Blinded Independent Central Review Research Articles

Abstract PO1-05-09: ASCENT-07: A phase 3, randomized, open-label study of sacituzumab govitecan versus treatment of physician’s choice in patients with HR+/HER2– inoperable, locally advanced, or metastatic breast cancer post-endocrine therapy

Abstract Background: Approximately 70% of all breast cancer (BC) cases are hormone receptor positive/human epidermal growth factor receptor 2-negative (HR+/HER2–), with ~65% of these being HR+/HER2-low (immunohistochemistry [IHC]1+, IHC2+/in situ hybridization [ISH]–). Despite an increasing number of available endocrine and targeted treatments for metastatic disease, tumors eventually develop resistance to endocrine therapy (ET). Chemotherapy, the standard of care for patients (pts) whose cancers no longer respond to ET, is associated with poor outcomes, representing a high unmet need in the first-line endocrine-resistant setting. Sacituzumab govitecan (SG) is a Trop-2–directed antibody-drug conjugate (ADC) that delivers SN-38 (the active metabolite of the topoisomerase inhibitor irinotecan) to tumor cells via internalization, and to the surrounding tumor microenvironment via the bystander effect. SG demonstrated a significant and clinically meaningful survival benefit in the phase 3, randomized TROPiCS-02 trial, and is approved in the US for inoperable, locally advanced, or metastatic HR+/HER2– BC after ET and ≥ 2 systemic therapies in the metastatic setting. ASCENT-07 will examine the efficacy and safety of SG in the first-line chemotherapy setting, ie, in patients with inoperable, locally advanced, or metastatic ET resistant HR+/HER2– BC. Study design: ASCENT-07 (NCT05840211) is a randomized, open-label, global study evaluating SG versus treatment of physician’s choice (TPC) chemotherapy in pts with HR+/HER2– inoperable, locally advanced, or metastatic BC who have received ET and are eligible for their first chemotherapy for advanced/metastatic disease. Pts aged ≥ 18 years with histologically confirmed HR+/HER2– (HER2 IHC0 or HER2-low [IHC1+, IHC2+/ISH–]) according to ASCO/CAP criteria, measurable disease per RECIST v1.1, and ECOG performance status of 0 or 1 will be included. Pts are eligible if they meet ≥ 1 of the following criteria: progressive disease (PD) in the metastatic setting on ≥ 2 lines of ET (± targeted therapy) (disease recurrence within the first 24 months of starting adjuvant ET is considered a line of therapy), PD within 6 months of first-line ET (± CDK 4/6 inhibitor) in the metastatic setting, or disease recurrence within 24 months of adjuvant ET with CDK 4/6 inhibitor initiation and no longer a candidate for additional ET. PD on the most recent therapy will be documented by CT or MRI per RECIST v1.1. Key exclusion criteria include prior treatment targeting topoisomerase I. Pts will be randomized to SG 10 mg/kg IV on days 1 and 8 of a 21-day cycle or TPC (capecitabine, paclitaxel, nab-paclitaxel). The primary endpoint is progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST v1.1 criteria or death from any cause, whichever comes first. Secondary endpoints include PFS (assessed by the investigator), overall survival, objective response rate and duration of response per BICR and investigator, and quality of life (QoL) assessed using the EORTC QLQ-C30 cancer questionnaire (primarily change in the Physical Functioning domain at week 16 and time to deterioration in the Global Health Status/QoL domain). Pharmacokinetics and immunogenicity analyses will be undertaken in pts receiving SG. Incidence of adverse events and serious adverse events, including relationship to study drug(s), will be reported. Laboratory and vital signs will be monitored. ASCENT-07 is currently open for recruitment and requires ~654 eligible pts to provide adequate power for assessment of the primary and key secondary endpoints. Citation Format: Hope Rugo, Javier Cortés, Giuseppe Curigliano, Carlos Barrios, Kevin Punie, Yeon Park, Hiroji Iwata, Alex Young, Xuehan Ren, Pelin Cinar, Komal Jhaveri. ASCENT-07: A phase 3, randomized, open-label study of sacituzumab govitecan versus treatment of physician’s choice in patients with HR+/HER2– inoperable, locally advanced, or metastatic breast cancer post-endocrine therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-05-09.

Abstract PO2-19-10: CAPItello-292 Phase 3: An open-label, randomized study of capivasertib, fulvestrant, and investigator’s choice of CDK4/6 inhibitor (palbociclib or ribociclib) in HR+/HER2– advanced breast cancer

Abstract Background: Overcoming resistance to endocrine therapy in advanced breast cancer (ABC) is a major challenge, and there remains an unmet need for safe and efficacious treatment options. AKT pathway activation is implicated in resistance to endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) ABC. In the Phase 3 CAPItello-291 study, capivasertib (a potent inhibitor of all three AKT isoforms) plus fulvestrant significantly improved progression-free survival (PFS) versus fulvestrant in patients with aromatase inhibitor-resistant HR+/HER2– ABC. Simultaneous inhibition of the AKT and CDK4/6 pathways may delay CDK4/6 inhibitor resistance or re-sensitize tumors to endocrine therapy plus CDK4/6 inhibitors, leading to improved clinical outcomes. CAPItello-292 is an ongoing Phase 1b/3 study examining the efficacy and safety of adding capivasertib to fulvestrant plus a CDK4/6 inhibitor in HR+/HER2– ABC. Phase 1b has previously confirmed the recommended Phase 3 dose (RP3D) in combination with palbociclib to be tolerable with preliminary signals of clinical activity; determination of the RP3D in combination with ribociclib is currently being explored. Trial design: The Phase 3 component of CAPItello-292 is an open-label, randomized study assessing the efficacy of the addition of capivasertib to fulvestrant and the investigator’s choice of CDK4/6 inhibitors (either palbociclib or ribociclib) in patients with HR+/HER2− ABC following recurrence or progression on or within 12 months of the end of (neo)adjuvant endocrine therapy (HER2− defined as immunohistochemistry [IHC] 0, or 1-positive or IHC2-positive/in situ hybridization-negative). Approximately 628 patients will be randomized 1:1 to receive capivasertib (400 mg, oral twice daily, 4 days on and 3 days off) plus fulvestrant (500 mg intramuscularly every 28 days plus loading dose on cycle 1, day 15) and investigator’s choice of CDK4/6 inhibitor (125 mg palbociclib once daily for 21 days of each 28-day cycle or ribociclib at the determined RP3D) or fulvestrant plus investigator’s choice of CDK4/6 inhibitor alone. Patients will be treated until disease progression, unacceptable tolerability, or withdrawal of consent. Treatment beyond progression is permitted for patients with clinical benefit at the investigator’s discretion. The primary endpoint is PFS (by blinded independent central review [BICR]). The secondary endpoints include PFS in patients with AKT pathway-altered tumors, overall survival, time to second progression or death, objective response rate, duration of response, clinical benefit rate (all by BICR), physical functioning, global health status/quality of life and safety. The study plans to enroll patients from 23 countries and is planned to start at the end of 2023. Clinical trial identification: NCT04862663. Funding: CAPItello-292 is supported by AstraZeneca Editorial acknowledgment: AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). Citation Format: Hope Rugo, Barbara Pistilli, Julie Collins, Celina D’Cruz, Christopher Gresty, Roberto Sommavilla, Dhivya Sudhan, Claire Miller, Juyoung Ha, Patrick Neven. CAPItello-292 Phase 3: An open-label, randomized study of capivasertib, fulvestrant, and investigator’s choice of CDK4/6 inhibitor (palbociclib or ribociclib) in HR+/HER2– advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-10.

