Duration Of Response Research Articles

Efficacy and safety of targeted therapy plus immunotherapy combined with hepatic artery infusion chemotherapy (FOLFOX) for unresectable hepatocarcinoma

BACKGROUND The advent of cutting-edge systemic therapies has driven advances in the treatment of hepatocellular carcinoma (HCC), and therapeutic strategies with multiple modes of delivery have been shown to be more efficacious than monotherapy. However, the mechanisms underlying this innovative treatment modality have not been elucidated. AIM To evaluate the clinical efficacy of targeted therapy plus immunotherapy combined with hepatic arterial infusion chemotherapy (HAIC) of FOLFOX in patients with unresectable HCC. METHODS We enrolled 53 patients with unresectable HCC who received a combination of targeted therapy, immunotherapy, and HAIC of FOLFOX between December 2020 and June 2021 and assessed the efficacy and safety of the treatment regimen. RESULTS The objective response rate was 60.4% (32/53), complete response was 24.5% (13/53), partial response was 35.9% (19/53), and stable disease was 39.6% (21/53). The median duration of response and median progression-free survival were 9.1 and 13.9 months, respectively. The surgical conversion rate was 34.0% (18/53), and 1-year overall survival was 83.0% without critical complicating diseases or adverse events (AEs). CONCLUSION The regimen of HAIC of FOLFOX, targeted therapy, and immunotherapy was curative for patients with unresectable HCC, with no serious AEs and a high rate of surgical conversion.

Efficacy and safety of BRAF/MEK inhibitors in BRAFV600E-mutated anaplastic thyroid cancer: a systematic review and meta-analysis.

Approximately 45% of anaplastic thyroid cancer (ATC) patients harbor a BRAFV600E mutation and are eligible for target therapy (TT) with BRAF and MEK inhibitors (BRAFi/MEKi), nevertheless, few data advocate for this. Hence, we've conducted a systematic review and meta-analysis investigating the effectiveness and safety of BRAFi/MEKi in BRAFV600E ATC patients. PubMed, Embase, and the Cochrane Library were systematically searched for BRAFi/MEKi TT in BRAFV600E ATC patients. Outcomes included objective response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), duration of response (DOR) and adverse events (AEs). Nine studies with 168 patients were included. Median follow-up ranged from 2.0 to 47.9 months. 75% of patients had stage IVc. In a pooled analysis, ORR was 68.15% (95% CI 55.31-80.99, I2 = 47%) and DCR was 85.39% (95% CI 78.10-92.68, I2 = 0), with a median DOR of 14.4 months (95% CI 4.6-14.4) and a median PFS of 6.7 months (95% CI 4.7-34.2). Moreover, 1-year OS rate was 64.97% (95% CI 48.76-81.17, I2 = 84%) and 2-years OS rate was 52.08% (95% CI 35.71-68.45, I2 = 79%). Subgroup analysis showed patients in the neoadjuvant setting had higher rates of 1 and 2-years OS and observational studies tended to report higher rates of ORR than clinical trials. No new or unexpected adverse events were found. Our study demonstrated BRAFi/MEKi have a decent activity for BRAFV600E ATC patients, especially in the neoadjuvant setting, with a tolerable safety profile. However, further clinical trials are warranted to investigate these findings.

Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial.

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements) and B (activating non-kinase domain mutations). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5%, 9.4% and 3.8%, respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .

Phase II study to determine the anti-tumor activity and safety of simlukafusp alfa (FAP-IL2v) combined with atezolizumab in esophageal cancer.

Reported here are results from the esophageal squamous cell carcinoma (SCC) cohort of a Phase II, non-comparative, basket study, evaluating the anti-tumor activity and safety of FAP-IL2v plus atezolizumab in patients with advanced/metastatic solid tumors (NCT03386721). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0-1; measurable metastatic, persistent, or recurrent esophageal SCC; progression on ≥1 prior therapy; and were checkpoint inhibitor naive. Patients received FAP-IL2v 10 mg plus atezolizumab 1200 mg intravenously every 3 weeks, or FAP-IL2v weekly for 4 weeks, then every 2 weeks, plus atezolizumab 840 mg intravenously every 2 weeks. Primary endpoint was investigator-assessed objective response rate (ORR). In the response-evaluable population (N=34), best confirmed ORR was 20.6% (95% confidence interval [CI]: 10.4-36.8) with a complete response (CR) seen in one patient and partial responses (PR) in six patients. Disease control rate was 44.1% (CR=2.9%; PR=17.6%; stable disease [SD]=23.5%) and median duration of response was 10.1 months (95% CI: 5.6-26.7). Median progression-free survival was 1.9 months (95% CI: 1.8-3.7). Analysis of response by PD-L1 expression (Ventana SP263) resulted in an ORR of 26.7 % for patients with PD-L1-positive tumors (tumor area positivity [TAP] cut-off ≥1%; n=15) and 7.1% for patients with PD-L1-negative tumors (TAP cut-off <1%; n=14). Overall, the treatment combination was tolerable and adverse events were consistent with the known safety profiles of each drug. FAP-IL2v plus atezolizumab demonstrated clinical activity and was tolerable in patients with previously treated esophageal SCC.

Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study.

Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treatedmostly on an outpatient basis with observation. No treatment-related deaths were observed. Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).

Response- and Progression-Based End Points in Trial and Observational Cohorts of Patients With NSCLC

Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making. To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC). This retrospective cohort study used patient-level data from the IMpower132 trial (conducted April 7, 2016, to May 31, 2017) and a nationwide electronic health record (EHR)-derived deidentified database (data collected January 1, 2011, to March 31, 2022). Patients in the observational cohort were selected according to the inclusion and exclusion criteria of the IMpower132 trial. All patients in the observational cohort had stage IV NSCLC. All patients were randomized to or received first-line carboplatin or cisplatin plus pemetrexed. End points included response rates, duration of response, and progression-free survival, compared between the trial and observational cohorts before and after weighting. Response rates for the observational cohort were derived from the EHR. A total of 769 patients met inclusion criteria, 494 in the observational cohort (median [IQR] age, 67 [60-74] years; 228 [46.2%] female; 45 [9.1%] Black or African American; 352 [71.3%] White; 53 [10.7%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial) and 275 in the trial cohort (median [IQR] age, 63 [56-68] years; 90 [32.7%] female; 4 [1.5%] Black or African American; 194 [70.5%] White; 65 [23.6%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial). All 3 end points were comparable between the study cohorts. Trial patients had a higher number of response assessments compared with patients in the weighted observational cohort. The EHR-derived response rate was numerically higher than the objective response rate after weighting (100.3 of 249.3 [40.2%] vs 105 of 275 [38.2%]) due to higher rates of observed partial response than RECIST-based partial response. Among patients with at least 1 response assessment, the EHR-derived response rate remained higher than the objective response rate (100.3 of 193.4 [51.9%] vs 105 of 256 [41.0%]) due to a higher proportion of patients in the observational cohort with no response assessment. In this study, response- and progression-based end points were similar between clinical trial and weighted observational cohorts, which increases confidence in the reliability of observational end points and can inform their interpretation in relation to trial end points. Additionally, the difference observed in response rates (including vs excluding patients with no response assessment) highlights the importance of future research adopting this 2-way approach when evaluating the relationship of EHR-derived and objective response rates.

Abstract LBO1-04: Primary results from a phase 2a study of zanidatamab (zani) + palbociclib (palbo) + fulvestrant (fulv) in HER2+/HR+ metastatic breast cancer (mBC)

Abstract Background: HER2+ mBC remains incurable, thus novel HER2-directed therapies including chemotherapy-free options are needed. Approximately 50% of HER2+ mBC is also HR+, making the estrogen pathway an additional therapeutic target. The CDK4/6 inhibitor palbo + endocrine therapy fulv is approved for HER2−/HR+ mBC. Targeting all 3 pathways may further improve outcomes in pts with HER2+/HR+ mBC. Zani is a bispecific HER2-targeted antibody that binds HER2 in a unique trans configuration, driving multiple mechanisms of action. A prior analysis of the current single-arm, phase 2a study (NCT04224272) demonstrated antitumor activity and a tolerable safety profile for zani + palbo + fulv in heavily pretreated pts with HER2+/HR+ mBC. Enrollment has been completed; here we report the primary endpoint of PFS at 6 mo (PFS6) and other endpoints. Methods: Eligible pts had HER2+ (by local HER2 testing) and HR+, unresectable, locally advanced or mBC; ECOG PS ≤1; prior treatment with at least trastuzumab, pertuzumab, and T-DM1; and no prior CDK4/6 inhibitor. Pts received zani (20 mg/kg Q2W) + palbo + fulv (standard doses)—recommended doses determined in Part 1 assessment. The Part 2 primary endpoint was PFS6. Other endpoints included median PFS (mPFS), confirmed objective response rate (RECIST v1.1), disease control rate, and duration of response. PAM50 analysis was exploratory. A centrally confirmed HER2+ (ccHER2) subset was analyzed post hoc. Results: As of August 3, 2023, 51 pts (median age [range] 54 yr [36-77]) received zani + palbo + fulv treatment with a median follow-up time of 16.1 mo. Of the 51 pts, 32 (63%) were ccHER2+. Nine pts (18%) remained on treatment; median (range) duration of zani treatment was 8.4 (1.0-29.5) mo. In the metastatic setting, pts received a median (range) of 4 (1-12) prior systemic regimens, 3 (1-10) prior different HER2-targeted therapies, and 1 (0-5) prior endocrine therapy; 12 (24%) pts had prior T-DXd and 11 (22%) had prior fulv. The primary endpoint of PFS6 was 67% (69% in ccHER2+ subset). The mPFS was 11.7 mo (14.9 mo in ccHER2+ subset). See Table 1 for other efficacy endpoints. PAM50 subtyping was available for 29 pts (57%; 1 basal like; 16 HER2 enriched; 12 luminal B). Compared with HER2 enriched, luminal B was associated with numerically, but not statistically, longer mPFS (11.7 vs 9.3 mo; P=0.74) and similar PFS6 (66.7% vs 62.5%). The most common (&amp;gt;20%) treatment (zani, palbo, and/or fulv)-related adverse events (TRAEs) were diarrhea (80%), neutrophil count decrease/neutropenia (59%), nausea (39%), stomatitis (37%), anemia (29%), vomiting (25%) and asthenia (24%). Grade ≥3 TRAEs in ≥2 pts were neutrophil count decrease/neutropenia (53%), diarrhea (14%), anemia (10%), thrombocytopenia (6%), hypokalemia (4%), and hypomagnesemia (4%). One serious TRAE (transaminases increased) was reported. AEs of special interest: 6 pts with cardiac events (all LVEF decrease; 5 pts with grade 1 or 2 events, 1 pt with a grade 3 event) and 2 pts with infusion-related reactions (both grade 1). Three pts discontinued palbo due to an AE; 1 pt discontinued zani and fulv due to an AE. No treatment-related deaths were reported. Conclusions: Zani + palbo + fulv showed a promising PFS6 and mPFS with durable responses. The safety profile was manageable. These results support further development of a novel chemotherapy-free treatment regimen for heavily pretreated pts with HER2+/HR+ mBC. Table 1. Efficacy of Triplet Regimen (Zani + Palbo + Fulv) for HER2+/HR+ mBC a Patients with measurable disease (n=46 all pts; n=29 ccHER2+ subset). b Defined as best response of CR, PR, non-CR/non-PD (for patients who have only non-target lesions) or SD per RECIST 1.1. c Patients with DOR (n=16 all pts; n=14 ccHER2+ subset). cBOR, confirmed best overall response; ccHER2+, centrally confirmed HER2+; CI, confidence interval; cORR, confirmed objective response rate; CR, complete response; DCR, disease control rate; DOR, duration of response; HER2+, human epidermal growth factor receptor 2 positive; HR+, hormone receptor positive; mBC, metastatic breast cancer; mo, month; PD, progressive disease; PFS, progression-free survival; PFS6, progression-free survival at 6 months; PR, partial response; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1; SD, stable disease. Citation Format: Santiago Escrivá-de-Romani, Juan Miguel Cejalvo, Emilio Alba, Jennifer Friedmann, Álvaro Rodríguez Lescure, Marie-France Savard, Rossanna C. Pezo, Maria Gion, Manuel Ruíz - Borrego, Erika Hamilton, Timothy Pluard, Marc Webster, Muralidhar Beeram, Hannah Linden, Cristina Saura, Diana Shpektor, Bob Salim, Phoebe Harvey, Sara Hurvitz. Primary results from a phase 2a study of zanidatamab (zani) + palbociclib (palbo) + fulvestrant (fulv) in HER2+/HR+ metastatic breast cancer (mBC) [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 LBO1-04.

Abstract RF02-06: AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658)

Abstract Background: Chemotherapy (chemo) + H is standard of care therapy for pts with refractory HER2+ MBC. It is unknown whether the addition of immune checkpoint inhibitor (ICI) or a 4-1BB agonist (U) improves efficacy of standard chemo + H for this population. Methods: Eligible pts had HER2+ MBC previously treated with H, pertuzumab (P), and T-DM1. Pts previously treated with N or ICI were excluded. 100 pts were randomized 1:2:2 to tx with NH, NHA, or NHAU. ER status and presence of liver metastases were stratification factors. The original co-primary objectives were to compare progression-free survival (PFS) of (1) NHA vs NH; and (2) NHAU vs NHA. In 2021, due to discontinuation of clinical development of U, an unplanned interim futility analysis reviewed by IDMC led to closure of NHAU and randomization of the final 13 pts to NH or NHA. For the comparison of NH vs NHA, with 60 pts randomized (20 vs 40) there was 88% power for a log-rank test to detect improvement in median PFS (mPFS) from 2 to 4 mos with one-sided alpha of 0.1. Corresponding 2-sided 80% confidence intervals (CI) were reported for the stratified Cox model hazard ratios (HR), along with stratified one-sided log-rank p-value. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and safety/tolerability. Results: 100 pts were randomized from 7/2018-3/2023, and 97 pts started tx on trial: 18 NH, 45 NHA, and 34 NHAU (prior to its closure). Pts were 99% female, with median age 54 yrs (range 26-78 yrs); 70% White, 14% Black, and 8% Asian; 7% were Hispanic. 66% of pts had hormone receptor-positive tumors, and 76% had visceral metastases. All pts were previously treated with H, P, and T-DM1, and 17% had prior trastuzumab deruxtecan. 63% of pts had received ≥3 lines of HER2 tx for MBC (range 1-13 lines), and median interval from MBC diagnosis to randomization was 32 mos (interquartile range 22-61 mos). mPFS and ORR results are shown in the Table. One patient remained progression-free on tx at analysis. NHA was associated with a statistically significant improvement in PFS compared to NH (HR=0.56 (80% CI 0.37-0.86, p=0.04)). No difference in PFS was observed between NHAU vs NHA (HR=1.20 (80% CI 0.84-1.73) as final estimate after closure of NHAU for futility). Of 9 pts with confirmed responses in NHA arm, 3 pts had DOR &amp;gt;12 mos. Grade 3-4 treatment-emergent adverse events (AEs) were similar by tx: 61% NH, 62% NHA, and 67% NHAU. There were no grade 5 treatment-related AEs. Immune-related all grade AEs in the A-containing arms (n=79 safety-evaluable pts treated with A) included: AST increase (n=15), ALT increase (n=9), hyper/hypothyroidism (n=8), adrenal insufficiency (n=2), and pneumonitis (n=1), of which two events were grade 3 (adrenal insufficiency and AST increase) and none were grade 4. Only 3 pts (1 in NHA; 2 in NHAU) stopped trial tx for unacceptable AEs. Required baseline and on-tx biopsies were performed; PD-L1 and TIL data will be presented. Conclusions: This trial demonstrated significant improvement in PFS with addition of avelumab to NH among pts with heavily pre-treated HER2+ MBC. 4-1BB agonist did not improve PFS. To our knowledge, this is the first randomized trial to report results of chemo/H +/- ICI in HER2+ MBC. Further investigation of ICI with chemo/H for pts with refractory HER2+ MBC is warranted, and the potential predictive value of immune biomarkers should be explored. *one-sided stratified log rank test p-value Citation Format: Adrienne Waks, Ruichao Shi, Meredith Regan, Chau Dang, Cesar Santa-Maria, Kelly Westbrook, Vandana Abramson, Rashmi Murthy, Rita Nanda, Hope Rugo, Amy Clark, Candace Mainor, Claire Dees, Valentina Hoyos, Kathy Miller, Erica Stringer-Reasor, Natasha Hunter, Sun Young Oh, Michelle DeMeo, Amanda Okpoebo, Erin Elias, Busem Kurt, Nancy Lin, Mothaffar Rimawi, Antonio Wolff, Elizabeth Mittendorf, Shom Goel, Sara Tolaney, Sherene Loi, Ian Krop. AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658) [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 RF02-06.

Abstract PO2-05-05: ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC)

Abstract Background: Currently, there are no approved systemic treatment options specifically for patients with ER+/HER2- BC who have brain metastasis. The prevalence of brain metastases from ER+/HER2- BC is approximately 14% of women (Aversa, 2014). Elacestrant is a next-generation oral SERD that was evaluated in a pivotal phase 3 trial, EMERALD, as monotherapy vs. standard of care (SOC) endocrine therapy. The EMERALD trial reported significantly prolonged progression-free survival (PFS) with elacestrant vs SOC endocrine therapy in patients with ER+/HER2− ESR1 mutated (ESR1-mut) mBC following progression on prior endocrine therapy (Bidard, 2022). Elacestrant was well tolerated with a manageable safety profile. Most adverse events, including nausea, were low-grade and consistent with other endocrine therapies. A clinical study in healthy postmenopausal women demonstrated the ability of elacestrant to cross the blood-brain barrier (Conlan, 2020). Abemaciclib, a CDK4/6i, has been shown to achieve therapeutic concentrations in brain metastases tissue (Tolaney, 2020). Given the lack of current systemic treatments, elacestrant is now being evaluated with abemaciclib in patients with ER+/HER2- BC and brain metastasis (NCT05386108). Methods: ELECTRA (NCT05386108) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib in patients with brain metastasis from ER+, HER2- BC. Eligibility are patients with ER+/HER2− locally advanced or mBC and measurable brain metastasis. For phase 1b, the presence of brain metastases is allowed but not required for eligibility. For phase 2, patients must have ≥ 1 active and measurable brain metastasis per RECIST v1.1. Patients must have received prior therapy in the metastatic setting, including ≥ 1 ET, ≤2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). The primary objectives of Phase 1b are to determine the recommended Phase 2 dose (RP2D). Phase 1b secondary objectives include safety, PK, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), PFS, and overall survival (OS). Phase 2 primary objective is ORR per RECIST version 1.1. Phase 2 secondary objectives include intracranial response rate (RR), DoR, CBR, PFS, OS, PK, and quality of life (QoL). The phase 1b portion evaluated dose-limiting toxicities (DLTs) of the combination during the first cycle (28 days) of treatment in up to three 6-patient cohorts, starting at elacestrant 300 mg daily plus abemaciclib 100 mg twice daily. Here we report initial safety results from the phase 1b portion. Results: As of June 2023, 15 patients have been enrolled in the phase 1b portion of the trial. At dose level 1, elacestrant 300 mg QD + abemaciclib 100 mg BID, no patient experienced DLTs, and the combination was feasible. Dose level 2, elacestrant 400 mg QD + abemaciclib 100 mg BID has been completed, and no patients experienced DLTs. In dose level 1, 4/7 patients remain on treatment at cycle 5. Additional safety and PK data for the cohorts will be provided. Conclusion: In the phase 1b portion of ELECTRA, dose level 1 and dose level 2 have been completed. No patients experienced DLTs in either dose level 1 or dose level 2, and the combination was considered feasible in the respective dose levels. Dose level 3 (elacestrant 400 mg QD + abemaciclib 150 mg BID) is proceeding. Recruitment is actively ongoing, enabling oral-oral combinations to determine a RP2D. Citation Format: Nuhad Ibrahim, Sung-Bae Kim, Nancy Lin, Ahmad Awada, Eva Ciruelos Gil, Giulia Tonini, Bartomeu Piza Vallespir, Kathy Puvana Theall, Erika Hamilton. ELECTRA: An open-label, multicenter, phase 1b/2 study of elacestrant in combination with abemaciclib in patients with brain metastasis (mets) from estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer (BC) [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 PO2-05-05.

Abstract PO1-06-10: Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer

Abstract Background Breast cancer is the most frequently diagnosed cancer and the 5th most common cause of cancer-related death in Chinese women with over 416,000 new cases and over 117,000 deaths estimated in 2020. Triple-negative breast cancer (TNBC) represents 10%-20% of cases in women with breast cancer. Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate and is approved for second-line or later (2L+) treatment of metastatic (m)TNBC in multiple countries, including the US and China. In the pivotal phase 3 study ASCENT, which enrolled predominantly non-Asian patients (pts), SG demonstrated improved efficacy outcomes vs treatment of physician’s choice (TPC) in pts with mTNBC treated in 2L+, with a manageable safety profile. For pts treated with SG, median progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were improved vs TPC (Bardia A et al, 2021). The single-arm phase 2b EVER-132-001 study was conducted to assess the efficacy and safety of 2L+ SG in Chinese pts with mTNBC. In preliminary findings from EVER-132-001, SG demonstrated substantial clinical activity and a manageable safety profile (Xu B et al, 2023). Here, we present additional efficacy and safety results from EVER-132-001, including the first report of median OS. Methods Pts with mTNBC who had received at least 2 prior lines of chemotherapy for mTNBC received SG (10 mg/kg IV on days 1 and 8, Q3W). The primary end point was ORR per independent review committee (IRC). Secondary end points included duration of response (DoR) per IRC, clinical benefit rate (CBR) per IRC, PFS per IRC, OS, and safety. Results Eighty pts were enrolled, with a median age of 48 years (range 24-70). Pts had received a median of 4 prior treatment regimens (range 2-8), and 59% of pts had ECOG performance status of 1. At the data cutoff, September 19, 2022, with a median follow-up of 14.7 mo (range 1.2-25.3), median OS was 14.7 mo (95% CI 10.3-18.3) and the OS rate at 12 months was 54% (95% CI 42-64) (Table). ORR was 40% (95% CI 29-52) with median DoR of 11.6 mo (95% CI 7.0-13.8), and CBR was 46% (95% CI 35-58) (Table). Median PFS was 5.6 mo (95% CI 4.1-8.3) (Table). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 79% of pts, and TEAEs leading to dose reduction, treatment interruption, and treatment discontinuation occurred in 20%, 48%, and 8% of patients, respectively (Table). The most common TEAEs of any grade were decreased neutrophil count (85%), anemia (84%), and decreased white blood cell count (83%). The most common grade ≥ 3 TEAEs were decreased neutrophil count (64%), decreased white blood cell count (50%), and anemia (23%). Conclusions SG continued to demonstrate substantial clinical activity, with OS, ORR, DoR, CBR, and PFS results in the EVER-132-001 trial, consistent with the phase 3 ASCENT trial of SG in mTNBC. TEAEs were manageable and no new safety signals were identified. These results support the use of SG as a new standard of care for Chinese pts with pretreated mTNBC. Table Citation Format: Fei Ma, Shusen Wang, Zhongsheng Tong, Wei Li, Xinhong Wu, Xiaojia Wang, Tao Sun, Yueyin Pan, Herui Yao, Xian Wang, Ting Luo, Jin Yang, Xiaohua Zeng, Weihong Zhao, Kimberly Komatsubara, Rachel Nakamura, Catherine Lai, Bo Zhang, Xiuyu Cong, Binghe Xu. Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-10.

Abstract PO1-19-07: A Phase I Study Accessing Immunotherapy Combination of Balstilimab and Ivermectin in Patients with Metastatic Triple Negative Breast Cancer

Abstract Background: Despite recent FDA approval of immune checkpoint inhibitor (ICI) and antibody-drug conjugates (ADCs), therapeutic options for metastatic triple negative breast cancer (mTNBC) remain limited. There is an unmet need to identify novel ICI combinations for improved efficacy. We recently demonstrated that ivermectin induces robust T cell infiltration into breast tumors and turning “cold” tumors “hot” in mouse model of TNBC. Balstilimab is a fully humanized IgG4 anti-PD-1 agent with proven safety and efficacy in metastatic cervical cancer. The current phase I/II trial is designed to test the safety and efficacy of the combination of ivermectin and balstilimab in patients with mTNBC. Methods: Key eligibility criteria include patients with unresectable or metastatic TNBC; progressed on 1-2 prior chemotherapies including an immune checkpoint inhibitor-containing regimen; ECOG 0-1; RECIST 1.1 measurable disease. Eligible patients receive balstilimab 450 mg, IV, on Day 1 and ivermectin (30, 45 or 60 mg po daily), PO, Days 1-3, 8-10, 15-17 of each 21 days cycle till disease progression or intolerance. The primary objection of the phase 1 portion of the study is t determine the recommended phase 2 dose of ivermectin in combination with balstilimab using NCI-CTCAE v5.0. The primary objective of the phase II portion of the study is to determine the efficacy of the combination in mTNBC who are PD-L1 negative using the objective response rate (ORR). Secondary objectives are progression free survival (PFS), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), and patients’ quality of life (QOL) by EORTC QLQ-C30. Peripheral blood, tumor tissue and gut microbiome will be collected for correlative aims include pharmacokinetics, tumor microenvironment ICDs and gut microbiota in association with response to therapy. In the Phase 1 portion, eligible patients will be enrolled to one of three doses using the IQ 3+3 design. In the Phase 2 portion, patients will continue to be accrued to the RP2D (either the MTD or a lower dose depending on clinical judgement considering all the clinical and correlative data available). The Phase 2 portion will be conducted in two stages. In stage 1, a total of 13 PDL1-negative TNBC breast cancer patients will be treated at the RP2D. If there are no responders, the Phase 2 portion will close. With at least one responder, accrual may continue until 25 patients are accrued to the Phase 2 portion. If at least 3 responders are noted in 25 patients, this will be sufficient to consider the combination promising. This rule provides a type I error of 12% for a true response rate of 5%, and a power of 88% for true response rate of 20%. The estimated targeted accrual is 34-41 (Phase 1: 14-16; Phase 2: 20-25). Clinical trial information: NCT05318469 Citation Format: Yuan Yuan, Stephen Shiao, Mourad Tighiouart, Monica Mita, Jin-Sun Bitar, Philomena McAndrew, Park Dorothy, Maryliza El-Masry, Paul Frankel, Peter Lee. A Phase I Study Accessing Immunotherapy Combination of Balstilimab and Ivermectin in Patients with Metastatic Triple Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-07.

Abstract PO4-06-07: Efficacy and safety of futibatinib in patients with locally advanced/metastatic triple-negative breast cancer harboring FGFR2 gene amplification: final results from the phase 2, open-label FOENIX-MBC2 study

Abstract Background: Triple-negative breast cancer (TNBC) accounts for ~15% of breast cancers and represents an aggressive subtype with limited targeted therapeutic options. Fibroblast growth factor receptor (FGFR) signaling plays an important role in breast tumorigenesis and metastasis. The phase 2 FOENIX-MBC2 study (NCT04024436) was designed to evaluate responses to futibatinib, a highly selective and potent irreversible covalent inhibitor of FGFR1–4 (FDA-approved for intrahepatic cholangiocarcinoma), in patients with metastatic breast cancer. Here, we report final efficacy and safety data for futibatinib in the cohort of patients with advanced/metastatic TNBC harboring FGFR2 gene amplification. Methods: Eligible patients had locally advanced/metastatic TNBC with measurable disease per RECIST v1.1, an ECOG performance status of 0/1, and progressive disease after ≥1 prior chemotherapy-containing regimen for advanced disease. Patients were positive for FGFR2 gene amplification determined by analysis of tumor tissue or circulating tumor DNA. Patients received oral futibatinib 20 mg once daily until disease progression, unacceptable toxicity, or other discontinuation criteria were met. The primary endpoint was objective response rate (ORR) by RECIST v1.1 in patients with centrally confirmed FGFR2 amplification. Responses (complete response and partial response) required confirmation after at least 4 weeks. Secondary endpoints included the 6-month progression-free survival (PFS) rate, PFS, duration of response (DOR), and overall safety. Results: Overall, 21 female patients with TNBC were enrolled (median age: 53 years) in this cohort. Patients had received a median 5 lines of prior systemic therapy. Overall, 2 patients had a confirmed partial response (ORR: 9.5%; 95% confidence interval [CI]: 1.2, 30.4), with a median DOR of 6.1 months (range: 3.1−9.2 months). Five (23.8%) patients had stable disease. PFS at 6 months was observed in 4 patients (19.0%; 95% CI: 5.4, 41.9) and the median PFS was 1.9 months (95% CI: 1.6, 4.0). Twenty patients (95.2%) had ≥1 treatment-related adverse event (TRAE), including 7 (33.3%) with a Grade 3 TRAE (no Grade 4 or 5). Common TRAEs (any grade) included hyperphosphatemia (85.7% of patients), constipation, diarrhea, fatigue, and dry skin (each in 23.8% of patients). Anemia was the only Grade 3 TRAE observed in more than 1 patient (n=2, 9.5%). Overall, 28.6% of patients had a serious adverse event (SAE; any cause), and 1 patient had an SAE leading to death (ischemic stroke). None of the SAEs or deaths were considered treatment-related. Conclusions: In heavily pretreated patients with metastatic TNBC harboring FGFR2 gene amplification, futibatinib monotherapy demonstrated modest anticancer activity. Futibatinib was tolerable and had an acceptable safety profile, consistent with previous data. Further biomarker work to identify patients who might benefit most from futibatinib is ongoing. Clinical trial information: NCT04024436 Citation Format: Antonio Giordano, Nisha Unni, Senthil Damodaran, Hope Rugo, Timothy Crook, Thomas Bachelot, Federico Piacentini, Hector Soto Parra, Ian Krop, Masashi Shimura, Gareth Tomlinson, Maciej Gil, Nicholas Turner, Fabrice André. Efficacy and safety of futibatinib in patients with locally advanced/metastatic triple-negative breast cancer harboring FGFR2 gene amplification: final results from the phase 2, open-label FOENIX-MBC2 study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-06-07.

Abstract PO1-06-12: Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer

Abstract Background: The combination of a PD-(L)1 inhibitor plus chemotherapy demonstrated promising anti-tumor activity as first-line therapy for patients (pts) with locally recurrent inoperable or metastatic PD-L1 positive triple-negative breast cancer (TNBC). However, for pts without PD-L1 expression and for those who have failed prior lines of treatment, therapeutic options are still limited. This multi-cohort, phase II trial aimed to evaluate the safety and antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination (70 mg sitravatinib plus tislelizumab) with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The efficacy of sitravatinib plus tislelizumab in cohort A and B has been reported with objective response rate (ORR) of 38.1% and 45.0%, respectively. Herein, the preliminary results of cohort C and updated results of cohort A and B were reported. Methods: Pts with untreated locally inoperable or metastatic TNBC were included in cohort C and received 70 mg sitravatinib orally once daily plus 200 mg tislelizumab intravenously on day 1 and 100mg/m2 nab-paclitaxel on days 1 and 8 every three weeks until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival (OS) rate and safety/tolerability. Based on Simon’s two-stage design, &amp;gt; 9 responders were need in stage 1 (n=18) for the study to continue, and &amp;gt;19 responders were needed by the end of study (n=35) to demonstrate statistical superiority with sitravatinib plus tislelizumab and nab-paclitaxel (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). Updated analyses were provided for cohort A (Simon’s 2 stage design) and B (Bayesian optimal phase II design). Results: Among the 18 pts in stage 1 of cohort C, 12 of them achieved confirmed response, and therefore the study proceeded to the enrollment in stage 2. As of April 30, 2023, a total of 32 pts were enrolled, with a median age of 51 years. Among the 23 efficacy evaluable pts, unconfirmed ORR was 87.0% (95% CI 66.4-97.2) (including 3 CRs and 17 PRs), with 7 pts not reaching next tumor assessment after reaching CR/PR, and confirmed ORR was 52.2% (95% CI 30.6-73.2). DCR was 95.7%. Any grade of treatment-related adverse events (TRAEs) occurred in 31 (96.9%) pts, and grade ≥3 TRAEs occurred in 5 (15.6%) pts. One (3.1%) patient experienced grade ≥3 immune-related adverse events. SAEs were reported in 3 (9.4%) pts. At the data cut-off date, the median follow-up duration for cohort A and B was 20.4 (range 1.3–24.3) months and 13.3 (range 5.1-19.1) months, respectively. The median PFS in cohort A was 8.2 (95% CI 2.8-12.4) months, and in cohort B was 5.4 (95% CI 4.2-10.9) months. Median OS was not reached in both cohorts. RNA-seq analysis showed that the suppression of immune regulatory pathways and the activation of metabolic pathways promoted early progression. Besides, baseline angiogenesis associated pathway held the potential to predict the favorable response to tislelizumab plus sitravatinib. Conclusion: In the first-line treatment of locally recurrent or metastatic TNBC, preliminary analysis of cohort C showed that sitravatinib combined with tislelizumab and nab-paclitaxel had promising anti-tumor activity with a high ORR, and the combination was generally well tolerated. In TNBC pts with less than three lines of therapy, the chemotherapy-free regimen with sitravatinib plus tislelizumab demonstrated promising PFS after a longer follow-up duration. Citation Format: Lei Fan, Xiyu Liu, Ying Xu, Xinyi Sui, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Song-Yang Wu, Han Wang, Yi Xiao, Li Chen, Jiong Wu, Ke-da Yu, Guangyu Liu, Xin Hu, Zhonghua Wang, Yi-Zhou Jiang, Zhi-Ming Shao. Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-12.

Abstract PO1-19-10: Durvalumab + datopotamab deruxtecan in patients with PD-L1 positive advanced/metastatic triple-negative breast cancer: Arm 8 of the phase 1b/2, open label, platform BEGONIA study

Abstract Background: Patients (pts) with advanced/metastatic triple-negative breast cancer (a/mTNBC) have limited treatment options and poor prognosis. Immune checkpoint inhibitors combined with chemotherapy is the standard of care for pts with PD-L1 positive tumors; still, most pts progress within a year, highlighting a need for new treatments. BEGONIA is an ongoing Simon 2-stage, multicenter, multi-arm platform study evaluating the safety and efficacy of durvalumab (D), an anti–PD-L1 monoclonal antibody, with or without paclitaxel, in combination with novel oncology therapies as first-line treatment for a/mTNBC (NCT03742102). Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-trophoblast cell surface antigen 2 (TROP2) IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a plasma stable, tumor selective, tetrapeptide-based cleavable linker. TROP2 is broadly expressed on breast and other epithelial tumors and Dato-DXd monotherapy showed antitumor activity in heavily pretreated mTNBC pts (Bardia SABCS 2022 P6-10-03). Pts treated with Dato-DXd+D in Arm 7 of BEGONIA showed a 74% objective response rate (ORR) with median 7.2 months follow-up (Schmid SABCS 2022 PD11-09). Although responses were observed in both PD-L1–high and –low-expressing tumors, most pts (87%) had PD-L1–low-expressing tumors. In Arm 8 of BEGONIA, pts determined to have PD-L1 positive tumors by pre-existing/local testing will be recruited and treated with Dato-DXd+D to evaluate efficacy and safety in a PD-L1–high population. Methods: Eligible female pts are aged ≥18 years with untreated unresectable, locally advanced or mTNBC; ≥6 months between completion of treatment for earlier-stage breast cancer and recurrence of distant disease; ≥12 months since prior taxane therapy; ECOG PS 0/1; adequate organ function; and ≥1 nonirradiated measurable lesion. For inclusion in Arm 8, a PD-L1 positive tumor as determined by local immunohistochemistry (IHC) testing is required (either pre-existing or obtained during prescreening). Exclusion criteria for Arm 8 are clinically significant corneal disease; history or suspicion of interstitial lung disease/pneumonitis; underlying pulmonary disorder; prior exposure to immune-mediated therapy; or prior treatment with an ADC containing a topoisomerase I inhibitor. Arm 8 will evaluate Dato-DXd (6 mg/kg) + D (1120 mg) given intravenously every 3 weeks until disease progression or unacceptable toxicity. Tumors will be assessed per RECIST v1.1 every 6 weeks for 48 weeks, then every 12 weeks thereafter. A safety run-in will not occur for Arm 8, as Dato-DXd+D was evaluated in Arm 7 and was tolerable with no DLTs reported. Part 1 of Arm 8 will enroll 30 pts. The primary endpoint of Part 1 is safety and tolerability. A futility analysis will be performed with an option to expand Arm 8 to Part 2, where an additional 27 pts will be enrolled if expansion criteria are met. The primary endpoint for Part 2 is ORR. Secondary endpoints include ORR (Part 1 only), testing for antidrug antibodies and treatment pharmacokinetics (Part 1 only), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). ORR will be summarized with descriptive statistics and 95% Clopper-Pearson confidence intervals. Kaplan-Meier analysis will be used for DoR, PFS, and OS. All tumor response and survival endpoints will be based on investigator assessments. Additional PD-L1 testing with the VENTANA PD-L1 (SP263) Assay will be performed on pretreatment tumor samples; high expression is defined as ≥10% of the tumor area populated by PD-L1–expressing tumor or immune cells. TROP2 expression will be assessed by IHC. Enrollment is ongoing. Funding: AstraZeneca/Daiichi Sankyo Citation Format: Peter Schmid, Cynthia Ma, Robert Huisden, Ross Stewart, Katrin Heider, Petra Vuković, Neelima Denduluri. Durvalumab + datopotamab deruxtecan in patients with PD-L1 positive advanced/metastatic triple-negative breast cancer: Arm 8 of the phase 1b/2, open label, platform BEGONIA study [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 PO1-19-10.

Abstract PS16-02: Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 trial

Abstract BACKGROUND Triple-negative breast cancer (TNBC) is an aggressive tumor characterized by poor outcomes and new treatment strategies are urgently required. The programmed cell death-ligand 1 (PD-L1) antibody (Ab) atezolizumab (ATZ) combined with first-line (1L) nab-paclitaxel (nab-PTX) is approved in multiple countries for the treatment of PD-L1-positive patients (pts) with advanced TNBC (aTNBC) based on a significant improvement in progression-free survival (PFS) and a numerically higher and clinically meaningful median overall survival (OS). A synergism between antiangiogenic therapy and immunotherapy (IO)-based strategies has been observed preclinically and in different tumor types, but data in aTNBC is lacking. METHODS ATRACTIB (NCT04408118) is an international, open-label, single-arm, phase 2 trial evaluating the efficacy and safety of 1L ATZ + BVZ + PTX for pts with aTNBC, regardless of their tumors’ PD-L1 status. Adult pts with untreated, unresectable locally advanced/metastatic TNBC were included. Pts who had received (neo)adjuvant taxane-based chemotherapy (CT) and/or IO and/or an antiangiogenic agent had to have had a relapse with a disease-free interval beyond 12 months (mo). Pts received intravenous ATZ 840 mg + BVZ 10 mg/kg on days (D)1 and D15 + PTX 90 mg/m2 on D1, 8, and 15 of every 28-day cycle until disease progression, intolerable toxicity, death, or patient withdrawal. Tumor assessments were performed every 8 weeks for the first 12 mo and every 12 weeks thereafter. Baseline PD-L1 expression was centrally assessed using 22C3 (combined positive score [CPS]) and SP142 (expression on tumor-infiltrating immune cells [ICs]) Abs. The primary endpoint was investigator-assessed PFS by RECIST v.1.1. Key secondary endpoints included OS, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), and safety. Median PFS was analyzed with exponential maximum likelihood estimation (H0: ≤7.0 mo; HA: ≥9.5 mo). We estimated that enrolling 100 pts would provide 80% power at one-sided α nominal level of 5%, assuming a 10% drop-out rate. RESULTS Between October 2020 and May 2022, 100 female pts from 28 centers across 5 European countries were included. Median age was 55.0 years (32.0 - 84.0), 57.0% of pts had visceral disease, 46.0% had ≥3 metastatic sites, and 70.0% had received prior treatment for early BC (taxane-based CT in 87.1% of them). A total of 82 and 85 tumor samples out of 100 pts were available for PD-L1 assessment using 22C3 and SP142 assays, respectively. Most pts had PD-L1-negative tumors (87.8% with 22C3 [CPS &amp;lt; 10] and 97.6% with SP142 [expression on &amp;lt; 1% positive of ICs]). At data cutoff (15th September 2023), 23 pts were still on therapy. With a median follow-up of 16.7 mo (1.1 - 34.1), median PFS was 11.0 mo (95% CI, 9.0 - 13.2). OS data were immature at data cutoff, with 30 events. Estimated 18-month OS was 69.4% (95% CI, 58.4% - 78.1%). ORR was 63.0% (95% CI, 52.8% - 72.4%), CBR was 79.0% (95% CI, 69.7% - 86.5%), and median DoR was 10.0 mo (95% CI, 7.2 - 13.8). Regarding safety, the most common treatment-emergent adverse events (TEAEs) were peripheral neuropathy (68.0%) and fatigue (62.0%). Grade (G) 3/4 treatment-related TEAEs occurred in 47.0% of pts, mainly peripheral neuropathy (13.0%) and neutropenia (12.0%). Any-grade immune-related TEAEs, thrombosis or embolism, and bleeding occurred in 13.0% (5.0%; G≥3), 4.0% (1.0%; G≥3), and 10.0% (0.0%; G≥3) of pts, respectively. There were no drug-related deaths. CONCLUSIONS 1L ATZ + BVZ + PTX demonstrated encouraging anti-tumor activity in aTNBC pts, most of them presenting with PD-L1-negative tumors. Median PFS seems to be much higher compared with that previously reported with other IO-based regimens in a similar patient population. The safety profile was consistent with the known safety data of ATZ and BVZ combined with CT, without significant added toxicity. These results merit further research of this combination for PD-L1-negative aTNBC. Citation Format: Maria Gion, Patricia Cortez-Castedo, Isabel Blancas, Alfonso Cortés, Frederik Marmé, Salvador Blanch, Serafin Morales Murillo, Nieves Díaz, Isabel Calvo-Plaza, Sabela Recalde, Alejandro Martínez-Bueno, Manuel Ruiz-Borrego, Elisenda Llabres, María Teresa Taberner, Michelino de Laurentiis, José Ángel García-Sáenz, Jana Repkova, Antonio Antón, Joseph Gligorov, Susana de la Cruz, Oliver Hoffmann, Jacques Medioni, Melissa Phillips, Miguel Sampayo-Cordero, Daniel Alcalá-López, José Manuel Pérez-García, Antonio Llombart-Cussac, Javier Cortés. Efficacy and safety of first-line atezolizumab + bevacizumab + paclitaxel in patients with advanced triple-negative breast cancer: the ATRACTIB phase 2 trial [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 PS16-02.

Abstract PO4-27-05: A phase I open-label dose escalation trial of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations

Abstract Background: Estrogen receptor (ER) signaling sits at center of the tumor biology in ER+/HER2- breast cancers. Current standard of care involves hormone therapy with agents including selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs). Unfortunately, most patients eventually develop resistance to these therapies. Mutations in estrogen receptor 1 (ESR1) are partially responsible for the acquired resistance. Mutated estrogen receptors are still sensitive to fulvestrant but with a much less sensitivity. In January 2023, elacestrant received its first approval for the treatment of postmenopausal women or adult men with breast cancer harboring ESR1 mutations in US. However, there is still great unmet medical need for this population. FWD1802 is a third-generation oral SERD for ER-positive breast cancer patients. It binds competitively to ER, with a much higher affinity than that of fulvestrant. Preclinically, FWD1802 alone and in combination with palbociclib exhibits significant anti-tumor activity in the ER+/HER2- models and in ESR1-mutated models in vitro and in vivo. This ongoing phase I study is to assess the safety, tolerability, pharmacokinetics (PK) and clinical activity of FWD1802 as monotherapy and in combination with palbociclib in ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations. Methods: This clinical study (CTR20232130) consists of three parts: monotherapy dose escalation (Part A), dose escalation in combination with palbociclib (Part B) and monotherapy dose expansion in ESR1-mutated patients (Part C). A conventional “3+3” design is used for this study. Approximately a total of 129 patients will be enrolled. FWD1802 is administered orally daily. In monotherapy dose escalation study (Part A), at each dose level, a single ascending dose (SAD) is followed by a 28-day continuous multiple ascending dose (MAD) period (defined as 1 cycle). In Part B dose, palbociclib (125 mg daily) is administered on a 28-day treatment cycle with 21-day on treatment and 7-day off treatment, along with the 28-day treatment cycle of FWD1802. The primary objectives include dose limiting toxicity (DLT), maximum tolerated dose (MTD), safety, tolerability, and the recommended phase 2 dose (RP2D) of FWD1802. Secondary objectives include pharmacokinetics characteristics of FWD1802 and its major metabolite as monotherapy and in combination with palbociclib. Preliminary anti-tumor activity including objective response rate (ORR), duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS) will also be evaluated. DLT evaluation will be conducted after the first cycle of multi-dose period, and tumor assessment will be conducted every 8 weeks by investigators according to RECIST version 1.1. Patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutation are eligible for the enrollment. Enrolled patients should have progressed disease, or failed from previous therapy, or intolerable or inaccessible to standard therapy. In addition, patients with ECOG score ≤1 and with adequate renal, cardiac, hepatic, and hematologic function are eligible for enrollment. The monotherapy dose escalation (Part A) is currently ongoing. The dose selection for Part B and Part C will be based on the data from the ongoing Part A. Clinical trial information: CTR20232130. Research Sponsor: Shenzhen Forward Pharmaceuticals Co., Ltd. (FORWARD PHARMA). Citation Format: Ling Zeng, Jin Liu, Dan Wu, Huiwen Ge, Zirui Bian, Chenggang Zhu. A phase I open-label dose escalation trial of FWD1802 as monotherapy and in combination with palbociclib in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-05.

Abstract PO2-19-09: INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive advanced breast cancer

Abstract Background The PI3K pathway plays a crucial role in HER2 signaling. Somatic mutations of PIK3CA, the gene that encodes the PI3K p110α subunit, may induce resistance to HER2-targeted therapies and are associated with poorer clinical outcomes (Swain SM, et al. SABCS 2022; P2-11-07). Inavolisib, a potent p110α-selective inhibitor that induces degradation of mutant p110α, has shown antitumor activity in PIK3CA-mutated HER2-positive breast cancer (HER2+ BC) and long-term tolerability with early intervention for common on-class toxicities, including hyperglycemia, diarrhea, and stomatitis (Bedard P, et al. ASCO 2022; 1052). The current study will assess the efficacy and safety of maintenance inavolisib + fixed-dose combination of pertuzumab + trastuzumab for subcutaneous injection (PH FDC SC) after first-line induction treatment in patients with PIK3CA-mutated, HER2+, advanced BC (aBC). Trial design INAVO122 is a multicenter, randomized, international, double-blind, placebo-controlled study. Patients will be enrolled for: first-line induction treatment if they are receiving/will receive PH + a taxane; or maintenance treatment completing induction treatment. In the maintenance phase, patients will be randomized 1:1 to receive inavolisib (9 mg orally once daily; Days 1–21 of 21-day cycles) + PH FDC SC (every 3 weeks), or placebo + PH FDC SC. Study treatment will continue until disease progression, unacceptable toxicity, death, consent withdrawal, or at the investigator’s discretion. ELIGIBILITY Enrolled patients must have centrally determined HER2+, PIK3CA-mutated tumors, with documented hormone receptor status per local assessment, and be disease-free for ≥ 6 months from completion of neoadjuvant/adjuvant systemic non-hormonal treatment. They must not have received any treatment for aBC prior to induction, and, at screening, fasting glucose must be &amp;lt; 126 mg/dL and HbA1c &amp;lt; 6.4%. To be randomized, patients must have completed induction therapy per standard of care without progression of disease and show left ventricular ejection fraction ≥ 50%. AIMS The primary endpoint is investigator-assessed progression-free survival. Secondary endpoints are overall survival; investigator-assessed objective response rate, duration of response, clinical benefit rate, and time to second disease progression; health-related quality of life; safety; and pharmacokinetics. STATISTICAL METHODS The primary endpoint analysis will utilize a two-sided stratified log-rank test at a two-sided significance level of 5%. A stratified Cox proportional hazards model will be used to estimate the hazard ratio between the two treatment arms and its 95% confidence intervals. ACCRUAL Target randomization is ~230 patients; recruitment began in July 2023. 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 NCT05894239. Citation Format: Sandra Swain, Carlos Barrios, Reva Basho, Giuseppe Curigliano, Nadia Harbeck, Chiun-Shen Huang, Sherene Loi, Nicholas Turner, Jessica Chen, Volkmar Henschel, Simon Warburton, Fabiola Amair-Pinedo, Javier Cortés. INAVO122: a Phase III study of maintenance inavolisib or placebo + pertuzumab + trastuzumab following induction with pertuzumab + trastuzumab + a taxane in patients with PIK3CA-mutated, HER2-positive 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 PO2-19-09.

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 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.