Premenopausal women must receive concomitant treatment with a GnRH agonist. Eligibility criteria: Eligible patients must have pre- or post-menopausal ER+, HER2- or HER2+, advanced BC or ER+ endometroid endometrial cancer. ER+, HER2- BC patients must have either untreated de novo disease or prior ET sensitivity. In dose escalation, BC patients may have received up to 3 prior therapies for metastatic disease. In dose expansion, prior therapy requirements are outlined in the Table below. ER+ endometroid endometrial cancer patients must have progressed on platinum-based therapy. Key Study endpoints: Recommended phase 2 dose determination; safety and tolerability assessment, PK evaluation, objective response rate and clinical benefit rate assessment per RECIST v1.1. Recruitment for the EMBER study is ongoing (NCT04188548). Table. Dose Expansion (Phase 1b)Patient SubgroupKey EligibilityStudy DrugsER+, HER2- BC Randomized (Part A)-≤1 prior metastatic therapy-LY3484356 + Abemaciclib-No prior CDK4 & 6 inhibitor-LY3484356 + Abemaciclib + Physician’s Choice AI*ER+, HER2- BC (Part B)-≤2 prior metastatic therapies (≤1 prior ET)-LY3484356 monotherapy-Prior CDK4 & 6 inhibitor required-LY3484356 + Everolimus-No prior Everolimus/Alpelisib-LY3484356 + Alpelisib-PIK3CA mutation required for AlpelisibER+, HER2+ BC Randomized (Part C)-≥2 prior HER2 therapies-LY3484356 + Trastuzumab-No prior fulv or CDK4 & 6 inhibitor-LY3484356 + Trastuzumab + AbemaciclibER+ endometroid endometrial cancer Randomized (Part D)-Progressed on platinum-based therapy-LY3484356 monotherapy-No prior AI or fulv-LY3484356 + Abemaciclib* anastrozole, letrozole, or exemestane Citation Format: Elgene Lim, Murali Beeram, Amy Prawira, Amita Patnaik, Xuejing A Wang, Suzanne RL Young, Lillian M Smyth, Erika P. Hamilton. EMBER: A phase 1a/b trial of LY3484356, a novel, oral selective estrogen-receptor degrader (SERD), in advanced ER+ breast cancer and endometroid endometrial 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-09-03.

Abstract PS5-12: Preliminary correlative analysis of clinical outcomes with PIK3CA mutation (mut) status from a phase I/Ib study of GDC-0077 in patients (pts) with hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC)

Abstract Background Mutations in p110α, encoded by PIK3CA, are present in ~40% of HR+/HER2- BCs. GDC-0077, a PI3Kα-selective inhibitor and mutant PI3Kα degrader, elicits antitumor activity in PIK3CAmut preclinical models as a single agent and when combined with endocrine therapy (ET). New evidence suggests BCs harboring multiple PIK3CAmut exhibit increased signaling through the PI3K/AKT pathway and are more sensitive to PI3Kα inhibitors compared with BCs with a single PIK3CAmut. We report a preliminary analysis of PIK3CAmut status with clinical outcomes from an ongoing study of GDC-0077 alone or with ET (letrozole/fulvestrant) ± palbociclib (palbo) in pts with PIK3CAmut HR+/HER2- mBC (NCT03006172). Methods Detectable PIK3CAmut from local tumor tissue/blood-based assay or tumor tissue by cobas PIK3CA assay were required to enroll. Plasma-derived circulating tumor (ct) DNA was collected at baseline (BL), cycle 1 day 15 (C1D15), and C2D1 (in the cohort where GDC-0077 starts at C1D15) to detect PIK3CAmut. Paired tumor samples were analyzed for Ki67 and pAKT/pS6 expression by immunohistochemistry. Single vs multiple PIK3CAmut was correlated with the percentage of pharmacodynamic (PD) inhibition of Ki67/pAKT/pS6 expression; with the PIK3CAmut allele frequency ratio between BL and C1D15 or C2D1 (MAFr15); with best overall response (BOR, RECIST v1.1); and with time on treatment (TOT) in days. Statistical analyses: Kruskal-Wallis and Mann-Whitney-Wilcoxon for group and pairwise comparisons, respectively, and two-sample proportion testing for categorical comparisons. Results Data cutoff was 03/20/2020. PIK3CAmut were detected in 87/103 (84.5%) pts with BL ctDNA available for sequencing. Multiple PIK3CAmut were detected in 21/87 (24.1%) BL ctDNA samples: 9 from pts treated with single-agent GDC-0077; 8 from pts treated with GDC-0077 + letrozole/fulvestrant; and 4 from pts treated with GDC-0077 + letrozole/fulvestrant + palbo. The median number of lines of prior therapy for metastatic disease was not different between pts with multiple (3.0 lines) vs single (2.5 lines) PIK3CAmut detected at BL (p = 0.205). Median percentage inhibition of Ki67/pAKT/pS6 expression was greater in pts with multiple (-65.8, -70.3, -66.8%, respectively) vs single (-42.1, -34.1, -29.5%) PIK3CAmut detected at BL (p = 0.095, 0.002, 0.056). Median MAFr15 was lower in pts with multiple (MAFr15 0.01) vs single PIK3CAmut (MAFr15 0.15) detected at BL (p = 0.004). Of 73 pts with both BL ctDNA-detected PIK3CAmut and BOR data, 16/16 (100%) with multiple PIK3CAmut experienced BOR of partial response (PR) or stable disease (SD) while 42/57 (73.7%) with single PIK3CAmut experienced BOR of PR or SD (p = 0.051). No pts with multiple PIK3CAmut detected experienced a BOR of progressive disease. Median TOT was greater in pts with multiple PIK3CAmut (196 days) vs single PIK3CAmut (140.5 days) detected at BL, but this was not significant (p = 0.1804). Conclusions The fraction of pts in which multiple PIK3CAmut were identified from BL ctDNA in this HR+/HER2- mBC dataset (24.1%) was slightly higher than reported elsewhere. This may be due to the method of detection (blood vs tissue) and/or the definition of multiple PIK3CAmut used. Pts in which multiple PIK3CAmut were detected by ctDNA exhibited greater depth of PD biomarker inhibition in tumors and experienced PR/SD more often compared with pts in which only one PIK3CAmut was detected. However, no significant associations were observed with the number of prior lines of therapy for metastatic disease or TOT. The dataset is currently too small to assess the impact of different treatment regimens in this study but will be re-evaluated as the data mature. Citation Format: Komal Jhaveri, Dejan Juric, Andrea Varga, Nicolas Turner, Peter Schmid, Cristina Saura, Mafalda Oliveira, Ian E Krop, Kevin Kalinsky, Antoine Italiano, Erika Hamilton, Valentina Gambardella, Andrés Cervantes, Philippe L Bedard, Bonnie P Liu, Jessica W Chen, Junko Aimi, Stephanie Royer-Joo, Jennifer L Schutzman, Katherine E Hutchinson. Preliminary correlative analysis of clinical outcomes with PIK3CA mutation (mut) status from a phase I/Ib study of GDC-0077 in patients (pts) with hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2- mBC) [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 PS5-12.