Abstract PO2-19-08: INAVO121: Phase III study of inavolisib + fulvestrant vs alpelisib + fulvestrant in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer

Abstract BACKGROUND Standard-of-care (SoC) endocrine therapy (ET) for patients (pts) with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer (HR+, HER2–, PIK3CA-mut LA/mBC) was transformed by combinations with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is); a CDK4/6i-based combination is approved in high-risk early BC. However, in most pts, mechanisms of resistance that emerge during or after treatment with a CDK4/6i and ET combination lead to relapse/disease progression. Dysregulating mutations in PIK3CA, occurring in ~40% of HR+, HER2– BCs, represent a common mechanism of resistance to CDK4/6is and ET combinations. Alpelisib (ALP; a selective PI3Kα inhibitor; PI3Kαi) + fulvestrant (FUL) is approved for pts with HR+, HER2–, PIK3CA-mut LA/mBC, but its widespread implementation in clinical practice has been challenging. As such, there is a significant need to develop PI3Kαis with a better therapeutic index. Inavolisib (INAVO) is a highly potent and selective PI3Kαi that also facilitates the degradation of mutated PI3Kα isoform. INAVO has demonstrated manageable safety/tolerability, alone and in combination with SoC treatments in HR+, HER2–, PIK3CA-mut LA/mBC. Moreover, an ongoing Phase I trial showed that INAVO + FUL elicited encouraging preliminary antitumor activity in heavily pretreated pts, including a CDK4/6i-based regimen. TRIAL DESIGN INAVO121 is a Phase III, randomized, open-label study. Pts are randomized 1:1 to receive INAVO (9 mg oral daily; PO QD) + FUL (500 mg intramuscularly on Days [D] 1 and 15 of Cycle 1, then D1 of subsequent cycles), or ALP (300 mg PO QD) + FUL. Randomization is stratified by visceral disease (yes vs no) and prior CDK4/6i therapy (adjuvant vs metastatic setting). Pts will receive treatment until disease progression or unacceptable toxicity. ELIGIBILITY CRITERIA Pts have HR+, HER2–, PIK3CA-mut LA/mBC (confirmed by circulating-tumor DNA or tumor tissue), adequate hematologic and organ function, and disease progression after or during treatment with a CDK4/6i-based regimen. Up to two prior lines of systemic therapy in LA/mBC, including one line of chemotherapy, are allowed. AIMS The primary endpoint is progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints include overall survival, BICR-objective response rate, BICR-best overall response, BICR-duration of response, BICR-clinical benefit rate, safety, tolerability, pt-reported outcomes, and pharmacokinetics. STATISTICAL METHODS A stratified log-rank test at an overall 0.05 significance level (two-sided) will be used for the primary endpoint analysis. Median PFS will be estimated using Kaplan–Meier methodology. An independent data monitoring committee will be in place for safety and efficacy. ACCRUAL The study is open for enrollment and has randomized four pts; the study is targeting 400 pts at ~200 sites globally. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT05646862. This abstract was originally presented at ASCO 2023 (TPS1123). Citation Format: Dejan Juric, Kevin Kalinsky, Seock-Ah Im, Eva Ciruelos, Giampaolo Bianchini, Carlos Barrios, William Jacot, Peter Schmid, Sherene Loi, Hope Rugo, Veronica Craine, Katherine Hutchinson, Aulde Flechais, Eirini Thanopoulou, Nadia Harbeck. INAVO121: Phase III study of inavolisib + fulvestrant vs alpelisib + fulvestrant in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-08.

Abstract PO3-18-09: OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy

Abstract Background: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC), adding a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to endocrine therapy (ET) has improved outcomes and is the current standard-of-care treatment in the first-line setting. However, resistance to first-line treatment develops in most patients (pts), which is often attributed to acquired mutations in ESR1. Limited data exist for ET-based treatment options after progression on prior ET and CDK4/6 inhibitors, and most pts will transition to chemotherapy for further treatment. Therefore, there is a significant unmet need for more effective ET in pts with ER-positive, HER2-negative MBC to improve outcomes and delay time to chemotherapy. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant demonstrated better tumor shrinkage in ESR1-wt and ESR1-mut models when compared to fulvestrant; it also showed efficacy in brain metastasis models. In a phase 1/2 monotherapy study in pts with heavily pretreated ER-positive, HER2-negative advanced breast cancer (BC) or MBC (NCT04505826), palazestrant showed a tolerable safety profile, promising antitumor efficacy, and favorable pharmacokinetics (PK) supporting once a day (qd) dosing. The recommended Phase 2 dose of palazestrant is 120 mg qd. Methods: The OPERA-01 trial is an international, multicenter, randomized, open-label, phase 3 clinical trial comparing the efficacy and safety of palazestrant as a single agent to standard-of-care ET (fulvestrant, anastrozole, letrozole, or exemestane) in pts with ER-positive, HER2-negative advanced BC or MBC that has relapsed or progressed on 1 or 2 prior lines of ET for MBC, which includes a CDK4/6 inhibitor. Eligible pts are women (pre- or post-menopausal) or men who have a confirmed diagnosis of ER-positive, HER2-negative locally advanced evaluable BC or MBC not amenable to curative therapy. ER and HER2 status are determined according to the American Society of Clinical Oncology/College of American Pathologists guidelines. Patients must have Eastern Cooperative Oncology Group performance status 0 or 1. Prior treatments must include 1 or 2 prior lines of ET as monotherapy or in combination with a CDK4/6 inhibitor for MBC; must have received CDK4/6 inhibitor in combination with ET and have disease progression during or within 28 days of completion of each line of prior treatment for MBC; most recent ET given for ≥6 months. Prior chemotherapy in the metastatic setting is not permitted. Patients (N∼500) are randomized to palazestrant or standard-of-care ET monotherapy, and are stratified by ESR1 mutation status, prior lines of ET for advanced disease (1 vs 2 lines), and presence or absence of visceral disease. The primary endpoint of progression-free survival will be assessed by blinded independent central review in pts with and without ESR1 mutations in the intent-to-treat population. Secondary endpoints include overall survival, antitumor activity (objective response rate, clinical benefit rate, and duration of response), safety, patient-reported outcomes, and PK in pts with and without ESR1 mutations. The study is planned to be conducted globally. Citation Format: Arlene Chan, Jane Meisel, Komal Jhaveri, Joo Hyuk Sohn, Meritxell Bellet- Ezquerra, Jason Schroeder, Mark Shilkrut, Barbara Pistilli. OPERA-01: A randomized, open-label, phase 3, study of palazestrant (OP-1250) vs standard-of-care treatment for ER+, HER2- advanced or metastatic breast cancer after endocrine and CDK4/6 inhibitor therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-09.

