Prior Lines Of Chemotherapy Research Articles

HOPE: Harnessing olaparib, palbociclib, and endocrine therapy for BRCA1/2-associated HR+, HER2- metastatic breast cancer.

10616 Background: Thepoly (ADP-ribose) polymerase inhibitor olaparib yields superior progression-free survival, response rates and patient-reported outcomes compared with chemotherapy in patients with BRCA1- or BRCA2- ( BRCA1/2) associated metastatic breast cancer (MBC). Fulvestrant and palbociclib improve outcomes in patients with hormone receptor-positive (HR+) MBC. HOPE (NCT03685331) is a phase I trial to evaluate combination olaparib (O), fulvestrant (F), and palbociclib (P) in patients with BRCA1/2-associated HR+, HER2 negative MBC. Methods: A 3+3 dose escalation was used to assess safety and preliminary efficacy of O, F and P. Eligible participants (pts) had HR+ MBC, a germline (g) or somatic (s) mutation in BRCA1/2, measurable/evaluable disease, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior PARPi and CDK4/6i were permitted but not in combination. Palbociclib was added after a 28-day safety run-in (Cycle 0) of O + F alone. Fulvestrant dose was 500mg IM on day 1 of each 28-day cycle. Dose level 0 (DL0, starting level) was F, O 300mg orally BID continuously, P 75mg orally daily on days 1-21; DL-1 was F, O 250mg orally BID, P 75mg orally daily on days 1-21. The primary endpoint was MTD (adverse events (AEs) based on CTCAE v5.0). Dose limiting toxicity (DLT) period included Cycles 0 and 1. A 30% DLT rate was acceptable; 6 pts had to be treated at a dose for it to be declared MTD. RECIST v1.1 was used to evaluate response. Results: Eight treated pts (s BRCA1:1 ;g BRCA2:6; s BRCA2:1 ) had median (M) age 47; M 0 (0-2) prior lines of endocrine therapy and 0 (0-1) prior chemotherapies for MBC. Three pts each had received O, F, and CDK4/6i as part of their standard of care treatment before study. At DL0, 2/2 pts had DLT with persistent grade(G) 3 neutropenia. Among 6 pts treated at DL-1, none experienced DLT, but 3 pts missed doses of study treatment due to cytopenias (G3 neutropenia, G3 leukopenia, G3 thrombocytopenia) during the DLT period. Following the DLT period, 1 pt reduced O to 200mg orally daily and 1 discontinued P based on provider discretion due to cytopenias (G3 neutropenia, G3 thrombocytopenia). Grade 3 AEs occurring in >1 pt related to study treatment were: neutrophil count decrease (G3/2, n=5/2); white blood cell decrease (G3/2/1, n=3/2/2); platelet count decrease (G3/2/1, n=2/0/1). Overall related AEs in >50% of pts were anemia (n=7), fatigue (n=6) and nausea (n=5). Best responses were CR/PR/SD/PD in 1/1/5/1 pts. Conclusions: MTDof O, F and P (DL-1) was reached and demonstrated antitumor activity. Although no AEs meeting protocol-specified DLT criteria were observed at MTD, hematologic toxicity at this dose complicated drug delivery and required close monitoring during and after the DLT period. Combinations utilizing PARP1 selective inhibitors, lower doses of therapy or sequential rather than combination therapy may improve feasibility. Clinical trial information: NCT03685331 .

Ipatasertib (IPA) combined with non-taxane chemotherapy (CT) for patients (pts) with previously treated advanced triple-negative breast cancer (aTNBC): The PATHFINDER phase IIa trial.

1098 Background: New therapies are urgently needed for aTNBC. The PI3K/AKT/mTOR pathway and its link to chemoresistance warrant further investigation in pre-treated TNBC patients. The pan-AKT inhibitor IPA, alone or combined, has shown promise for treating advanced solid tumors. This study assessed the toxicity and efficacy of IPA with non-taxane CT in aTNBC pts. Methods: PATHFINDER (NCT04464174) is a multicenter, open-label, non-comparative, phase IIa trial with a safety run-in phase. Taxane-pretreated aTNBC pts with 1-2 prior CT lines for advanced disease and ECOG 0-1 were eligible. Based on prior treatment and available slots, pts received 21-day cycles of IPA (oral, 400 mg/d for 14 d) either with capecitabine (CA) (oral, 2 g/m2/d for 14 d) (arm A); eribulin (E) (IV, 1.23 mg/m2 on d1 and d8) (arm B); or carboplatin plus gemcitabine (CG) (IV, AUC 5 on d1 and 1000 mg/m2 on d1 and d8, respectively) (arm C) until disease progression (PD) or unacceptable toxicity. Initially, the safety run-in phase included 3 pts/arm to determine phase IIa doses based on the toxicity observed after 2 cycles. The primary endpoint was incidence of adverse events (AEs) as per NCI-CTCAE v.5.0. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Analysis was exploratory with no hypothesis testing. Results: From September 2020 to October 2022, 54 pts were assigned to arms A (n = 22), B (n = 25), and C (n = 7). In arm C, 4 additional pts received a lower dose level of IPA (300 mg/d) in the safety run-in phase. Based on the toxicity profile, this arm did not proceed with the expansion phase. At data cutoff (10th November 2023), median follow-up was 13.8 (2.4-35.5, arm A) and 11.2 (0.2-36.9, arm B) months (mo). All pts discontinued treatment, mainly because of PD (74.1%). Discontinuations due to AEs were 4.5% and 4% in arms A and B, respectively. Incidence of treatment-related (1) any grade (G) TEAEs was 81.8% and 88% and (2) SAEs was 4.5% and 20% for arms A and B, respectively. G≥3 TEAEs occurring in ≥10% of pts are shown (Table). No treatment-related deaths were reported. Median PFS was 2.7 (95%CI, 1.5-4.1) and 3.8 (95%CI, 1.5-9.6) mo; median OS was 15.5 (95%CI, 11.8-19.2) and 11.5 (95%CI, 8.8-25.1) mo; and ORR was 9.1% and 36% for arms A and B, respectively. Conclusions: Combining IPA with CA and E presented an acceptable safety profile. However, adding IPA to CG was not tolerable. E + IPA showed promising efficacy regardless of PI3K/AKT status that merits further evaluation. Clinical trial information: NCT04464174 . [Table: see text]

Real-world efficacy and safety of capecitabine with oxaliplatin in patients with advanced adenocarcinoma of the ampulla of Vater

BackgroundAdenocarcinoma of the ampulla of Vater (AoV) is one of the rare periampullary cancers, and due to its anatomical location, it is categorized into various histologic subtypes. Its rarity and diversity pose challenges in treatment decision-making for patients with advanced AoV carcinoma. This study investigated the efficacy and safety of the combined regimen of capecitabine and oxaliplatin (CAPOX) in a real-world clinical setting.MethodsThis investigation encompassed patients with advanced AoV carcinoma who underwent CAPOX treatment. Histologic phenotypes were identified through a combination of histopathological analysis and protein expression markers, including MUC1, CDX2, CK20, and MUC2. The correlation between histopathological determinants and survival outcomes was explored, in addition to an evaluation of the safety profile of CAPOX therapy.ResultsFrom January 2010 to June 2023, 42 patients received CAPOX. Of these, 14 patients (33.3%) had not received any prior palliative chemotherapy, while 28 patients (66.7%) had undergone one prior line of chemotherapy. At a median follow up of 9.0 months, the median progression-free survival (PFS) was 4.38 months (95% CI, 2.78–5.69) and the median overall survival (OS) was 9.57 months (95% CI 7.56–11.6). The objective response and disease control rates were 38.1% and 61.9%, respectively. Patients who received CAPOX as a second-line treatment had poorer PFS (HR = 2.62; 95% CI, 1.49–4.90, p = 0.003) and OS (HR = 2.82, 95% CI, 1.47–5.38, p = 0.001) compared to those who received CAPOX as a first-line chemotherapy. There were no statistically significant differences in PFS (p = 0.185) and OS (p = 0.097) between groups based on histologic subtypes. Neutropenia (14.3%) emerged as the predominant grade 3–4 toxicity. Notably, treatment cessation occurred in select instances owing to grade 3 fatigue (9.5%) and peripheral neuropathy (9.5%).ConclusionsThis study confirmed the therapeutic efficacy and safety of CAPOX in a real-world setting, consistent with prior phase II trial results. While CAPOX proved feasible for advanced AoV carcinoma regardless of histologic subtype, its reduced effectiveness in second-line settings necessitates further research to determine its optimal palliative use.

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial

Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200mg/day for patients with bodyweight <77kg and/or platelet count <150×103/μL at baseline and 300mg/day otherwise. OS was a secondary endpoint. Totally, 265 patients were randomised to receive niraparib (n=177) or placebo (n=88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Abstract GS02-01: Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01

Abstract Background: The global, phase 3 TROPION-Breast01 trial (NCT05104866) assessed the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) compared with investigator’s choice of chemotherapy (ICC) in patients (pts) with inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2‒) breast cancer (BC). Primary results were presented at ESMO 2023 (Bardia A, et al. Abstract LBA11). Here we report expanded data from TROPION-Breast01. Methods: Pts aged ≥18 years who had inoperable or metastatic HR+/HER2‒ BC, had disease progression on endocrine therapy (ET) and for whom ET was unsuitable, and had received 1‒2 prior lines of systemic chemotherapy (CT), were eligible. Pts were randomized 1:1 to Dato-DXd (6 mg/kg Q3W) or ICC (eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. The dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1, and overall survival (OS). Results: In total, 732 pts were randomized: 365 to the Dato-DXd arm and 367 to ICC. At data cut-off (Jul 17, 2023), 93/39 pts in the Dato-DXd/ICC groups were ongoing treatment. Pts receiving Dato-DXd had significantly improved PFS vs ICC (HR 0.63 [95% CI 0.52‒0.76]; p&amp;lt;0.0001). Hazard ratios for PFS favored Dato-DXd over ICC across prespecified pt subgroups, including prior lines of CT in the metastatic setting (1 vs 2), prior use of CDK4/6 inhibitor (≤12 months vs &amp;gt;12 months), prior use of endocrine therapy in the metastatic setting ( &amp;lt;6 months vs ≥6 months) and brain metastases (yes vs no). OS data were not mature at this data cut-off. In the Dato-DXd vs ICC arms, 192 (53%) vs 247 (67%) pts had received a subsequent therapy after study treatment discontinuation, including 15 (4%) vs 52 (14%) who received subsequent ADC therapy, and 165 (45%) vs 186 (51%) who received subsequent CT. Median time to first subsequent therapy was 8.2 months in the Dato-DXd arm vs 5.0 months in the ICC arm (HR 0.53 [95% CI 0.45–0.64). Overall, rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was less than half that with ICC. The secondary patient-reported outcome endpoints showed that time to deterioration in physical functioning, pain, and global health status/quality of life were delayed in the Dato-DXd arm compared with ICC. Conclusions: TROPION-Breast01 met its dual primary endpoint of PFS, demonstrating statistically significant and clinically meaningful improvement in PFS with Dato-DXd compared with ICC across all subgroups. Overall, the safety profile and QoL with Dato-DXd was favorable compared with ICC. These data support Dato-DXd as a potential new therapeutic option for pts with inoperable or metastatic HR+/HER2‒ BC who have received 1‒2 prior lines of CT. Citation Format: Aditya Bardia, Komal Jhaveri, Seock-Ah Im, Michelino De Laurentiis, Binghe Xu, Sonia Pernas, Giuliano Borges, David Cescon, Masaya Hattori, Yen-Shen Lu, Noelia Martínez-Jáñez, Erika Hamilton, Shusen Wang, Junji Tsurutani, Kevin Kalinsky, Lu Xu, Sabrina Khan, Neelima Denduluri, Hope Rugo, Barbara Pistilli. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-01.

Abstract PO4-19-11: A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer

Abstract Background The androgen receptor (AR) is expressed in approximately 30% of breast cancers. Phase I and II trials of bicalutamide in HR-negative and enzalutamide in both triple negative breast cancer (TNBC) and hormone receptor (HR) positive populations have shown safety and favorable clinical benefit rates (CBR). Additionally, cell cycle (CC) inhibitors, such as abemaciclib, have demonstrated improved progression free survival (PFS) for patients with HR-positive metastatic breast cancer (MBC) in combination with ET in the first line and subsequent lines of therapy. A preclinical study showed that anti-androgen therapies enhanced CKD4/6 induced cytostatic effect in AR-positive TNBC cell lines. We performed a retrospective, institutional study evaluating metastatic HR+ tumor samples with immunohistochemistry (IHC) from patients treated with CDK4/6 inhibitor, palbociclib. We found a statistically significant increase in event free survival (EFS) for those that had any expression of AR (&amp;gt;0%, median EFS 19 months vs 5 months, HR 0.26, p=0.01). Additionally, AR expression was associated with intact phosphorylated retinoblastoma (Rb) expression (100%, P=0.02), which may represent a mechanism by which CC inhibition is effective in AR+ MBC. Trial Design NCT 05095207 is an ongoing, Phase Ib/II, open label, multi-center study. The primary objective for the phase I portion is to determine the recommended phase II dose (RP2D) of abemaciclib in combination with bicalutamide. The primary objective for the phase II portion is to determine the disease control rate (DCR) at 6-month treatment with abemaciclib and bicalutamide. Patients with HER2-negative MBC who are AR+ (IHC &amp;gt;1%) are eligible. HR-positive participants must have had one prior line of ET in the metastatic setting and no more than 2 prior lines of cytotoxic chemotherapy. HR-negative participants may have had up to 4 prior lines of cytotoxic chemotherapy. In the Phase I portion, up to 12 patients are given abemaciclib 100 mg oral, twice daily on days 1 to 28 and bicalutamide 150 mg oral, daily on days 1 to 28. If there is no toxicity after cycle 1 for the first 3 patients, the dose of abemaciclib will increase to 150 mg twice daily. However, if there is a dose limiting toxicity (DLT) within the first cycle (28 days) of therapy, the dose will decrease to 50 mg twice daily. In the Phase II portion, 51 patients will receive abemaciclib at the RP2D twice daily in addition to bicalutamide 150 mg daily on days 1 to 28. The estimated study duration is 36 months. The drugs will be administered until disease progression or unacceptable toxicity. The primary end points include the DLT and the RP2D for abemaciclib administered with bicalutamide and the DCR at 6 months. The secondary end points include the frequency of adverse effects, the DCR stratified by HR status, and PFS. Exploratory endpoints are to determine whether Ki67, cyclin D1, p16, and phosphorylated Rb expression at baseline are predictors of response to abemaciclib and to determine potential mechanisms for resistance to treatment. For Phase Ib, we will utilize the Bayesian optimal interval (BOIN) design, the RP2D will be selected as the dose closest to the target toxicity rate of 0.3. The observed DLT rate at the current dose is ≤ 0.236, the next cohort will be treated at the next higher dose level, if it is ≥ 0.359 the next cohort will be treated with the next lower dose level. For Phase II, we will assess the DCR using a Simon 2 stage optimal design. If among the 46 evaluable patients, 12 or fewer achieve disease control, the treatment will be rejected, however if 13 or more have disease control, the treatment will be considered worthy for further study. We define inactivity as DCR of 0.20 and activity as DCR of 0.35. To date, the study has recruited 21 participants, the goal accrual is 60 patients. Citation Format: Nicole Casasanta, Chrystal Landry, Theresa Shao, Paula Klein, Julie Fasano, Aarti Bhardwaj, Natalie Berger, Erin Moshier, Gargi Atul Joshi, Rita Vaccaro, Joseph Sparano, Amy Tiersten. A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-11.

Abstract PO3-04-11: Unmet clinical need in patients with pre-treated hormone receptor-positive/HER2-negative (HR+/HER2–) metastatic breast cancer in routine care: a targeted literature review

Abstract Background Treatment options remain limited to chemotherapy (CT) for patients with HR+/HER2− metastatic breast cancer (MBC) who have progressed on endocrine therapy (ET) with/without CDK4/6 or PI3K pathway inhibitors (i). We aimed to review the current unmet need in patients who had received ≥ 1 prior systemic therapy in terms of ET resistance as well as CT survival outcomes, tolerability and discontinuation. Methods MEDLINE, Embase and the Cochrane Library were searched via Ovid for observational studies (≥ 50 patients who had received ≥ 1 prior systemic therapy, January 2018 – January 2023). Abstracts from relevant congresses (January 2021 – February 2023) were reviewed. All screening was performed in a single-blind manner by one reviewer and any uncertainties were resolved by a senior reviewer. Results We included 72 full-text publications and 48 congress abstracts (US based 39%, European 28%, Asian 23%). Median treatment duration was 1.9–16.2 months (m) for ET (7 studies) and 2.0–24.5 m for ET-based therapy (5 studies). Exceptional responders (10% of patients treated for the longest time) received ET for ≥ 43.6 m (1 study, N = 4195). The proportion of patients with ET-resistant disease ranged widely (3–100%; 22 studies) and increased by line (L) of therapy: 14–19% of patients treated in 1L had primary resistance, 14–49% in ≥ 2L and 27–68% in ≥ 3L; acquired resistance was reported for 26–38% of patients in 1L, 51–57% in ≥ 2L, 32–60% in ≥ 3L (2 studies). One or more prior lines of CT had a negative impact on median overall survival (mOS; 5 studies) and median progression-free survival (mPFS; 11 studies) in subsequent therapy lines regardless of the chosen treatment; prior CT had no effect on mOS in 3 studies, no effect on mPFS in 4 studies. Consecutive CT cycles (primarily after ET + CDK4/6i) steadily lost clinical benefit (Table), with mPFS with 2 to 5 lines of CT: 7.6 m, 4.8 m, 4.2 m and 3.2 m, and mOS: 13.5 m, 9.1 m, 6.8 m and 7.2 m, respectively (1 study, N = 266). Paclitaxel + bevacizumab as second CT had a mPFS and a mOS of 8.6 m and 19.8 m, respectively (1 study, N = 538). Eribulin use in ≥ 2L had a mPFS of 4.6–10.0 m (2 studies) and a mOS of 10.1–11.2 m (2 studies). Patients who progressed on CDK4/6i as best response and those with a mPFS of &amp;lt; 6 m on ET benefited more from CT than ET in ≥ 2L with a mPFS of 7.1–8.1 m compared with 1.7–3.9 m, respectively (2 studies). Discontinuation due to toxicity was 2–36% (3 studies) for CT in 2L and dose reduction was required in 19–37% of patients (2 studies). Common grade 3/4 adverse events in patients receiving CT were leukopenia (17%), neutropenia (7%), thrombocytopenia (3%) and pneumonitis (1–3%) (3 studies). Conclusions Our review of real-world evidence highlights the limitations of repeated CT for patients with ET-resistant HR+/HER2− MBC, characterized by diminishing clinical benefit and significant toxicity burden. Results are limited by treatment and study population heterogeneity. Clinical outcomes are expected to improve with the use of new therapies, for which real-world evidence has yet to accrue. Table Real-world clinical outcomes with chemotherapy from observational studies CI, confidence interval; CT, chemotherapy; L, line; mOS, median overall survival; mPFS, median progression-free survival; NR, not reported Citation Format: Laura Spring, Simon M Collin, Inderjit K Dhillon, Gráinne Long, Evelina Bertranou, Komal Jhaveri, Aditya Bardia. Unmet clinical need in patients with pre-treated hormone receptor-positive/HER2-negative (HR+/HER2–) metastatic breast cancer in routine care: a targeted literature review [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-11.

Abstract PS08-09: Impact of HER2 expression dynamics on the real-world activity of trastuzumab deruxtecan for metastatic breast cancer (RELIEVE)

Abstract Background: trastuzumab deruxtecan (T-DXd) is a standard treatment for patients (pts) with HER2-positive (HER2+) and HER2-low metastatic breast cancer (MBC). HER2-low expression has been shown to be a highly unstable biomarker, and no data exists on the activity of T-DXd among pts with changes in HER2 status over time. Furthermore, limited data exists on the performance of regimens administered after progression on T-DXd. Methods: We analyzed data for pts with MBC receiving T-DXd at Dana-Farber Cancer Institute between 7/2017 - 2/2023 and at Duke Cancer Center between 3/2020 - 4/2022. The disease was categorized HER2+ if IHC 3+ or ISH-amplified at any time point; HER2-negative cases were categorized as HER2-low (IHC 2+/ISH- or IHC 1+) or HER2-0 (IHC 0) based on the last biopsy before T-DXd; the HER2 status for the primary tumor and at first metastatic diagnosis were also collected. We determined time to next treatment (TTNT), overall survival (OS), toxicities with T-DXd, TTNT based on dynamic HER2 status and TTNT with post-T-DXd regimens. Genomic data was available for 58 pts using an in-house NGS assay on archival tumor samples. Results: A total of 191 pts were included in the analysis (126 HER2+, 44 HER2-low, 21 HER2-0). Median age at metastatic diagnosis was 50.9 (range 21 - 78), 26% had de-novo MBC and 38% had history of brain metastases before T-DXd. The proportion of hormone receptor (HR)-positive tumors based on the last biopsy prior to T-DXd was 53% in HER2+, 68% in HER2-low and 57% in HER2-0; pts within each cohort had received a median of 2 prior lines of chemotherapy before T-DXd (range 0 - 9). With a median follow-up of 10.4 months, median TTNT was 10.4 months for HER2+, 7.6 months for HER2-low and 3.7 months for HER2-0 MBC (p &amp;lt; 0.001). Switch in HER2 status between primary tumor and pre-T-DXd biopsy significantly impacted outcomes, with the shortest TTNT observed in pts switching from HER2-low to HER2-0 (TTNT 3.0 months) compared with 5.6 months if switching from HER2-0 to HER2-low, and 9.4 months if having stable HER2-low status (p=0.006). Conversely, HER2 status switch within the metastatic setting did not impact outcomes (Table 1). No difference in TTNT was seen regardless of HR status (negative vs positive, 7.4 vs 10.2 months, p=0.25) or number of prior chemotherapies (≤2 vs &amp;gt;2, 10.1 vs 8.8 months, p=0.50). Median OS is shown in Table 1. At last follow-up, 55 pts remain on T-DXd (28.8%), 108 progressed (56.5%), 28 stopped due to toxicity (14.7%). A total of 22 pts (11.5%) developed interstitial lung disease (ILD, 6.2% grade [G]1, 3.1% G2, 1.6% G3, 0.5% G4, no G5). ILD occurred after a median of 8 months from T-DXd initiation and resolved in 63.6% of the cases, with a median time to resolution of 4 months (2 months for grade 1 events). 5 pts (2.6%) developed cardiotoxicity. T-DXd was dose reduced in 61 pts (31.9%), most often for fatigue (14.7%), nausea/vomiting (9.9%) or hematological toxicity (6.3%). Among 105 pts receiving post-T-DXd treatments, TTNT was 4 months for HER2+, 3.1 months for HER2-low and 4.3 months for HER2-0 MBC (p=0.62). Pts with HER2-negative tumors and ERBB2 hemizygous deletions (6/58, 10.3 %) had a TTNT with T-DXd of 4.1 months, vs 7.6 months without ERBB2 deletions (p=0.41). Additional biomarker data will be presented at the meeting. Conclusions: T-DXd showed promising real-world activity in pretreated pts with MBC, with the longest TTNT observed among pts with HER2+ disease or with stable HER2-low disease over time. Real world TTNT is relatively short post-T-DXd and further studies evaluating resistance mechanisms and optimal treatments in this setting are needed. Table 1 – TTNT and OS among patients with metastatic breast cancer receiving T-DXd and post-T-DXd regimens according to HER2 status The activity of T-DXd significantly differed according to the HER2 status of the disease, with the longest TTNT observed among patients with HER2+ disease (at any timepoint in time) and among patients with stable HER2-low disease over time. Regimens administered immediately after T-DXd achieved a similar performance irrespective of the HER2 status of the disease, with a TTNT ranging between 3.1 and 4.3 months. Citation Format: Paolo Tarantino, Melissa Hughes, Ross Kusmick, Laura Alder, Alyssa Pereslete, Laura Noteware, Heather Moore, Amanda Van Swearingen, Tianyu Li, Hersh Gupta, Kalie Smith, Stefania Morganti, Janet Files, Kerry Sendrick, Simone Buck, Deborah Dillon, Rinath Jeselsohn, Yvonne Li, Andrew Cherniack, Aleix Prat, Nay Nwe Nyein Chan, David Rimm, Giuseppe Curigliano, Sarah Sammons, Carey Anders, Nancy Lin, Sara Tolaney. Impact of HER2 expression dynamics on the real-world activity of trastuzumab deruxtecan for metastatic breast cancer (RELIEVE) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS08-09.

Abstract PO3-16-10: Real-world outcomes with first-line ribociclib + endocrine therapy in patients with metastatic HR+, HER2– breast cancer: Fourth interim analysis of REACH AUT trial

Abstract Background: Ribociclib (RIB), a cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) in combination with endocrine therapy (ET) yielded significant improvement in progression-free survival (PFS) and overall survival (OS) across three phase III MONALEESA trials including patients (pts) with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC) in first-line (1L) and second-line (2L) setting. In the previous interim analyses of REACH AUT trial, 1L RIB + ET showed tolerable safety and favorable PFS results in a real-world setting. Results from the preplanned fourth interim analysis are reported here. Methods: REACH AUT is a noninterventional study conducted in Austria reporting data on the real-world clinical experience of RIB + ET (aromatase inhibitor [AI] or fulvestrant [FUL]) in premenopausal, perimenopausal, or postmenopausal pts with HR+, HER2– MBC. Pts with no prior ET for advanced disease and maximum up to 1 prior line of chemotherapy (CT) in the advanced setting were included. Results: At data cutoff (March 27, 2023) with a median duration of follow-up of 23.8 months, out of 281 analyzed pts (12.5% of premenopausal/perimenopausal and 85.1% of postmenopausal, 2.5% of unknown status) 31.7% of pts were receiving ongoing treatment. The most common reasons for treatment discontinuations (68.3%) were disease progression (39.1%) and adverse events (AEs, 22.1%). The median age was 63 years (&amp;lt; 65 years, n=156, 55.5%; ≥65 years, n=125, 44.5%) and ECOG PS ≥2: 1.8%. In 106 pts (37.7%), de novo metastatic disease was reported. Visceral metastases (lung, liver) were present in 116 pts (41.3%) and bone-only metastases in 80 pts (28.5%). Prior adjuvant therapy was received by 139 pts (49.5%): AI ± GnRH: n=80 (26.7% without and 1.8% with GnRH); tamoxifen ± GnRH: n=74 (21.7% without and 4.6% with GnRH); CT: n=56 (19.9%); antibody therapy n=3 (1.1%). In the metastatic setting, 1L RIB was prescribed in combination with an AI in 223 pts (79.4%; letrozole: n=139 [49.5%]; anastrozole: n=48 [17.1%]; exemestane: n=47 [16.7%]) and with FUL in 52 pts (18.5%). Prior CT for MBC was received by 5 pts (1.8%). The median PFS was 29.7 months in the overall population; 28.3 months in pts with bone only and 26.9 months in pts with visceral metastatic disease. In pts evaluable for response, the objective response rate and clinical benefit rate were 31.3% and 60.9%, respectively. The OS rates were 91.9%, 81.7%, and 63.7% at 12 months, 24 months, and 36 months, respectively. The trial is ongoing with ~40% of subjects end of documentation and ~27% of deaths. In total, 69.4% of pts had RIB dose interruptions and 48.8% of pts had a RIB dose reduction. The majority of all reported AEs were grade 1 (50.1%) or grade 2 (31.2%); the median time to first AE was 0.5 months. The most common AE was neutropenia (all grades: n=143, 50.9%; grade 1: n=39, 13.9%; grade 2: n=68, 24.2%; grade 3: n=98, 34.9%; grade 4: n=5, 1.8%). QTc prolongation of any grade was observed in 32 pts (11.4%; grade 1: n=24, 8.5%; grade 2: n=11, 3.9%; grade 3: n=1, 0.4%). Hepatobiliary toxicity of any grade was observed in 42 pts (14.9%; grade 1: n=12, 4.3%; grade 2: n=18, 6.4%; grade 3: n=22, 7.8%; grade 4: n=3, 1.1%). Overall, currently 101 pts (35.9%) received a follow-up therapy after progression on RIB + ET. The most common first subsequent therapies were targeted therapies + ET (40.0%), followed by cytotoxic chemotherapy (22.0%) and endocrine monotherapy (19.0%). Conclusion: 1L RIB + ET continues to show favorable efficacy and a tolerable safety profile in the routine clinical practice. The results are consistent with the data from MONALEESA trials. The OS is showing a positive trend but is still immature during this study follow-up. Efficacy Outcomes With RIB + ET in Patients With HR+, HER2– MBC (Overall Population, Nf281) XX XX Citation Format: Christian F. Singer, Daniel Egle, Richard Greil, Edgar Petru, Leopold Oehler, Marija Balic, Laurenz Schöffmann, Georg Pfeiler, Maximilian Marhold, Christine Brunner, Karin Haider, Arik Galid, Ursula Pluschnig, Ferdinand Haslbauer, Michael Hubalek, Andreas Redl, Julia Flatschacher, Shanow Uthman, Bernhard Mraz, Rupert Bartsch. Real-world outcomes with first-line ribociclib + endocrine therapy in patients with metastatic HR+, HER2– breast cancer: Fourth interim analysis of REACH AUT trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-10.

Abstract PO5-19-03: 1st-in-human CAR T targets MUC1 transmembrane cleavage product

Abstract Background: huMNC2-CAR44 and huMNC2-CAR22 are autologous CAR T cell therapies under study in an ongoing 1st-in-human trial for metastatic breast cancers (NCT04020575), being performed at City of Hope. Both CARs are targeted to the tumor by an antibody, huMNC2, that recognizes a cryptic binding site on MUC1*, which is the transmembrane cleavage product of MUC1. The antibody binds to an epitope that is only unmasked when MUC1 is cleaved to MUC1* by enzymes in the tumor microenvironment. huMNC2 strongly reacts with over 90% of breast cancers. No therapeutic that targets MUC1* had ever been tested in humans before this trial. We note that neither 5E5 nor antibodies that bind to a MUC1 “heterodimer” recognize MUC1*. Eight patients have already been treated with huMNC2-CAR44. The next 8 patients will be treated with huMNC2-CAR22 to enable comparison and inform decision as to which CAR to bring forward for completion of Phase 1 and entry into Phase 2. huMNC2-CAR22 differs from huMNC2-CAR44 in that it is resistant to exhaustion. CAR22 achieves greater in vivo persistence due to Sadelain’s “1XX” mutations of Tyr to Phe in 2 of the 3 ITAMs, which prevent Tyr phosphorylation and signaling, leaving signaling through ITAM 1 alone. Trial Design: Dose escalation or de-escalation is tested in cohorts of 3 patients each using standard “3+3” dose-finding, with the starting dose of 3.3x105 CAR+ T cells/kg up to a maximum of 1.0x107 CAR+ T cells/kg. Patients receive cyclophosphamide (300 mg/m2/day) and fludarabine (30 mg/m2/day) for 3 days prior to CAR T cell infusion. Safety will be evaluated by CTCAE version 5.0 and Lee criteria. Anti-tumor activity will be assessed by imaging studies completed between 1 and 3 months after huMNC2-CAR T cell infusion for determination of response by RECIST 1.1 or by FDG PET modified PERCIST for patients with predominant bone disease. Inclusion Criteria: Patients with confirmed diagnosis of breast cancer, with documented ER, PR, and HER2 status per ASCO/CAP guidelines. Patients with MUC1* expression of at least 30% by IHC. Patients must have received standard metastatic systemic therapy per NCCN guidelines which are known to confer benefit. No maximum on number of prior treatments. Patients must have received at least 2 or 3 prior lines of chemotherapy in the metastatic setting. Exclusion Criteria: Patients requiring &amp;gt;15 mg of prednisone per day or immunosuppressives; patients with major organ dysfunction; Serum creatinine &amp;gt; 2 mg/dL; Bilirubin ≥ 1.5 mg/dL; AST/ALT ≥ 2.5 x upper limit normal; 3x upper limit for patients with known liver metastasis; significant pulmonary dysfunction; significant cardiovascular abnormalities; ANC &amp;lt; 1000/mm3. Primary Objectives: To determine the safety and maximally tolerated cell dose (MTD) and recommended phase 2 cell dose (RP2D) of ex vivo expanded autologous huMNC2-CAR T cells for patients with advanced MUC1* positive breast cancer using CTCAE version 5.0 and Lee criteria. Secondary: Determine duration of in vivo persistence and phenotype of adoptively transferred huMNC2-CAR T cells. Determine antitumor activity by RECIST 1.1. Determine MTD/RP2D. Contact: City of Hope Comprehensive Cancer Center Joanne Mortimer, MD 1-800-826-4673 Minerva18625@coh.org Citation Format: Cynthia Bamdad, Joanne Mortimer, Yuan Yuan, Jennifer M. Specht, Benoit Smagghe, Stephen Chi-Min Lin, Andrew Stewart, Danica Walkley, Mark Carter, Timothy Synold, Vishwas Parekh, Kevin Yi, Jac-Leen Nash, Michael Nash, Qing Liu-Michael, Stanley Hamilton, Stephen Forman. 1st-in-human CAR T targets MUC1 transmembrane cleavage product [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-03.

Abstract PO2-27-12: Genomic determinants of benefit to nivolumab (NIVO) plus low dose ipilimumab (IPI) among patients (pts) with hypermutated HER2-negative metastatic breast cancer (MBC): results of NIMBUS trial

Abstract Background: Genomic determinants of benefit to immune checkpoint inhibitors (ICI) among pts with MBC and high tumor mutational burden (TMB-H) are largely unknown. NIMBUS was an open-label, single-arm, multicenter, phase 2 study assessing the efficacy of NIVO 3 mg/kg intravenously every 14 days plus IPI 1 mg/kg IV every 6 weeks in pts with TMB-H HER2-negative MBC. The objective of this current study was to evaluate genomic profiling of pts included in NIMBUS and its association with benefit to ICI. Methods: In NIMBUS, eligible pts were required to have measurable HER2-negative MBC, TMB ≥9 Mut/Mb assessed by a cancer-gene panel evaluating &amp;gt; 300 genes and performed in a CLIA-certified laboratory, and 0-3 prior lines of chemotherapy in the advanced setting. The primary objective was overall response rate (ORR) according to RECIST 1.1. Secondary objectives include progression-free survival (PFS), and overall survival (OS). We performed genomic analyses on the pre-treatment tissue, and on baseline and on treatment plasma from pts run on the Foundation Medicine Inc (Boston, MA) FoundationOne®CDx (F1CDx®) and FoundationOne®Liquid CDx (F1LCDx®) panel, respectively. Results: A total of 30 pts (21 with estrogen receptor (ER)-positive and 9 with triple-negative breast cancer) were included in this study. After a median follow-up of 30.6 months, 6 pts (20%) achieved partial response (PR) for a confirmed ORR of 20% (95% CI: 7.7-38.6%). Exploratory analyses did not reveal differences in ORR based on ER status, PD-L1 status, or stromal TIL. The median PFS was 1.4 months (95% CI: 1.3 – 4.6), and the median OS was 16.9 months (95% CI: 7.1-not reached). Pts who achieved PR had a 3-year OS of 75% versus 25% in non-responders. A total of 29 pts (6 responders and 23 non-responders) had at least one pre-treatment genomic panel performed: 16 had both, 5 had pretreatment F1CDx only and 8 had F1LCDx panel only. Blood TMB (bTMB) was highly correlated with tissue TMB by F1CDx (r = 0.95). Using data from the most recent genomic panel available, (24 for baseline blood, and 5 for pretreatment tissue), the most frequently mutated genes ( &amp;gt; 30%) in this population were: TP53 (66%); PIK3CA (45%), ESR1 (35%), CDH1 (35%), ROS1 (31%). ESR1 and PTEN mutations were associated with absence of PR while PALB2 was associated with objective response. We observed a significant correlation between ESR1 mutations and a decrease in OS among pts with ER+ disease. Among the entire 29 pts, a negative correlation between PTEN with PFS and OS, and positive correlation between PALB2 with PFS was observed (Table). Among the 24 pts with baseline F1LCDx panel evaluable, the median TMB was 7.6 Mut/Mb ([interquartile range 0.0–113.8). Median TMB was 8.9 Mut/Mb and 41.7 Mut/mB among pts without and with PR, respectively. Baseline TMB &amp;gt; 20 mut/Mb was found in all pts with PR and in one of those without response. Paired serial blood samples demonstrated that among responding pts, TMB was significantly reduced from baseline to end of treatment (EOT) compared to those with no clinical benefit [n=16, p=0.0015]. Lastly, the tumor fraction (TF) estimates from 7 paired baseline to EOT samples demonstrated that all responders had a decrease or no change in TF compared to an increase in non-responders [n=7, p=0.017]. Conclusion: In the NIMBUS trial, all pts with PR to NIVO plus low dose IPI had a TMB &amp;gt; 20 Mut/Mb and had a decrease in TMB during treatment. ESR1 and PTEN mutations were associated with lack of benefit, while PALB2 mutation was associated with increased benefit. If validated, these results could help tailor the use of ICI among pts with TMB-H MBC. Association between genomic alterations in ESR1, PTEN and PALB2 and benefit to nivolumab and low dose ipilimumab among patients with HER2-negative MBC and TMB-H HR: hazard ratio; MBC: metastatic breast cancer; mOS: median overall survival (months); mPFS: median progression-free survival (months); TMB-H: tumor mutational burden above &amp;gt; 9 mutations/megabase. Citation Format: Romualdo Barroso-Sousa, Tyler Chinsky, Tianyu Li, Sangeetha Reddy, Leisha Emens, Beth Overmoyer, Saud AlDubayan, Hoyin Chu, Paulina Lange, Julie Kasparian, Ameer Basta, Molly DiLullo, Victoria Attaya, Melissa Hughes, Nancy Lin, Nabihah Tayob, Rinath Jeselsohn, Elizabeth Mittendorf, Sara Tolaney. Genomic determinants of benefit to nivolumab (NIVO) plus low dose ipilimumab (IPI) among patients (pts) with hypermutated HER2-negative metastatic breast cancer (MBC): results of NIMBUS trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-27-12.

Abstract PO4-04-12: A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or metastatic breast cancer

Abstract Background: Endocrine therapy (ET) when administered with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has improved outcomes in patients (pts) with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (BC) or metastatic breast cancer (MBC) and is the current standard of care for first-line treatment. Addition of the PIK3 inhibitor alpelisib to ET significantly improved progression-free survival in pts with PIK3CA-mutated, ER-positive, HER2-negative MBC, and alpelisib + fulvestrant is the standard of care for second or later-line treatment. Most pts will acquire resistance to ET, with mutations in ESR1 constituting the most common mechanism of resistance. Palazestrant (OP-1250) is a small molecule oral complete ER antagonist (CERAN) and selective ER degrader (SERD) that binds the ligand binding domain of ER and completely blocks ER-driven transcriptional activity in both wild-type (ESR1-wt) and mutant (ESR1-mut) forms of ER. In preclinical studies, palazestrant in combination with ribociclib demonstrated activity in both ESR1-wt and ESR1-mut xenograft models and showed efficacy in brain metastasis xenograft models. In a Phase 1/2 monotherapy study in pts with ER-positive, HER2-negative MBC, palazestrant was well tolerated with demonstrated antitumor efficacy and favorable pharmacokinetics (PK) supporting once a day (qd) dosing at the recommended Phase 2 dose (RP2D) of 120 mg. The aim of this study is to evaluate the safety, PK, and antitumor activity of palazestrant + ribociclib or alpelisib in pts with ER-positive, HER2-negative advanced BC or MBC. Methods: Eligible pts have evaluable ER-positive, HER2-negative advanced BC or MBC; ≤2 prior ETs (prior CDK4/6 inhibitors allowed); and ≤1 prior line of chemotherapy. In the alpelisib arm, pts must have a PIK3CA mutation in the tumor or ctDNA. Patients are administered oral palazestrant at escalating doses of 30, 60, and 120 mg qd in combination with the approved dose of oral ribociclib (600 mg qd; days 1–21 of 28-day cycle) or approved dose of oral alpelisib (300 mg qd) in a 3+3 design to identify the RP2D. The dose-expansion part will assess additional safety and PK parameters and the antitumor activity of palazestrant in combination with ribociclib or alpelisib (NCT05508906). Results: As of June 15, 2023, 10 pts have received 30 mg and 60 mg doses of palazestrant in combination with ribociclib (n=6) or alpelisib (n=4). No dose-limiting toxicities have been observed. After administration in the first two combination dose levels of 30 and 60 mg, palazestrant exposure was consistent with monotherapy administration; exposure data show no drug–drug interactions (DDI) when compared to published exposure parameters. Most reported treatment-emergent adverse events (TEAEs) were grade 1 or 2 and consistent with the known safety profiles of all 3 drugs. In the ribociclib arm, the TEAEs occurring in ≥2 pts included grade 1 nausea (n=4), grade 1 constipation (n=2), and neutropenia (grade 2, n=1; grade 3, n=3). For the 3 pts in the 30 mg palazestrant + alpelisib cohort, the only TEAE occurring in ≥2 pts was grade 1 diarrhea. One pt had grade 1 hyperglycemia. Conclusions: In this ongoing study, palazestrant in combination with ribociclib or alpelisib was well tolerated, and enrollment to the palazestrant 120 mg dose with ribociclib or alpelisib is ongoing. No new safety signals were observed for the 3 drugs, and no clinically significant DDIs were observed between palazestrant and ribociclib or alpelisib at the doses evaluated. Exposure of each drug was consistent with observed monotherapy exposure levels. Updated data will be presented. Citation Format: Virginia Borges, Carlos Alemany, Nancy Lin, Sara Nunnery, Cynthia Ma, Margaret Tonda, Morena Shaw, Arlene Chan. A Phase 1b/2 study of palazestrant (OP-1250) in combination with ribociclib or alpelisib in patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, advanced and/or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-12.

Abstract PO5-15-12: Spatial immune correlates of response to eribulin and pembrolizumab in metastatic triple negative breast cancer (mTNBC) on the ENHANCE1 trial

Abstract Background: PD-L1 is the only approved biomarker for pembrolizumab in metastatic breast cancer for response to combination chemo-immunotherapy. As it is not predictive of response in all cases, additional biomarkers are needed. Previously we have demonstrated that stromal tumor infiltrating lymphocytes (sTILs) are associated with response to therapy in patients treated with front-line combination chemoimmunotherapy on the ENHANCE-1 study with eribulin and pembrolizumab. However, sTILs was not predictive of response in patients treated with prior lines of chemotherapy in the metastatic setting. We used multiplexed immunofluorescence on whole slide images to characterize associations between specific immune populations and outcomes in patients treated prospectively on the ENHANCE-1 study. Methods: ENHANCE-1 was a single arm phase Ib/II trial which evaluated the efficacy and safety of eribulin and pembrolizumab in 167 patients (pts) with mTNBC who had received 0-2 prior lines of therapy (66 pts in the first line setting [stratum 1] and 101 pts with 1-2 prior lines of therapy [stratum 2]). 138 patient samples were evaluable for our study: 58 samples from stratum 1 and 80 samples from stratum 2. Objective response rate (ORR) was defined as percentage of pts with either complete response (CR) or partial response (PR) by RECIST 1.1. The ORR was 25.8% in stratum 1 and 22.5% in stratum 2 for the 138 patients analyzed. We utilized whole tissue sections and quantitative multiplexed immunofluorescence (qmIF) stained with: CD4, FoxP3, CD8, CD56 and pancytokeratin to characterize T-cells, NK cells and tumor cells. Halo (Indica labs) was used to segment and threshold cells for positive markers as well as to identify tumor and stromal tissue areas. Results: We found that the ratio of CD8+ to CD4+FoxP3+ T-cells were associated with response, irrespective of stratum (p=0.005). As biopsies were not required immediately prior to enrollment on ENHANCE-1, we also evaluated samples based on prior number of treatments since biopsy to enrollment. We found that only 58/138 patient samples evaluated were obtained without intervening treatment: 35 out of 58 from stratum 1 and 12 out of 80 from stratum 2. When samples were evaluated by stratum and the timing of tissue acquisition we found the ratio of CD8+ to CD4+FoxP3+ T-cells was more significantly associated with response (&amp;lt; 0.001) in patients whose sample were collected prior to enrollment, regardless of patient stratum. The ratio was not predictive in samples taken prior to treatments before enrollment. In addition, we found stromal and intratumoral CD8+ T-cell density is associated with response (p=0.02 and p=0.03 respectively) across both stratum. We did not find any significant changes assessed by qmIF in patient samples which had intervening treatment between sample collection and enrollment onto ENHANCE-1 trial. Conclusion: In this population of patients with mTNBC treated prospectively with eribulin and pembrolizumab, we find that a higher ratio of CD8+ to CD4+FoxP3+ T-cells and stromal and intratumoral CD8+ T-cell density is associated with response in patients with biopsy samples obtained prior to enrollment without intervening treatments after sample collection. The tumor microenvironment on patient samples obtained before one or more lines of therapy prior to enrollment on study are not predictive of response to treatment. Further characterization of the TME via quantitative immunofluorescence is ongoing. This study was funded by Eisai Citation Format: Matthew Kearney, Hua Guo, Rami Vanguri, Qi Wang, Eileen Connolly. Spatial immune correlates of response to eribulin and pembrolizumab in metastatic triple negative breast cancer (mTNBC) on the ENHANCE1 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-15-12.

Abstract RF01-06: Efficacy and safety of toripalimab plus metronomic chemotherapy in HER2 negative metastatic breast cancer: a multicenter phase II trial based on a Bayesian adaptive randomized design

Abstract Background: Combining Immune checkpoint blockade (ICB) with chemotherapy may significantly improve efficacy in patients with breast cancer. Metronomic chemotherapy is based on more frequent and low-dose drug administrations compared with conventional chemotherapy. Some clinical studies with small samples have tried the combination of metronomic chemotherapy and ICB in patients with advanced tumors. However, whether metronomic chemotherapy is more suitable for ICB than conventional chemotherapy is still unclear. Thus, we performed the first clinical trial, to our knowledge, of metronomic chemotherapy combined with PD-1 blockade comparing with the efficacy of combined conventional chemotherapy and ICB. Methods: This study is a multicenter randomized phase 2 trial using a multi-arm design with Bayesian adaptive randomization and efficacy monitoring. Eligible patients have advanced HER2 negative breast cancer, with no more than one prior line of standard chemotherapy. Patients were randomized to 5 groups: ① metronomic vinorelbine (NVB, 40 mg/day, TIW) monotherapy (the control cohort); ② NVB + Toripalimab (anti-PD1 antibody, 240 mg Q3W); ③Bevacizumab (5 mg/kg Q3W) + NVB+ Toripalimab (the BEV cohort); ④ Cisplatin (50mg/m Q3W) + NVB + Toripalimab (the DDP cohort), ⑤Cyclophosphamide (50mg/day, QD) + Capecitabine (500 mg, TID) + NVB+ Toripalimab (the VEX cohort). The primary endpoint is disease control rate (DCR), and secondary endpoints are objective response rate (ORR), progression free survival (PFS), and overall survival (OS). The safety profile has also been assessed. Mass cytometry time-of-flight (CyTOF) analyses of paired blood samples were performed to demonstrate dynamic changes in systemic immune profile. Results: A total of 103 patients were randomized. Characteristics were as expected for advanced breast cancer and balanced between cohorts. Adverse events of any grade occurred in 64 patients, with 5.2% grade &amp;gt;3. The rate of nausea was significantly higher in the cisplatin cohort than in the others (P&amp;lt; 0.001). Toripalimab was not associated with any previously unreported toxicity. Among the five treatment cohorts, the VEX cohort and the cisplatin cohort had the highest DCR, 69.7% (95% CI 51.7–85.9%) and 73.7% (95% CI 56.1–88.7%), respectively. Followed by the bevacizumab cohort, DCR is 55.7% (95% CI 37.4%–73.6%). Most objective responses were observed in the VEX cohort (ORR: 18.5%; 95% CI 5.6–34.1%), followed by cisplatin (ORR 14.5%; 95% CI 3.3–29.0%). It is worth noting that the PFS of patients in the VEX cohort was the longest, reaching 6.6 months (95% CI 4.0-5.9), followed by 4.0 months (95% CI 2.4-10.4) in patients of the bevacizumab cohort. The PFS of patients receiving the cisplatin regimen was relatively short, only 3.5 months (95% CI 2.2-5.3). Similarly, patients in the cisplatin cohort had shorter OS than those in the VEX and bevacizumab cohorts. In the TNBC subgroup, again, patients in the VEX cohort had the highest DCR (74.1%, 95%CI 47.9%-95.4%) and longest PFS (9.8 months, 95%CI 3.8-21.9). We obtained over 63 million cells in total and clustered CD45+ immune cells into 32 clusters. The systemic immune profile of patients changed dramatically over 2 cycles of PD-1 blockade. However, only the change of cluster 30 differed between responders and non-responders. This is a group of intermediate monocytes with a high expression of CD38, which decreased in responders but significantly increased in non-responders. CD38-NAD+ axis regulates the PD1+ exhausted T cell function. Meanwhile, the overall expression of CD38 in monocytes was significantly increased by DDP and BEV treatment compared with baseline, but not in the VEX groups. DDP significantly increased the expression level of CD38 on NK cells, while BEV or VEX treatment did not affect it. Conclusions: These data suggest promising clinical efficacy and evidence of cooperativity between metronomic VEX chemotherapy and PD-1 blockade. Citation Format: Hongnan Mo, Xiaoying Sun, Jingtong Zhai, Jiashu Han, Hewei Ge, Yuhan Wei, Xiuwen Guan, Haili Qian, Fei Ma. Efficacy and safety of toripalimab plus metronomic chemotherapy in HER2 negative metastatic breast cancer: a multicenter phase II trial based on a Bayesian adaptive randomized design [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-06.

Abstract PO5-21-09: Clinical outcomes by age subgroups in the phase 3 TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in HR+/HER2‒ metastatic breast cancer

Abstract Background Sacituzumab govitecan (SG) is a Trop-2directed antibody-drug conjugate approved for second-line or later (2L+) treatment of metastatic triple-negative breast cancer in multiple countries and for 2L+ treatment of HR+/HER2‒ (IHC 0, 1+, or 2+/ISH) metastatic breast cancer (mBC) in the US. SG significantly improved progression-free survival (PFS) and overall survival (OS) vs treatment of physician’s choice (TPC) in patients (pts) with pretreated, endocrine-resistant HR+/HER2‒ mBC in the TROPiCS-02 study. The incidence of HR+/HER2‒ mBC increases with age, especially after 65, and older pts often have poorer prognosis due to comorbidities, increased toxicity, and reduced efficacy of chemotherapy. In TROPiCS-02, pts aged ≥ 65 years (yr) derived consistent PFS benefit and clinically meaningful improved OS with SG vs TPC. In this analysis, we present additional efficacy and safety outcomes by age subgroup. Methods Pts with HR+/HER2‒ mBC who had received at least 1 endocrine therapy, taxane, and CDK4/6 inhibitor, and 2 to 4 prior lines of chemotherapy for mBC, were randomized to either SG (10 mg/kg IV days 1 and 8, Q3W) or TPC. The primary end point was PFS, and secondary end points included OS, objective response rate (ORR), and safety. A post hoc analysis was conducted by age subgroups (&amp;lt; 65 vs ≥ 65, &amp;lt; 75 vs ≥ 75). Results In total, 543 pts were randomized to the SG (n = 272; 73 [27%] ≥ 65, 16 [6%] ≥ 75) and TPC (n = 271; 67 [25%] ≥ 65, 8 [3%] ≥ 75) groups. Baseline characteristics were generally similar across treatment arms in each age subgroup, but a higher proportion of pts had performance status 1 vs 0 in the ≥ 65 vs &amp;lt; 65 and ≥ 75 vs &amp;lt; 75 subgroups, respectively. The data cutoff date was July 1, 2022. SG demonstrated longer median PFS and OS vs TPC across age subgroups. Hazard ratios (HR) for PFS with SG vs TPC were 0.69, 0.59, 0.70, and 0.30 for the &amp;lt; 65, ≥ 65, &amp;lt; 75, and ≥ 75 subgroups, respectively (Table). The HR for OS were 0.81, 0.80, 0.82, and 0.56 in these subgroups, respectively (Table). Median duration of response (DoR) was also longer with SG vs TPC across age subgroups, although median DoR was not estimable in the ≥ 75 subgroup (Table). ORR was higher with SG vs TPC, except in the ≥ 75 subgroup (Table). Safety was generally similar with SG vs TPC across subgroups with the following differences. Grade ≥ 3 treatment-emergent adverse events were more common in the ≥ 75 subgroup than the other subgroups (SG, 81% in ≥ 75 vs 68%-73% for all others; TPC, 71% in ≥ 75 vs 60%-61% for all others). TEAEs leading to dose reduction were also more common in pts treated with SG in the ≥ 75 subgroup, but were consistent across other subgroups (Table). However, sample sizes in the ≥ 75 subgroup were small, which limits interpretation (Table). TEAEs leading to treatment discontinuation were more common in older pts, irrespective of treatment group (Table). Conclusions SG showed benefit in PFS and OS vs TPC in pts with HR+/HER2‒ mBC across age subgroups, consistent with the intent to treat population. SG was associated with a slight increase in toxicity for elderly pts, as expected. SG demonstrated a favorable benefit/risk profile, with efficacy benefit and acceptable toxicity, for elderly pts. Table. Citation Format: Aditya Bardia, Peter Schmid, Sara Tolaney, Frederik Marmé, Javier Cortés, Theresa Valdez, Hao Wang, Wendy Verret, Hope Rugo. Clinical outcomes by age subgroups in the phase 3 TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in HR+/HER2‒ metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-21-09.

Abstract PS12-02: Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer

Abstract Background The PACE trial for HR+/HER2- metastatic breast cancer (MBC) prospectively evaluated whether continuation of the CKD4/6 inhibitor (CDK4/6i) palbociclib (P) beyond progression on prior CDK4/6i and aromatase inhibitor (AI), with a change in endocrine therapy (ET) to fulvestrant (F), improved outcomes beyond change to F alone, as well as explored the activity of a palbociclib, fulvestrant, and avelumab (P+F+A) triplet. The primary analysis did not show improvement in progression-free survival (PFS) with F+P versus F alone. In this analysis, an evaluation of serial translational PACE samples was performed to gain insights into the mutational landscape of HR+/HER2- MBC after prolonged exposure to CDK4/6i, evaluate early mutational dynamics with ongoing therapy, and identify potential genetic markers predictive of treatment response. Additionally, the identification of acquired mutations at the time of tumor progression could provide valuable information about mechanisms of treatment resistance. Methods PACE is a multicenter randomized open-label investigator-initiated phase II trial. Eligible patients (pts) had HR+/HER2- evaluable MBC with prior progression on AI and any CDK4/6i after &amp;gt; 6 months (mo) of therapy in the MBC setting, or during/within 12 mo in the adjuvant setting, with no more than 1 prior line of chemotherapy for MBC. Pts were randomized 1:2:1 to F alone, F+P, or F+P+A, with tumor assessments every 8 weeks. Correlative samples including circulating tumor DNA (ctDNA) were collected at baseline (BL), times of tumor assessments (C3D1), and end of study/progression (EOT). Targeted NGS (Guardant360) to evaluate mutations (somatic single nucleotide variants and indels) was performed. Kaplan-Meier survival curves were used for assessing PFS and the log-rank test for comparisons. McNemar’s test with continuity correction was used to test the changes in the frequency of mutations. Results Of the 220 randomized pts, 211 contributed ctDNA samples (200 at BL, 129 at C3D1, 146 at EOT). Characteristics of the correlative science population were similar to the intention to treat population. At BL, the most common mutations observed were ESR1 (57%), TP53 (38%), PIK3CA (36%), GATA3 (20%) ATM (12%) and Rb1 (12%). The presence of a PIK3CA mutation vs WT-PIK3CA at BL was associated with shorter PFS in the F alone arm (p=0.001) but not in the F+P or F+P+A arms. ESR1 mutations present at baseline were D538G (34%), Y537S (21%), Y537N (15%), E380Q (10%) and L536H (4%). At C3D1, the most common mutations observed were ESR1 (47%), TP53 (33%), PIK3CA (26.1), GATA3 (18.1), ATM (13%) and PTEN (8.6%). Including only BL and C3D1 matched samples (N=124), the prevalence of ESR1 mutations decreased after 2 cycles of treatment (57% at BL vs 44% at C3D1), predominantly observed in the F+P+A arm. For those in any arm with at least 6 months of disease stability on study (N=53), the presence of an ESR1 D538G mutation decreased during therapy, with 38% having a mutation at BL, 24% at C3D1, and no pts gaining ESR1 D538G at C3D1. The prevalence of PIK3CA mutations also decreased on treatment (32% at BL to 24% at C3D1), with the greatest decrease in the F+P arm. A predictive model correlating early genomic dynamics and associations with outcome will be presented. Conclusions The PACE trial offers one of the largest clinical trial cohorts describing the genomic landscape of HR+/HER2- MBC post-CDK4/6 exposure. Results from this correlative study provide a comprehensive mutational landscape post-CDK4/6i, demonstrate associations between mutations and clinical outcomes, and suggest the potential value of early ctDNA dynamics in this setting. Citation Format: Rinath Jeselsohn, Jingxin Fu, Yue Ren, Reshma Mahtani, Cynthia Ma, Angela DeMichele, Massimo Cristofanilli, Jane Meisel, Kathy Miller, Yara Abdou, Elizabeth Riley, Rubina Qamar, Priyanka Sharma, Sonya Reid, Naomi Ko, Yuan Liu, Harold Burstein, Michelle DeMeo, Sara Tolaney, Erica Mayer. Exploration of ctDNA Dynamics in the PACE Trial: A Randomized Phase II Study of Fulvestrant, Palbociclib, and Avelumab for HR+/HER2- Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS12-02.

Abstract PO1-06-10: Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer

Abstract Background Breast cancer is the most frequently diagnosed cancer and the 5th most common cause of cancer-related death in Chinese women with over 416,000 new cases and over 117,000 deaths estimated in 2020. Triple-negative breast cancer (TNBC) represents 10%-20% of cases in women with breast cancer. Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate and is approved for second-line or later (2L+) treatment of metastatic (m)TNBC in multiple countries, including the US and China. In the pivotal phase 3 study ASCENT, which enrolled predominantly non-Asian patients (pts), SG demonstrated improved efficacy outcomes vs treatment of physician’s choice (TPC) in pts with mTNBC treated in 2L+, with a manageable safety profile. For pts treated with SG, median progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were improved vs TPC (Bardia A et al, 2021). The single-arm phase 2b EVER-132-001 study was conducted to assess the efficacy and safety of 2L+ SG in Chinese pts with mTNBC. In preliminary findings from EVER-132-001, SG demonstrated substantial clinical activity and a manageable safety profile (Xu B et al, 2023). Here, we present additional efficacy and safety results from EVER-132-001, including the first report of median OS. Methods Pts with mTNBC who had received at least 2 prior lines of chemotherapy for mTNBC received SG (10 mg/kg IV on days 1 and 8, Q3W). The primary end point was ORR per independent review committee (IRC). Secondary end points included duration of response (DoR) per IRC, clinical benefit rate (CBR) per IRC, PFS per IRC, OS, and safety. Results Eighty pts were enrolled, with a median age of 48 years (range 24-70). Pts had received a median of 4 prior treatment regimens (range 2-8), and 59% of pts had ECOG performance status of 1. At the data cutoff, September 19, 2022, with a median follow-up of 14.7 mo (range 1.2-25.3), median OS was 14.7 mo (95% CI 10.3-18.3) and the OS rate at 12 months was 54% (95% CI 42-64) (Table). ORR was 40% (95% CI 29-52) with median DoR of 11.6 mo (95% CI 7.0-13.8), and CBR was 46% (95% CI 35-58) (Table). Median PFS was 5.6 mo (95% CI 4.1-8.3) (Table). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 79% of pts, and TEAEs leading to dose reduction, treatment interruption, and treatment discontinuation occurred in 20%, 48%, and 8% of patients, respectively (Table). The most common TEAEs of any grade were decreased neutrophil count (85%), anemia (84%), and decreased white blood cell count (83%). The most common grade ≥ 3 TEAEs were decreased neutrophil count (64%), decreased white blood cell count (50%), and anemia (23%). Conclusions SG continued to demonstrate substantial clinical activity, with OS, ORR, DoR, CBR, and PFS results in the EVER-132-001 trial, consistent with the phase 3 ASCENT trial of SG in mTNBC. TEAEs were manageable and no new safety signals were identified. These results support the use of SG as a new standard of care for Chinese pts with pretreated mTNBC. Table Citation Format: Fei Ma, Shusen Wang, Zhongsheng Tong, Wei Li, Xinhong Wu, Xiaojia Wang, Tao Sun, Yueyin Pan, Herui Yao, Xian Wang, Ting Luo, Jin Yang, Xiaohua Zeng, Weihong Zhao, Kimberly Komatsubara, Rachel Nakamura, Catherine Lai, Bo Zhang, Xiuyu Cong, Binghe Xu. Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-10.

Pooled analysis of pralatrexate single-agent studies in patients with relapsed/refractory peripheral T-cell lymphoma

AbstractPatients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate’s performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.

Phase 1/2 trial of oral EPI-7386 (masofaniten) in combination with enzalutamide (Enz) compared to Enz alone in patients with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 (P1) results and phase 2 (P2) design.

141 Background: EPI-7386 (masofaniten) is a next-generation aniten that inhibits androgen receptor (AR) activity by binding the N-terminal domain and blocking transcription, irrespective of ligand-binding domain resistance mechanisms. Preclinically, the combination of masofaniten with Enz results in a deeper blockade of the AR pathway and greater antitumor activity than either agent alone. Methods: This is a Phase 1/2 multicenter clinical trial (NCT05075577) enrolling patients (pts) with mCRPC on androgen deprivation therapy and naïve to second-generation antiandrogens (one line of prior chemotherapy in the metastatic hormone-sensitive setting allowed). P1 examines escalating doses of masofaniten + Enz at 120 or 160 mg QD. Primary and secondary endpoints of P1 evaluate the safety and pharmacokinetics (PK) of masofaniten + Enz when co-administered to establish the recommended P2 combination doses (RP2CDs). P2 is designed as a two arm, 2:1 randomized, open-label trial evaluating the antitumor activity of masofaniten in combination with Enz versus Enz alone; approximately 120 pts will be randomized with masofaniten 600 mg BID + Enz 160 mg QD (n=80) vs single agent Enz at 160 mg QD (n = 40). Results: P1 completed enrollment with 18 pts in 4 cohorts with 16 pts evaluable for efficacy as per protocol. The combination regimen was well tolerated with a safety profile consistent with Enz monotherapy. One grade 3 rash was observed in cohort 4 evaluating masofaniten 600 mg BID + Enz 160 mg QD. PK results demonstrated Enz exposure was not impacted by concomitant administration of masofaniten, allowing testing of the full dose of Enz (160 mg). By contrast, masofaniten exposure was consistently reduced by concomitant administration of Enz (CYP3A4 inducer that metabolizes masofaniten) but remained within the clinically relevant range with the highest exposures and Cmin observed using masofaniten BID dosing. Although efficacy data are still maturing, to date, response rates were PSA50 88% (14/16 pts), PSA90 69% (11/16 pts) and PSA &lt;0.2 ng/mL 56% (9/16 pts) in evaluable pts, regardless of their previous chemotherapy status. Conclusions: The RP2CD for P2 was established at masofaniten 600 mg BID + Enz 160 mg QD. Updated results, including long term follow-up of the dose escalation patients, and P2 study design, will be presented. Clinical trial information: NCT05075577 .

An Open-Label Study of Subcutaneous CpG Oligodeoxynucleotide (PF03512676) in Combination with Trastuzumab in Patients with Metastatic HER2+ Breast Cancer.

CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in utilizing CpG ODN as an adjuvant to improve clinical efficacy of current treatments and immunogenicity of breast cancers not traditionally responsive to active immunotherapy, such as those that are human epidermal growth factor receptor 2 (HER2)-positive. This study aimed to study the efficacy and safety of combination CpG ODN plus anti-HER2 antibody trastuzumab treatment in patients with advanced/metastatic breast cancer. This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response. Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment. CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored.