CLEOPATRA. Trastuzumab + docetaxel + placebo, n PHEREXA. Trastuzumab + capecitabine, n

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1 Onkologikoa Foundation, San Sebastian, GEICAM, Spain; 2 Seoul National University, Seoul, Korea; 3 Hospital Clínic and Translational Genomics and Targeted Therapeutics in Solid Tumors IDIBAPS, Barcelona, GEICAM, Spain; 4 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 5 Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA; 6 Roche Products Ltd., Welwyn Garden City, United Kingdom; 7 F. Hoffmann-La Roche Ltd., Basel, Switzerland; 8 Georgetown University Medical Center and Lombardi Comprehensive Cancer Center,, Washington, DC, USA. BC, breast cancer; EBC, early breast cancer; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; MBC, metastatic breast cancer;, category not collected in the respective study; PR, progesterone receptor; T-DM, trastuzumab emtansine. a versus no T-DM. CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival; T-DM, trastuzumab emtansine Received T-DM No T-DM Number at risk Month Received T-DM No T-DM OS, overall survival; T-DM, trastuzumab emtansine Received T-DM No T-DM Number at risk Month Received T-DM No T-DM OS, overall survival; T-DM, trastuzumab emtansine T-DM, trastuzumab emtansine. Additional Resources Efficacy of Trastuzumab Emtansine (T-DM) in Patients With HER2-Positive Metastatic Breast Cancer Previously Treated With Pertuzumab Ander Urruticoechea, Seock Ah Im, 2 Montserrat Munoz, 3 Jose Baselga, 4 Denise A Yardley, 5 Sarah Heeson, 6 Adam Knott, 6 Hannah Douthwaite, 6 Tanja Badovinac Crnjevic, 7 Sandra M Swain 8 23 Introduction T-DM is approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) previously treated with trastuzumab and a taxane based on the phase 3 EMILIA study Pertuzumab in combination with trastuzumab plus docetaxel is the first-line standard of care for HER2-positive MBC based on the CLEOPATRA study 2 The availability of data on the efficacy of T-DM in patients who were previously treated with pertuzumab is limited A retrospective, observational report of 78 patients in routine clinical practice showed a clinically-relevant benefit of T-DM in patients who previously received pertuzumab treatment. Physician-reported tumor response rate (non-recist) was 8%, and 3% of patients had a prolonged ( 6 months) duration of therapy. Furthermore, treatment outcomes were improved when T-DM was used as second-line or earlier treatment compared with use as later-than second-line treatment 3 To further evaluate the efficacy of T-DM in patients previously treated with pertuzumab, we conducted exploratory analyses using data obtained from patients who received T-DM at any time after pertuzumab in two phase 3 studies: CLEOPATRA and PHEREXA 2,4 6 CLEOPATRA examined first-line pertuzumab, trastuzumab, and docetaxel compared with trastuzumab plus docetaxel in patients with HER2-positive MBC 2,5,6 The addition of pertuzumab to trastuzumab + docetaxel led to a statistically significant improvement in median progression-free survival (PFS) by 6. months at the time of the primary analysis (median PFS of 2.4 months in the control arm versus 8.5 months in the pertuzumab arm; median follow-up 9.3 months for both arms) 2 In the final analysis of overall survival (OS), median OS was 56.5 months in the pertuzumab group and 4.8 months in the control group; thus, the addition of pertuzumab improved median OS by 5.7 months (median follow-up 49.5 months for the pertuzumab group and 5.6 months for the control group) 6 PHEREXA examined trastuzumab + capecitabine with or without pertuzumab for patients who progressed during/after line of trastuzumab-based therapy in the HER2-positive MBC setting 4 A 2-month increase in median PFS was observed with the pertuzumab-containing regimen, although these results were not statistically significant At the interim OS analysis, a numerical 8-month increase in median OS was observed with the pertuzumab regimen (median OS of 36. months) compared with the trastuzumab + capecitabine arm (median OS of 28. months), although confirmatory statistical testing was not performed due to the study statistical analysis plan Methods CLEOPATRA (NCT5679) and PHEREXA (NCT2642) are both phase 3, randomized, 2-arm trials evaluating