Abstract PO2-20-03: VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is a selective, orally administered PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader. In the phase 2 portion (VERITAC) of a first-in-human phase 1/2 study (NCT04072952), vepdegestrant 200 mg once daily (QD) was well tolerated and had clinical activity in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer and was selected as the recommended phase 3 dose (RP3D) for vepdegestrant monotherapy. A phase 1b cohort of the phase 1/2 study is evaluating the safety and clinical activity of vepdegestrant plus palbociclib in patients with ER+/HER2- breast cancer after prior endocrine-based therapy; prior cyclin-dependent kinase (CDK)4/6 inhibitor therapy was permitted. Preliminary results showed encouraging activity for the combination based on clinical benefit rate (CBR; rate of confirmed complete response, partial response, or stable disease ≥24 weeks); an increase in palbociclib exposure was observed relative to historical palbociclib pharmacokinetic data and was accompanied by a higher incidence of grade 3/4 neutropenia compared with prior palbociclib and endocrine therapy combination studies, which was managed by monitoring and standard palbociclib dose modifications. The global, randomized phase 3 VERITAC-3 study (NCT05909397) will compare the efficacy and safety of vepdegestrant plus palbociclib vs letrozole plus palbociclib as first-line treatment for patients with ER+/HER2- advanced breast cancer. An open-label study lead-in (SLI) will evaluate the safety and tolerability of vepdegestrant 200 mg QD plus 2 doses of palbociclib (100 mg QD and 75 mg QD) in patients with ER+/HER2- advanced breast cancer to select the RP3D of palbociclib for this combination. Trial Design: Approximately 50 and 1130 patients will be enrolled in the SLI and the phase 3 parts of the study, respectively. Eligible patients (aged ≥18 years) must have histologically or cytologically confirmed ER+/HER2- locoregionally recurrent or metastatic breast cancer, with no prior treatment in the advanced setting, and no prior treatment in any setting with CDK4/6 inhibitors, vepdegestrant, fulvestrant, elacestrant, or other investigational agents (including novel endocrine therapy, selective ER degraders, selective ER covalent antagonists, and complete ER antagonists). Patients with measurable disease per RECIST v1.1 or nonmeasurable bone-only disease are eligible. Patients with disease recurrence during or ≤12 months after completion of adjuvant endocrine therapy are excluded. For the SLI, patients are randomized 1:1 to receive vepdegestrant 200 mg QD in combination with palbociclib 100 mg QD or 75 mg QD and are treated in 28-day cycles with vepdegestrant given continuously and palbociclib given for 21 days followed by 7 days off treatment. The objective of the SLI is to identify the RP3D of palbociclib in combination with vepdegestrant, which will be determined through the primary outcome measures of incidence of grade 4 neutropenia, study drug dose reduction, and study drug discontinuation within the first 4 cycles of treatment. Secondary outcome measures include safety, antitumor activity (objective response rate, CBR, and duration of response), and plasma concentrations of study drugs. In the planned phase 3 portion of the trial, patients will be randomized to vepdegestrant plus palbociclib or letrozole plus palbociclib. The primary efficacy endpoint of the phase 3 portion is progression-free survival based on blinded independent central review. Enrollment began June 2023 and is ongoing. Citation Format: Seth Wander, Erika Hamilton, Mario Campone, Michael Danso, Sara Hurvitz, Hiroji Iwata, Colombe Chappey, Derek Yang, Julia Perkins Smith, Yuan Liu, Yuanyuan Zhang, Sibyl Anderson, Michelino de Laurentiis. VERITAC-3: A randomized phase 3 study, with a lead-in, of first-line vepdegestrant + palbociclib vs letrozole + palbociclib in estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-03.

