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Background Tucatinib (TUC) is a highly selective oral tyrosine kinase inhibitor of HER2 with minimal inhibition of EGFR. It was recently approved by the FDA for patients (pts) with HER2+ metastatic breast cancer (MBC), including pts with brain metastases (BM) whose cancers have progressed on at least 1 prior anti-HER2 regimen in the metastatic setting. In the HER2CLIMB (NCT02614794) pivotal trial, pts with HER2+ MBC previously treated with trastuzumab (T), pertuzumab, and trastuzumab emtansine (T-DM1) were randomized to receive TUC or placebo in combination with T and capecitabine (C). The addition of TUC resulted in clinically meaningful and statistically significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in HER2+ MBC pts. Primary methods and outcomes have been reported previously (Murthy, NEJM 2019). Here we present an exploratory analysis describing the outcomes in the HER2CLIMB trial based on hormone receptor (HR) status. Methods Pts were randomized 2:1 to receive TUC or placebo in combination with T and C. All pts had a baseline brain MRI and randomization was stratified by presence of BM, ECOG status, and geographic region. All pts with HER2+ MBC who were positive for either or both estrogen receptor and progesterone receptor (> 1%) were assigned to the HR “positive” subgroup. Pts not meeting the above criteria were assigned to the HR “negative” subgroup. For the exploratory HR+/HR- efficacy analysis presented here, PFS per RECIST 1.1 by blinded independent central review was evaluated in the first 480 pts enrolled. OS, PFS in pts with baseline BM, and confirmed ORR in pts with measurable disease were evaluated in the total study population. P values presented for PFS are nominal. Results Overall, 612 pts were enrolled to HER2CLIMB; 370 pts (60%) had HR+ and 242 (40%) had HR- tumors. Baseline demographics and disease characteristics in HR+/HR- subgroups were generally balanced between treatment arms. In the HR+ group, there was a 42% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.58; 95% CI: 0.42, 0.80; P=0.0008); median (95% CI) PFS was 7.6 mo (7.4, 9.5) in the TUC arm vs 5.6 mo (4.3, 7.4) in the control arm. In the HR- group, there was a 46% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.54; 95% CI: 0.34, 0.86; P=0.008); median (95% CI) PFS was 8.1 mo (7.0, 11.6) in the TUC arm vs 4.2 mo (3.1, 8.6) in the control arm. In the total population, median OS was 21.7 mo vs 18.2 mo in HR+ in the TUC arm vs control arm, respectively; median OS in HR- was 31.1 mo in the TUC arm vs 14.1 mo in the control arm. In pts with BM in the HR+ group (n=166 [45%]), there was a 52% reduction in the risk of progression or death (hazard ratio: 0.48; 95% CI: 0.31, 0.75; P=0.0008); median (95% CI) PFS was 7.5 mo (5.6, 9.5) in the TUC arm vs 5.1 mo (4.1, 5.7) in the control arm, and median OS was 18.1 mo vs 12.8 mo, respectively. In pts with BM in the HR- group (n=125 [52%]), there was a 50% reduction in the risk of progression or death (hazard ratio: 0.50; 95% CI: 0.27, 0.95; P=0.03); median (95% CI) PFS was 7.8 mo (6.1, 11.6) in the TUC arm vs 5.4 mo (2.9, 8.6) in the control arm, and median OS was 18.5 mo vs 11.5 mo, respectively. In the total population, ORR was numerically higher in the TUC arm vs the control arm regardless of HR status (HR+: 37.4% [95% CI: 30.8, 44.5] vs 27.1% [95% CI: 19.0, 36.6], respectively and HR-: 45.3% [95% CI: 36.7, 54.0] vs 15.6% [95% CI: 7.8, 26.9], respectively). Conclusions Among pts with HER2+ MBC previously treated with T, pertuzumab, and T-DM1, the addition of TUC to T and C showed clinically meaningful improvements of PFS, OS, and ORR independent of HR status. Furthermore, pts with HR+ and HR- MBC with BM derived similar benefit from the addition of TUC to T and C. Citation Format: Erika Hamilton, Mattea Reinisch, Sherene Loi, Alicia Okines, Paula R. Pohlmann, Eva Harder Brix, Hugues Bourgeois, Belinda Yeo, Cheryl Aylesworth, Melody Cobleigh, Anthony Goncalves, Rebecca Moroose, Katherine H.R. Tkaczuk, Michaela Tsai, Christine Simmons, Michael Andersson, Hatem Soliman, Michelina Cairo, Lisa A. Carey, David Cameron, Jorge Ramos, Wentao Feng, Mafalda Oliveira. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-08.

Background Trophoblast cell-surface antigen-2 (Trop-2) is expressed in epithelial cancers, including hormone receptor-positive (HR+) metastatic breast cancer (mBC). Sacituzumab govitecan (SG; Trodelvy®) is an antibody–drug conjugate composed of a humanized anti-Trop-2 monoclonal antibody coupled to SN-38 at a high drug-to-antibody ratio via a unique hydrolyzable linker that delivers SN-38 intracellularly and in the tumor microenvironment. SG was granted accelerated FDA approval for metastatic triple-negative BC treatment in April 2020. Patients and methods We analyzed a prespecified subpopulation of patients with HR+/human epidermal growth factor receptor 2-negative (HER2−) HR+/HER2− mBC from the phase I/II, single-arm trial (NCT01631552), who received intravenous SG (10 mg/kg) and whose disease progressed on endocrine-based therapy and at least one prior chemotherapy for mBC. End points included objective response rate (ORR; RECIST version 1.1) assessed locally, duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety. Results Fifty-four women were enrolled between 13 February 2015 and 1 June 2017. Median (range) age was 54 (33-79) years and all received at least two prior lines of therapy for mBC. At data cut-off (1 March 2019), 12 patients were still alive. Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Two patients discontinued treatment due to treatment-related adverse events. No treatment-related deaths occurred. At a median follow-up of 11.5 months, the ORR was 31.5% [95% confidence interval (CI), 19.5%–45.6%; 17 partial responses]; median DOR was 8.7 months (95% CI 3.7–12.7), median PFS was 5.5 months (95% CI 3.6–7.6), and median OS was 12 months (95% CI 9.0–18.2). Conclusions SG shows encouraging activity in patients with pretreated HR+/HER2− mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing (NCT03901339). Trial registration ClinicalTrials.gov NCT01631552; https://clinicaltrials.gov/ct2/show/NCT01631552

Supplemental Digital Content is available in the text., The aims of this study were (i) to evaluate the effect of talazoparib (1 mg once daily) on cardiac repolarization in patients with advanced solid tumors by assessing corrected QT interval (QTc) and (ii) to examine the relationship between plasma talazoparib concentration and QTc. In this open-label phase 1 study, patients had continuous 12-lead ECG recordings at baseline followed by time-matched continuous ECG recordings and collection of talazoparib plasma pharmacokinetic samples predose and at 1, 2, 4, and 6 h postdose on treatment days 1 and 22 and before talazoparib administration on day 2. ECG recordings were submitted for independent central review where triplicate 10-s ECGs, extracted up to 15 min before pharmacokinetic samples, were assessed for RR, PR, QRS, and QT intervals and ECG morphology. QT interval was corrected for heart rate using Fridericia’s (QTcF) and Bazett’s (QTcB) formulae. Linear mixed-effects modeling was used to examine the relationship between QTc and RR interval change from baseline and plasma talazoparib concentration. Thirty-seven patients received talazoparib. Mean change in QTcF from time-matched baseline ranged from −3.5 to 6.9 ms, with the greatest change 1 h postdose on day 22. No clinically relevant changes in PR, QRS, QTcB, QTcF, or RR intervals, heart rate, or ECG morphology were observed. No concentration-dependent effect on heart rate or QTc was observed. No deaths, permanent treatment discontinuations due to adverse events were reported. Talazoparib (1 mg once daily) had no clinically relevant effects on cardiac repolarization.

