e13107
Background: Breast cancer has an unacceptably high recurrence rate when residual disease is found following neo-adjuvant treatment of high-risk disease. Based on clinical data suggesting an ...adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. Methods: A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2 negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3mg to 5mg and capecitabine 800mg/m2 to 1000mg/m2. Results: Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar- plantar erythrodysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a pre-specified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase. Conclusions: The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer patients. Entinostat clinical investigation in breast cancer was halted while this study was ongoing. Clinical trial information: NCT03473639 .
e13067 Background: CDK4/6 inhibitors (CDKi) + endocrine therapy (ET) comprise the standard 1st line treatment for ER+ HER2- metastatic breast cancer (MBC). However, there is a gap in understanding ...how timing of MBC recurrence affects clinical outcomes on CDKi. We conducted a study to compare clinical outcomes of MBC patients on CDKi based on timing of MBC recurrence. Methods: This retrospective study enrolled ER+ HER2- MBC patients diagnosed from Jan 2015 to Jan 2023, who received CDKi + ET as 1st line treatment for MBC. Patients were categorized as de novo MBC (dMBC), if they had 1. Stage 4 disease at initial diagnosis or 2. MBC diagnosed < 6 months of the primary breast cancer (PBC) diagnosis and before starting any systemic treatment for PBC. Patients with distant recurrence occurring < 5 years, 5-10 years, and >10 years from PBC were categorized as early, intermediate, and late MBCs (eMBC, iMBC, laMBC). Endpoints were Progression-Free Survival (PFS) and Overall Survival (OS) from MBC diagnosis. Baseline variables were compared using t-tests (continuous) and Chi-square tests (categorical). Endpoint analyses were conducted using Kaplan-Meier method and compared using Log rank test. Multivariate analyses were performed using Cox models. Results: Out of 280 patients enrolled, 67 were dMBC, 75 eMBC, 56 iMBC, and 82 laMBC. The laMBC group had a higher mean age (years) compared to other groups (71 vs. 62 in dMBC+ eMBC + iMBC, p<0.001). 64.5% of laMBC had visceral disease compared to 50.5% of dMBC + eMBC + iMBC (p=0.031). 65.7% of dMBC patients were treated with palbociclib compared to 80.8% of eMBC + iMBC + laMBC (p=0.010). Higher % of eMBC were PR- vs other cohorts (41.3 vs 23.9 dMBC + iMBC + laMBC, p<0.001). Among the 3 non dMBC groups, prior ET sensitivity (no recurrence for 2 years on adjuvant ET) was lower in eMBC (45.3%) compared to iMBC + laMBC (81.9%, p<0.001). 61.3% of eMBC patients were on adjuvant ET at recurrence compared to 17.4% of iMBC + laMBC (p<0.001). Other variables were similar. Table shows unadjusted endpoint analyses. In multivariate analyses, the risk of PFS events were not significantly different among cohorts (age<=65, ECOG performance status (PS) >=2 and PR- were independently associated with shorter PFS); risk of death was higher in eMBC vs laMBC (HR 1.73, p=0.047). Conclusions: In this retrospective study of ER+ HER2- MBC patients treated with 1st line CDKi + ET, timing of MBC recurrence was not associated with PFS differences after adjusting for other variables. However, patients with MBC recurring < 5 years of PBC had the higher likelihood of death compared to those recurring >10 years of PBC. Table: see text
e14005 Background: Patients with Metastatic Breast Cancer (MBC) and brain metastasis (BM) have poor prognosis. There is a lack of data on the effects of timing of MBC diagnosis de novo (d) vs ...recurred (r) MBC and BM diagnosis dBM vs later onset (lo) BM on overall survival (OS). We conducted a natural history-type study to investigate these effects among MBC BM patients. Methods: The data for this retrospective single institute study was extracted from a database of MBC BM patients diagnosed with BM from Jan 2010 to June 2021. Definitions: dMBC= MBC at initial diagnosis (Dx); rMBC= MBC with prior history of early stage BC; dBM= BM diagnosed< 6 weeks (wk) from MBC Dx; loBM= BM diagnosed ≥ 6 wk from MBC Dx. The following endpoints were compared between dMBC vs rMBC: 1. interval from MBC to BM Dx (Interval MBC-BM) 2. OS from MBC Dx 3. OS from BM Dx. OS from BM Dx was compared between dBM vs loBM. Median endpoints were estimated using the Kaplan-Meier method and reported with 95% confidence intervals (CI). Cohorts were