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

Abstract Background: The global, phase 3 TROPION-Breast01 trial (NCT05104866) assessed the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) compared with investigator’s choice of chemotherapy (ICC) in patients (pts) with inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2‒) breast cancer (BC). Primary results were presented at ESMO 2023 (Bardia A, et al. Abstract LBA11). Here we report expanded data from TROPION-Breast01. Methods: Pts aged ≥18 years who had inoperable or metastatic HR+/HER2‒ BC, had disease progression on endocrine therapy (ET) and for whom ET was unsuitable, and had received 1‒2 prior lines of systemic chemotherapy (CT), were eligible. Pts were randomized 1:1 to Dato-DXd (6 mg/kg Q3W) or ICC (eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. The dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1, and overall survival (OS). Results: In total, 732 pts were randomized: 365 to the Dato-DXd arm and 367 to ICC. At data cut-off (Jul 17, 2023), 93/39 pts in the Dato-DXd/ICC groups were ongoing treatment. Pts receiving Dato-DXd had significantly improved PFS vs ICC (HR 0.63 [95% CI 0.52‒0.76]; p<0.0001). Hazard ratios for PFS favored Dato-DXd over ICC across prespecified pt subgroups, including prior lines of CT in the metastatic setting (1 vs 2), prior use of CDK4/6 inhibitor (≤12 months vs >12 months), prior use of endocrine therapy in the metastatic setting ( <6 months vs ≥6 months) and brain metastases (yes vs no). OS data were not mature at this data cut-off. In the Dato-DXd vs ICC arms, 192 (53%) vs 247 (67%) pts had received a subsequent therapy after study treatment discontinuation, including 15 (4%) vs 52 (14%) who received subsequent ADC therapy, and 165 (45%) vs 186 (51%) who received subsequent CT. Median time to first subsequent therapy was 8.2 months in the Dato-DXd arm vs 5.0 months in the ICC arm (HR 0.53 [95% CI 0.45–0.64). Overall, rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was less than half that with ICC. The secondary patient-reported outcome endpoints showed that time to deterioration in physical functioning, pain, and global health status/quality of life were delayed in the Dato-DXd arm compared with ICC. Conclusions: TROPION-Breast01 met its dual primary endpoint of PFS, demonstrating statistically significant and clinically meaningful improvement in PFS with Dato-DXd compared with ICC across all subgroups. Overall, the safety profile and QoL with Dato-DXd was favorable compared with ICC. These data support Dato-DXd as a potential new therapeutic option for pts with inoperable or metastatic HR+/HER2‒ BC who have received 1‒2 prior lines of CT. Citation Format: Aditya Bardia, Komal Jhaveri, Seock-Ah Im, Michelino De Laurentiis, Binghe Xu, Sonia Pernas, Giuliano Borges, David Cescon, Masaya Hattori, Yen-Shen Lu, Noelia Martínez-Jáñez, Erika Hamilton, Shusen Wang, Junji Tsurutani, Kevin Kalinsky, Lu Xu, Sabrina Khan, Neelima Denduluri, Hope Rugo, Barbara Pistilli. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-01.

Abstract PO3-04-02: Exposure-efficacy and safety analysis of trastuzumab deruxtecan (T-DXd) in patients with advanced/metastatic HER2+ breast cancer (BC): Analyses from Phase 3 Studies DESTINY-Breast02 (DB-02) and DESTINY-Breast03 (DB-03)

Abstract Exposure-efficacy and exposure-safety analyses of trastuzumab deruxtecan (T-DXd) in patients with advanced/metastatic HER2+ breast cancer (BC): Analyses from Phase 3 Studies DESTINY-Breast02 (DB-02) and DESTINY-Breast03 (DB-03) Authors: Claire Li1, Russ Wada2, Hanbin Li2, Helen Kastrissios2, Malaz Abutarif1, Tushar Garimella1 , Amit Khatri1 1Quantitative Clinical Pharmacology, Daiichi Sankyo, Basking Ridge, NJ, USA 2QuanTx Consulting Mountain View, CA, USA Background: T-DXd, an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for adult patients with unresectable or metastatic HER2+ BC with a prior anti-HER2–based therapy either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. The analysis evaluated the relationship between T-DXd pharmacokinetic (PK) exposure and efficacy/safety endpoints following 5.4 mg/kg Q3W in HER2+ BC subjects. Methods: Exposure-efficacy (E-E) analyses were evaluated from BC subjects in two Phase 3 studies, DB-02 (N=404 for T-DXd; 3L+ BC) and DB-03 (N=257 for T-DXd; 2L+ BC). In studies DB-02 and DB-03, 202 and 263 subjects in control arm were treated with treatment of investigator’s/physician’s choice (TPC) and T-DM1, respectively. Exposure-safety (E-S) analyses were conducted using 12 clinical studies ranging from Phase 1 to 3 (N=2216, 68.7% BC), including DB-02 and DB-03. Population PK-predicted exposure metrics included T-DXd and DXd peak concentration, trough concentration, and AUC in Cycle 1 and at steady state. Key efficacy endpoints were progression-free survival (PFS) based on blinded independent central review (BICR) and overall survival (OS). Safety endpoints included any Grade and Grade ≥ 3 adjudicated drug-related interstitial lung disease (ILD). Exploratory analyses were conducted for other safety endpoints (i.e., Grade ≥ 3 TEAEs). Results: T-DXd exposure was a significant predictor (p< 0.01) of OS in DB-02. In study DB-03, T-DXd exposure was a marginally significant covariate (p< 0.05) for OS in univariate Cox regression but was dropped in the multivariate analysis. The relationship between T-DXd exposure and PFS in both studies were not statistically significant (p >0.01), suggesting a flat E-E relationship due to the narrow exposure range resulting from the single-dose level (5.4 mg/kg Q3W) in both studies. Clinically meaningful efficacy in the T-DXd arm relative to the control arm was observed in both studies (PFS: 17.8 months [T-DXd arm] vs. 6.9 months [TPC arm] in study DB-02 and 28.8 months [T-DXd arm] vs. 6.8 months [T-DM- arm] in study DB-03). Therefore, the E-E analyses supports clinically meaningful efficacy across the entire exposure range with the T-DXd 5.4 mg/kg dose in BC subjects. For E-S, a statistically significant relationship (p< 0.001) was observed between increasing T-DXd exposures across all the dose levels (0.8 to 8 mg/kg) and increasing hazard of any Grade and Grade ≥ 3 ILD. The predicted Day 360 incidence rate of any Grade and Grade ≥3 ILD at 5.4 mg/kg Q3W T-DXd in BC subjects was 14.8% and 3%, respectively. These findings are consistent with previous safety analyses. Observed rates of the exploratory safety endpoints were also generally consistent with previous model-predicted rates of adverse events in BC1. Conclusions: The E-E analyses support clinically meaningful efficacy (PFS and OS) relative to control with a flat exposure-response relationship in HER2+ BC subjects at the T-DXd 5.4 mg/kg dose. The E-S analyses showed any Grade and Grade ≥ 3 ILD event rates for this dose are comparable to prior studies1. Those event rates appeared to increase with increasing T-DXd exposures. Overall, these model-based analyses continue to support T-DXd 5.4 mg/kg Q3W dosing in previously treated HER2+ BC. Reference: Yin O, Iwata H, Lin, C, et al. Exposure-Response Relationships in Patients with HER2-Positive Metastatic Breast Cancer and Other Solid Tumors Treated with Trastuzumab Deruxtecan. J Clin Pharm Ther. 2021; 110(4):986-96 Citation Format: Claire Li, Russ Wada, Hanbin Li, Helen kastrissios, malaz Abutarif, Tushar Garimella, Amit Khatri. Exposure-efficacy and safety analysis of trastuzumab deruxtecan (T-DXd) in patients with advanced/metastatic HER2+ breast cancer (BC): Analyses from Phase 3 Studies DESTINY-Breast02 (DB-02) and DESTINY-Breast03 (DB-03) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-02.

Abstract PO2-20-02: A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1)

Abstract Patients who receive frontline CDK4/6 inhibitor (CDK4/6i) therapy eventually experience disease progression. Resistance to CDK4/6i is likely a transient adaptive mechanism that may be reversed by inhibition of the PI3K/mTOR pathway. Thus, combination of CDK4/6i and PI3K/mTORi after disease progression on CDK4/6i could restore sensitivity to CDK4/6i and prevent activation of the PI3K/mTOR pathway. This hypothesis was evaluated in a Phase 1b study (Layman SABCS 2021) of gedatolisib (geda), a potent inhibitor of PI3K and mTOR. Subjects with HR+/HER2- ABC treated with prior CDK4/6i received geda (180 mg IV weekly for 3 weeks, then one week off) with palbociclib (P) and fulvestrant (F). Median PFS was 12.9 months with 63% overall response rate. Efficacy was observed regardless of PIK3CA mutation status (Wesolowski SABCS 2022). Geda was well tolerated, with few discontinuations due to treatment-related adverse events (4%). The most common AE was stomatitis; hyperglycemia of any grade occurred in 26% of patients. This preliminary data, dosing schedule, and study population characteristics form the basis for the Phase 3 trial, VIKTORIA-1. This Phase 3 multinational clinical trial will evaluate geda and F with or without P in patients with HR+/HER2- ABC previously treated with any CDK4/6i in combination with a non-steroidal aromatase inhibitor (AI) therapy. Those without tumor PIK3CA mutations will be assigned to Study 1 (n=351) and randomized to Arm A (geda, P, and F), Arm B (geda and F), or Arm C (F). Those with PIK3CA mutations will be assigned to Study 2 (n=350) and randomized to Arm D (geda, P, and F), Arm E (alpelisib and F), or Arm F (geda and F). Key eligibility criteria include adults with confirmed metastatic or locally advanced breast cancer, any menopausal status, radiologically evaluable disease, and prior CDK4/6i treatment in combination with a non-steroidal AI. Prior hormonal therapy, including SERDs, is allowed. Key exclusion criteria include prior treatment with a PI3K, Akt, or mTOR inhibitor, prior treatment with chemotherapy for advanced disease, more than two lines of prior endocrine therapy, bone only disease with no soft tissue components, active CNS metastases, and type 1 diabetes or uncontrolled type 2 diabetes. The primary endpoint is PFS assessed by blinded independent central review per RECIST v1.1. Secondary endpoints included overall survival (OS), safety and tolerability, ORR, duration of response, time to response, CBR, quality of life, and pharmacokinetics. Enrollment is ongoing. This trial abstract was previously presented at the 2022 San Antonio Breast Cancer Symposium, December 6-10, 2022. Citation Format: Sara Hurvitz, Fabrice André, Massimo Cristofanilli, Giuseppe Curigliano, Antonio Giordano, Hyo Han, Miguel Martín, Barbara Pistilli, Hope Rugo, Robert Wesolowski, Igor Gorbatchevsky, Sibylle Loibl. A Phase 3 study of gedatolisib plus fulvestrant with and without palbociclib in patients with HR+/HER2- advanced breast cancer previously treated with a CDK4/6 inhibitor plus a non-steroidal aromatase inhibitor (VIKTORIA-1) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-02.

Abstract PO1-19-12: VERITAC-2: a phase 3 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer

Abstract Background: Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds to and degrades wild-type ER and clinically relevant mutants. Vepdegestrant directly recruits the ubiquitin-proteasome system to degrade ER, whereas selective ER degraders (SERDs) indirectly cause ER degradation. In a first-in-human phase 1/2 study (NCT04072952), vepdegestrant monotherapy was well tolerated and showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The phase 3 monotherapy dose (200 mg once daily [QD]) was chosen due to comparable efficacy and favorable tolerability relative to 500 mg QD and robust ER degradation in paired tumor biopsies. The global, randomized phase 3 VERITAC-2 study (NCT05654623) will compare efficacy and safety of vepdegestrant vs the SERD fulvestrant in patients with ER+/HER2- advanced breast cancer after prior combination cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy and endocrine therapy (ET). Trial design: Eligible patients (aged ≥18 years) have a confirmed diagnosis of ER+/HER2- locoregional recurrent or metastatic breast cancer not amenable to surgical resection or radiation; 1 prior line of combination CDK4/6 inhibitor therapy and ET; ≤1 additional line of ET; most recent ET given for ≥6 months before disease progression; and radiological disease progression during or after the last line of therapy. Prior chemotherapy in the locally advanced or metastatic setting and prior fulvestrant are not permitted. Patients (N≈560) are randomized 1:1 to receive vepdegestrant 200 mg orally QD continuously or fulvestrant intramuscularly on days 1 and 15 in the first 28-day cycle and on day 1 in subsequent cycles; patients are stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint, progression-free survival, will be assessed by blinded independent central review in the intention-to-treat population and the ESR1 mutation subpopulation. Secondary outcome measures include overall survival, antitumor activity (objective response rate, duration of response, and clinical benefit rate), safety, and quality of life assessments. Citation Format: Mario Campone, Cynthia Ma, Michelino de Laurentiis, Hiroji Iwata, Sara Hurvitz, Seth Wander, Michael Danso, Dongrui Lu, Julia Perkins Smith, Yuan Liu, Lana Tran, Sibyl Anderson, Erika Hamilton. VERITAC-2: a phase 3 study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, vs fulvestrant in ER–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-12.

Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial

In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. Daiichi Sankyo and AstraZeneca.

Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2- and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study.

Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized antitrophoblast cell-surface antigen 2 (TROP2) monoclonal antibody linked to a potent, exatecan-derived topoisomerase I inhibitor payload via a plasma-stable, selectively cleavable linker. TROPION-PanTumor01 (ClinicalTrials.gov identifier: NCT03401385) is a phase I, dose-escalation, and dose-expansion study evaluating Dato-DXd in patients with previously treated solid tumors. The primary study objective was to assess the safety and tolerability of Dato-DXd. Secondary objectives included evaluation of antitumor activity and pharmacokinetics. Results from patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC) or triple-negative BC (TNBC) are reported. At data cutoff (July 22, 2022), 85 patients (HR+/HER2- BC = 41, and TNBC = 44) had received Dato-DXd. The objective response rate by blinded independent central review was 26.8% (95% CI, 14.2 to 42.9) and 31.8% (95% CI, 18.6 to 47.6) for patients with HR+/HER2- BC and TNBC, respectively. The median duration of response was not evaluable in the HR+/HER2- BC cohort and 16.8 months in the TNBC cohort. The median progression-free survival in patients with HR+/HER2- BC and TNBC was 8.3 and 4.4 months, respectively. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 100% and 41.5% of patients with HR+/HER2- BC and 100% and 52.3% of patients with TNBC. Stomatitis was the most common TEAE (any grade, grade ≥3) in both HR+/HER2- BC (82.9%, 9.8%) and TNBC (72.7%, 11.4%) cohorts. In patients with heavily pretreated advanced HR+/HER2- BC and TNBC, Dato-DXd demonstrated promising clinical activity and a manageable safety profile. Dato-DXd is currently being evaluated in phase III studies.

RESILIENT Part 2: A Randomized, Open-Label Phase III Study of Liposomal Irinotecan Versus Topotecan in Adults With Relapsed Small Cell Lung Cancer.

The phase III RESILIENT trial compared second-line liposomal irinotecan with topotecan in patients with small cell lung cancer (SCLC). Patients with SCLC and progression on or after first-line platinum-based chemotherapy were randomly assigned (1:1) to intravenous (IV) liposomal irinotecan (70 mg/m2 every 2 weeks in a 6-week cycle) or IV topotecan (1.5 mg/m2 daily for 5 consecutive days, every 3 weeks in a 6-week cycle). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) and objective response rate (ORR). Among 461 randomly assigned patients, 229 received liposomal irinotecan and 232 received topotecan. The median follow-up was 18.4 months. The median OS was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan (hazard ratio [HR], 1.11 [95% CI, 0.90 to 1.37]; P = .31). The median PFS per blinded independent central review (BICR) was 4.0 months with liposomal irinotecan and 3.3 months with topotecan (HR, 0.96 [95% CI, 0.77 to 1.20]; nominal P = .71); ORR per BICR was 44.1% (95% CI, 37.6 to 50.8) and 21.6% (16.4 to 27.4), respectively. Overall, 42.0% and 83.4% of patients receiving liposomal irinotecan and topotecan, respectively, experienced grade ≥3 related treatment-emergent adverse events (TEAEs). The most common grade ≥3 related TEAEs were diarrhea (13.7%), neutropenia (8.0%), and decreased neutrophil count (4.4%) with liposomal irinotecan and neutropenia (51.6%), anemia (30.9%), and leukopenia (29.1%) with topotecan. Liposomal irinotecan and topotecan demonstrated similar median OS and PFS in patients with relapsed SCLC. Although the primary end point of OS was not met, liposomal irinotecan demonstrated a higher ORR than topotecan. The safety profile of liposomal irinotecan was consistent with its known safety profile; no new safety concerns emerged.

Abstract CT283: Phase 3 MK-2870-007 study: MK-2870 (SKB264) plus pembrolizumab vs pembrolizumab alone as first-line treatment for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score (TPS) ≥50%

Abstract Background: Pembrolizumab (anti-PD-1) monotherapy is a standard of care first-line treatment for advanced or metastatic non-small-cell lung cancer (NSCLC) with PD-L1 TPS ≥50% without actionable genetic alterations; however, some patients do not respond to therapy or experience disease progression. Trophoblast cell-surface antigen 2 (TROP2) is another candidate for anticancer treatment and overexpression of TROP2 is associated with poor prognosis in patients with NSCLC. MK-2870 (SKB264) is an antibody-drug conjugate (ADC) composed of the humanized TROP2 monoclonal antibody, a hydrolytically cleavable linker, and the cytotoxic drug KL610023. In patients with relapsed or refractory locally advanced or metastatic NSCLC, MK-2870 monotherapy showed encouraging antitumor activity with a manageable safety profile. The complementary mechanisms of action of MK-2870 and pembrolizumab may provide more potent antitumor activity when given in combination compared with each therapy alone. To investigate this further, the MK-2870-007 study will evaluate the efficacy and safety of the addition of MK-2870 to pembrolizumab vs pembrolizumab alone in patients with previously untreated metastatic NSCLC with PD-L1 TPS ≥50%. Trial Design: Approximately 614 eligible patients aged ≥18 y with previously untreated histologically or cytologically confirmed stage IV (per American Joint Committee on Cancer v8.0) NSCLC, PD-L1 TPS ≥50% and no EGFR, ALK, or ROS1 alterations (nonsquamous only); ECOG PS 0 or 1; and measurable disease per RECIST v1.1 will be enrolled. Patients with well-controlled HIV are permitted. Patients will be randomized 1:1 to receive either pembrolizumab 400 mg Q6W for up to 18 cycles plus MK-2870 4 mg/kg Q2W or pembrolizumab 400 mg IV Q6W alone until progressive disease, intercurrent illness, patient withdrawal, unacceptable toxicity, prolonged interruption of study drug, or until maximum number of cycles (18 cycles for pembrolizumab). Randomization stratification factors include ECOG PS (0 vs 1), histology (squamous vs nonsquamous), TROP2 expression (low vs medium vs high), and geographic region (East Asia vs North America/Western Europe/Australia vs Rest of World). The primary endpoint is OS. Secondary endpoints include PFS, ORR, and duration of response per RECIST v1.1 by blinded independent central review, patient-reported outcomes, and safety. Tumor imaging will occur at baseline, Q6W until wk 48, and Q12W thereafter until PD, start of new anticancer treatment, or withdrawal of consent. PD-L1 TPS will be assessed centrally using PD-L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA). AEs will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Enrollment began in December 2023 and is currently ongoing. Citation Format: Nikolaj Frost, Razi Ghori, Ananya Roy, Ana Tablante Nunes, James Chih-Hsin Yang. Phase 3 MK-2870-007 study: MK-2870 (SKB264) plus pembrolizumab vs pembrolizumab alone as first-line treatment for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score (TPS) ≥50% [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 CT283.

Abstract CT152: FURTHER: A global study to evaluate furmonertinib in patients with EGFR mutant NSCLC including uncommon EGFR mutations

Abstract Background: Furmonertinib (AST2818) is an oral, highly brain-penetrant, and broadly active mutation-selective epidermal growth factor receptor (EGFR) inhibitor engineered for broad activity and selectivity across EGFR mutations (mts) (Musib et al., NACLC 2022). Furmonertinib is approved in China for first-line advanced NSCLC with EGFR Ex19del or L858R mts based on the positive Phase 3 study (FURLONG) versus gefitinib. Furmonertinib has also demonstrated promising interim efficacy and safety in patients (pts) with NSCLC with EGFR exon 20 insertion (ex20ins) mts with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median duration of response (DoR) of 15.2 months in the front-line setting (FAVOUR study; see Han et al., WCLC 2023). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the treatment of pts with advanced NSCLC with EGFR ex20ins mts. P-loop and αC-helix Compressing (PACC) mts represent another subset of uncommon EGFR mts (Robichaux et al., 2021) that are similar to ex20ins mts in narrowing the drug-binding pocket; including G719X, S768I, E709X, L747X, V774M. Preclinical data indicating that furmonertinib is potent in models harboring EGFR PACC mts will be presented at this meeting (Nilsson et al., Abstract #4174). Developing efficacious, well-tolerated, and CNS-penetrant medicines for NSCLC pts with EGFR ex20ins mts and PACC mts remains an unmet need. Methods: FURTHER (FURMO-002) is the first global trial evaluating furmonertinib in NSCLC pts with EGFR and HER2 mts in North America, Europe, and the Asia-Pacific. FURTHER is a phase 1b, open-label, multicenter study in which pts will be treated orally with furmonertinib daily. For Stage 1 dose-escalation, the primary endpoint is incidence and severity of adverse events, including dose limiting toxicities and has been completed. For Stage 2 dose expansion, approximately 120 pts will be enrolled across 4 expansion cohorts. Stage 2 Cohorts 1-3 dose expansion cohorts will enroll pts with previously treated, locally advanced or metastatic NSCLC pts with either EGFR ex20ins mts, HER2 ex20ins mts, or EGFR activating mts, respectively. Cohorts 1-3 allow enrollment of pts with prior EGFR or HER2-directed therapy. Stage 2 Cohort 4 will enroll EGFR TKI-naïve NSCLC pts with EGFR PACC mts. Key inclusion criteria include documented EGFR or HER2 mts by local testing and measurable disease per RECIST v1.1. Stage 2 primary endpoint is ORR using RECIST v1.1. Key secondary endpoints include progression-free survival and overall survival. Stage 2 enrollment is ongoing. Clinical trial information: NCT05364073. Citation Format: Xiuning Le, Alexander Spira, Shirish Gadgeel, Yan Yu, Yanqiu Zhao, Ying Cheng, Jonathan Riess, Oscar Juan-Vidal, Bo Gao, Kiyotaka Yoh, Martin Forster, Satoru Kitazono, Hidetoshi Hayashi, David Planchard, Yong Jiang, Jack Huang, Nichole Baio, Marcin Kowanetz, Shirley Wang, William Leung, Jerry Y. Hsu, Jie Wang. FURTHER: A global study to evaluate furmonertinib in patients with EGFR mutant NSCLC including uncommon EGFR mutations [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 CT152.

Abstract CT280: FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004)

Abstract Introduction: EGFR exon 20 insertion mutations occur in approximately 2% of non-small cell lung cancer (NSCLC) and overall account for approximately 9% of all the EGFR mutations in NSCLC (Robichaux et al., 2021). Current first-line standard of care for NSCLC patients with these mutations is platinum-based chemotherapy (NCCN NSCLC, 2023). Furmonertinib is an oral, highly brain penetrant, broadly active mutant-selective EGFR inhibitor that targets EGFR exon 20 insertions and other EGFR mutations (Musib et al., NACLC 2022). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the first line treatment of patients with advanced NSCLC with EGFR ex20ins based on the data from the FAVOUR study. Promising preliminary clinical activity was observed in the FAVOUR study testing furmonertinib (240 mg daily [QD]) in patients with treatment naïve locally advanced or metastatic NSCLC, with EGFR exon 20 insertion (ex20ins) mutations showing confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) with a preliminary median DOR of 15.2 months (Han et al., WCLC 2023). In previously treated patients both the 240 mg and 160 mg QD dose levels were active with confirmed ORR of 46.2% (n=26) and 38.5% (n=26) respectively, and included patients harboring near and far loop mutations.Furmonertinib showed a generally well-tolerated safety profile with expected EGFR-TKI class toxicities. Additional furmonertinib preclinical data in uncommon EGFR mutations, including P-loop and αC-helix Compressing (PACC) and ex20ins mutations will be presented at the AACR 2024 Annual Meeting (Nilsson et al., AACR 2024 Abstract #4174). Methods: The FURVENT (FURMO-004) study is a registrational global, phase 3, randomized, multicenter, open-label study. Eligible patients havetreatment-naïve, locally advanced or metastatic non-squamous NSCLC with EGFR exon 20 insertion mutations. Key inclusion criteria include documented EGFR exon 20 insertion mutation and measurable disease per RECIST 1.1. Key exclusion criteria include prior systemic anticancer therapy in the locally advanced or metastases setting or any prior EGFR TKI therapy. Approximately 375 patients will be randomized 1:1:1 to receive furmonertinib 160 mg QD, furmonertinib 240 mg QD, or platinum-based chemotherapy (cisplatin or carboplatin plus pemetrexed for 4 cycles followed by pemetrexed maintenance therapy). Stratification factors include the history or presence of central nervous system metastases at baseline, geographic region, and sex at birth. Patients from the platinum-based chemotherapy arm with documented disease progression are eligible to participate in the crossover phase of this trial to furmonertinib therapy. The primary endpoint is progression-free survival comparing between the treatment arms (furmonertinib 160 mg or 240 mg vs chemotherapy) based on BICR assessment. The key secondary endpoint is overall survival. Study enrollment is ongoing. Clinical trial information: NCT05607550. Citation Format: Alexander Spira, Byoung Chul Cho, Enriqueta Felip, Edward Garon, Koichi Goto, Melissa Lynne Johnson, Natasha B. Leighl, Antonio Passaro, David Planchard, Sanjay Popat, James Yang, Xiaoqian Lu, Yong Jiang, Jack Huang, Morgan Lam, Marcin Kowanetz, Shirley Wang, John Le, Jerry Hsu, Caicun Zhou. FURVENT, Phase 3 trial testing furmonertinib vs chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions (FURMO-004) [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 CT280.

