Line Endocrine Therapy Research Articles

Abstract 5247: Using real-world data to evaluate the performance of endocrine therapies in ER+/Her2- metastatic breast cancer patients

Abstract Background Real-world data (RWD) has been increasingly used in drug development. A reliable evaluation of efficacy for current treatments is challenging with very limited publication data of clinical trials available. The RWD provides a unique value and an alternative way to achieve such goal. Use data from metastatic Breast Cancer (mBC) patients in the real world clinical practice, we examine the treatment patterns and durations of different endocrine monotherapies in various clinical settings. Methods We obtained Flatiron Health subject-level mBC data set which consists a group of 20645 mBC patients. The analysis set consisted of subjects who were ER+/Her2-/(PgR+ or PgR-), received at least one prior line of CDK4/6 inhibitor (mono or combo) and one prior line of endocrine therapy (mono or combo) in the mBC settings, and had an ECOG performance score<=2. Time to treatment discontinuation (TTD) was used as real world endpoint. We assessed the median TTD of endocrine monotherapies in various mBC ER+/Her2- patient subgroups using Kaplan-Meier estimates. Result Out of all subjects in the mBC RWD database, 263 subjects met the inclusion criteria and were included in the analysis set. Among all 263 ER+/Her2- subjects, the median TTD of endocrine monotherapies was 3.0 months (95% CI: 2.8-3.7 months, N=263) in all subjects, 3.7 months (95% CI: 3.0-4.3 months, N=186) in PgR+ group and 2.1 months (95% CI: 1.9-2.9 months, N=77) in PgR- group. Among 186 ER+/PgR+/Her2- subjects, 1) the median TTD of endocrine monotherapies was 3.3 months (95% CI: 2.8-4.6 months, N=153) in ECOG<=1 group and 3.7 months (95% CI: 3.2-6.0 months, N=33) in ECOG=2 group; 2) the median TTD of endocrine monotherapies was 3.4 months (95% CI: 2.3-5.4 months, N=47) in Aromatase inhibitors group, 3.7 months (95% CI: 2.8-5.6 months, N=110) in Fulvestrant group, and 3.1 months (95% CI: 2.3-6.0 months, N=29) in Tamoxifen group; 3) the median TTD of endocrine monotherapies was 3.6 months (95% CI: 2.8-5.9 months, N=74) in one prior treatment line group, 3.7 months (95% CI: 2.0-6.0 months, N=57) in two prior treatment lines group, and 3.7 months (95% CI: 2.3-5.4 months, N=55) in >=3 prior treatment lines group. Conclusion By investigating the RWD, we observed that the PgR status is prognostic in post CDK setting: endocrine monotherapies in PgR+ group has longer TTD compared to PgR- group in ER+/Her2- mBC subjects. By further looking into ER+/PgR+/Her2- subjects, we observed different treatment durations of endocrine therapies in various clinical scenarios, which may provide a helpful understanding of the mBC monotherapy treatments. Citation Format: Tenghui Chen, Zhaojie Zhang, Lei Gao, Catherine Scholz, Antonio Gualberto, Lihua Yu, Kun Yu. Using real-world data to evaluate the performance of endocrine therapies in ER+/Her2- metastatic breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5247.

Integrated DNA and RNA Sequencing Reveals Drivers of Endocrine Resistance in Estrogen Receptor-Positive Breast Cancer.

Endocrine therapy resistance (ETR) remains the greatest challenge in treating patients with hormone receptor-positive breast cancer. We set out to identify molecular mechanisms underlying ETR through in-depth genomic analysis of breast tumors. We collected pre-treatment and sequential on-treatment tumor samples from 35 patients with estrogen receptor-positive breast cancer treated with neoadjuvant then adjuvant endocrine therapy; 3 had intrinsic resistance, 19 acquired resistance, and 13 remained sensitive. Response was determined by changes in tumor volume neoadjuvantly and by monitoring for adjuvant recurrence. Twelve patients received two or more lines of endocrine therapy, with subsequent treatment lines being initiated at the time of development of resistance to the previous endocrine therapy. DNA whole-exome sequencing and RNA sequencing were performed on all samples, totalling 169 unique specimens. DNA mutations, copy-number alterations, and gene expression data were analyzed through unsupervised and supervised analyses to identify molecular features related to ETR. Mutations enriched in ETR included ESR1 and GATA3. The known ESR1 D538G variant conferring ETR was identified, as was a rarer E380Q variant that confers endocrine hypersensitivity. Resistant tumors which acquired resistance had distinct gene expression profiles compared with paired sensitive tumors, showing elevated pathways including ER, HER2, GATA3, AKT, RAS, and p63 signaling. Integrated analysis in individual patients highlighted the diversity of ETR mechanisms. The mechanisms underlying ETR are multiple and characterized by diverse changes in both somatic genetic and transcriptomic profiles; to overcome resistance will require an individualized approach utilizing genomic and genetic biomarkers and drugs tailored to each patient.

Subgroup analysis of patients with no prior chemotherapy in EMERALD: A phase 3 trial evaluating elacestrant, an oral selective estrogen receptor degrader (SERD), versus investigator’s choice of endocrine monotherapy for ER+/HER2-advanced/metastatic breast cancer (mBC).

1100 Background: EMERALD demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for elacestrant vs standard of care endocrine therapy (SOC) in patients with ER+/HER2- mBC following progression on prior endocrine and CDK4/6 inhibitor therapy. Benefit was observed in the overall study population and in patients with ESR1 mutations (mESR1). Here, we report a subgroup analysis from EMERALD in patients with no prior chemotherapy. Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled patients with ER+/HER2− mBC who had 1–2 lines of endocrine therapy, mandatory pretreatment with a CDK4/6 inhibitor, and ≤1 chemotherapy. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SOC (investigator’s choice of fulvestrant or aromatase inhibitor). Primary endpoints were PFS in all patients and patients with mESR1. In this analysis, we compared PFS between elacestrant and SOC in patients without prior chemotherapy. Results: Among the 477 patients enrolled in the trial, 77.8% (n = 371) had not received prior chemotherapy for mBC (median age = 64). Among patients without prior chemotherapy, treatment with elacestrant was associated with significantly prolonged PFS compared to SOC in both the overall population (hazard ratio [HR] = 0.68 [95% CI, 0.52-0.89] P = 0.004; median PFS 3.7 vs 2.0; 6-mo PFS 38% vs 23%; 12-mo PFS 27% vs 12%), and patients with mESR1 (HR = 0.54 [95% CI, 0.36-0.80] P = 0.002; median PFS 5.3 vs 1.9; 6-mo PFS 44% vs 24%; 12-mo PFS 31% vs 12%). Key treatment-related adverse events (AEs) in the no prior chemotherapy elacestrant group were nausea (25.9%), fatigue (12.7%), and hot flush (11.1%). There were no treatment-related deaths in either group. Conclusions: Among patients with ER+/HER2− mBC without prior chemotherapy, elacestrant significantly prolonged PFS compared to SOC endocrine therapy and showed favorable outcomes in this subgroup. Clinical trial information: NCT03778931.