compared using the Logrank test and adjusted for other variables using Cox models. Results: Interval MBC-BM, OS from MBC Dx, and BM Dx were not statistically different between dMBC and rMBC groups in unadjusted analyses (See Table) and when adjusted in multivariate analyses. Median OS from BM Dx was significantly longer in dBM group vs loBM group (See Table). In multivariate model adjusting for variables at BM Dx (age, race, performance status, visceral disease, number of BM >1cm, leptomeningeal disease, BC receptor types), risk of death was higher in loBM group vs dBM group (Hazard Ratio, HR = 0.499; p=0.006). In dMBC group, 28.1% had dBM compared to 45.6% in the rMBC (p=0.083, Chi-square test). Subset analyses: Among rMBC group, median OS from BM Dx with dBM (n=42, OS=44.3 months (m), 95% CI 19.0-Not evaluable (NE)) was significantly longer compared to loBM (n=50, OS=13.7m (6.6-21.4)), p=0.002 (LogRank Test); but among dMBC group, there was no significant difference in OS from BM Dx with dBM (n=9, OS=32.4m (12.9-122.5)) vs. with loBM (n=23, OS= 17.8m (6.6-NE)), p=0.885. Conclusions: In a retrospective database of patients with BM from BC, time from MBC to BM diagnosis, OS from MBC diagnosis, and OS from BM diagnosis did not differ between those with recurrent vs de novo MBC. Interestingly, in unadjusted and adjusted analyses, OS from BM diagnosis was longer for those with de novo BM diagnosed at/around MBC diagnosis than those whose BM was later in onset. Earlier-onset BM in the MBC disease course could be more sensitive to cancer-directed therapies. Studies are needed to test this hypothesis.Table: see text
1572
Background: In addition to being required by the Federal Policy for the Protection of Human Subjects for United States-based institutions that receive federal funding and are engaged in ...cooperative research projects, the use of a central Institutional Review Board (cIRB) has multiple benefits. Yet more advanced trial designs have unique needs and challenges that may hinder adoption of an efficient cIRB. Platform trials, which require both a master protocol and successive individual protocol amendments for each new agent, are prone to high regulatory burden that can slow trial recruitment, representing a significant workload for study personnel. Specific challenges for platform trials include high burden of new amendments and IRB review schedules staggered across sites, making it challenging to have all sites operating under the same amendment concurrently. Methods: Administrative assessments were collected over the course of the I-SPY2 trial. The primary outcome of interest was time from amendment submission to approval (calculated as the number of days from submission to the local IRB by the site investigators to approval by the local IRB). Quantitative data in terms of hours spent on regulatory tasks pre- and post-cIRB implementation was estimated. Site investigators were asked in December 2022 to complete a brief questionnaire to investigate perceptions on changes to workload and level of comfort using a cIRB. Results: Amendments were activated when 50% of high accruing sites had IRB approval. The number of sites with approval for an amendment to go live was < 25% prior to cIRB adoption, and 83% after. Following transition to the cIRB in February 2021, the mean time from amendment submission to approval decreased from 54.4 to 20.7 days by Jan 2023. Changes to the informed consent were possible once the cIRB was adopted, including: standardizing site-specific IRB language in a section of the consent, so it need not be adjusted with every new agent amendment; standardizing site-specific workflows; shortening consent and making it more patient friendly. The average time that CRCs spent on regulatory work at each site decreased by an average of 160 minutes, but was variable, revealing continued use of local IRB, other committees at some sites. A total of 14 respondents completed the survey; most respondents indicated that keeping up with the amendment approval process was easier post-cIRB and 94% were comfortable relying on a cIRB. The short time for cIRB approval revealed the inefficiency of other processes, including coverage analysis and building of drug order sets. Conclusions: Active engagement of cIRB leadership and IRB working group has enabled regulatory review that now takes less than 30 days. The cIRB is now the standard for the I-SPY family of trials. Other services can also be shared and will continue to drive efficiency and reduce the regulatory burden for sites.
LBA501 Background: I-SPY2.2 is a multicenter phase 2 platform sequential multiple assignment randomized trial (SMART) in the neoadjuvant breast cancer setting that evaluates novel experimental ...regimens as first in a sequence (Block A) followed by standard chemo/targeted therapies (Blocks B/C) if indicated. The goal is to achieve a pCR after novel targeted agents alone or in sequence with standard therapies, with the optimal therapy assigned based on the tumor response predictive subtype (RPS). RPS incorporates expression-based immune, DNA repair deficiency (DRD), and luminal signatures with hormone receptor (HR) and HER2 status to subset patients into 6 subtypes: S1: HR+HER2-Immune-DRD-; S2: HR-HER2-Immune-DRD-; S3: HER2-Immune+; S4: HER2-Immune-DRD+; S5: HER2+/non-Luminal; S6: HER2+/Luminal. Methods: RPS S1, S2, S3, and S4 were eligible for assignment to Dato+Durva in Block A. Patients were followed by MRI during treatment (at 3, 6, and 12 weeks after start of Blocks A and B). Predicted responders by MRI and biopsy at the end of Block A or B have the option of going to surgery early; otherwise, they proceed to next treatment Block (B +/- C). Randomization to Block B includes a taxane-based regimen specific to the RPS, and options include S1: paclitaxel; S2 and S3: paclitaxel + carboplatin + pembrolizumab; S4: paclitaxel + carboplatin vs. paclitaxel + carboplatin + pembrolizumab. Patients who did not go to surgery after Block B proceeded to Block C (AC or AC + Pembrolizumab if HR-HER2-). The primary endpoint is pCR. Efficacy is evaluated within each RPS and HR+HER2- and HR-HER2- signatures. To estimate the arm's efficacy as a stand-alone therapy, we use a Bayesian covariate-adjusted model to estimate the pCR rate and compare the posterior distribution to a subtype-specific fixed threshold. This model uses pCR data when available and MRI data when pCR is not. To estimate pCR rate in the context of a multi-decision treatment regimen, we use a Bayesian model based on if and when a pCR occurred in the trial. The posterior is compared to a subtype-specific dynamic control generated from historical I-SPY data. Results: 106 patients were randomly assigned to the Dato+Durva arm between September 2022 and August 2023. The results for Dato+Durva as a stand-alone therapy are summarized in Table. After completion of Block A, 36 patients proceeded to surgery without completing Blocks B/C. Conclusions: Dato+Durva meets threshold for graduation within the RPS S3 subtype based on estimated pCR rate of 72% and warrants further investigation in a larger randomized controlled trial. Clinical trial information: NCT01042379 . Table: see text
LBA612
Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) status to evaluate novel neoadjuvant agents in ...high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Oral Paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar. Dostarlimab (D) is an intravenous (IV) PD-1 inhibitor. Methods: Women with tumors ≥ 2.5cm and MP high risk cancers (MP1 = MP high; MP2 = MP ultra-high) were treated starting Oct 5, 2020. Treatment included OPE (Oral P 205mg/m2 + encequidar 12.9mg) on days 1-3 weekly x 12 and D 500 mg IV given q 3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q 2-3 weeks x 4. Patients with HER2+ disease received IV weekly trastuzumab (T) during the first 12 weeks. The control arm was weekly IV P x 12 with or without trastuzumab followed by AC q 2-3 weeks x 4. OPE + D was eligible to graduate 85% chance of success in a 300-person phase 3 neoadjuvant trial with a pCR endpoint in any of the pre-defined signatures. Results: 113 (78 HR+HER2-, 17 HR-HER2- and 18 HER2+ patients) received OPE + D +/- T. The control arm included 388 historical controls (201 HR+Her2-, 156 HR-HER2-, 31 HER2+). 77 patients (70 HR+ and 7 HR-) were MP1 and 36 patients (24 HR+ and 12 HR-) were MP2. Safety events of note for OPE + D versus IV P include increased rates of nausea (85% vs. 72%) diarrhea (77% vs. 41%). There was no significant difference in rates of neutropenia (23% vs.17%). Peripheral neuropathy (37% vs. 64%) and alopecia (59% vs. 66%) were significantly decreased. Immune related adverse events (irAEs) were lower than expected. Conclusions: Although both OPE and D have both been shown to have efficacy in other settings, combination therapy with OPE + D did not graduate in any of the predefined subtypes. In the HR+ signature where we would not expect a benefit of D, we see equal response to OPE with decreased rates of peripheral neuropathy and alopecia, which suggest this oral agent may be an attractive alternative to IV P in this subgroup and is under consideration in ISPY 2.2. We did not observe the expected improvement in pCR rates seen with PD-1 inhibitors in the HR- or MP2 subtypes (over P alone historic control). In addition, the irAEs were less than expected. Together these findings suggest interference of OPE with D. A potential mechanism of interference could be change in microbiome with the use of OPE vs. IV P, as the microbiome is known to influence the efficacy of immunotherapy. The source of interference is being investigated. Clinical trial information: NCT01042379 . Table: see text
LBA520
Background: I-SPY 2 is a multicenter trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) risk to evaluate novel neoadjuvant agents in high-risk ...breast cancer. Oral paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar, to enhance gastrointestinal (GI) absorption. Dostarlimab (D) is an anti-PD-1 monoclonal antibody. Methods: Women with tumors ≥ 2.5cm and MP high-risk cancers were screened and treated starting Oct 5, 2020. Treatment included Oral Paclitaxel 205mg/m2 and encequidar 12.9 mg on days 1-3, Carboplatin (Cb) AUC 1.5 on day 1 weekly x 12, and Dostarlimab (D) 500 mg every 3 weeks x 4, followed by doxorubicin/ cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was IV P weekly x 12 followed by AC every 2-3 weeks x 4. For patients with HER2+ disease, weekly Trastuzumab (T) was administered during the first 12 weeks. The arm was eligible for graduation > 85% chance of success in a 300-person phase 3 neoadjuvant trial with a pathologic complete response (pCR) endpoint in 10 predefined signatures. Results: 106 patients (44 HR+HER2-, 56 HR-HER2- (TN), 6 HER2+) received OPE/Cb/D ± T. The control arm included 388 historical controls (201 HR+HER2-, 156 TN, 31 HER2+). 22 patients (20 HR+, 2 HR-) in OPE/Cb/D were MP1 (MP high) and 84 patients (29 HR+, 55 HR-) were MP2 (MP ultra-high). OPE/Cb/D graduated in the TN signature and accrual was stopped. Conclusions: OPE/Cb/D graduated in the TN signature with a higher predicted pCR rate compared to control. OPE and D have been, individually, shown to have efficacy in other settings. The lower-than-expected pCR rate and lower irAEs with triplet therapy (taxane, platinum, immune checkpoint inhibitor ICI) in TN compared to prior IV chemo + ICI arms on I-SPY 2 suggests a possible interference of OPE with ICI. Changes in gut microbiome is being investigated as an explanation. Clinical trial information: NCT01042379 . Table: see text
1012
Background: In preclinical studies, the oncolytic reovirus pelareorep promoted an inflammatory tumor microenvironment (TME) by promoting greater infiltration of tumor infiltrating lymphocytes ...and upregulating PD-1/PD-L1 expression, potentially increasing the efficacy of immune checkpoint blockade. The addition of pelareorep to paclitaxel (PTX) was associated with improved survival (10.4 vs. 17.4 mos., HR = 0.65, p = 0.1) in a prior trial, with the greatest benefit in patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) disease (N = 57; 10.8 vs. 21.0 mos., HR 0.60, p = 0.1). Methods: This is a randomized phase 2 study in pts with HR+/HER2- metastatic breast cancer. Patients must have progressed on at least one hormone therapy with a CDK4/6 inhibitor. After a safety run-in for Cohort 3, patients were randomized 1:1:1 to PTX-alone (Cohort 1), PTX + pelareorep (Cohort 2), or PTX + pelareorep + avelumab (Cohort 3). The primary endpoint was overall response rate (ORR) at week 16 according to RECIST v1.1 without formal comparison across groups. Toxicity, progression-free survival (PFS) and overall survival were secondary endpoints. Blood samples were collected at cycle 1-day 1 (C1D1), C2D1 and C4D1, and T-cell receptor sequencing was performed. Results: Forty-eight pts were enrolled between June 2020 and June 2022. Median age was 55.5 yrs, range 37-74. Forty pts (83%) had visceral disease. Six pts (12%) previously received everolimus, and 3 alpelisib. Thirteen pts (27%) received prior taxanes in the neo/adjuvant setting. Three pts who withdrew consent prior to starting therapy and 2 pts who discontinued treatment after week 1 were considered non-responders and were censored for PFS. The most common pelareorep-associated toxicities were fever, chills, and flu-like infusion reactions, which were occasionally severe enough to require hospitalization in 5 (15%) pts despite acetaminophen prophylaxis. Nine pts (33%) discontinued pelareorep and 6 (35%) discontinued avelumab due to toxicity. Pelareorep increased T-cell repertoire turnover, with identification and expansion of new and pre-existing T-cell clones by C2D1. Conclusions: The addition of pelareorep to PTX is an active regimen with a high 6-month PFS rate worthy of further study. One third of patients discontinued either pelareorep or avelumab due to toxicity, highlighting the need for attentive supportive care. Survival data is maturing. Clinical trial information: NCT04215146 . Table: see text
Abstract only
