Combination effect of inavolisib and FGFR inhibitors in FGFR2-expressing cell lines

FGFR2 controls HER3 to induce p85β binding and signaling in FGFR2 high-expressing cell lines

Proposed mechanistic model of FGFR2-mediated inavolisib sensitivity

PURPOSE:PIK3CA mutations frequently drive solid tumors, particularly hormone receptor-positive breast cancer. Inavolisib, an ATP-competitive p110α inhibitor, also promotes the degradation of mutated p110α. PI3K inhibitors have generally shown modest single-agent activity and have safety concerns. PATIENTS AND METHODS:A first-in-human phase 1 study (NCT03006172) evaluated oral inavolisib in patients with PIK3CA-mutated solid tumors to determine the maximum tolerated dose and safety. Correlative analyses included ctDNA. Preclinical studies in cell lines and xenografts elucidated the role of FGFR2. RESULTS:The maximum tolerated dose was 9 mg daily, with a manageable safety profile (e.g., hyperglycemia and diarrhea). Inavolisib showed linear pharmacokinetics, consistent pharmacodynamic modulation, and antitumor activity in hormone receptor-positive PIK3CA-mutated breast cancer (26% objective response rate and 45% clinical benefit rate). FGFR2 hotspot mutations in ctDNA were strongly associated with clinical benefit. Preclinically, oncogenic FGFR2 signaling enhanced inavolisib sensitivity by engaging HER3, RAS, and p85β, that facilitated mutated p110α degradation, surpassing nondegrading inhibitors. Combination therapy with FGFR2 inhibitors showed synergy and delayed resistance. CONCLUSIONS:These findings highlight a novel cooperativity between FGFR2 and p110α that boosts the effectiveness of inavolisib. The data support advancing precision oncology beyond single biomarkers to complex algorithms utilizing co-occurring alterations, suggesting that combining inavolisib with FGFR2 inhibitors may offer enhanced and more durable responses in PIK3CA/FGFR2-altered tumors.

Representativeness of study participants

Evaluation of the anti-tumor activity of FGFR2 inhibitor in combination with inavolisib in MFM223x2.2 xenograft model

Abstract Brain metastases (BM) represent a significant unmet need in ER+/HER2– mBC. Although endocrine therapy (ET) plus CDK4/6i is the 1L systemic treatment, most agents have limited BBB penetration, and tumors eventually develop resistance to ET, leading to disease progression. Elacestrant is the only single-agent oral SERD to significantly improve PFS versus standard-of-care ET in the EMERALD trial in both the overall population (HR = 0.70; 95% CI:0.55-0.88; P = 0.0018) and in patients with ESR1-mutant tumors (HR = 0.55; 95% CI:0.39-0.77; P = 0.0005), with a manageable safety profile (Bidard, 2022). Preclinical data demonstrate both elacestrant and abemaciclib cross the BBB (Conlan, 2020; Tolaney, 2020), providing a rationale for evaluating this combination in patients with BM. ELECTRA (NCT05386108) is an open-label, multicenter, phase 1b/2 study evaluating elacestrant plus abemaciclib in patients with BM from ER+/HER2– breast cancer. Eligibility includes locally advanced/mBC with ≥1 active, measurable BM (RECISTv1.1), prior therapy in the metastatic setting including ≥1 ET, ≤2 chemotherapy regimens, and 0-2 prior CDK4/6i (excluding abemaciclib). Phase 1b established the RP2D. Phase 2 primary endpoint is ORR (RECISTv1.1). Secondary endpoints include iORR, DoR, CBR, PFS, OS, PK, and QoL. Exploratory endpoints include CSF PK of elacestrant plus abemaciclib. This analysis reports phase 2 CSF PK results. In evaluable patients (n = 7), elacestrant achieved clinically meaningful CSF concentrations, with levels exceeding the target engagement threshold in 50% of patients. Abemaciclib attained CSF levels sufficient for CDK4/6 inhibition. These findings confirm that the combination achieves pharmacologically relevant drug exposure in the CNS. Updated safety, and clinical efficacy data, including intracranial-response assessments, will be presented (n = 33). Both elacestrant and abemaciclib successfully penetrated the BBB, achieving clinically meaningful CSF concentrations in most patients. These PK data support the continued evaluation of this all-oral BBB-penetrant combination for patients with ER+/HER2– mBC and BM. The phase 2 portion of ELECTRA is actively enrolling worldwide.

Effects of FGFR1/2/3/4 knockdown on inavolisib sensitivity

Study NCT03006172 Arm A participants whose liquid biopsies harbored an FGFR2 mutation

Effects of inavolisib and FGFR2 inhibition on downstream signaling in FGFR2-high and FGFR2-low expressing cell lines

Supplementary Table 1. Statistical Assumption and Sample Size Estimates for MUCE Design

Abstract Background: Disease progression in pts with ER+/HER2- mBC on 1L ET + CDK4/6i is associated with mechanisms of resistance that impact the efficacy of subsequent therapy. Ela improved PFS vs SOC ET (ESR1m tumors HR 0.55; 95% CI 0.39-0.77; all pts HR 0.70; 95% CI 0.55-0.88) with manageable safety in the Ph3 EMERALD trial (Bidard 2022). ELEVATE is evaluating Ela combined with Eve, alpelisib, capivasertib, Abema, ribociclib, or palbociclib to address resistance mechanisms. Based on encouraging Ph1b results, we evaluated Ph2 combinations of Ela + Eve or Abema in all pts and subgroups. Methods: Pts with ER+/HER2- mBC, 1-2L of prior ET are eligible regardless of ESR1m status. Prior CDK4/6i is required for Arm B (Ela + Eve) and Arm C (Eve + Abema). Pts with no prior CDK4/6i were enrolled in Arm D (Ela + Abema). Ph2 evaluates PFS with each combination. ESR1 and PIK3CA mutation status were evaluated in pts for both combinations Ela + Eve (n=48) and Ela + Abema (n=50). Results: As of Sept 2025, 50 pts enrolled in Arm B (Ela + Eve), and 60 enrolled in Arms C and D (Ela + Abema combinations, n=30 each). Baseline characteristics are pts with visceral mets (72% Arm B, 92% Arms C/D), primary ET resistance (20% Arm B, 15% Arms C/D), ESR1m (42% Arm B, 33% Arms C/D), and PIK3CAm (50% Arm B, 27% Arms C/D). PFS was consistent across subgroups (Table 1). Safety results were consistent with the known profiles of Eve or Abema + SOC ET. Ph2 Ela + Eve ORR was 19.5%, DCR 82.9%, mDOR 8.54 mo. Ph2 Ela + Abema ORR was 24.6%, DCR 91.2%, mDOR 14.75 mo. Conclusion: Ela combinations show a consistent clinically meaningful PFS irrespective of ESR1m status in pts with ER+/HER2- mBC after progressive disease on ET ± prior CDK4/6i, and could become an ET backbone for combination strategies, supporting an all-oral approach. Citation Format: Hope S. Rugo, Sara M. Tolaney, Nancy Chan, Giuliano Borges, Rinat Yerushalmi, Marina N. Sharifi, Wassim McHayleh, Thaddeus Beck, Neelima Vidula, Erika Hamilton, Kristine J. Rinn, Joyce O’Shaughnessy, Giuseppe Curigliano, Javier Cortés, Paula Muñoz Romero, Giulia Tonini, Alessandro Paoli, Monica Binaschi, Li Cheng, Jennifer A. Crozier, Tomer Wasserman, Virginia Kaklamani. Elacestrant (Ela) in combination with everolimus (Eve) or abemaciclib (Abema) in patients with ER+/HER2- locally advanced or metastatic breast cancer mBC: phase 2 results from ELEVATE, an open-label, umbrella study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT262.

PURPOSE:Establish the safety, tolerability, and preliminary activity of trastuzumab deruxtecan (T-DXd) in combination with other anticancer therapies in human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). PATIENTS AND METHODS:DESTINY-Breast08 was a two-part, open-label, multicenter, phase Ib study. Patients with locally confirmed HER2-low mBC received T-DXd plus capecitabine, durvalumab + paclitaxel, capivasertib, anastrozole, or fulvestrant. Eligibility criteria for hormone receptor status varied across modules and between study parts. Primary objectives were safety/tolerability and determining recommended phase II doses (RP2D); secondary endpoints included objective response rate (ORR; per investigator). RESULTS:In the dose-finding phase, 37 patients were assigned to a module. RP2Ds were determined for T-DXd plus capecitabine, capivasertib, anastrozole, or fulvestrant. For strategic reasons, T-DXd + durvalumab + paclitaxel was not pursued beyond the dose-finding phase (n = 3). In the dose-expansion phase, 101 patients were assigned to a module. For T-DXd + capecitabine, grade ≥3 adverse events (AE) occurred in 55% (11/20) of patients, and the ORR was 60%. For T-DXd + capivasertib, grade ≥3 AEs occurred in 67.5% (27/40) of patients, and the ORR was 60%. For T-DXd + anastrozole, grade ≥3 AEs occurred in 47.6% (10/21) of patients, and the ORR was 71.4%. For T-DXd + fulvestrant, grade ≥3 AEs occurred in 55% (11/20) of patients, and the ORR was 40%. Adjudicated drug-related interstitial lung disease/pneumonitis events were reported for T-DXd + capecitabine (3/20; grade 2, n = 2; grade 5, n = 1), T-DXd + capivasertib (8/40; all grade ≤2), and T-DXd + fulvestrant (5/20; all grade 2). CONCLUSIONS:Safety results were generally consistent with known individual profiles for T-DXd and combination drugs. T-DXd plus capecitabine, capivasertib, anastrozole, or fulvestrant demonstrated preliminary clinical activity in patients with HER2-low mBC.

BACKGROUND:The NATALEE and monarchE trials showed significant invasive disease-free survival benefits with the addition of a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to endocrine therapy (ET) in patients with hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer (EBC). This study evaluates outcomes in real-world patients prior to widespread availability of adjuvant CDK4/6is, depending on nodal status, including N0 disease with and without high-risk features. METHODS:Anonymized data from the Flatiron Health US electronic health record database (2011 to 2023) were analyzed. Adults with American Joint Committee on Cancer anatomic stage I-III HR+/HER2- EBC who underwent surgery and adjuvant ET were included. Overall and distant recurrence and all-cause mortality risks were assessed descriptively across nodal subgroups using Cox proportional hazards models. Recurrence-free survival, distant recurrence-free survival (DRFS), and overall survival were evaluated using Kaplan-Meier methods in the NATALEE- and monarchE-eligible populations. RESULTS:Among 7481 analyzed patients, 5387 (72.0%) had N0 disease, including 604 (11.2%) with high-risk features and 4783 (88.8%) without. Additionally, 1626 (21.7%) had N1 and 468 (6.3%) had N2-N3 disease. At a potential median follow-up of 78.0 months, the N0 high-risk subgroup showed overall and distant recurrence and mortality risks similar to those in the N1 subgroup. Overall, 2534 patients (33.9%) were NATALEE-eligible, and 1157 (15.5%) were monarchE-eligible. Both populations showed relatively high 5-year distant recurrence rates (DRFS, 83.1% and 74.6%, respectively). CONCLUSIONS:This contemporary real-world analysis highlights a meaningful recurrence risk in the broader HR+/HER2- EBC population, irrespective of nodal status, and emphasizes the need for effective treatment strategies.

Abstract Background: Endocrine resistance is a major challenge in ER+/HER2− metastatic breast cancer (mBC). Histone lysine acetyltransferases KAT6A/B regulate lineage-specific gene transcription via H3K23 acetylation. Prifetrastat (PRIFET; PF-07248144) is a first-in-class, potent, and selective KAT6A/B inhibitor. In an ongoing phase 1/2a study, PRIFET + fulvestrant (FUL) demonstrated an acceptable safety profile and durable antitumor activity in patients with ER+/HER2- mBC after prior CDK4/6 inhibitor + endocrine therapy. Here, we report exploratory pharmacodynamic (PD) effects of KAT6 inhibition on tumor gene expression and circulating tumor DNA (ctDNA) dynamics to further support phase 3 dose selection and elucidate mechanism of action. Methods: Patients with ER+/HER2− mBC were enrolled in a phase 1/2a dose-escalation/expansion study and received PRIFET (1 mg and 5 mg QD) monotherapy or with FUL. Serial blood, plasma, and paired tumor biopsies were collected before and after PRIFET treatment. H3K23Ac was quantified in PBMCs (MSD assay) and tumor biopsies (IHC). Tumor gene expression was profiled by RNA sequencing. ctDNA mutation burden and variant allele frequency were assessed using Guardant 360 assay (74-gene panel). Early ctDNA clearance was defined as a change from detectable to nondetectable status within 9 weeks of treatment. Results: Patients received PRIFET 5 mg QD (N = 36), 1 mg QD + FUL (N = 29), and 5 mg QD + FUL (N = 43). All treatment groups achieved ≥50% reduction of H3K23Ac in PBMCs and tumor tissues, confirming target engagement. PRIFET 5 mg QD + FUL induced the strongest tumor gene expression changes, including upregulation of tumor suppressors (FOXD3, MXI1, ING4) and downregulation of proliferation/cell cycle genes (CCNE1, CCNB1, TK1, TYMS) and ER-responsive genes (TFF3). Early ctDNA clearance rates were highest with PRIFET 5 mg QD + FUL (n = 34, overall 26%, ESR1 63%, PIK3CA/AKT1/PTEN 31%) versus PRIFET 1 mg QD + FUL (n = 23, 9%, 8%, 15%, respectively) or PRIFET 5 mg QD monotherapy (n = 24, 4%, 14%, 13%, respectively). Early ctDNA clearance at 5 mg QD + FUL occurred regardless of baseline mutation status and correlated with durable clinical responses. Conclusions: PRIFET 5 mg QD + FUL robustly inhibited KAT6 and ER signaling, resulting in early ctDNA clearance, including resistance-associated ESR1 variants. These findings further support PRIFET 5 mg QD + FUL as the recommended phase 3 regimen and provide mechanistic insight into overcoming ER resistance and inhibiting cell cycle/tumor proliferation in ER+/HER2− mBC. Integration of tumor and ctDNA PD markers offers a powerful approach for dose selection, patient stratification, and real-time monitoring of molecular response in future clinical trials. ctDNA analysis limitations include small sample size and short follow-up duration; additional evaluation is ongoing. Citation Format: Li Liu, Rachel M. Layman, Xinmeng Jasmine Mu, Vinicius Bonato, Patricia M. LoRusso, Toru Mukohara, David Sommerhalder, Geoffrey J. Lindeman, Kan Yonemori, Erika Hamilton, Sung-Bae Kim, Hope S. Rugo, Toshinari Yamashita, Fengting Yan, Fumikata Hara, Gunmin Kim, Shusen Wang, Sean Kent, Karey Kowalski, Shreya Badhrinarayanan, Athanasia Skoura, Meng Li, Yeon Hee Park. Unlocking endocrine resistance: Co-targeting KAT6 and ER with prifetrastat (PF-07248144) and fulvestrant drives tumor and ctDNA response in ER+/HER2− metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT174.

Abstract Background: Apoptosis modulation may enhance the efficacy of standard-of-care chemotherapy (CT) and concurrent chemoradiotherapy (cCRT) in solid tumors. BGB-24714, a selective SMAC mimetic that antagonizes Inhibitor of Apoptosis Proteins (IAPs), has demonstrated promising preclinical antitumor activity. This open-label, multicenter, first-in-human Phase (Ph) 1 study evaluated BGB-24714 as monotherapy or in combination with CT or cCRT in patients (pts) with advanced or metastatic solid tumors (NCT05381909). Methods: The study included dose-escalation (1a) and -expansion (1b) Phs. Ph1a Part A assessed BGB-24714 monotherapy; Part B: BGB-24714 + weekly paclitaxel; Parts C/D: BGB-24714 + cCRT in NSCLC and esophageal squamous cell carcinoma (ESCC), respectively. Ph1b enrolled pts with second-line or later metastatic NSCLC and platinum-resistant ovarian cancer (PROC) to receive BGB-24714 + docetaxel or paclitaxel, respectively. Primary endpoints were safety/tolerability (Ph1a) and preliminary antitumor activity (Ph1b). Results: As of July 25, 2025, 157 pts were enrolled and treated (132 in Ph1a; 25 in Ph1b [11 NSCLC; 14 PROC]). 9 dose levels (DLs; 30 mg to 900 mg QD) of BGB-24714 were assessed (n=68) in Ph1a Part A and 7 DLs (60 mg to 650 mg QD) in Ph1a Parts B to D (n=64). No MTD was reached in Ph1a monotherapy or combination dose escalation.The most common BGB-24714-related TEAEs varied by study part and were predominantly low grade: nausea (33.8%) in Ph1a Part A, diarrhea (25%) in Part B, neutrophil count decreased (43.8%) in Parts C/D, diarrhea and fatigue (45.5% each) in Ph1b-NSCLC, and stomatitis, ALT/AST increased (28.6% each) in Ph1b-PROC. The most common Grade ≥3 BGB-24714-related TEAEs were ALT increased (5.9%) in Ph1a Part A, lipase increased and fatigue (6.3% each) in Part B, neutrophil count decreased (31.3%) in Parts C/D, anemia (27.3%) in Ph1b-NSCLC, and neutrophil count decreased (28.6%) in Ph1b-PROC. The most common serious BGB-24714-related TEAEs (≥5%) were pneumonitis (6.3%) in Ph1a Part B, diarrhea (18.2%) in Ph1b-NSCLC, and febrile neutropenia and fatigue (7.1% each) in Ph1b-PROC. Treatment discontinuation due to BGB-24714-related TEAEs occurred in 12.1% of Ph1a and 24.0% of Ph1b pts. Confirmed ORRs in Ph1a were 0% (Part A), 12.8% (Part B), 54.5% (Part C), and 66.7% (Part D); DCRs were 40.0%, 59.6%, 81.8%, and 100.0%, respectively. In Ph1b, confirmed ORRs were 0% in NSCLC and 28.6% in PROC; DCRs were 70.0% and 85.7%, respectively; median PFS was 162 days for both NSCLC and PROC. Pharmacodynamics showed rapid and sustained cIAP1 degradation in a dose-dependent manner, demonstrating strong target engagement in apoptosis regulatory pathway. Conclusion: BGB-24714 demonstrated antitumor activity with a manageable safety profile in pts with advanced or metastatic solid tumors. Citation Format: Andreas Varkaris, Erika Hamilton, Jermaine Coward, Rafael Santana-Davila, Jinming Yu, Byoung Chul Cho, Jung Yun Lee, Yongsheng Li, Sanjeev Deva, Youngjoo Lee, Huai Liu, Yuping Sun, Zhe Yang, Wen Xu, Sook Ryun Park, Se-Hoon Lee, Andrew Z. Wang, Hui Shao, Jinhui Zhang, Zhaoyin Zhu, Runzhe Chen, Hua-Xin Gao, Judy S. Wang. A phase 1 study of BGB-24714, a second mitochondrial-derived activator of caspases (SMAC) mimetic, as monotherapy or in combination with chemotherapy or concurrent chemoradiotherapy in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT120.

Antitumor activity (dose-expansion phase).