Damodaran, Senthil

1057 Background: Endocrine therapy (ET), particularly aromatase inhibitors (AIs), for estrogen receptor (ER)-positive breast cancer can lead to acquired ESR1 mutations ( mESR1) driving endocrine resistance and tumor progression. Treatments for mBC with mESR1 are limited, especially after progression on ET/cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) combinations. In ELAINE 2, LAS, a next-generation ET (breast ER antagonist) plus Abema had a median progression-free survival (PFS) of ~13 mos, objective response rate (ORR) of 33%, and 24-wk clinical benefit rate (CBR) of 62% with a favorable safety profile in patients with resistant mESR1 mBC (Damodaran S, et al. J Clin Oncol. 2022;40:16 suppl 1022). Here, we report ELAINE 2 data with longer patient follow up (Jan 31, 2023). Methods: In this open-label, phase 2, single-arm study, 29 women with mESR1, ER+/HER2- mBC that progressed on prior ET took oral LAS 5 mg/day and Abema 150 mg BID until disease progression/toxicity. The primary endpoint was safety/tolerability; secondary included PFS, CBR, and ORR. Data were summarized descriptively with no formal hypothesis testing. Results: Patients (median age 60 yrs) had received a median of 2 prior therapy lines for mBC; all but one had prior CDK4/6i exposure and 14 (48%) had prior chemotherapy for mBC. LAS/Abema was well tolerated with primarily grade 1/2 treatment-emergent adverse events (most commonly diarrhea, nausea, fatigue, and vomiting). One treatment withdrawal occurred due to grade 2 diarrhea. No deaths occurred. LAS dose was not reduced; Abema dose was reduced to 100 mg BID in 6 (21%) patients. Median PFS was 56.0 wks (~13 mos) and CBR 65.5% (95% CI, 47.3‒80.1). Median overall survival was not estimable. In 18 patients with measurable lesions, ORR was 55.6% (95% CI, 33.7‒75.4), with median time to response of 5.7 mos and median duration of response of 6.4 mos. Seventy-six percent, 56%, and 39% of patients were progression free at 6, 12, and 18 mos, respectively. Three (10%) patients had scan-identified venous thromboembolic events, with one symptomatic pulmonary embolism and one symptomatic deep vein thrombosis. In 26 patients with evaluable baseline and wk 4 ctDNA, ESR1 mutant allele fraction decreased from baseline to wk 4 in 81% of patients and was not detected in 54%. Conclusions: With longer ELAINE 2 follow up, LAS/Abema continues to be well tolerated with clinically meaningful efficacy in women with mESR1, ER+/HER2- mBC that had progressed on ET and CDK4/6is. Decreases in mESR1 ctDNA suggest effective target engagement of LAS. The PFS (median ~13 mos) and ORR (56%) with LAS/Abema are promising and a confirmatory phase 3 study (ELAINE 3) will begin in 2023. If ELAINE 2 results are confirmed, the combination of LAS and Abema would address a critical unmet need, providing a practice changing option for treating mESR1 breast cancer. Clinical trial information: NCT04432454 .