e12075
Background: Markers of tumor proliferative status, e.g., Ki67 and grade (G), are prognostic for early distant recurrence (DR) in HR+ breast cancer and integrated in adjuvant ...chemotherapy decisions; however, their impact on late DR and extended endocrine therapy (EET) decisions is less clear. BCI is a genomic assay that provides 2 results: BCI Predictive, based on HoxB13/IL17BR (H/I ratio), reports a prediction of likelihood of benefit from EET; BCI Prognostic, based on the algorithmic combination of H/I and proliferation genes, reports risk of late DR. In this study, BCI results were examined within clinicopathologic risk categories based on Ki67 and G. Methods: The BCI Clinical Database for Correlative Studies is an IRB-approved de-identified database that contains > 50 clinicopathologic and molecular variables from cases submitted for BCI testing in clinical practice (N = 14,463). Clinicopathologic variables were abstracted from pathology reports, and were available for a subset of cases. High Ki67 was defined as ≥14%. Chi-squared tests were used to compare BCI results between Ki67 and G subgroups. Results: Analyses included 3395 LN- pts (median age 59.1y; 73% ≥ 50y). BCI Prognostic showed a wide distribution of individual risk assessments in pts with high or low Ki67. A greater proportion of pts with high Ki67 was classified by BCI as high risk of late DR compared to low Ki67 (68.2% vs 26.5%; P < 0.0001); however, substantial proportions of high Ki67 pts were classified as BCI low risk (31.8%) and pts with low Ki67 classified as BCI high risk (26.5%). Overall, there was a moderate correlation between individual BCI Scores and individual Ki67 scores (Correlation = 0.519). 45.5% of pts with high Ki67 were classified as High BCI Predictive (H/I) compared to 35.5% of pts with low Ki67 (p < 0.001). Both BCI Prognostic and BCI Predictive (H/I) classified increasing proportions of pts as high risk or high benefit with increasing G (P < 0.0001). Conclusions: These findings help characterize differential stratification based on tumor biology vs Ki67/G for pts considering EET. While moderately correlated, both BCI Prognostic and BCI Predictive (H/I) identified distinct populations compared to Ki67 and G.
525
Background: Homologous recombination deficiency (HRD) status can be used to identify patients who are eligible for treatment with DNA damaging agents. Using a 3-biomarker Genomic Instability ...Score (GIS) threshold of ≥42, studies have previously examined the association between HRD status and outcomes in patients with triple negative breast cancer (TNBC). However, evidence suggests that a GIS threshold of ≥33 may be more appropriate. Here, we conducted an exploratory analysis evaluating the ability of ≥33 and ≥42 GIS thresholds to predict response to platinum-based treatment in patients with TNBC. Methods: Patients across 5 cohorts (TBCRC030
1
, TBCRC008
2
, NCT01372579
3
, PrECOG 0105
4
, combined cisplatin cohort
4
) were included in this analysis if they had a primary TNBC diagnosis, received neoadjuvant platinum-based treatment, had a valid GIS, and had known pathologic complete response (pCR) status. GIS was determined by a combination of loss of heterozygosity, telomeric-allelic imbalance, and large-scale state transitions.
4,5
BRCA mutation status was defined by loss of function resulting from a pathogenic variant in BRCA1 or BRCA2. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), were calculated by comparing binary threshold status and binary pCR status. Results: A total of 204 tumors (158 BRCAwt; 33 BRCAm; 13 unknown) were included; pCR to platinum-based treatment occurred in 55 cases (39 BRCAwt; 14 BRCAm; 2 unknown). Sensitivity, specificity, PPV, and NPV were comparable between the ≥33 and ≥42 GIS thresholds, with the ≥33 threshold producing higher sensitivity values. This was true when thresholds were applied to all samples and to BRCAwt samples only (Table). Among patients who achieved pCR in response to platinum-based treatment, 5.5% of patients in the full cohort and 7.7% of those in the BRCAwt cohort had a GIS between 33-41. Conclusions: To ensure that the majority of patients likely to benefit from treatment are identified, a GIS of ≥33 may be the most appropriate threshold to predict response to platinum-based treatment in patients with TNBC; however, a prospective trial will be needed to confirm these findings. Additional studies will be important to determine whether this threshold may be appropriate to determine eligibility for other DNA-damaging agents such as PARP inhibitors. 1. Ann Oncol. 2020;31(11):1518-25 2. J Nucl Med. 2015;56(1):31-7. 3. Breast Cancer Res Treat. 2015;151(3):629-38. 4. Clin Cancer Res. 2016;22(15):3764-73. 5. Breast Cancer Res Treat. 2014;16(6):1-9. Table: see text