Eribulin combined with anlotinib for patients with HER2-negative metastatic breast cancer: A single-arm, multicenter, phase II study.

e13051 Background: The group of HER2-negative accounts for 70-80% of breast cancer and effective treatments for heavily pretreated patients with HER2-negative metastatic breast cancer are urgently needed. Eribulin mesylate is a non-taxane microtubule dynamics inhibitor with a distinct mode of action which can be used as a chemotherapeutic agent for HER2-negative breast cancer after failure of anthracycline and taxanes treatments. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study aimed to evaluate the efficacy and safety of combined treatment with eribulin and anlotinib in patients with HER2-negative metastatic breast cancer (NCT04624711). Methods: This open-label, single-arm, phase II study enrolled females with HER2-neagtive breast cancer who underwent ≥1 line chemotherapy, including anthracyclines and taxanes, for metastatic breast cancer. Patients with hormone receptor positive breast cancer have underwent ≥1 line endocrine therapy. All patients were treated with Eribulin mesylate (1.4mg/m2, administered intravenously on Days 1 and 8 of each 21 day cycle) and anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle). The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From November 2020 to February 2022, 25 patients were enrolled in this study. Median follow-up was 3.45 months (95% CI 3.16-5.06). Median PFS was 4.6 months (95% CI 3.55-5.65). Of all the patients whose efficacy could be evaluated (21/25), no patient achieved complete response (CR); 9 (40.91%) and 10 (45.45%) patients got partial response (PR) and stable disease (SD), respectively. ORR was 40.91% and DCR was 86.36%. OS has not reached. The major treatment-related adverse events (incidence≥10%) were neutropenia(48.00%), anemia(37.93%), platelet count decreased (34.48%), fatigue (31.03%), hypoalbuminemia (20.69%), constipation (13.79%), elevated lactate dehydrogenase(13.79%), lymphocyte count decreased (10.34%) and hypertriglyceridemia (10.34%). The most common grade 3/4 adverse events were neutropenia (20.00%). 16.00% (4/25) of patients had dose reductions. Conclusions: The combination of eribulin and anlotinib showed a better treatment response and tolerable toxicity in HER2-negative metastatic breast cancer patients. Further studies enrolling more patients are still needed. Clinical trial information: NCT04624711.

DOLAF: An international multicenter phase II trial of durvalumab (MEDI4736) plus olaparib plus fulvestrant in patients with metastatic or locally advanced ER-positive, HER2-negative breast cancer selected using criteria that predict sensitivity to olaparib.

TPS1116 Background: PARP inhibitors have documented clinical activity in patients with HER2 negative breast cancer (BC) and a germline pathogenic variant (PV) in BRCA1 or BRCA2. Defects in other genes involved in homologous recombination DNA repair (HRR) or mismatch repair pathway (microsatellite instability MSI) have been associated with preclinical cellular sensitivity to PARP inhibitors. Several preclinical and clinical studies have suggested synergy between immune checkpoint blockade and PARP inhibitors. Indeed, tumors with deficiency in HRR have higher mutagenic potential and produce a larger number of neoantigens. Around 60% of BC with a germline PV in BRCA1/ 2 are ER+/HER2- tumors, and the ER-pathway remains a key target of their therapy. The combination of PARP inhibitors with endocrine therapy has shown to be superior to monotherapy. Methods: DOLAF is an open-label, international, multicentric, phase II trial assessing the combination of olaparib, fulvestrant, and durvalumab in ER+/HER2- metastatic or locally advanced BC with somatic or germline PV in BRCA1, BRCA2 or other genes implicated in the HRR pathway (ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other actionable genes ( AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central tumor NGS. Further an amendment in May 2021, patients with only alterations in these other actionable genes can no longer be included. Patients must have received 1 prior line of endocrine therapy for their metastatic BC, including CDK4/6 inhibitor and maximum of 1 line of chemotherapy in the metastatic setting. Patients receive olaparib (twice daily at 300 mg), fulvestrant (2 intramuscular injections of 250 mg every 28 days) and durvalumab (1500 mg intravenous every 4 weeks). The primary objective is to evaluate the progression-free survival rate at 24 weeks. Secondary endpoints include safety, overall survival, objective response rate, in the overall population and in the germline BRCA mutated population. With an optimum two-stage Simon design, α = 2.5%, β = 5%, p0 (probability of inefficiency maximum) = 50%, p1 (probability of minimum efficiency) = 65%, it is necessary to include 158 patients. The strategy could be considered sufficiently effective if there are at least 87 patients without progression at 24 weeks. Given the lack of safety data from this association, a safety run-in phase including 6 patients has been completed without DLT. As of December 31, 2021, 266 patients have been screened of whom 102 have been treated. The first interim analysis occured in November 2021 after the inclusion of 64 evaluable patients. IDMC suggested that the trial continue as planned. Clinical trial information: NCT04053322.

174P Clinical effectiveness and safety of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer in a real-world setting: Phase IIIb LUCY final analysis

LUCY interim findings confirmed the clinical effectiveness of olaparib 300 mg twice daily in patients with metastatic breast cancer (mBC) in a real world setting. Findings were consistent with the OlympiAD trial of olaparib vs chemotherapy of physician’s choice. We report results of the final planned analysis. Eligible adults had germline (g) or somatic (s) BRCA1- and/or BRCA2-mutated (BRCAm), HER2-negative mBC and had received taxane and/or anthracycline in early or metastatic settings and ≤2 previous lines of chemotherapy for mBC. Pts with hormone receptor-positive (HR+) mBC had previously completed ≥1 line of endocrine therapy (ET) in any setting or were unsuitable for further ET. Primary endpoint: investigator-assessed progression-free survival (PFS; gBRCAm cohort). Overall survival (OS) and safety were secondary endpoints. Final analysis was planned at 130 OS events (gBRCAm). Results are in all pts (gBRCAm and sBRCAm). Prespecified subgroups (gBRCAm only): HR status (HR+ vs triple-negative breast cancer [TNBC]); line of therapy (1st line vs 2nd line+). During 2018, 255 pts were enrolled (252 gBRCAm, 3 sBRCAm; median [m] age: 45.0 [range 22–75] years; 98.4% female). mPFS: 8.2 months (95% CI 7.0–9.2; 208 events, 81.6%). mOS: 24.9 months (95% CI 21.1–27.9; 142 events, 55.7%). OS rate at 30 months: 41.7% (95% CI 35.2–48.1). Treatment-related adverse events (AEs, >10% pts): nausea (47.8%), anaemia (34.5%), asthenia (20.8%), fatigue (18.0%), vomiting (17.6%), neutropenia (15.3%) and diarrhoea (11.0%). Grade ≥3 AEs (17.6% pts) included anaemia (11.8%). Few pts (4.3%) discontinued treatment due to an AE. Post study therapies will be reported. The benefit of olaparib was similar across HR status and treatment lines. mOS was longer than reported in OlympiAD. No new safety signals were observed. These results strongly support olaparib as a chemotherapy-free alternative for gBRCAm, HER2-negative mBC.Table: 174PSubgroup analyses (full analysis set)HR statusLine of therapyHER2-negativeHER2-negative1st line2nd line+HR+TNBCn134118136116PFSEvents, n (%)113 (84.3)94 (79.7)107 (78.7)100 (86.2)Median8.386.878.387.5995% CI7.92, 10.555.52, 9.177.20, 10.285.88, 9.07OSEvents, n (%)73 (54.5)67 (56.8)71 (52.2)69 (59.5)Median27.4321.0627.4322.7495% CI22.74, 33.4517.05, 27.3021.36, 37.4218.04, 27.20 Open table in a new tab

Abstract PD13-01: Balixafortide (a CXCR4 antagonist)+eribulin versus eribulin alone in patients with HER2 negative, locally recurrent or metastatic breast cancer: An international, randomized, phase 3 trial (FORTRESS)

Abstract Background: Balixafortide (B), a synthetic cyclic peptide, is a potent selective CXCR4 antagonist with high affinity for the human CXCR4 receptor in pre-clinical studies and is currently being investigated in metastatic breast cancer (mBC). Encouraging safety and efficacy data were previously published from a Phase 1 trial investigating B + eribulin (E) in patients (pts) with human epidermal growth factor receptor 2 negative (HER2-) mBC. Methods: In this multicenter, open-label trial, pts were randomized 1:1 to receive B (5.5 mg/kg) + E (1.4 mg/m2) or E alone. Eligible pts had HER2- locally advanced or mBC and had previously received 1−4 lines of chemotherapy in the advanced setting. Pts with hormonal receptor positive (HR+) disease must have received ≥1 line of endocrine therapy. The primary efficacy endpoints included objective response rate (ORR) and progression free survival (PFS) in the ≥3rd line population and PFS in the overall population. Overall survival (OS) was a key secondary endpoint. Results: 432 pts (aged 29-82 years) were enrolled with 348 treated in the ≥3rd line setting. Most pts (66.4%) were treated in the 3rd or 4th line, 96.1% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and 35.6% had triple negative breast cancer. ORR and clinical benefit rate (CBR) data for the ≥3rd line population are presented in the table below. PFS and OS were not improved in the 3rd line population [mPFS 3.5 months (m) vs 4.0 m; hazard ratio 1.07 (96% CI: 0.81, 1.41); interim mOS 11.0 m vs 11.2 m hazard ratio 1.08 (99.9% CI: 0.66, 1.77)]. Results were consistent in the overall population and per investigator assessment.For the overall safety population, serious treatment-emergent adverse events (STEAEs) (28% versus 26.5%), treatment-emergent adverse events (TEAEs) leading to death (6.9% versus 6.4%) and TEAEs ≥Grade 3 (68.3% versus 64.2%) were broadly similar between the two arms. Infusion Related Reactions (IRR) were reported in 43.6% of patients treated with B + E. Conclusions: In this Phase 3 randomized trial, no differences in ORR, CBR, mPFS, or mOS were observed for B + E compared to E alone in any population of HER2-mBC patients. Efficacy parameters for E alone were similar to those reported previously. The combination was B + E was well-tolerated overall. ≥3rd Line Population(N=330)B + E(N=162)E(N=168)Objective Response Rate (95% CI)Per Independent Review Committee13.0% (8.2, 19.1)13.7% (8.9, 19.8)Per Investigator13.6% (8.7, 19.8)13.1% (8.4, 19.2)Clinical Benefit Rate (95% CI)Per Independent Review Committee16.7% (11.3, 23.3)19.6% (13.9, 26.5)Per Investigator21.6% (15.5, 28.7)21.4% (15.5, 28.4) Citation Format: Peter Kaufman, Miguel Martin, Ingrid Mayer, Linda Vahdat, Sonia Pernas, Peter Schmid, Heather McArthur, Rebecca Dent, Hope S Rugo, Carlos Barrios, Alexandra Bobirca, Francois Ringeisen, Daniela Schmitter, Javier Cortes. Balixafortide (a CXCR4 antagonist)+eribulin versus eribulin alone in patients with HER2 negative, locally recurrent or metastatic breast cancer: An international, randomized, phase 3 trial (FORTRESS) [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 PD13-01.

Abstract PD13-02: Phase Ib expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women with ER+ metastatic breast cancer

Abstract Background: The addition of CDK4/6, PI3K-α, or mTOR inhibitors to endocrine therapy (ET) improves progression free survival (PFS) in first and later lines of therapy for estrogen receptor positive (ER+), HER2-negative metastatic breast cancer (MBC). We hypothesized that simultaneous inhibition of these pathways would improve treatment efficacy. We conducted a phase Ib study of triplet therapy with gedatolisib (G), a dual inhibitor of PI3K/mTOR, palbociclib (P) a CDK4/6 inhibitor, and ET with letrozole (L) or fulvestrant (F) in women with ER+/HER2-negative MBC. Manageable toxicity and preliminary antitumor activity were observed in 35 patients enrolled on the dose escalation portion of the study (ASCO 2018). We now report results from the dose expansion study arms. Methods: Patients with ER+/HER2- MBC were treated in four-arms: A) G+P+L as first-line treatment, B) G+P+F as 2-line treatment in patients without prior CDK4/6 inhibitor therapy; C) G+P+F in patients with prior CDK4/6 inhibitor therapy; D) G+P+F in patients whose most recent regimen included a CDK4/6 inhibitor. Palbociclib, letrozole and fulvestrant were administered at standard doses. Gedatolisib 180 mg was intravenously administered weekly in Arms A, B, and C and three weeks on/one week off in Arm D. Pre-/peri-menopausal women received ovarian suppression. The primary endpoint was objective response assessed by the investigator. Secondary endpoints included safety, duration of response (DOR), and PFS.Results: A total of 103 patients were enrolled: Arm A (n=31); Arm B (n=13); Arm C (n=32); Arm D (n=27). Median age was 54, 62, 59.5, and 59 years in each arm respectively. Progressed on last line of endocrine therapy in < 6 months (refractory): Arms B: 4/13 (31%), Arm C: 15/32 (47%), Arm D: 7/27 (26%). ORR in evaluable patients, including unconfirmed responses: 84%; 75%, 33% and 64%. Median PFS (months) was not reached in Arm A, and for arms B, C and D was 11.9, 5.1, 12.9 respectively. Most common (≥50%), treatment emergent adverse events (TEAE) across all arms were: nausea 81.6% (all Gr1-2, no ≥Gr3), stomatitis 80.6% (27.2% Gr3), fatigue 79.6% (10.7% Gr3), vomiting 51.5 % (1% Gr3), neutropenia/neutrophil count decrease 79.6% (66.7% ≥Gr3). Most common (≥2%) treatment emergent SAEs were febrile neutropenia 4.9%, acute kidney injury and pyrexia 2.9% each. Hyperglycemia was reported in 26.2% (6.8% ≥Gr3) of patients regardless of relation to treatment. Most common reason for treatment discontinuation was disease progression.; 8.7% (9 out of 103) patients discontinued therapy due to a related AE across all arms. No treatment discontinuation due to TEAE and no SAE of stomatitis were observed in Arm D. Seventeen patients are continuing therapy at the time of data cut of May 10, 2021.Conclusions: The addition of Gedatolisib to palbociclib and endocrine therapy demonstrated promising antitumor activity in both first and later line settings for ER+ MBC that compared favorably to historical controls. Responses were also observed in patients refractory to the last treatment. Therapy was well tolerated with manageable toxicity and low number of treatment discontinuation due to related AE. The favorable safety profile and antitumor activity observed in patients treated with the three weeks on/one week off gedatolisib regimen supports use of this dosing schedule in future studies. A phase 3 study evaluating gedatolisib in patients with ER+/HER2- MBC is planned. Table 1.Arm A, n=31Arm B, n=13Arm C, n=32Arm D, n=27EfficacyEvaluable for response25122725ORR in evaluable patients84% (21/25)75% (9/12)33% (9/27)64% (16/25)DCR (CR, PR, SD)92%92%48%85%Treatment DiscontinuationAll64.5% (20/31)76.9% (10/13)100% (32/32)85.2% (23/27)PD/general deterioration38.7% (12/31)61.5% (8/13)75% (24/32)70.4% (19/27)TEAE (related)9.7% (3/31)7.7% (1/13)12.5% (4/32)3.7% (1/27)Stomatitis3.2% (1/31)7.7% (1/13)9.4% (3/32)0TEAE (not related)07.7% (1/13)00Withdrew9.7% (3/31)012.5% (4/32)0Other6.5% (2/31)0011.1% (3/27)Treatment Emergent SAEAll22.6% (7/31)30.8% (4/13)21.9% (7/32)14.8% (4/27)Stomatitis3.2% (1/31)000 Citation Format: Rachel Layman, Robert Wesolowski, Hyo Han, Jennifer M Specht, Erica M Stringer-Reasor, E. Claire Dees, Peter Kabos, Ingrid A Mayer, Ulka Vaishampayan, Janice Lu, Keerthi Gogineni, Aditya Bardia, Anne F Schott, Maysa Abu-Khalaf, Doug Howkins, Brian Sullivan, Igor Gorbatchevsky, Hope Rugo. Phase Ib expansion study of gedatolisib in combination with palbociclib and endocrine therapy in women with ER+ metastatic breast cancer [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 PD13-02.

Abstract OT2-19-02: Clinical evaluation of the efficacy and liquid molecular analysis of abemaciclib rechallenge upon progression to abemaciclib combination therapies for ER-positive HER2-negative metastatic breast cancer patients

Abstract Background: Abemaciclib is a drug approved for ER-positive and HER2-negative metastatic or recurrent breast cancer and those treatable in an early setting. Some patients with ER-positive and HER2-negative breast cancer pretreated with abemaciclib and endocrine therapy may still benefit from abemaciclib rechallenge, especially in case of acquired resistance to endocrine therapy. However, there is no evidence for abemaciclib rechallenge. To address this, a single-arm phase 2 trial is planned to determine whether abemaciclib rechallenge has clinical benefits. Translational research to evaluate the gene alteration and immunohistochemistry will be conducted as an accompanying research to determine the predictive biomarkers of resistance or sensitivity to abemaciclib. Patients and Methods: The eligible patients are histologically confirmed with ER-positive and HER2-negative invasive breast cancer, locally advanced or metastatic, and previously received no more than two lines of endocrine therapy. The patients who previously received abemaciclib in combination with endocrine therapy led to a clinical benefit, including complete response, partial response, or stable disease, during abemaciclib-based treatment (≥6 months). The patients who previously received chemotherapy, immune checkpoint inhibitors (excluding perioperative systemic treatment), everolimus, olaparib, and palbociclib for advanced or metastatic diseases are excluded. The patients will be treated with abemaciclib 150 mg orally q12h on days 1 to 28 of a 28-day cycle. The other endocrine drug prescribed was not used in previous treatment. We will evaluate the gene mutations and/or amplification of ESR1, PIK3CA, CCNE1, FGFR1, RB1, TP53, NF1, MYC, AR, and MET at the time of inclusion and three months after day 1 and ctDNA and immunostaining levels of HER3, PTEN, CCNE1, FGFR1/2, and AR at the time of inclusion. The primary endpoint is progression-free survival (PFS), while the secondary endpoints are overall response rate, clinical benefit rate, chemotherapy-free interval, overall survival (OS), safety, and evaluation of the mechanism of sensitivity and resistance to abemaciclib. The expected median PFS for the study treatment arm is 5.0 months compared to the previous data of 3.0 months. The number of necessary cases is 59, with a significance level of 5% (two-sided) and power of 80% during the two-year recruitment period and one-year follow-up period. In the planned total of 65 cases, 10% is considered inappropriate. The planned duration of enrollment and follow-up is two years and one year, respectively. The planned total study duration is four years. Subgroup analysis will be performed on ESR1 and PIK3CA mutations, disease site (visceral/bone only/other), previous lines of therapy for advanced or metastatic disease (first and second), endocrine therapy for pretreatment (aromatase inhibitors/fuluvestrant), performance status (0/1), organs involved (1/2/≥3), age (<65/≥65 years), and disease-free interval (<36 months/≥36 months) to examine the interaction of treatment effects on PFS and OS. This study was funded by Eli Lilly and Company. Citation Format: Meiko Nishimura, Takahiro Kogawa, Yuko Akaishi, Misato Ogata, Jun Masuda, Mitsuo Terada, Hitomi Sakai, Kazuki Nozawa, Sasagu Kurozumi, Takamichi Yokoe, Yukinori Ozaki Ozaki, Shu Yazaki, Mai Onishi, Tsutomu Iwasa, Takuma Onoe, Yuta Okumura, Sayaka Nakayama, Kanako Hagio, Yuko Takahashi, Hirokazu Tanino, Junji Tsurutani, Koji Matsumoto, Mototsugu Shimokawa, Toshimi Takano. Clinical evaluation of the efficacy and liquid molecular analysis of abemaciclib rechallenge upon progression to abemaciclib combination therapies for ER-positive HER2-negative metastatic breast cancer patients [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 OT2-19-02.

Abstract PD14-09: APOBEC signature, clinical characteristics, and outcome in hormone receptor-positive (HR+) HER2-negative (HER2-) breast cancer (BC) patients (pts) in real-world data (RWD)

Abstract Background: APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including BC. In our clinical experience, HR+HER2- BC with an APOBEC signature do poorly on standard of care (SOC) first line endocrine therapy (ET) + CDK4/6 inhibitor (CDK4/6i) and need additional treatment options. Here we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival (OS) on SOC and immune checkpoint inhibitors (ICI).Methods: Hybrid capture-based comprehensive genomic profiling (CGP) results from 29,833 formalin-fixed paraffin-embedded tissue biopsies of all BC subtypes were analyzed. For outcomes (TTD and OS), this study used a de-identified nationwide (US-based) BC clinico-genomic database (CGDB, ~800 sites of care, 1/2011 - 12/2020). HR+HER2- metastatic BC pts who received first line ET + CDK4/6i were included (CGDB cohort).TTD was defined as the difference between the first and last drug episode within a given line of treatment (LOT). LOT were derived based on FH algorithms. OS was defined as the time from LOT start to the date of death or data cutoff. Log-rank test and Cox model were used to evaluate the difference in outcomes. To reduce the impact of confounding variables (Age at Dx, Stage at Dx, Tumor Type, Metastases sites, TMB group (≥10 vs <10), SOC treatment group, PIK3CA), inverse probability of treatment weighting (IPTW) was used. Eligible pts from Mayo Clinic and Duke University were HR+HER2- mBC with sequencing data from FMI between 9/2013-7/2020. Clinical data were manually extracted from Mayo and Duke EHR. Results: Of all 29,833 BC samples in the CGP cohort, 7.9% were APOBEC+ with high rate in invasive lobular carcinoma (ILC) 16.7% vs. 4.9% in invasive ductal carcinoma (IDC) and metastatic lesions 9.7% vs. 4.3% from breast. APOBEC+ samples had a higher median TMB 12.5 vs. 2.5 mut/Mb. In CGDB, 857 HR+HER2- BC met inclusion criteria; 69 (8%) pts were APOBEC+ and 788 (9.2%) were APOBEC-. APOBEC+ pts had significantly shorter TTD on SOC ET+CDK4/6i than APOBEC- pts, 7.8 (95% CI 4.3-14.6) vs. 12.4 (95% CI 11.2-14.1) months (p=0.0036). APOBEC+ pts also had noticeably shorter OS compared to APOBEC- pts, 32.4 (95%CI 19.8-47.4) vs. 40.5 (95%CI 36.9-45.7) months (p=0.06).Cox regression results indicate that the relative risk of shorter TTD for the APOBEC+ vs the APOBEC- was 1.6 (95%CI 1.03-2.39). Also, APOBEC+ pts had almost twice the risk that APOBEC- pts had of death (HR=1.96, 95%CI 1.2-3.3). In CGDB, there were 10 APOBEC+ pts who received ICI, 9/10 had evaluable TTD data, 4/9 were still on treatment as of Dec 2020. 5/9 received ICI monotherapy, 4 pts received ICI + chemotherapy. TTD ranged from 0.3 to 11.3 mo, 1 pt’s TTD was > 6 mo. In Mayo and Duke cohort, there were 6 pts, 5/6 received ICI + chemotherapy. The TTD was 0.9-40.5 months with longest 2 pts receiving 5-FU plus ICI (11 and 40.5 months). To better understand the ICI treatment landscape, TTD in HR+HER2- hTMB MSS APOBEC- CGDB cohort (N=6) was analyzed: 5/6 had evaluable treatment data, 4/5 finished ICI treatment, 1 pt’s TTD was > 3 mo, 0/5 had TTD > 6 mo. Conclusions: APOBEC+ occurs in ~7% of BC and is more common in ILC and metastatic lesions. APOBEC+ HR+HER2- pts had shorter TTD and OS on SOC ET+CDK4/6i relative to APOBEC- pts. However, TTD on ICI tended to be longer in APOBEC+ pts, but our data is limited, and more research is needed. CGDB APOBEC+ vs. APOBEC- with SOC 1st lineAPOBEC+ (N=69)APOBEC- (N=788)p adjusted (FDR)*Age at Dx, Median (IQR)59.0 (53.0, 65.0)56.0 (47.0, 65.0)0.102Stage at Dx0.067- 0-III52 (75.4%)505 (64.1%)- IV11 (15.9%)245 (31.1%)- Not documented6 (8.7%)38 (4.8%)Metastasis free interval, yrs, Median (IQR)5.2 (3.0, 10.5)5.1 (2.8, 9.3)0.734Tumor Grade0.104- Grade 12 (2.9%)49 (6.2%)- Grade 234 (49.3%)259 (32.9%)- Grade 311 (15.9%)163 (20.7%)- Not documented22 (31.9%)317 (40.2%)Tumor Type0*- IDC7 (10.1%)251 (31.9%)- ILC30 (43.5%)138 (17.5%)- Other /Not documented32 (46.4%)399 (50.6%)Metastases sites0.734- Bone-only17 (24.6%)169 (21.5%)- CNS11 (15.9%)104 (13.2%)- Visceral41 (59.4%)514 (65.3%)TMB, Median (IQR)11.3 (8.8, 18.8)2.5 (1.3, 3.8)0*MSI0.946- MSI-H0 (0.0%)4 (0.5%)- MSI-I0 (0.0%)1 (0.1%)- MSS68 (98.6%)728 (97.2%)- Not documented1 (1.4%)16 (2.1%)BRCA5 (7.2%)45 (5.7%)0.734PIK3CA46 (66.7%)341 (43.3%)0.001*Treatments0.005*- AI + CDK4/6i31 (44.9%)510 (64.7%)- Fulvestrant + CDK4/6i38 (55.1%)278 (35.3%) Citation Format: Saranya Chumsri, Kira Raskina, Sarah Sammons, Laura Alder, Natalie Danziger, Alexa B Schrock, Kim McGregor, Ethan Sokol. APOBEC signature, clinical characteristics, and outcome in hormone receptor-positive (HR+) HER2-negative (HER2-) breast cancer (BC) patients (pts) in real-world data (RWD) [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 PD14-09.

Abstract OT1-14-02: Phase 3 study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09

Abstract Background: A combination of a taxane, trastuzumab, and pertuzumab (THP) is the standard-of-care (SOC) 1L treatment for patients (pts) with HER2+ mBC; THP demonstrated median progression-free survival (mPFS) of 18.7 mo and overall survival (OS) of 56.5 mo (Swain et al. N Engl J Med. 2015;372:724-734). However, pts eventually develop resistance to treatment. Novel treatment options are necessary in order to delay the emergence of resistance and provide better clinical outcomes, improve quality of life (QOL), and prolong survival in the 1L setting. T-DXd has demonstrated efficacy in pts with heavily pretreated HER2+ mBC, with an objective response rate (ORR) of 61.4%, duration of response (DOR) of 20.8 mo, and mPFS of 19.4 mo (Modi et al. Cancer Res. 2021. Abstract PD3-06). Data from DESTINY-Breast01 supported global approvals of T-DXd in HER2+ mBC. Here we describe a phase 3 trial evaluating the efficacy and safety of T-DXd ± pertuzumab compared with THP in the 1L treatment of HER2+ mBC. Trial design: DESTINY-Breast09 (NCT04784715) is a global, multicenter, randomized, phase 3 trial assessing the efficacy and safety of T-DXd with or without pertuzumab compared with SOC THP as 1L treatment in pts with HER2+ (IHC 3+ or ISH+ assessed locally per ASCO-CAP guidelines and centrally confirmed) advanced or mBC. This study consists of 3 treatment arms: arm A (T-DXd + placebo), arm B (T-DXd + pertuzumab), and arm C (THP). Randomization is 1:1:1 and pts will be stratified by prior treatment status (de novo vs recurrent), hormone receptor status (positive vs negative), and PIK3CA mutation status (detected vs not detected). Pts (N≈1134) must have had no prior chemotherapy or HER2-targeted therapy for advanced or mBC (1 prior line of endocrine therapy is allowed for mBC). The primary endpoint is PFS by blinded independent central review. Secondary endpoints include PFS by investigator assessment, OS, ORR, DOR, PFS2, health-related quality of life (QOL), pharmacokinetics, immunogenicity, and safety. Citation Format: Sara M Tolaney, Romualdo Barroso-Sousa, Zefei Jiang, Yeon Hee Park, Mothaffar Rimawi, Cristina Saura, Andreas Schneeweiss, Masakazu Toi, Tinghui Yu, Jagdish Shetty, Pia Herbolsheimer, Sibylle Loibl. Phase 3 study of trastuzumab deruxtecan (T-DXd) with or without pertuzumab vs a taxane, trastuzumab and pertuzumab in first-line (1L), human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): DESTINY-Breast09 [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 OT1-14-02.

Eye metastasis in breast cancer: case report and review of literature

The paradigm of breast cancer management has been revolutionised, resulting in prolonged survival that echoes an increasing incidence of metastasis in uncommon sites. With orbital metastases – despite being rare – the incidence scales up to 13% of breast cancer cases with no specific management guidelines. We report a case of a 31-year-old luminal B breast cancer patient who initially presented with T2N2M0 disease and received six cycles of adjuvant chemotherapy (5-Fluorouracil (5-FU) 600 mg/m2 IV, Doxorubicin 60 mg/m2 IV, Cyclophosphamide 600 mg/m2 IV), followed by radiotherapy (RTH) and adjuvant Tamoxifen. Two years later, the patient experienced successive bone metastasis, so she received several lines of endocrine therapy as Fulvestrant and aromatase inhibitors in combination with luteinizing hormone-releasing hormone (LHRH) analogues. Later on, she presented with right eye ptosis and magnetic resonance imaging (MRI) showed a soft tissue mass in the superior and lateral rectus muscles. The patient received six cycles of chemotherapy with no improvement. Further disease progression occurred 3 months later, so the patient received palliative RTH resulting in no response. One month later, the patient was deceased, secondary to progressive disease. With the rising incidence of ocular metastasis due to breast cancer, oncologists should be aware of symptoms and use the proper diagnostic modalities. Here we provide a literature review on similar cases and discuss possible treatment modalities for those patients. The main concern is to evaluate the need for chemotherapy in such cases in the presence of highly effective endocrinal treatment.

A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer

AimsFulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. Materials and methodsMedical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. ResultsData from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21–95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0–1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0–5) prior lines of endocrine therapy and median 0 (range 0–6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1–88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0–88). ConclusionsThis is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

Clinical Translation: Targeting the Estrogen Receptor.

Estrogen Receptor alpha (ERα) stands as one of the most successfully prosecuted drug targets in oncology, beginning with the approval of tamoxifen for women with ERα positive (ER+) breast cancer over 40years ago. The field continued to advance with the development of aromatase inhibitors and the pure antiestrogen fulvestrant. With multiple endocrine therapies approved for the treatment of ER+ breast cancer, efforts to generate novel ERα-targeted therapeutics somewhat diminished in the early 2000s. Today however, there are at least eight new molecular entities targeting ERα under active clinical investigation, each with the aim of bringing further benefit to patients. This remarkable re-energizing of the field was spurred in part by the discovery of highly prevalent ERα mutations as a mechanism of resistance to standard-of-care therapies, which provided unequivocal evidence of the continued, and broad, dependence of tumors on ERα, despite relapsing after earlier lines of endocrine therapy. Re-engagement of the pharmaceutical and biotechnology industries with ERα as a drug target has been further underpinned by the impressive advances made in medicinal chemistry, enabling desirable mechanistic features - high potency full ERα antagonism - to be combined with improved drug-like properties - oral bioavailability and optimized pharmacokinetics. In this chapter, we describe the rich history and science behind the currently evolving landscape of ERα targeting in breast cancer.

247P Efficacy and safety of ribociclib (RIB) in combination with letrozole (LET) in patients with estrogen receptor–positive advanced breast cancer (ABC): Secondary and exploratory results of phase 3b RIBECCA study

RIBECCA was a phase 3b, multicentre, open-label study of RIB + LET in patients (pts) of any menopausal status with HR+, HER2–ABC, who were not amenable to curative treatment (tx). The study investigated RIB + LET in pt settings broader than those considered in MONALEESA (ML) studies. Data on primary endpoint, clinical benefit rate (CBR) at week 24 in cohorts A (tx naive postmenopausal pts) and B (comprising cohort B1 [tx naive pre- and perimenopausal pts] and B2 [pre-, peri- and postmenopausal pts pretreated with ≤1 prior chemotherapy and ≤2 lines of endocrine therapy]) were reported previously.

259P Weekly ladiratuzumab vedotin monotherapy for metastatic triple-negative breast cancer

LIV-1 is highly expressed in breast cancer. Ladiratuzumab vedotin (LV) is an investigational anti-LIV-1 antibody-drug conjugate with a protease-cleavable linker conjugated to monomethyl auristatin E (MMAE). LV 2.5 mg/kg given every 3 weeks (q3w) was generally well tolerated and has demonstrated encouraging efficacy in patients with pre-treated metastatic triple-negative breast cancer (mTNBC). Here, we evaluated the efficacy and tolerability of weekly LV dosing (q1w). SGNLVA-001 (NCT01969643) is an ongoing, multi-part, open label study investigating the safety and efficacy of LV in patients with metastatic breast cancer (mBC). Part E evaluated LV q1w in escalation and expansion starting at LV 1.0 mg/kg q1w. Patients with first (1L) or second line (2L) endocrine therapy refractory hormone receptor-positive (HR+)/HER2-negative (HER2-) mBC or 2L mTNBC were enrolled. Tumor assessments occurred every 6 weeks per RECIST v1.1. As of March 19, 2021, 81 patients were treated in Part E (median age 55 years, female 100%, ECOG-0 62%, subtype: mTNBC 49%, HR+/HER2- 51%). No dose limiting toxicities occurred with either LV 1.0, 1.25, or 1.5 mg/kg q1w. At LV 1.5 mg/kg, neutropenia was reported in 6 of 9 patients (66%; 1 Grade 1, 1 Grade 2, 1 Grade 3, and 3 Grade 4). Subsequent enrollment continued only in the LV 1.25 mg/kg cohort. The most common treatment emergent adverse events (TEAEs) observed with LV 1.25 mg/kg q1w (n=52) were nausea (60%), fatigue (58%), peripheral sensory neuropathy (54%), decreased appetite (44%), and constipation (39%). The most common ≥ Grade 3 TEAEs were neutropenia (21%), fatigue (14%), and hyperglycemia, hypokalemia, and hypophosphatemia (12% each). The most common serious adverse events were pneumonia (6%) and abdominal pain (4%). In the 29 patients with 2L mTNBC who received LV 1.25 mg/kg, the confirmed objective response rate was 28% (95% CI: 13, 47). Pharmacokinetic analyses indicate q1w dosing reduced peak-trough fluctuations, lowered Cmax while maintaining a higher Ctrough compared to q3w dosing. LV 1.25 mg/kg q1w is associated with a manageable safety profile and favorable preliminary efficacy data in patients with 2L mTNBC. Further studies of LV q1w in patients with breast cancer and other tumors are underway.

Clinical case of the use of oral metronomic vinorelbin in patient with metastatic Her2 negative breast cancer

Endocrine therapy in combination with inhibitors of cyclin-dependent kinases 4/6 in first lines is the current standard of treatment of metastatic ER positive Her2 negative breast cancer. After progression on several lines of endocrine therapy according to current principles we apply sequential lines of monochemotherapy. If possible non-toxic agents are prefered in order to maintain high quality of life. The special role in this context may play oral agents, when regular visits in clinic and intravenous injection are not needed. The efficacy of oral vinorelbine is well explored, unfortunately the standard dosage regimen сan have quite high especially hematologic toxicity. The metronomic dosing regimen is believed to be as effective as the standard, but is less toxic. In addition, the anti-angiogenic properties of the metronomic mode are described. Taking into account the increasing use of combination of endocrine therapy with CDK4/6 inhibitors in first treatment lines, it is extremely important to study the efficacy and tolerability of various regimens and drugs after progression on combined endocrine therapy. In this article, we represent a clinical case of the use of oral vinorelbine in the metronomic mode in the patient after progression on combination of fulvestrant and palbociclib. Long-term disease control with satisfactory quality of life has been demonstrated.