Abstract Introduction: Use of long-term endocrine therapy (ET) for ER+ breast cancer often leads to acquired ESR1 mutations (mutESR1), causing endocrine resistance, tumor progression, and poor prognosis. An unmet clinical need exists for treating ER+ mBC patients with mutESR1, particularly after progression on CDK4/6 inhibitors (CDK4/6i). ELAINE 2 is an open-label, phase 2, multicenter trial evaluating safety and efficacy of lasofoxifene (LAS [selective estrogen receptor modulator]) plus abemaciclib (Abema [CDK4/6i], provided by Eli Lilly) in patients with ER+/HER2- and mutESR1 mBC who progressed after prior ET. Preliminary data with LAS plus Abema showed median progression-free survival of 55.7 wks, objective response rate of 50%, and 24-wk clinical benefit (CB) rate of 69%, with an acceptable safety and tolerability profile. Here, we report ESR1 ctDNA mutant allele frequency (MAF) and correlations of ESR1 MAF changes with CB. Methods: ELAINE 2 patients with detectable ctDNA mutESR1 at baseline (BL) were analyzed. Oral LAS 5 mg/day and Abema 150 mg BID were taken until disease progression, death, unacceptable toxicity, or withdrawal from the study. ctDNA was assessed by the Sysmex-Inostics SafeSeq assay—which detects mutESR1 at low allele fractions—at BL, every 4 wks, and end of treatment. MAF changes from BL to wk 4 were characterized as decreased (decrease in ESR1 MAF or none detected [ND]), increased (increase in MAF), or equivocal (in polyclonal patients [>1 mutESR1] with some MAF increasing and decreasing trends). Correlations of MAF change at 4 wks with CB at 24 wks were explored. Results: 29 patients (median of 2 prior metastatic therapies: 97% CDK4/6i, 79% fulvestrant, 48% chemotherapy) had BL mutESR1 of Y537S (66%), D538G (45%), Y537N (28%), and other less frequently detected mutations; 14 (48.3%) patients were polyclonal. 26 of 29 patients had evaluable BL and wk-4 ctDNA results: 21 patients had decreased MAF (81% [54% with ND]), 3 (12%) had increased, and 2 (8%) had equivocal ESR1 MAF changes (Table). CB at 24 wks was seen in 17 patients with a decrease, 2 with an increase, and 1 with equivocal MAF change. A sensitivity of 89.5% and specificity of 20% were calculated for predicting CB based on direction of ESR1 MAF change. The positive predictive value (PPV) for CB with decreased MAF was 81% and the negative predictive value (NPV) for an increased MAF was 33%. Of the 14 (54%) patients with ND ESR1 MAF, 13 had CB resulting in 87% sensitivity, 50% specificity, 93% PPV, and 33% NPV. Conclusion: In ELAINE 2, 81% of patients had decrease/cleared (ND) mutESR1 after 4 wks of LAS plus Abema, which correlated with clinical benefit. All mutESR1 detected appear targeted with this therapy. High sensitivity and favorable PPV were observed in patients with decreased MAF, and even more so in those with ND MAF; however, increased MAF was less specific and not as predictive of treatment failure. Our results indicate that ESR1 liquid biopsy evaluation may be an adequate non-invasive surrogate marker for monitoring patients on treatment. Further study in a larger population of women with endocrine-resistant mBC and acquired mutESR1 is warranted to explore this potential for monitoring treatment response or resistance to this novel LAS-Abema combination. Table. Change from baseline to week 4 in ESR1 MAF and clinical benefit at 24 weeks. CI, confidence interval; MAF, mutant allele fraction; ND, none detected; NPV, negative predictive value; PPV, positive predictive value. *Sensitivity and specificity analyses do not include equivocal results. Citation Format: Senthil Damodaran, Halle Moore, Ciara C. O’Sullivan, Paul V. Plourde, Gary Riordan, Hillary S. Sloane, Debu Tripathy, Dominic Carroll, David J Portman. Estrogen receptor 1 (ESR1) mutations in circulating tumor DNA (ctDNA) from patients with ER+/HER2- metastatic breast cancer (mBC) treated with lasofoxifene plus abemaciclib in the ELAINE 2 study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-05-02.

1504 Background: Trial recruitment that requires specific actionable mutations based on next-generation sequencing (NGS) is challenging. Barriers can include competing studies, physician study awareness, site proximity, mutation incidence, among other concerns. Methods: This study (NCT04432454) opened clinical sites using two methods during the COVID-19 pandemic. The “Traditional” approach included site selection, IRB and contract approval, and trial activation prior to a patient being identified for enrollment. The second approach used the Tempus “TIME” Trials network that would only open a site after identifying a patient with a mutation of interest and eligible for the trial. Results: The first patient enrolled was on 10/12/20 and the last patient was on 6/24/21. A total of 16 sites (6 Traditional and 10 TIME) participated. All Traditional sites, and none of the TIME sites, were affiliated with major academic institutions. Duration for full CTA execution for Traditional sites averaged 200.5 days (range 142 to 257) and for TIME sites averaged 7.6 days (range 2 to 14). IRB approval time average for Traditional sites was 27.5 days (range 12 to 71) and TIME sites was 3.0 days (range 1 to 12 days). Days from site selection to activation letter for Traditional sites was on average 250.0 days (range 187 to 281) and for TIME sites was 131.6 days (range 22 to 248). Time from study activation to first consent was 33.3 days (range 18 to 58) for Traditional sites and 8.8 days (range 1 to 35) for TIME sites. The first patient on-study was at a TIME site 115 days prior to a Traditional site and the first 7 patients enrolled were at TIME sites. Traditional sites consented 23 and enrolled 16 patients while the TIME sites consented 16 and enrolled 13. The trial enrolled all 29 patients in 8 months with the anticipated enrollment duration being 12 to 18 months. Conclusions: Although the Traditional and TIME programs had different operational models, they both contributed a significant number of patients and reduced the projected enrollment timeline. TIME sites enrolled the initial patients. These results demonstrate that the “Just-in-Time model,” in conjunction with a Traditional model, can reduce projected overall time to enrollment in biomarker-driven studies. [Table: see text]