Background: Talazoparib (TAL), an oral poly ADP-ribose polymerase inhibitor, is under investigation in multiple oncologic clinical trials and has been submitted to the US FDA for use in patients (pts) with germline BRCA-mutated, HER2-negative advanced breast cancer. International Conference on Harmonisation guidance recommends all new drugs be evaluated for effects on cardiac repolarization in a well-controlled clinical study. For drugs for which such evaluation cannot be conducted in healthy volunteers (eg, most anticancer agents), collection of robust corrected QT (QTc) interval data from a dedicated QTc study (hybrid thorough QT/QTc study) in pts is required in the registration dossier. The effect of steady-state (ss) TAL (1 mg once daily) on cardiac repolarization in pts with advanced solid tumors was evaluated in an open-label phase 1 study (NCT03042910). Methods: Continuous 12-lead electrocardiogram (ECG) recordings were collected at baseline (Day -1); time-matched pharmacokinetic (PK) samples and continuous ECG recordings were obtained on Days 1, 2, and 22 (when TAL concentrations achieved ss). On Day -1, pts had continuous 12-lead ECG recording starting at Time 0 (Day 1 dosing time) for 6 hrs. On Days 1 and 22, ECG recording started 45 min before TAL administration and continued for 6 hrs post dose and blood samples for PK were collected before dose and at 1, 2, 4, and 6 hrs post dose. On Day 2, a 30-min ECG recording and a PK sample were obtained before dose at Time 0. Continuous ECG recordings were submitted to a central laboratory; triplicate 10-sec ECGs were extracted from a 5-min extraction window beginning 15 min before each PK collection time. ECG measurements were reported via blinded manual adjudication process and included PR interval, QT interval, RR interval, and QRS complex. The QT interval was corrected for effect of heart rate using Fridericia's correction (QTcF) and Bazett's correction (QTcB). The estimate of change from time-matched baseline and its 2-sided 90% confidence interval (CI) was calculated for each nominal time point using PROC MEANS. Additionally, a prespecified PK/pharmacodynamic (PD) model was used to describe the relationship between plasma TAL concentrations ([TAL]) and QTc. The prespecified linear mixed-effects model included [TAL], time (categorical), and treatment with random pt effects on [TAL] and the intercept. If the upper bounds (UB) of 1-sided 95% CIs of time-matched ΔQTc for all ECG time points were Results: 37 of 38 pts enrolled received TAL and were included in the ECG and PK/PD analyses. No pts had a postbaseline absolute maximum QTcF or QTcB ≥500 msec or ΔQTc ≥60 msec. The UB of the 1-sided 95% CI for the time-matched ΔQTcF and ΔQTcB were Conclusion: TAL does not have a clinically relevant effect on QTc. Funding: Medivation LLC, acquired by Pfizer. Citation Format: Hoffman J, Chakrabarti J, Wainberg ZA, Plotka A, Babu S, Milillo Naraine A, Kanamori D, Moroose R, Nguyen L, Wang D. Evaluation of the effects of talazoparib on QT interval prolongation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-14-07.

Background: Sacituzumab govitecan is an antibody-drug conjugate consisting of SN-38, the active metabolite of irinotecan, conjugated to a humanized mAb targeting Trop-2 (trophoblastic antigen-2), which is highly expressed in many epithelial cancers. A phase I/II basket trial (NCT01631552) investigated its activity in patients (pts) with advanced epithelial cancers. Herein, we summarize pooled safety and efficacy findings in 162 pts with HER2-negative metastatic breast cancer (mBC) accrued between 7/2013 and 6/2017 who received at least 2 prior therapies for metastatic disease and were treated with sacituzumab govitecan at the 10 mg/kg dose level. Methods: Patients with triple-negative (N=108) and patients with hormone-receptor positive (N=54) mBC received 10 mg/kg sacituzumab govitecan on days 1 & 8 of a 21-day cycle continued until progression or unacceptable toxicity. All pts had measurable disease by CT or MRI. Efficacy was assessed locally by RECIST 1.1 including overall response rate (ORR) and Kaplan-Meier estimates of duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Adverse events (AE) were evaluated according to CTCAE v4.0 Results: The patient cohort (161 female /1 male; median age 55 yrs, range 31-80) received a median of 4 prior therapies for metastatic disease (range 2-17), with prior chemotherapy agents in the metastatic setting including taxane (68%), capecitabine (60%), platinum (59%), gemcitabine (44%), eribulin (41%), and anthracycline (38%). 77 pts have died, with 57 in long-term follow-up and 28 still on treatment at data cutoff. The median number of administered sacituzumab govitecan doses was 14 (range 1-88). Treatment was generally well tolerated. 29% of pts had dose reductions, 3% discontinued treatment due to drug-related AEs, and there were no treatment-related deaths. Based on currently available AE data, grade ≥ 3 toxicity included neutropenia (43%), anemia (9.5%), diarrhea (7.0%) and febrile neutropenia (6.3%). For the TNBC subgroup, with a median follow-up of 9.3 months, the ORR was 33% (3 CRs + 33 PRs /108) with a median DOR of 8.3 months (95% CI: 4.8 – 11.6). For the ER+ subgroup, with a median follow-up of 10.0 months, the ORR was 31% (17 PRs/54) with a median DOR of 7.4 months (95% CI: 4.4 – 18.3). The combined HER2Neg ORR was 33% (3 CRs+50 PRs/162), with a median DOR of 8.3 months (95% CI: 4.9 - 10.8), PFS of 5.6 months (95% CI: 5.1 – 6.9) and OS of 13.0 months (95% CI: 11.5 - 15.0). The ORR was comparable for pts ≤ 50 yrs. old [32.2% (19/59)] vs. > 50 yrs old [33.0% (34/103)] and little different for pts with 2 prior therapies [35.4% (17/48)] vs. >2 prior therapies [31.6% (36/114)]. Conclusions: Monotherapy with sacituzumab govitecan was well tolerated with a manageable safety profile, and achieved a 30+% objective response rate among heavily pre-treated patients with HER2-negative metastatic breast cancer regardless of ER status. Citation Format: Kalinsky K, Isakoff SJ, Tolaney SM, Juric D, Mayer IA, Vahdat LT, Diamond JR, O'Shaughnessy J, Moroose RL, Santin AD, Shah NC, Abramson V, Goldenberg DM, Sharkey RM, Washkowitz SA, Wegener WA, Iannone R, Bardia A. Safety and efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) as ≥3rd-line therapeutic option for treatment-refractory HER2-negative metastatic breast cancer (HER2Neg mBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-11-01.

Background Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. Patients and methods Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. Results In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR). Conclusions SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

This abstract was withdrawn by the authors.

This abstract was not presented at the symposium.

Background: mTNBC has an aggressive course with limited therapeutic options. Sacituzumab govitecan (IMMU-132) is a novel antibody drug conjugate consisting of SN-38, the active metabolite of the topoisomerase I inhibitor, irinotecan, conjugated to a humanized mAb targeting Trop-2, which is highly expressed in most epithelial cancers, including TNBC. A phase I/II basket trial (NCT01631552) was conducted in patients (pts) with multiple, advanced epithelial cancers. We previously reported preliminary results in mTNBC (N=69; objective response rate [ORR] = 30%, Bardia et al., JCO 2017;35:2141-2148). In 2016, sacituzumab govitecan was granted Breakthrough Designation based on this encouraging data, and we resumed enrollment in a more defined patient population (≥3rd-line setting in mTNBC). Methods: Pts received sacituzumab govitecan on days 1 & 8 of a 21-day cycle until progression or unacceptable toxicity. Eligibility included > 2 prior lines of therapy for metastatic disease, measurable disease by CT or MRI and prior taxane. Efficacy was assessed locally by RECIST 1.1 and confirmed by independent centralized blinded review. ORR, DOR, progression-free survival (PFS) and overall survival (OS) were determined. Adverse events (CTCAE v4.0), immunogenicity, and Trop-2 expression in archived tumor samples, when available, were evaluated. Results: 110 mTNBC pts (109 female, 1 male; median age 55 yrs, range 31-81), including 53 from the previously reported cohort of 69 pts who had received ≥2 prior regimens for metastatic disease, were accrued between 7/2013 and 2/2017. As of data cutoff on 6/30/2017, 71 are deceased, 23 in long-term follow-up, and 16 still on treatment. All pts were treated at the 10 mg/kg IMMU-132 dose level, receiving 14.5 median doses (range 1-88). Treatment was well tolerated, with no treatment-related deaths, 2 treatment discontinuations for toxicity, and no anti-drug antibodies detected. Grade ≥ 3 toxicity (≥10%) included neutropenia, 39%; leukopenia, 14%; anemia, 10%; the incidence of febrile neutropenia was low (7%). By local radiologist assessment, the ORR is 34% (37/110), including 3 CRs and 34 PRs, the clinical benefit rate (CBR: CR+PR+SD>6 mo.) is 46%, the KM median DOR and PFS are 7.6 mo. (95% CI: 4.8 to 11.3) and 5.5 mo. (95% CI: 4.8 to 6.6), respectively, including 10% (11 pts) with long-term PFS (12 to 30+ mo.), and the KM median OS is 12.7 mo. (95% CI: 10.8 to 13.6). Results of the independent central blinded review along with sensitivity analyses of prior treatment regimens, including checkpoint inhibitor use, and exploratory biomarker analysis of Trop-2 expression will be presented at the meeting. Conclusions: Sacituzumab govitecan demonstrated significant clinical activity as a single agent in the ≥3rd-line setting for patients with relapsed/refractory mTNBC. Given the high unmet medical need, data from this trial is being submitted for consideration of accelerated approval, and a global confirmatory randomized Phase III trial (NCT02574455) is underway. Additional studies including rational combinations are currently being evaluated for mTNBC and other breast cancer subsets. Citation Format: Bardia A, Vahdat LT, Diamond J, Kalinsky K, O'Shaughnessy J, Moroose RL, Isakoff SJ, Tolaney SM, Santin AD, Abramson V, Shah NC, Govindan SV, Maliakal P, Sharkey RM, Wegener WA, Goldenberg DM, Mayer IA. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS1-07.

Background: Pertuzumab, a monoclonal antibody targeting subdomain II of HER2 and blocking dimerization , was approved by the FDA in 2013 for use in combination with trastuzumab and docetaxel as neoadjuvant therapy for pts with HER2+, locally advanced, inflammatory or early-stage breast cancer (>2cm and/or node-positive). This accelerated approval was based on results from the NeoSphere and the TRYPHAENA trials. In NeoSphere, pathologic complete response in the breast and nodes [pCR] was 39.3% after 4 cycles of neoadjuvant pertuzumab/trastuzumab/docetaxel. In TRYPHAENA, pCR was 63.6% among 76 patients treated with 6 cycles of neoadjuvant TCHP(47.5% in pts with ER+and/or PR+/HER2+ tumors and 81.1% in those with ER-/PR-/HER2+ tumors). Aside from TRYPHAENA, we have limited information on clinical outcomes, with neoadjuvant TCHP. Here we report our institutional experience at UF Health Cancer Center, Orlando (UFHCC) with Neoadjuvant TCHP in patients with operable or locally advanced breast cancer. Patients and Methods: After IRB approval, electronic medical record search was performed in order to identify HER2+ patients with tumors T2-T4/N0-3 or Tany/N1-3, treated with neoadjuvant TCHP between 10/13 and 5/16. Information from chart review included patient and tumor characteristics at the time of diagnosis , details of neoadjuvant chemotherapy plus anti-HER2 therapy, clinical, radiologic and pathologic assessment of tumor response to neoadjuvant TCHP, type of breast and axillary nodal surgery, surgical outcomes as well as disease outcomes. Results: 76 patients (75 female, 1 male) met the inclusion criteria; median age: 52 yrs; 83% of pts presented with clinical stage II and 17% with clinical stage III; 62% were ER+ and/or PR+ and 38% were ER-/PR-negative. 49 patients received all planned 6 cycles without dose reduction. The remaining 27 patients required dose reduction due to rash, diarrhea, nausea, vomiting, neuropathy or neutropenia; 5 patients requested dose reduction due to poor quality of life and fatigue; 2 patients required dose delay due to asymptomatic cardio-toxicity with ≥ 10% drop in EF. None had symptomatic CHF; 37% of patients underwent breast conserving surgery, 7% unilateral mastectomy and 55% bilateral mastectomy. Surgical lymph node assessment was performed after neoadjuvant chemotherapy and included sentinel lymph node biopsy (SLNB) in 74%, axillary dissection (ALND) in 8% or both in 18% of pts. Overall pCR rate (ypT0/is, ypN0) was 63.2%. pCR rate was 53.1% in pts with ER+ and/or PR+ tumors and 79.3% in those with ER-/PR- tumors. pCR by stage was 61% for Stage IIA, 65% for Stage IIB, 67% for Stage IIIA and 71% for Stage IIIC. Toxicity profile was consistent with what has been observed in the TRYPHAENA trial with fatigue, nausea, vomiting and neuropathy being the more commonly noted grade 3/4 toxicities. With median follow up of 18 months, all patients are disease-free with no documented recurrences observed. Conclusion: Our clinical experience with neoadjuvant TCHP confirms the efficacy and safety data from the TRYPHAENA trial in a single-institution, tertiary care center setting. Citation Format: Tariq R, Ajaz B, Shah N, Mamounas E, Moroose R. A single-institution clinical experience with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP): A safety and efficacy analysis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-28.

Background. mTNBC has an aggressive course with limited effective therapy options and a median progression-free survival (PFS) of 2-4 months (mos) with standard therapy. Sacituzumab govitecan (IMMU-132) is an ADC targeting Trop-2, an antigen present in many epithelial cancers, including TNBC, and delivering SN-38, a topoisomerase I inhibitor as its therapeutic moiety. IMMU-132 was awarded Breakthrough Therapy designation by FDA based on its previously reported activity in relapsed/refractory mTNBC patients. Here we present updated results from the mTNBC cohort of an ongoing phase I/II study (ClinicalTrials.gov, NCT01631552). Methods. mTNBC patients (pts) received IMMU-132 10 mg/kg on days 1 and 8 every 21 days. Trop-2 expression was not required for enrollment, but available tumor specimens underwent immunohistological (IHC) testing. Efficacy was assessed locally by RECIST 1.1; ORR, PFS and overall survival (OS) were determined for all pts. Pharmacokinetic parameters were estimated in select pts with adequate blood sampling. Immunogenicity to IMMU-132 was examined in all pts. Results. We previously reported preliminary efficacy results in 51 mTNBC patients. Here we present data on 69 patients with data cutoff June 5, 2016. Median age was 56 years (31-81) and a median of 5 prior therapies (range 1-12), with 66 evaluable for response; ORR was 29% (19/66) 2 confirmed complete (CR) and 17 confirmed partial responses (PR). The median intention-to-treat PFS is 5.6 mos (95% CI, 3.6-7.1 mos) and median OS is 14.3 mos (95% CI, 10.5-18.8 mos). PRs included 2 pts whose tumors did not respond to anti-PD-L1 therapy. The duration of response in the 19 confirmed responders (8 continuing therapy) is 11.5 mos (95% CI = 7.6 to 12.7). The clinical benefit rate (CR+PR+SD>6 mos) for the 66 assessable patients is currently 45.5%. The majority (88%) of archival tumor specimens were moderately (2+) to strongly (3+) positive by IHC for Trop-2, precluding using Trop-2 expression as a selection criterion. Among current adverse events, grade >3 drug-related toxicities included neutropenia (35%), leukopenia (16%), anemia (13%), vomiting (9%), diarrhea (10%), and febrile neutropenia (4%). Clearance kinetics in 8 pts showed IMMU-132 and IgG had a terminal half-life of 15.3 ± 2.7 h and 86.5 ± 40.5 h, respectively, with area under the curve for free SN-38 (unbound) only 3% of the total amount of SN-38 (e.g., IgG bound). Thus, most SN-38 remains bound to the conjugate, and is released at a rate predicted from in vitro serum stability studies. No pt developed anti-IMMU-132 antibodies. Conclusion The Trop-2-targeting ADC, IMMU-132, delivering cytotoxic doses of SN-38, shows high objective and durable tumor responses with manageable toxicity in heavily-pretreated pts with mTNBC in this updated cohort, supporting further development in this population with an unmet medical need. Citation Format: Bardia A, Diamond JR, Mayer IA, Isakoff SJ, Abramson V, Starodub AN, O'Shaughnessy J, Kalinsky K, Moroose R, Shah N, Juric D, Shapiro GI, Guarino M, Ocean AJ, Messersmith WA, Berlin JD, Wegener WA, Sharkey RM, Goldenberg DM, Vahdat LT. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory, metastatic triple-negative breast cancer (mTNBC): Updated results [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-15.

Current methods for assessing circulating tumor cells (CTC) in blood focus on capture and enumeration with epithelial markers that provide little information about the aggressive and invasive potential of CTC. As a result, valuable knowledge that improves monitoring of cancer recurrence and metastasis is lacking. To provide actionable information on CTC, we developed a CTC identification method based on detection of the second subunit of Chaperonin Containing TCP1 (CCT2). CCT is a macromolecular protein folding complex composed of eight subunits (CCT1-8) that drives expression of many tumorigenic factors. Bioinformatic analysis in multiple cancers, such as breast cancer, revealed increased gene expression in tumor tissue compared to normal tissue for CCT1-8 (p< 0.0001), with the largest differences observed in CCT2 and CCT3. Genomic alteration of CCT2 inversely correlated with cancer patient survival, and depletion of CCT2 prevented growth of murine breast tumors. In a correlative study of blood and tumor tissues from metastatic breast cancer patients, high CTC counts positively correlated with detectable CCT2 in tumor tissues. These results support CCT2 as a possible marker for CTC. To determine this, antibodies to CCT2 were validated for use in the CellSearch System (CSS), currently the only FDA approved CTC enrichment platform, and tested with breast cancer cells spiked into healthy human blood. Recovery using CCT2 for identification, led to increased collection up to 6% of spiked breast cancer cells that would have been lost by standard CTC classification using cytokeratin (CK). With prognostic thresholds around 3-5 CTC/tube of blood, increased detection of even 1-2 more CTC can be significant for assessing patients' risks. Analysis in an open software program called ACCEPT (Automated CTC Classification, Enumeration and PhenoTyping) confirmed that the majority of recovered spiked cancer cells expressed CCT2. Flow cytometry analysis of spiked cancer cells confirmed that CCT2+ enriched cells expressed cancer markers CD44 or estrogen receptor (ER). These results show that the addition of CCT2 staining to a CTC detection protocol has positive implications for enumeration of CTC from blood, such as increased detection of CTC with low expression of epithelial markers. This experiment was repeated using small cell lung cancer cell lines with similar results. The combined bioinformatics, histologic and experimental results indicate that identification of CCT2-expressing CTC can be incorporated into CTC detection platforms to monitor those patients with a heightened risk for cancer recurrence or metastasis. Citation Format: Amanda Cox, Ana Martini, Eunkyung Lee, Rebecca Moroose, Amr Khaled, Annette R. Khaled. Using chaperonin containing TCP1 as a marker to track clinically relevant circulating tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2601.

Background: Triple-negative breast cancer (TNBC) comprises about 15% of all breast cancer types, and has a particularly aggressive course. Following first-line therapy, the median PFS is 90% of TNBC, as measured by IHC, we conducted a trial to evaluate the safety and efficacy of a humanized anti-Trop-2 monoclonal antibody conjugated to a high concentration of SN-38, a camptothecin that is a topoisomerase I inhibitor and the active metabolite of the prodrug irinotecan, with 2-3 logs higher potency than the prodrug. Methods: After establishing the optimal repeated dose in a Phase I trial (ClinicalTrials.gov, NCT01631552) involving many different solid cancer types, an expanded Phase II was undertaken in a number of cancers, including TNBC. Patients received 8 or 10 mg/kg IMMU-132 i.v. on days 1 and 8 of 21-day repeated cycles. Assessments of safety and response by RECIST1.1 were made weekly and bimonthly, respectively. Tumor biopsies (archival, at baseline prior to treatment, and at disease progression) were obtained when safe and feasible. Results: As of May 10, 2015, 58 patients with TNBC, with a median of 4 prior therapies (range, 1-11), were treated with IMMU-132. Grade 3-4 toxicities included neutropenia (26%), febrile neutropenia (2%), diarrhea (2%), anemia (4%), and fatigue (4%). No patient developed antibodies to SN-38 or the antibody, and no patient discontinued therapy due to toxicity. Tumor responses were defined as ORR (CR+PR) in 31% of 49 evaluated patients, including 2 with CR, and a clinical benefit ratio (CR+PR+SD>6 mo) of 49% (63% with SD>4 mo; 23 patients continuing treatment after 1st assessment). The current median progression-free survival is 7.3 months with 44% maturity in 50 patients treated at the 8 or 10 mg/kg dose level. Overall survival data are still not mature 20 months after enrollment of first patient. Clinical efficacy correlated to biomarker studies, including Trop-2 expression (target of antibody), topoisomerase-1 expression (target of SN-38), and homologous recombinant deficiency (HRD) assay (marker of DNA repair), is being studied. Immunohistochemistry results in archival specimens currently show 97% positivity of Trop-2 among 34 specimens evaluated, with 79% having high intensity (2+/3+) staining. Conclusions: The Trop-2-targeting IMMU-132, delivering cytotoxic doses of the topoisomerase I inhibitor, SN-38, shows manageable toxicity, and encouraging anti-tumor activity in relapsed/refractory patients with TNBC. This ADC appears to have a high therapeutic index in heavily pretreated patients. Citation Format: Bardia A, Diamond JR, Mayer IA, Starodub AN, Moroose RL, Isakoff SJ, Ocean AJ, Guarino MJ, Berlin JD, Messersmith WA, Thomas SS, O'Shaughnessy JA, Kalinsky K, Maurer M, Chang JC, Forero A, Traina T, Gucalp A, Wilhelm F, Wegener WA, Maliakal P, Sharkey RM, Goldenberg DM, Vahdat LT. Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-06.

Background: Combining endocrine therapy (ET) with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor significantly improves progression-free survival (PFS) over ET alone in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, optimal management of disease that progresses on this therapy is not established. In Phase 1 of the TRINITI-1 study (ClinicalTrials.gov identifier: NCT02732119), continuous ribociclib 300 mg/d + everolimus (EVE) 2.5 mg/d + exemestane (EXE) 25 mg/d, the recommended Phase 2 dose, resulted in 1 dose-limiting toxicity. Clinical benefit at week 24 was found in 3 of 6 patients whose disease had progressed on a CDK4/6 inhibitor. Here we report Phase 2 efficacy and safety in patients whose disease progressed on a CDK4/6 inhibitor. Methods: Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on ≤3 lines of therapy for ABC (1-3 lines of ET and ≤1 line of chemotherapy) and had measurable disease and/or lytic/mixed bone lesions were eligible. Progression on 1 CDK4/6 inhibitor, as the last therapy before enrollment, after ≥4 months of treatment for ABC was required. Dexamethasone mouthwash was required for the first 8 weeks. The primary objective of clinical benefit at 24 weeks in Phase 2 would be met if ≥9 of 42 patients had clinical benefit at 24 weeks. Secondary objectives included PFS, tumor response, safety, and tolerability. Results: Of 46 enrolled patients, 44 were evaluable; among 42 evaluable for efficacy, 6 had prior chemotherapy, 13 had ≥2 prior lines of therapy (median, 1 line), and 13 were on therapy on December 15, 2017. At week 24, 17 patients (40.5%) had clinical benefit by local assessment; the overall response rate was 7.1% (n=3; all had partial response at week 24). Median PFS was 8.8 months (95% CI, 1.9 months-not evaluable). In the safety set (n=44), there was 1 on-treatment death unrelated to study drug; 1 patient discontinued with Grade 4 hypophosphatemia. Common (≥25%) any-grade adverse events were neutropenia (68.2%), stomatitis (45.5%), fatigue (38.6%), nausea (34.1%), thrombocytopenia (34.1%), diarrhea (29.5%), and anemia (25.0%). Seven patients (15.9%) had Grade 1/2 pneumonitis, 23 (52.3%) had Grade 3/4 neutropenia, 2 (4.5%) had Grade 3/4 increased aspartate aminotransferase, and 1 (2.3%) had Grade 3/4 increased alanine aminotransferase. Febrile neutropenia, Grade 3/4 stomatitis or pneumonitis, and corrected QT interval (Fridericia's formula) >480 ms were not observed. Conclusion: TRINITI-1 is the first trial to demonstrate promising clinical benefit and tolerability of continuous ribociclib 300 mg/d, EVE 2.5 mg/d, and EXE 25 mg/d following progression on a CDK4/6 inhibitor, warranting further evaluation of this combination. Citation Format: Stacy Moulder, Megan Karuturi, Denise A. Yardley, Gail Shaw Wright, Sara Hurvitz, Rebecca Moroose, Tara Sanft, Cynthia Ma, Amelia Zelnak, Angela DeMichele, Amy Clark, Das Purkayastha, Alisha Khullar, Nicola Caria, Aditya Bardia. Ribociclib in combination with everolimus and exemestane in men and postmenopausal women with HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Efficacy and safety results from phase II of the TRINITI-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT107.

LBA509 Notice of Retraction: “Therapy of relapsed/refractory metastatic triple-negative breast cancer (mTNBC) with an anti-Trop-2-SN-38 antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): Phase II results.” ASCO's Confidentiality Policy requires that abstracts be considered confidential and embargoed from the time of submission until the findings have been publicly released in conjunction with the ASCO Annual Meeting. Abstract LBA509, published in the 2016 ASCO Annual Meeting Proceedings Part II, violated this policy and was retracted from publication and presentation at the 2016 ASCO Annual Meeting.