Abstract CT282: MK-2870-004: A phase 3 study of MK-2870 (SKB264) versus chemotherapy for previously treated advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) with EGFR mutations or other genomic alterations

Abstract Background: Trophoblast cell-surface antigen 2 (TROP2), a cell surface glycoprotein involved in the regulation of tumor growth and invasion, is broadly expressed and upregulated in several cancers, including NSCLC. MK-2870 (SKB264) is an antibody-drug conjugate (ADC) composed of the humanized anti-TROP2 monoclonal antibody, a hydrolytically cleavable linker, and the cytotoxic drug KL610023. MK-2870 has demonstrated encouraging antitumor activity and manageable toxicity in phase 1 and 2 studies of patients with solid tumors, including heavily pretreated EGFR-mutant NSCLC. We describe the design of the ongoing phase 3 MK-2870-004 study (NCT06074588) that will evaluate the efficacy and safety of MK-2870 vs chemotherapy for previously treated advanced or metastatic nonsquamous NSCLC with EGFR mutations or other genomic alterations. Trial design: The global, randomized, open-label, phase 3 MK-2870-004 study will enroll ~556 patients, including 456 with exon 19del or L858R EGFR mutations, and 100 with other genomic alterations. Eligible patients are aged ≥18 years with histologically or cytologically documented advanced (stage III not eligible for resection or curative radiation) or metastatic nonsquamous NSCLC with exon 19del or exon 21 L858R EGFR mutations or other genomic alterations in ALK, ROS1, BRAF V600E, NTRK, MET exon 14 skipping, or RET and those with less common EGFR mutations (exon 20 S768I, exon 21 L861Q, and/or exon 18 G719X). Patients must have progressive disease on or after 1 or 2 lines of prior tyrosine kinase inhibitor (TKI) therapy and a platinum-based therapy (may contain anti-PD-[L]1), measurable disease per RECIST v1.1, an available tumor sample, and adequate organ function. Prior EGFR TKI therapy must include a third-generation TKI for patients with T790M EGFR-mutant NSCLC. Patients with active central nervous system metastases or carcinomatous meningitis are ineligible, although those with previously treated and untreated stable brain metastasis are eligible for enrollment. Patients will be randomized (1:1) to MK-2870 4 mg/kg Q2W on Days 1, 15, and 29 of every 6-week cycle, or chemotherapy (docetaxel 75 mg/m2 Q3W or pemetrexed 500 mg/m2 Q3W) on Days 1 and 22 of every 6-week cycle. Randomization will be stratified by EGFR mutations with prior third generation TKI vs EGFR mutations with no prior third generation TKI vs other genomic alterations, brain metastasis (yes vs no), and TROP2 expression (low vs medium vs high). Dual primary endpoints are PFS (per RECIST v1.1 by blinded independent central review) and OS in patients with EGFR-mutant NSCLC. Key secondary endpoints include PFS and OS in all patients with NSCLC, ORR, DOR, patient-reported outcomes, and safety. Enrollment started in November 2023 and is currently ongoing. Citation Format: Federico Cappuzzo, Edward B. Garon, Myung-Ju Ahn, Shun Lu, Terufumi Kato, Enriqueta Felip, Parneet Cheema, Nicolas Girard, Mark Shamoun, Guoqing Wang, Bin Zhao, Rina Hui. MK-2870-004: A phase 3 study of MK-2870 (SKB264) versus chemotherapy for previously treated advanced or metastatic nonsquamous non-small-cell lung cancer (NSCLC) with EGFR mutations or other genomic alterations [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 CT282.

Phase 1/2 multicenter trial of acalabrutinib in Chinese patients with relapsed/refractory mantle cell lymphoma

Acalabrutinib studies have limited Asian participation. This phase 1/2 study (NCT03932331) assessed acalabrutinib in Chinese patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). Primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). Overall, 34 patients were enrolled. Most patients were men (88%); median age was 63 years and 59% had ≥3 prior treatments. Median treatment duration was 14 months (range, 1–24). Any-grade adverse events (AEs) and grade ≥3 AEs occurred in 85.3% and 44.1% of patients, respectively. AEs causing treatment discontinuation were aplastic anemia, thrombocytopenia, and gastrointestinal infection (n = 1 each). Fatal AEs occurred in 2 patients (aplastic anemia and multiple organ dysfunction syndrome [n = 1 each]). BICR-assessed ORR was 82.4% (95% confidence interval [CI]: 65.5, 93.2); 12 (35.3%) patients achieved complete response. Estimated 12-month OS was 84.5% (95% CI: 66.6, 93.3). Acalabrutinib yielded tolerable safety and high response rates in Chinese patients with R/R MCL.

FDA Approval Summary: Enfortumab Vedotin Plus Pembrolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma.

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multi-cohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR) determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% CI: 59, 76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA.

US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer.

The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). The approval was based on the HRR gene-mutated (HRRm) population of TALAPRO-2, a randomized, double-blind trial that randomly assigned 1,035 patients with mCRPC to receive enzalutamide with either talazoparib or placebo. Two cohorts enrolled sequentially: an all-comer population (Cohort 1), followed by an HRRm-only population (Cohort 2). The independent primary end points were radiographic progression-free survival (rPFS) per blinded independent central review (BICR) in Cohort 1 (all-comers) and in the combined HRRm population (all HRRm patients from Cohorts 1 and 2). Overall survival (OS) was a key secondary end point. A statistically significant improvement in rPFS by BICR was demonstrated in both the all-comers cohort and the combined HRRm population, with hazard ratio (HR) of 0.63 (95% CI, 0.51 to 0.78; P < .0001) and 0.45 (95% CI, 0.33 to 0.61; P < .0001), respectively. In an exploratory analysis of the 155 patients with BRCA-mutated (BRCAm) mCRPC, rPFS HR was 0.20 (95% CI, 0.11 to 0.36). In the non-HRRm/unknown stratum of Cohort 1 (n = 636), the rPFS HR was 0.70 (95% CI, 0.54 to 0.89). OS was immature. Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer

BackgroundNo treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma.MethodsWe conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin–pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival.ResultsA total of 886 patients underwent randomization: 442 to the enfortumab vedotin–pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin–pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin–pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin–pembrolizumab group and in 69.5% of those in the chemotherapy group.ConclusionsTreatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.)