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.

Abstract Background: Two PARP inhibitors are approved for germline BRCA1/2 mutant metastatic breast cancer (MBC), based on clinical trials demonstrating an improvement in patient outcomes and quality of life. However, germline BRCA1/2 mutations are identified in 5-10% of breast cancer, limiting their potential applicability. Our prior work demonstrated that somatic BRCA1/2 mutations can be detected in cell-free DNA (cfDNA) in a proportion of patients with MBC who are not germline BRCA1/2 carriers, and that a PARP inhibitor caused growth inhibition in a circulating tumor cell line generated from a patient with MBC and a pathogenic somatic BRCA1 mutation (Vidula, Dubash, CCR, 2020). Thus, we hypothesize that a PARP inhibitor may have efficacy in somatic BRCA1/2 mutant MBC identified by cfDNA. Trial Design: This phase II investigator initiated open label clinical trial is enrolling 30 patients who have pathogenic somatic BRCA1/2 mutations found in cfDNA. Patients must not be known germline BRCA1/2 carriers. Patients receive treatment with the PARP inhibitor, talazoparib, until disease progression. Serial imaging (CT chest, abdomen, pelvis, and bone scan) occurs every 3 months, and cfDNA is collected monthly to evaluate changes in the genomic environment. Patients will also have blood collected at baseline for the Cancer Risk B assay (CR-B), a novel flow variant assay to assess double strand break repair mutations in circulating blood cells (Syeda, Genetics, 2017). Eligibility criteria: Patients with MBC (TNBC with ≥ 1 prior chemotherapy or HR+/HER2- with ≥ 1 prior hormone therapy or ineligible for hormone therapy) with a somatic BRCA1/2 mutation identified in cfDNA (established pathogenic variant) are being enrolled. Patients should not be known germline BRCA1/2 carriers (genetic testing is not required but can be obtained per physician discretion) and may not have previously received a PARP inhibitor. There is no limit on the number of prior therapies, and a prior platinum chemotherapy is allowed in the absence of disease progression on the platinum. Patients must have adequate performance status and organ function. Specific Aims: The primary endpoint is progression-free survival (PFS) using RECIST 1.1. Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory objectives include evaluating serial changes in BRCA1/2 mutant allelic frequency in cfDNA, evaluating the impact of BRCA1/2 reversion mutations, comparing pre- and post-treatment cfDNA results to identify markers of resistance, evaluating the CR-B assay positivity rate, and ultimately correlating these analyses with treatment response. Statistical Methods: A two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha) is being used. Accrual: This study (NCT03990896) is currently open at Massachusetts General Hospital, where 4 patients are completing screening for enrollment. This study will be activated soon at the University of California San Francisco, MD Anderson, Mayo Clinic Rochester and Jacksonville, Northwestern, and Emory (7 academic centers). Funding: Support for this study is provided by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Erica Blouch, Erin Basile, Nathan Royce Ruffle-Deignan, Nora Horick, Senthil Damodaran, Alvaro Moreno Aspitia, Manali Bhave, Ami Shah, Minetta C. Liu, Joseph Sparano, Harry Ostrer, Hope Rugo, Leif W. Ellisen, Aditya Bardia. Phase II study of a PARP inhibitor in metastatic breast cancer with somaticBRCA1/2mutations identified by cell-free DNA: Genotyping based clinical trial [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 OT2-24-03.

TPS1110 Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .