Turner, Nicholas C.

LBA507 Background: In monarchE (NCT03155997), 2 years of adjuvant abemaciclib + ET resulted in sustained improvement in invasive disease-free survival (IDFS; HR=0.680, 7.6% absolute benefit at 5 years) in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. Here, we investigate the prognostic value of ctDNA detection and dynamics in pts from monarchE. Methods: Samples were analyzed from a selected pt subset (n=1397; abemaciclib + ET arm, n=685; ET arm, n=712), enriched for overall IDFS events compared to the total monarchE study population (IDFS event rate: 31% [433/1397] vs 18% [992/5637]). Pts had blood collected pre-study treatment (baseline) and at 3, 6, or 24 months. ctDNA detection was performed using the personalized, tumor informed Signatera ctDNA assay (Natera, Inc) and whole exome sequencing (WES) of matched primary tumor and normal required for assay design was performed. Results: Among 1397 pts, 65% (n=910) had sufficient plasma samples and WES performed, and all 910 had successful ctDNA assay testing. Among these 910 pts, the IDFS event rate was 27% (abemaciclib + ET, 23% [101/438]; ET alone, 31% [146/472]). Rates of ctDNA positivity (at baseline and any change from baseline) and associated IDFS events are shown in Table. Among pts with ctDNA positivity, 87% had an IDFS event in comparison to 15% with persistent ctDNA negative (-) status during the study. Conclusions: In a pt subset from monarchE enriched for IDFS events, ctDNA detection was relatively infrequent (<20%); however, its detection at any time during the 24 months of study therapy was adversely prognostic. As compared to pts who had remaining ctDNA positive (+), pts who had clearance of ctDNA on therapy had lower risk of IDFS events, but the event risk still remained clinically meaningful in these pts. Clinical trial information: NCT03155997 . [Table: see text]

Abstract Background Two years of adjuvant abemaciclib + endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer (EBC) in the monarchE trial (NCT03155997). The benefit of abemaciclib was sustained beyond completion of treatment and deepened in magnitude at 4 years for IDFS and DRFS. This pilot study investigated the technical feasibility of ctDNA detection beginning prior to study treatment, as well as rates of persistence and clearance in a subset of EBC pts from monarchE using the clinically validated SignateraTM ctDNA assay. Methods Samples were analyzed from a selected subset of pts (n=178; 84 from abemaciclib+ET arm; 94 ET alone) who had blood collected both before initiating protocol directed therapy, Visit 1 (V1; randomization + ≤ 3 days) and near completion of the 2-year treatment period, Visit 27 (V27; 24 months +/- 5 days from V1). This cohort of pts was enriched for overall IDFS events compared to the total monarchE study population, however pts with relapses occurring prior to V27 were excluded. Primary tumors from selected pts were subjected to whole exome sequencing (WES). Selected samples included those from pts with a range of tumor mutation burden. Cell-free DNA was extracted from 356 plasma samples. A Signatera ctDNA assay was developed for each pt based on up to 16 variants detected by WES from each baseline tumor sample. Results The IDFS event rate for the selected subset (n=178) was 39.3% (abemaciclib+ET 34.5% [29/84] and ET alone 43.6% [41/94]). Ten pts (5.6%) were initially ctDNA+ and 42 pts (23.6%) were persistently (7 pts, 3.9%) or became (35 pts, 19.7%) ctDNA+ at V27. Notably, 70% of pts who were initially ctDNA+ and 100% of pts who were either persistently ctDNA+ or became ctDNA+ experienced recurrence (see Table 1). In contrast, none of the 3 pts that cleared ctDNA+ developed recurrence. In pts persistently ctDNA negative (neg), 28 (21.1%) experienced recurrence. Overall, 10% (7/70) of pts with IDFS events were initially ctDNA+ and 50% (35/70) had detectable ctDNA at V27. Conclusions Detection of ctDNA soon after completing neoadjuvant chemotherapy was infrequent, but also associated with a high-risk of recurrence. ctDNA positivity was common at the end of the 2-year treatment period and was highly prognostic with all pts subsequently developing disease recurrence. Importantly, ~30% of pts with early ctDNA detection ultimately dropped below detection limits during the 2-year treatment period and none developed recurrence. Although some pts remained persistently ctDNA neg during this study and experienced recurrence, the delay in recurrence may indicate longitudinal benefit from remaining ctDNA neg. Future planned analysis of an expanded cohort reflective of the intent to treat population including additional timepoints within the 2-year treatment period will further define how ctDNA dynamics may identify pts at high-risk of recurrence. Table 1. Summary of Subset Positivity Rates. + positive; - negative; NA, not applicable. Citation Format: Sherene Loi, Stephen Johnston, Carlos Arteaga, Stephanie Graff, Sarat Chandarlapaty, Matthew Goetz, Christine Desmedt, Jorge Reis-Filho, Hironobu Sasano, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Deli Liu, Lacey M. Litchfield, Nicholas Turner. Results from a pilot study exploring ctDNA detection using a tumor-informed assay in the monarchE trial of adjuvant abemaciclib with endocrine therapy in HR+, HER2-, node-positive, high-risk early 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 PS06-01.

Abstract Background: Fibroblast growth factor receptor 1 (FGFR1) gene amplification and overexpression is associated with an adverse prognosis in hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) breast cancer and is observed in ~10% of all invasive breast cancers. The phase 2 FOENIX-MBC2 study (NCT04024436) was designed to evaluate the effect of futibatinib, a highly selective and potent irreversible covalent inhibitor of FGFR1–4 (FDA-approved for intrahepatic cholangiocarcinoma), used either alone or in combination with fulvestrant in patients with metastatic breast cancer. Here, we report final efficacy and safety data for the cohort of patients receiving futibatinib plus fulvestrant for HR+/HER2− breast cancer harboring high-level FGFR1 gene amplification. Methods: Patients were eligible if they had disease progression after prior therapy for advanced/metastatic disease, had measurable disease per RECIST v1.1, had an ECOG performance status of 0 or 1, were fulvestrant-naïve, and had previously received 1–2 endocrine-containing therapies, ≤1 chemotherapy regimen, and a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor for advanced cancer (unless ineligible). High-level FGFR1 gene amplification, determined in tumor tissue using next-generation sequencing, fluorescence in situ hybridization (FISH), or similar assays, was defined as FGFR1/centromere 8 ratio ≥5 or FGFR1 copy number ≥10 signals per cell. Local FGFR1 determination results were confirmed in tumor tissue by a central laboratory using FISH. Patients received oral futibatinib 20 mg once daily and standard fulvestrant dosing until disease progression, unacceptable toxicity, or other discontinuation criteria were met. The primary endpoint was the 6-month progression-free survival (PFS) rate. Key secondary endpoints included objective response rate (ORR), PFS, and overall safety. Results: Overall, 22 female patients were enrolled in this cohort. Patients were a median age of 58 years, had received a median of 3 lines of any prior systemic anticancer therapy, and had all received CDK4/6 inhibitor pretreatment. PFS at 6 months was observed in 10 (45.5%) patients (95% CI: 24.4, 67.8) and the median PFS was 7.2 (95% confidence interval [CI]: 2.1, 7.6) months. Four patients had a confirmed partial response (ORR: 18.2%; 95% CI: 5.2, 40.3). The median duration of response was 6.3 (range: 3.3–12.8) months. All patients had ≥1 treatment-related adverse event (TRAE), the most common being hyperphosphatemia (95.5%), alopecia (54.5%), constipation (45.5%), and dry mouth (40.9%). There were 5 (22.7%) patients with a Grade 3 TRAE (no Grade 4 or 5). TRAEs leading to study treatment interruption or reduction were seen in 9 (40.9%) and 15 (68.2%) patients, respectively. There were 2 (9.1%) patients who had TRAEs leading to study treatment discontinuation. No treatment-related serious adverse events were reported. Conclusions: Futibatinib plus fulvestrant showed antitumor activity in patients with advanced HR+/HER2− breast cancer with FGFR1 amplification progressing on prior CDK4/6 inhibitors, with a numerically higher ORR and doubling in PFS relative to historical fulvestrant results in post-CDK4/6 patients. The safety profile was consistent with those of the individual study drugs. Further biomarker work is ongoing. Citation Format: Senthil Damodaran, Fabrice André, Nisha Unni, Marta Ferreira, Karthik Giridhar, Brooke Daniel, Marco Colleoni, Luis Costa, Thomas Bachelot, Ciara O’Brien, Gail Wright, Masashi Shimura, Gareth Tomlinson, Maciej Gil, Nicholas Turner. Final results from the phase 2, open-label FOENIX-MBC2 study: efficacy and safety of futibatinib in adult patients with locally advanced/metastatic HR+/HER2− breast cancer harboring high-level FGFR1 gene amplification [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 RF01-04.

Abstract Background Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in significant and clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE trial (NCT03155997). Abemaciclib benefit was sustained beyond the completion of treatment (tx) with deepening magnitude of absolute benefit in IDFS and DRFS at 5 years. Here, we evaluate comprehensive molecular profiling of archived primary tumor tissue and association with clinical outcomes. Methods For biomarker analysis, a proportionally stratified random sampling case-cohort design was utilized to include all patients who experienced an IDFS event at a pre-specified interim analysis with a median follow up of 54 months. A cohort of 895 pts (189 with IDFS event) in the abemaciclib + ET arm was matched 1:1 with 903 pts (270 with IDFS event) in the ET arm. Baseline primary tumor samples underwent exome-capture RNA sequencing (RNAseq; n=1324, 23% intent-to-treat (ITT) population) and paired tumor-normal (germline blood samples) whole-exome sequencing (WES; n=1234, 22% ITT population). Expression-based intrinsic subtypes (i.e., luminal A (LumA), luminal B (LumB), HER2-enriched (HER2E), basal- and normal-like) were characterized using the Absolute Intrinsic Molecular Subtyping model. The 21-gene expression signature score (Oncotype DX test) was inferred from RNAseq; samples were categorized into lower (0-25) and high (26-100) risk groups. To investigate associations of biomarkers with abemaciclib benefit, WES genomic events including oncogenic and hotspot mutations by OncoKB, and copy number events, of incidence &gt;9% were pre-selected. Results The biomarker subset of monarchE was reflective of the ITT population. A total of 1190 tumors (abemaciclib+ET n= 605; ET alone n=585) yielded adequate RNAseq results. Intrinsic subtype distribution was consistent across tx arms (Table A). Low tumor purity limited assessment of the normal-like subtype. The 4-year IDFS benefit of abemaciclib was consistent across all subtypes. LumA cancers had the lowest risk of recurrence while HER2E and basal-like subtypes had the highest. Inferred 21-gene expression signature score showed similar benefits from abemaciclib in both lower and high-risk groups (Table B). A total of 1173 tumors yielded adequate WES results (abemaciclib+ET n=580; ET alone n=593). Consistent abemaciclib benefit was observed across the most frequently altered genes (Table C). In exploratory analysis, lower benefit from abemaciclib was seen in the subset of focal-high level MYC amplified tumors (n=176, HR 1.30, 95% CI, 0.77, 2.20) compared to MYC non-amplified tumors (n=997, HR 0.62, 95% CI, 0.47, 0.80, nominal interaction p=0.014). The treatment benefit of abemaciclib was observed across all subpopulations of altered genes based on gene expression data. Conclusions Adjuvant abemaciclib+ET maintained IDFS benefit compared to ET alone across all molecular subtypes as measured by RNAseq. Benefit was consistent across most altered genes assessed by WES, except for the subset of tumors with MYC amplification. Additional research is necessary to confirm these findings. Table. Citation Format: Nicholas Turner, Jorge Reis-Filho, Matthew Goetz, Christine Desmedt, Sarat Chandarlapaty, Hironobu Sasano, Carlos Arteaga, Sherene Loi, Stephanie Graff, Deli Liu, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval Rubenstein, Helen Won, Lacey M. Litchfield, Maria Munoz, Stephen Johnston. Genomic and transcriptomic profiling of primary tumors from patients with HR+, HER2-, node-positive, high-risk early breast cancer in the monarchE 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 GS03-06.

Abstract Background: FGFR gene amplifications are found in 18% of breast cancers (BCs), with FGFR1 amplifications occurring in ≈10% of cases, predominantly in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) MBCs. FGFR1 amplifications are associated with resistance to endocrine therapy, and in preclinical experiments, FGFR pathway inhibition has been shown to overcome resistance to hormone therapy in BC harboring FGFR1 amplifications. Futibatinib, a highly selective, irreversible FGFR1-4 inhibitor, has shown preclinical activity in BC xenograft models harboring FGFR1/2 amplifications. In a phase 1 study, futibatinib showed promising clinical activity and tolerability across tumor types, including MBC, harboring various FGFR aberrations. A multicohort phase 2 trial (FOENIX-MBC2; NCT04024436) was designed to evaluate futibatinib alone (cohorts 1-3) or in combination with fulvestrant (cohort 4) in patients with MBC harboring FGFR2 or FGFR1 amplifications, respectively. Here, we report preliminary safety data from cohort 4 of FOENIX-MBC2, including data from a safety lead-in. Methods: Cohort 4 of FOENIX-MBC2 enrolled adult patients with HR+ HER2− MBC harboring high levels of FGFR1 amplification (FGFR1:CEN8 ratio ≥5 or FGFR1 copy number ≥10 signals per cell), Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function. Patients were fulvestrant naive and had previously received 1-2 endocrine-containing therapies, ≤1 chemotherapy regimen, and a CDK4/6 inhibitor (if eligible). Cohort 4 began with a safety lead-in to assess dose-limiting toxicities (DLTs) during the first treatment cycle. Patients received oral futibatinib 20 mg once daily continuously, and intramuscular fulvestrant 500 mg was administered on days 1 and 15 of cycle 1 and day 1 of every subsequent 28-day cycle. Patients were treated until disease progression, unacceptable toxicity, or another discontinuation criterion was met. Results: As of data cutoff (March 31, 2021), cohort 4 had enrolled 8 female patients with HR+ HER2− MBC harboring high-level FGFR1 amplification. The median age was 55.5 years (range: 31-62 years), and all patients had received ≥2 prior therapies for advanced/metastatic BC. The median duration of treatment was 8.0 weeks (range: 3.0-32.7 weeks); 3 of 8 patients (38%) were continuing treatment at time of data cutoff. All patients experienced treatment-related adverse events (TRAEs; grade ≥3: 25%). The most common TRAE was hyperphosphatemia (88%), followed by constipation (62%), transaminase elevation (50%), dry mouth (38%), and alopecia (38%). Among these TRAEs, grade ≥3 events were only reported for hyperphosphatemia (12%), and no serious adverse events were reported. In this cohort, TRAEs led to dose reductions in 4 patients, dosing interruptions in 3 patients, and treatment discontinuation in 1 patient; no patients died due to TRAEs. DLTs were evaluated in 5 patients following 1 treatment cycle (1 patient was enrolled after data cutoff, and 4 of 9 patients were not evaluable for DLTs); DLTs were not experienced by any of the 5 evaluable patients. Conclusions: Based on these preliminary safety results, the combination of futibatinib and fulvestrant appears to be safe and tolerable in patients with HR+ HER− MBC harboring high-level FGFR1 amplification. The safety profile was consistent with the individual profiles of both drugs, and the treatment combination did not appear to result in synergistic toxicity. As no DLTs were observed in 5 evaluable patients, the recommended futibatinib dose in combination with fulvestrant is 20 mg once daily. Efficacy will be evaluated in the complete 28-patient post-lead-in cohort, in which enrollment is ongoing. Citation Format: Senthil Damodaran, Nisha Unni, Karthik V. Giridhar, Brooke Daniel, Sacha Howell, Luis Costa, Marta Ferreira, Masashi Shimura, Gareth Tomlinson, Maciej Gil, Nicholas Turner. Futibatinib in combination with fulvestrant in patients with metastatic breast cancer (MBC) harboring high-level FGFR1 amplification: Preliminary data from a phase 2 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-35.