Niraparib for Advanced Breast Cancer with Germline BRCA1 and BRCA2 Mutations: the EORTC 1307-BCG/BIG5-13/TESARO PR-30-50-10-C BRAVO Study.

To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (gBRCAm) advanced breast cancer. BRAVO was a randomized, open-label phase III trial. Eligible patients had gBRCAm and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician's choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor-positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety. After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm (n = 141) versus 3.1 months in the PC arm [n = 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65-1.44; P = 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63-1.42) and 0.65 (95% CI, 0.46-0.93), respectively. ORR was 35% (95% CI, 26-45) with niraparib and 31% (95% CI, 19-46) in the PC arm. Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib's activity in this patient population.

Fermented Wheat Germ Extract (FWGE) as a Treatment Additive for Castration-Resistant Prostate Cancer: A Pilot Clinical Trial

Castration-resistant prostate cancer (CRPC) is a devastating and incurable disease. Combined therapy using conventional anticancer drugs and a proprietary medical nutriment, fermented wheat germ extract (FWGE), also known as Avemar, has been suggested as a treatment for progressing prostate cancer (PCa) patients, who have become resistant to first line hormonal therapy (gonadotropin releasing hormone, GnRH). The primary aim of this study was to test if this combined therapy would slow down disease progression in CRPC patients. We tested the nontoxic, readily available, inexpensive FWGE, together with the conventional treatment, GnRH analogue, in 36 CRPC patients. Although this is a pilot study, with the drawback of a statistically small sample size, some anticancer clinical activity of FWGE could be seen in the CRPC patients, as measured by prostate specific antigen doubling time (PSADT). We found that the intake of GnRH with FWGE for at least 4 months, improved the overall health as well as the quality of life (QOL) in 4 patients (11%) and was instrumental in extending the PSADT in about 17 (out of 26) patients (65.4%), six of whom were significant. Since no mentionable adverse events were noticed, this treatment may permit the postponement of chemotherapy for these patients.

Abstract CT028: A pilot study of pembrolizumab and exemestane/leuprolide in premenopausal hormone receptor positive/HER2 negative locally advanced or metastatic breast cancer (PEER)

Abstract Interim Analysis Background: Despite the success of immunotherapy in triple negative breast cancer, no approved immunotherapy is available for HR+, HER2- MBC patients. Among HR+/HER2- patients(pts), luminal subtype B pts who are more resistant to endocrine therapy, demonstrate higher tumor infiltrating lymphocytes, higher immune score, and higher expression of PD-L1 than luminal subtype A pts. In addition, estrogen is known to result in immunosuppressive microenvironment. Exemestane, as a steroidal aromatase inhibitor, provides less than 10% overall response rate in second or third line of endocrine therapy for MBC pts. This pilot study aims to observe the efficacy of a combination of exemestane, leuprolide, and pembrolizumab in pre-/perimenopausal HR+, HER2- locally advanced or MBC pts who failed front-line endocrine therapy. Methods: This single-center, nonrandomized, open-label, phase Ib/II study of exemestane/leuprolide plus pembrolizumab enrolled a cohort of endocrine resistant HR+, HER2-, pre-/perimenopausal, locally advanced or MBC pts who 1) had failed adjuvant endocrine therapy within 12 months, 2) had failed at least 2 lines of prior endocrine therapy for MBC, 3) had failed 1st line endocrine therapy within 6 months or 1st line endocrine therapy+ CDK4, 6 inhibitor within 12 months. No prior chemotherapy for locally advanced or MBC was allowed. Patients received 25mg exemestane orally daily, 3.6mg leuprolide subcutaneous injection every 28 days, and pembrolizumab 150mg IV on day 1/day 15 every 28 days. Primary objective was to estimate the efficacy of the exemestane, leuprolide plus pembrolizumab combination defined by progression-free survival (PFS) rate at 8 months. Secondary objectives included safety, objective response rate (ORR), clinical benefit rate (CBR), and PFS. Results: Of 14 pts enrolled, 6 (42.9%) received 1 line and 8 (57.1%) received 2 lines of prior endocrine therapy in the locally advanced/metastatic setting. Safety of the combination was generally consistent with known side effects of exemestane, leuprolide, and pembrolizumab and was generally manageable. Grade 3/4 adverse events in ≥1 pt included AST increase (4 pts/28.6%), ALT increase (4 pts/28.6), and hypo/hyperthyroidism (1 pt, 7.1%). Nine pts did not progress or die at 8 months (64.3% PFS rate at 8th month). In the 13 evaluable pts, 5 had confirmed partial response [PR] (ORR=38.4%), 6 had confirmed stable disease[SD, 46.2%]. The disease control rate (complete response [CR]+partial response [PR]+stable disease [SD]) was 84.6%. CBR (CR+PR+SD persisting for ≥6 months) was 76.9%. Median PFS of the evaluable pts, PR pts, SD pts, and PD pts were 10.2 months, 15.8months, 10.1 months, and 2.4 months respectively. Conclusions: Combination of exemestane, leuprolide plus pembrolizumab demonstrated a generally tolerable safety profile with numerically higher rate of transaminase elevations than reported for the individual treatments. Compared to historical data for exemestane/leuprolide or for pembrolizumab monotherapy in a similar pt population, a meaningful higher ORR and longer PFS were observed. Citation Format: I-Chun Chen, Ching-Hung Lin, Dwan-Ying Chang, Tom Wei-Wu Chen, Ming-Yang Wang, Wei-Li Ma, Yi-Ting Lin, Shu-Min Huang, Yen-Shen Lu. A pilot study of pembrolizumab and exemestane/leuprolide in premenopausal hormone receptor positive/HER2 negative locally advanced or metastatic breast cancer (PEER) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT028.