pertuzumab-based regimens for the treatment of HER2-positive MBC CLEOPATRA study design: trastuzumab + docetaxel + pertuzumab versus trastuzumab + docetaxel + placebo in patients with no prior anti-her2 treatment or chemotherapy for MBC 2 PHEREXA study design: trastuzumab + capecitabine with or without pertuzumab in patients who progressed during/after previous trastuzumab treatment for MBC 4 The clinical databases for both CLEOPATRA and PHEREXA were queried for patients who, after experiencing disease progression, received T-DM treatment as a subsequent anti-cancer therapy versus patients who did not receive T-DM Patients with and without T-DM as subsequent anti-cancer therapy were identified from both the pertuzumab and control groups of each study Patients were allocated to the T-DM group if they had recorded trastuzumab emtansine as a subsequent anti-cancer therapy; otherwise, they were allocated to the no T-DM group Demographics and baseline characteristics were summarized for patients who received T-DM The exploratory analyses reported in this poster assessed OS, i.e., time from randomization to death at any point, in the T-DM and no T-DM groups For patients treated with pertuzumab, time from discontinuation of pertuzumab to initiation of T-DM and duration of T-DM treatment were also investigated Of note, case report forms did not collect the information that would be needed to evaluate overall response rate and PFS for T-DM as a subsequent anti-cancer therapy Results from these analyses are descriptive and no formal statistical comparisons have been made Limitations of analyses Collection of information on the use of subsequent anti-cancer therapies (including T-DM) was requested in both studies; however, this was not mandatory and, therefore, the information may not be complete Analyses of data are retrospective and based on limited information (n=75 patients reported receiving T-DM as subsequent therapy across both studies) Statistical analyses do not attempt to match patients with similar characteristics in the T-DM and no T-DM groups, which may lead to potential bias in the patient/disease characteristics between groups Patients who died during randomized therapy or who otherwise had not received subsequent therapy at the time of the analysis cutoff have been included in the no TDM group Results Patients Of 48 patients who received trastuzumab + docetaxel + pertuzumab in CLEOPATRA and 228 patients who received trastuzumab + capecitabine + pertuzumab in PHEREXA, 32 and 43 patients, respectively, received subsequent treatment with T-DM Demographics and baseline characteristics of patients with subsequent T-DM treatment are summarized in Table Table. Demographic and baseline characteristics of patients treated with T-DM as a subsequent anti-cancer therapy from CLEOPATRA and PHEREXA CLEOPATRA PHEREXA Trastuzumab + Trastuzumab + Trastuzumab + docetaxel + docetaxel + Trastuzumab + capecitabine + placebo pertuzumab capecitabine pertuzumab n (%) (n=34) (n=32) (n=39) (n=43) Prior treatment status EBC 9 (55.9) 4 (43.8) 4 (.3) 4 (9.3) De novo BC 5 (44.) 8 (56.3) MBC 8 (46.2) 2 (46.5) EBC and MBC 7 (43.6) 9 (44.2) Disease type at screening Visceral disease 3 (88.2) 24 (75.) 23 (59.) 23 (53.5) Non-visceral disease 4(.8) 8 (25.) 6 (4.) 2 (46.5) ER/PR Status Positive 4 (4.2) 5 (46.9) 23 (59.) 23 (53.5) Negative 9 (55.9) 7 (53.) 4 (35.9) 9 (44.2) Unknown (2.9) 2 (5.) (2.3) No. of prior HER2 therapies before study randomization 24 (7.6) 28 (87.5) (29.4) 4 (2.5) 39 () 43 () Efficacy There was a numerical difference in median OS between those who received T-DM as a subsequent therapy and those who did not receive T-DM (Table 2, Figures and 2) In the trastuzumab + docetaxel + pertuzumab arm of CLEOPATRA, median OS was not reached for patients who received T-DM and 6.4 months for patients who did not receive T-DM In the trastuzumab + capecitabine + pertuzumab arm of PHEREXA, median OS was 38.3 months for patients who received T-DM and 32.8 months for patients who did not receive T-DM The median time from discontinuation of pertuzumab to initiation of T-DM in CLEOPATRA and PHEREXA was 3.5 months and.6 months, respectively (Table 3) The median duration of T-DM treatment was 7. months and 4.2 months in CLEOPATRA and PHEREXA, respectively (Table 3) Table 2. Overall survival by receipt of T-DM as a subsequent anti-cancer therapy No T-DM T-DM CLEOPATRA Trastuzumab + docetaxel + placebo, n (54.7) 2 (58.8) 39.6 (35 47) 46.2 (34 57).93 (.58.49) Trastuzumab + docetaxel + pertuzumab, n (42.) (34.4) 6.4 (49 NR) NR (49 NR).62 (.33.4) PHEREXA Trastuzumab + capecitabine, n (54.7) 6 (4.) 23.7 (2 29) 4. (3 57).45 (.26.8) Trastuzumab + capecitabine + pertuzumab, n (44.3) 6 (37.2) 32.8 (28 39) 38.3 (34 NR).53 (.3.94) Figure. Kaplan Meier curve of OS (in months) for patients in CLEOPATRA who received pertuzumab and subsequently received T-DM versus those who did not Proportion surviving Figure 2. Kaplan Meier curve of OS (in months) for patients in PHEREXA who received pertuzumab and subsequently received T-DM versus those who did not Proportion surviving Table 3. Duration of T-DM and time between stopping pertuzumab treatment to start of treatment with T-DM Trastuzumab + docetaxel + Trastuzumab + capecitabine + pertuzumab (CLEOPATRA) pertuzumab (PHEREXA) Median months (range) n=32 n=43 Duration of T-DM 7. ( 44) 4.2 ( 22) Time from discontinuation of study drug to start of T-DM 3.5 ( 47).2 ( 28) Time from randomization to start of T-DM 27 (6 59) 2. (8 52) Discussion and Conclusions These exploratory, retrospective analyses of data from CLEOPATRA and PHEREXA suggest that patients who received T-DM as a subsequent therapy following disease progression on pertuzumab + trastuzumab had numerically longer OS than those who did not receive T-DM as a subsequent therapy In CLEOPATRA, patients had a median treatment duration of T-DM of 7. months; whereas, in PHEREXA median treatment duration was 4.2 months This finding may be due to differences in the lines of therapy in which T-DM was received within these trials, as the studies had different designs: the majority of patients receiving T-DM after discontinuation from the CLEOPATRA study were likely treated in the second- or third-line setting, whereas, for PHEREXA, patients were likely treated with T-DM in a later setting Interpretation of results should be made with caution As noted earlier, there are multiple limitations associated with the present analysis Differences between the CLEOPATRA and PHEREXA studies may impact the data presented herein, including differences in study design and patient population, timing, and location, as well as the availability/approval statuses of the various treatments studied The duration of T-DM therapy in patients previously treated with pertuzumab appeared to be longer when T-DM was given earlier in comparison with use in later lines. These results are consistent with prior studies conducted in the respective second- and third-line settings,6 and provide further support for early use of T-DM in the therapeutic sequence for patients with HER2-positive MBC References. Verma S, et al. N Engl J Med. 22;367: Swain SM, et al; CLEOPATRA Study Group. Lancet Oncol. 2. Baselga J, et al; CLEOPATRA Study Group. N Engl J Med. 23;4: ;366: Swain SM, et al; CLEOPATRA Study Group. N Engl J Med. 3. Dzimitrowicz H, et al. J Clin Oncol. 26 Jun 3 [Epub ahead 25;372: of print]. 7. Krop IE, et al. Lancet Oncol. 24; 5: Urruticoechea A, et al. J Clin Oncol. 27 Apr 24 [Epub ahead of print]. Acknowledgments Funding for the CLEOPATRA and PHEREXA studies is provided by Genentech, Inc./F. Hoffmann-La Roche Ltd. Third-party writing assistance was provided by Meredith Kalish, MD, of CodonMedical, an Ashfield Company, part of the UDG Healthcare plc, and funded by F. Hoffman-La Roche Ltd. Please contact Ander Urruticoechea (anderu@onkologikoa.org) with questions and comments. Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO and the author of this poster. ES/KAD/77/34 American Society of Clinical Oncology Annual Meeting; June 2 6, 27; Chicago, IL. MetaPHER: A phase IIIb multicenter, open-label, single-arm safety study of subcutaneous trastuzumab, in combination with pertuzumab and docetaxel in patients with HER2-positive advanced breast cancer. Sant Antonio Breast Cancer Symposium 26 poster OT3--3. BACKGROUND: In patients (pts) with HER2-positive metastatic breast cancer (BC), the phase III CLEOPATRA study (NCT5679) demonstrated significant improvement in progression-free (PFS) and overall survival (OS) from firstline treatment with intravenous (IV) pertuzumab (PERJETA [P IV]) plus trastuzumab (Herceptin [H IV]) plus docetaxel (D IV). HannaH (NCT953), a phase III trial in pts with HER2-positive early BC demonstrated that fixed-dose trastuzumab subcutaneous (Herceptin [H SC]) is non-inferior to weight-based H IV infusion in the co-primary endpoints of serum trough concentration and pathologic complete response, which was supported by the long-term efficacy endpoints of event-free survival (EFS) and OS. The safety profile of H SC was consistent with the known safety profile of H IV. H SC is comprised of 6 mg trastuzumab and recombinant human hyaluronidase (rhuph2) as an excipient, allowing a significantly reduced administration time compared with H IV (5 mins versus 3 9 mins, respectively). The MetaPHER study is designed to investigate the safety and efficacy of H SC in combination with P IV and D IV in pts with HER2-positive advanced BC. TRIAL DESIGN: MetaPHER is a phase IIIb multicenter, open-label, single-arm study, with eligible pts receiving H SC 6 mg/5 ml q3w, P IV (84 mg loading dose, then 42 mg at each subsequent cycle q3w), and D IV (at least 6 cycles at 75 mg/m² q3w with possible escalation to mg/m² q3w; after Cycle 6, continuation of docetaxel is at the investigator s discretion). Study treatment is administered until disease progression, unacceptable toxicity, withdrawal of consent, death, or predefined study end, whichever occurs first. Pts will receive post-treatment follow-up for safety and survival. ELIGIBILITY: Women aged 8 years with metastatic or locally recurrent HER2- positive BC, ECOG performance status or, and a left ventricular ejection fraction 5% are eligible. Exclusion criteria include disease-free interval of <6 months from completion of adjuvant or neoadjuvant non-hormonal treatment to disease recurrence; previous systemic nonhormonal therapy for metastatic or locally recurrent BC; history of persistent grade 2 hematological toxicity; current grade 3 peripheral neuropathy; or clinically significant cardiovascular disease. AIMS: The primary objective is to evaluate the safety and tolerability of H SC in combination with P IV and D IV in pts with HER2-positive advanced BC. Secondary endpoints include PFS, OS, objective response rate and incidence of anti-trastuzumab and anti-rhuph2 antibody formation. STATISTICAL METHODS: Safety and efficacy results will be summarized descriptively to include all enrolled pts who received at least one dose of any study drug; the study is not designed for formal hypothesis testing. A sample size of 4 pts provides reasonable precision for the estimation of grade 3 AEs and cardiac AEs.

2 2. Loi S, Giobbe-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, Bartsch R, Rabaglio-Poretti M, Kammler R, Maibach R, Smyth MJ, Di Leo A, Colleoni M, Viale G, Regan MM, Andre F. International Breast Cancer Study Group and Breast International Group. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive metastatic breast cancer: Results from the PACEA (IBCSG 45-3/BIG 4-3/KEYNOTE-4) study. DOI:.58/ SABCS7-GS2-6. BACKGROUND: Preclinical and clinical data suggest that HER2-positive (HER2+) breast cancer (BC) will be amendable to immunotherapeutic approaches. We evaluated pembrolizumab with trastuzumab in patients (pts) with trastuzumab-resistant HER2+, PD-L positive (PD-Lpos), unresectable loco-regional or metastatic BC and a parallel cohort of pts with HER2+, PD-L negative (PD-Lneg) BC during the phase II study. METHODS: Pts with advanced BC and progression on prior trastuzumab-based therapies, ECOG, and a metastatic tumor biopsy in the last year were eligible. HER2 positivity and quantity of tumorinfiltrating lymphocytes (TILs) on H&E slide were centrally evaluated. PD-L score was assessed by Merck central lab. Tumor imaging was performed at weeks 2, 8, 24 and every 2 weeks, thereafter. Primary endpoints were safety of the combination (phase Ib) and objective response rate (ORR) per RECIST. (phase II). Secondary endpoints were PFS, duration of response, and OS. Phase Ib was a 3+3 dose-escalation of 2 pembrolizumab doses (2 mg/kg, mg/kg) Q3W. In phase II, pts received pembrolizumab 2 mg Q3W for 24 months or until disease progression. Clinically stable pts with progression were allowed to continue pembrolizumab until confirmation on subsequent assessment. Pts with isolated CNS progression were also allowed to continue pembrolizumab after local treatment. Planned total enrollment was 6 pts. For the phase II PD- Lpos cohort, a Simon two-stage design (N = 4; proceed if 2/7 respond) was used which had 85% power to compare ORR of 7% vs. 22% (-sided α =.5). For the PD- Lneg cohort, a single-stage design with 5 pts had >95% power to compare ORR of % vs. 2% (-sided α =.4). Clinicaltrials.gov: NCT RESULTS: 6 pts enrolled in phase Ib between April and July 25; no DLTs were observed. The PD-Lpos cohort enrolled 4 pts between August 25 and September 26. The PD-Lneg cohort enrolled May 26 to April 27, stopping after 2 pts due to low rate of PD-L negativity, maintaining >9% power to detect the target difference in ORR. PD-L testing labs changed in April 26. Prior to this time, QualTek PD-L positive was defined as % on tumor or TILs. Using the Dako 22C3 antibody, positive was defined as tumor PD-L combined positive score (CPS) %. 46 pts were screened to enroll 58 pts. Of screened pts, median stromal TILs was % (mean: 4.8%, SD: 9.%, range: to 6%; n = 27); 52% of pts were PD-Lpos, with higher positivity rates while using the Dako assay compared with Qualtek (65% vs. 43%, P =.9). Median TILs of pts in the PD-Lpos cohort was 2% (mean: 8.%, SD:.2%, range: to 4%) and % (mean:.2%, SD: 2.2%, range: to 5%) in the PD-Lneg cohort. Of enrolled pts, median age was 5 yrs (range: 28 72), 69% had visceral metastases. 29% of pts received prior pertuzumab, 72% had prior T-DM, 4% prior lapatinib. 38% of pts were ER-positive, 62% were ERnegative. Median TILs in enrolled ER pos and ER neg pts were.5% and 2.%, respectively. PD-L positivity rates were also not significantly different by ER status (p =.5). 3. Nancy U, Lin, Alisha Stein, Alan Nicholas, Anita M. Fung, Priya Kumthekar, Nuhad K. Ibrahim, Mark D. Pegram. Planned interim analysis of PATRICIA: An open-label, single-arm, phase II study of pertuzumab (P) with high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression post radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC). DOI:.2/JCO _suppl.274. Journal of Clinical Oncology 27;35(5 Suppl): BACKGROUND: There is currently no clear standard of care to address the management of recurring/multiple intracranial metastases post RT in HER2-positive MBC. The ongoing PATRICIA study (NCT ) is evaluating the safety and efficacy of P in combination with high-dose h for patients with HER2-positive MBC with CNS metastases who have CNS progression following RT. Reported herein are results from the protocol-specified interim analysis of PATRICIA. METHODS: All eligible patients must have measurable ( mm) CNS progression post RT, and stable non-cns disease. Patients receive P (84-mg loading dose, then 42 mg every 3 weeks) and high-dose h (6 mg/kg weekly). The primary efficacy endpoint is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The interim analysis was planned after 5 patients were enrolled and had 2 left ventricular ejection fraction (LVEF) measurements, 2 cycles of study drugs, and 2 response measurements. The study would proceed to full enrollment (n = 4) if objective response or stable disease in the CNS was observed in of 5 patients and <2 of 5 patients develop congestive heart failure (CHF) related to P or H. RESULTS: As of Sept 6, 26, 5 patients had been enrolled across 9 sites. Median treatment duration was 4.4 (range.2 8.3) months. Six patients discontinued treatment (5 for disease progression; for symptomatic deterioration). Range for duration of response was months. There were no new safety signals for P combined with high-dose h treatment. No patients had CHF or a clinically significant drop in LVEF. CONCLUSIONS: Based on early evidence of clinical benefit (ORR 2%) and a lack of new safety signals, the safety 2

3 and futility boundaries for PATRICIA have been passed and study enrollment continues. Clinical trial information: NCT Efficacy within CNS per RANO-BM criteria (%) Complete response (CR) Partial response (PR) 3 (2) Stable disease (SD) 9 (6) Disease progression 3 (2) ORR a 3 (2) 95% CI CR + PR + SD 4 months 6 (4) 95% CI a CR or PR 4. Tripathy D, Sohn J, Im S-A, Colleoni M, Franke F, Bardia A, Harbeck N, Hurvitz S, Chow L, Lee KS, Campos-Gomez S, Villanueva Vazquez R, Jung KH, Carlson G, Hughes G, Diaz-Padilla I, Germa C, Hirawat S, Lu Y-S. First-line ribociclib vs. placebo with goserelin and tamoxifen or a non-steroidal aromatase inhibitor in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer: Results from the randomized phase III MOLEESA-7 trial. DOI:.58/ SABCS7-GS2-5. BACKGROUND: Endocrine therapy (ET) with ovarian function suppression is an established first-line treatment for pre- and peri-menopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2 ) advanced breast cancer (ABC). Addition of ribociclib (orally bioavailable, selective cyclin-dependent kinase [CDK] 4/6 inhibitor) to first-line ET prolonged progression-free survival (PFS) in a Phase III trial of postmenopausal women with HR+, HER2 ABC (MOLEESA-2). Here we report results from MOLEESA-7 (NCT22782), the first doubleblind, randomized, Phase III trial evaluating ribociclib + tamoxifen/non-steroidal aromatase inhibitor (NSAI) and goserelin specifically in pre- and peri-menopausal patients. METHODS: Pre- or peri-menopausal women with HR+, HER2 ABC who had received line of chemotherapy and no prior ET for ABC were randomized (:) to ribociclib (6 mg/day, 3-weeks-on/-week-off) or placebo in combination with either tamoxifen (2 mg/day) or an NSAI (letrozole [2.5 mg/day] or anastrozole [ mg/day]) + goserelin (3.6 mg every 28 days). The primary endpoint was locally assessed PFS. Secondary endpoints included overall response rate (ORR), clinical benefit rate (CBR), and safety. RESULTS: 672 patients were enrolled. Baseline patient characteristics were balanced between treatment arms. The primary analysis was conducted after 38 events had occurred; median time from randomization to data cut-off date was 9.2 months. The study met its primary objective: PFS was significantly improved in the ribociclib arm (median PFS = 23.8 months; 95% CI: 9.2 not reached) vs. the placebo arm (median PFS = 3. months; 95% CI:. 6.4), with a hazard ratio of.553 (95% CI: ; p = ). Subgroup analyses demonstrated consistent PFS benefits for ribociclib vs. placebo. In patients with measurable disease at baseline, ORR was 5% vs. 36% (ribociclib vs. placebo arm; P = ) and CBR was 8% vs. 67% (P = ). The most frequent all-grade adverse events (Aes; 25% of patients; ribociclib vs. placebo arm) were neutropenia (76% vs. 8%), hot flush (34% vs. 34%), nausea (32% vs. 2%), leukopenia (3% vs. 6%), and arthralgia (3% vs. 27%). Of these, neutropenia (6% vs. 4%) and leukopenia (4% vs. %) were the only Grade 3/4 events reported in 5% of patients (ribociclib vs. placebo arm). Febrile neutropenia (ribociclib vs. placebo arm) occurred in 2% vs. <% of patients. Grade 3/4 QT prolongation (ribociclib vs. placebo arm) was reported in % vs. <% of patients. Aes leading to permanent discontinuation of ribociclib + tamoxifen/ NSAI + goserelin vs. placebo + tamoxifen/nsai + goserelin occurred in 4% vs. 3% of patients. CONCLUSIONS: MOLEESA-7, the first dedicated trial investigating a CDK4/6 inhibitor in pre- and peri-menopausal women with HR+, HER2 ABC, demonstrated that addition of ribociclib to first-line ET (tamoxifen/nsai + goserelin) significantly prolonged PFS and had a manageable safety profile. The trial validates the clinical utility of ribociclib with multiple endocrine therapies, including tamoxifen, in premenopausal women with HR+, HER2 ABC. 5. Goetz MP, O Shaughnessy J, Sledge Jr GW, Martin M, Lin Y, Forrester T, Mockbee C, Smith IC, Di Leo A, Johnston S. The benefit of abemaciclib in prognostic subgroups: An exploratory analysis of combined data from the MORCH 2 and 3 studies. DOI:.58/ SABCS7-GS6-2. BACKGROUND: Abemaciclib is an orally administered, selective inhibitor of cyclin-dependent kinases 4 & 6 that is dosed on a twice daily continuous schedule. Abemaciclib has demonstrated clinical efficacy with a generally tolerable safety profile in patients with hormone receptorpositive (HR+), human epidermal growth factor receptor 2-negative (HER2 ) advanced breast cancer in combination with fulvestrant in MORCH 2 (NCT2773) and in combination with non-steroidal aromatase inhibitors (NSAI) in MORCH 3 (NCT224662). These analyses were conducted to evaluate if patient and disease characteristics may better inform in whom and when abemaciclib should be initiated to define optimal treatment strategies. METHODS: MORCH 2 and 3 enrolled patients with HR+, HER2 advanced breast cancer. In MORCH 3

4 2, patients whose disease had progressed while receiving endocrine therapy were treated with abemaciclib/placebo plus fulvestrant. In MORCH 3, patients were treated with abemaciclib/placebo plus NSAI as initial therapy for advanced disease. An exploratory pooled analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (progression-free survival [PFS] and objective response rate [ORR] in patients with measurable disease) were examined for patient subgroups corresponding to each of the identified significant prognostic factors. Subpopulation treatment effect pattern plot (STEPP) methodology was performed to examine the association between treatment-free interval (TFI) following adjuvant endocrine therapy and outcomes of endocrine therapy alone or in combination with abemaciclib in MON- ARCH 3. RESULTS: Analyses of clinical factors in over patients confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor (PgR) status, and ECOG performance status. Prognosis was poor in patients with liver metastases, PgR-negative tumors, and high-grade tumors. While all subpopulations benefited from the addition of abemaciclib to endocrine therapy regardless of prognosis, substantial benefit of abemaciclib was observed in poor prognosis subgroups, characterized by large increases in PFS (hazard ratios =.4 to.5) and ORR (over 3%). In addition, STEPP analysis of TFI on a subset of the MORCH 3 population showed that patients with the shortest TFI appeared to have a poorer prognosis and received more benefit from the addition of abemaciclib compared to patients with longer TFI. CONCLUSIONS: This exploratory analysis has provided data that could help optimize treatment strategies by identifying that patients with poor prognostic factors may receive greater benefit from the addition of abemaciclib to endocrine therapy. 6. Rugo HS, Barry WT, Moreno-Aspitia A, Lyss A, Huebner L, Mayer EL, Naughton M, Layman RM, Carey LA, Somer RA, Toppmeyer D, Velasco M, Perez EA, Hudis CA, Winer E. Long-term follow-up of CALGB 452/NCCTG N63H (Alliance): A randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) +/ bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer (MBC). DOI:.58/ SABCS7-GS3-6. BACKGROUND: CALGB 452/NCCTG N63H (Alliance) compared weekly NP or Ix to P; most patients received bevacizumab. Ix was inferior to P, and NP was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms compared to P (Rugo et al, JCO 25). We report long-term follow-up (FU) of this trial with an unplanned subset analysis in hormone receptor positive (HR+) and triple negative (TNBC) breast cancer. METHODS: Patients were randomized :: to receive P (9 mg/m 2 ), Ix (6 mg/m 2 ) or NP (5 mg/m 2 ) on a 3 week (wk) on, wk off schedule, stratified by prior adjuvant taxane use and hormone receptor status. B was initially given to all patients, but became optional in 3/2 and was added to stratification. The primary endpoint was progressionfree survival (PFS); secondary endpoints included safety and overall survival (OS). With a target N = 9 patients, the study was powered to detect a hazard ratio of.36 (median PFS vs. 3.6 months). Eligibility included no prior chemotherapy for MBC, >2 mo from adjuvant P and measurable disease. RESULTS: 799 patients were randomized between /8 and/ (283 to P, 27 to NP, 245 to Ix); 98% received bevacizumab. 68% (546) had HR+ disease, 25% (2) had TNBC. Median FU is 5 years. Median PFS is unchanged at.8, 9.2 and 7.4 mo for P, NP and Ix with hazard ratios (95% CIs) of.3 (.94.34) and.44 (.2.72) for NP and Ix to P, respectively. Median OS was 27., 24.2 and 23.6 months for P, NP and Ix with hazard ratios of. (.9.34) and.3 (.7.57) for NP and Ix to P, respectively. The effects of NP vs. P on PFS and OS were significantly modified by subtype (interaction p =.8 and.73), whereas Ix vs. P was unchanged (interaction p s >.9, Table ). More patients discontinued treatment due to adverse events in the experimental arms (4 vs. 27 vs. 23% for P, NP and Ix). CONCLUSION: In patients with chemotherapy-naive MBC, Ix was inferior to P for PFS, and P was better tolerated than either NP or Ix. In this retrospective subset analysis, Ix and NP were inferior to P in HR+ disease, with a suggestion of improved PFS and OS with NP in patients with TNBC. Further investigation is required to explain and validate the subtype specificity seen in this exploratory analysis. TABLE TNBC, PFS HR+, PFS TNBC, OS HR+, OS P (mo) NP (mo) NP to P; HR (95% CI) (.55.2) (.4.59) (.5.7) (.99.58) 2 Ix (mo) Ix to P, HR (95% CI) (.99.96) (.2.86) (.9.82) (.7.7) 4 Interaction tests:. p =.8; 2. p =.73; 3. p =.96; 4. p =.92. mo, months; HR, hazard ratio. 4

5 7. 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 and IA Mayer. Sacituzumab govitecan (IMMU-32), an anti-trop-2-sn-38 antibody-drug conjugate, as 3rdline therapeutic option for patients with relapsed/ refractory metastatic triple-negative breast cancer (mtnbc): efficacy results. DOI:.58/ SABCS7-GS-7. BACKGROUND: mtnbc has an aggressive course with limited therapeutic options. Sacituzumab govitecan (IMMU-32) 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 (NCT63552) was conducted in patients (pts) with multiple, advanced epithelial cancers. We previously reported preliminary results in mtnbc (N = 69; objective response rate [ORR] = 3%, Bardia et al., JCO 27;35:24 248). In 26, 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 & 8 of a 2-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. and confirmed by independent centralized blinded review. ORR, DOR, progression-free survival (PFS) and overall survival (OS) were determined. Adverse events (CTCAE v4.), immunogenicity, and Trop-2 expression in archived tumor samples, when available, were evaluated. RESULTS: mtnbc pts (9 female, male; median age 55 yrs, range 3 8), including 53 from the previously reported cohort of 69 pts who had received 2 prior regimens for metastatic disease, were accrued between 7/23 and 2/27. As of data cutoff on 6/3/27, 7 are deceased, 23 in long-term followup, and 6 still on treatment. All pts were treated at the mg/kg IMMU-32 dose level, receiving 4.5 median doses (range 88). Treatment was well tolerated, with no treatment-related deaths, 2 treatment discontinuations for toxicity, and no anti-drug antibodies detected. Grade 3 toxicity ( %) included neutropenia, 39%; leukopenia, 4%; anemia, %; the incidence of febrile neutropenia was low (7%). By local radiologist assessment, the ORR is 34% (37/), 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.3) and 5.5 mo. (95% CI: 4.8 to 6.6), respectively, including % ( pts) with long-term PFS (2 to 3+ mo.), and the KM median OS is 2.7 mo. (95% CI:.8 to 3.6). 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 (NCT ) is underway. Additional studies including rational combinations are currently being evaluated for mtnbc and other breast cancer subsets. 8. Litton J, Rugo HS, Ettl J, Hurvitz S, Gonçalves A, Lee K-H, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, Roché H, Im Y-H, Quek RGW, Tudor IC, Hannah AL, Eiermann W, Blum JL MD. EMBRACA: A phase 3 trial comparing talazoparib, an oral PARP inhibitor, to physician s choice of therapy in patients with advanced breast cancer and a germline BRCA mutation. DOI:.58/ SABCS7-GS6-7. BACKGROUND: Talazoparib (TALA) is a highly potent, dual-mechanism PARP inhibitor that inhibits the PARP enzyme and effectively traps PARP on single-stranded D breaks, preventing D damage repair and causing cell death in BRCA/2-mutated cells. METHODS: EMBRACA is an open-label, randomized, 2-arm, phase 3 trial comparing the efficacy and safety of TALA ( mg/day) with standard single-agent physician s choice of therapy (PCT) (capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with advanced breast cancer (abc) and a germline BRCA/2 mutation (gbrcamut). The primary objective was PFS assessed by blinded independent central review (BICR). Secondary objectives: OS, ORR, CBR at 24 weeks (CBR24), and safety. Exploratory objectives: patient-reported QoL and DOR. Eligibility criteria: age 8 years; HER2-negative abc; deleterious or suspected deleterious gbrcamut; 3 prior cytotoxic regimens for abc; and ECOG PS 2. Prior platinum was allowed. Patients were randomized 2: and stratified by receptor status, extent of prior therapy, and CNS metastases (NCT945775). RESULTS: 43 patients were randomized (median age 46 years; 54% hormonereceptor [HR]+ BC; 45% BRCA+ and 55% BRCA2+; 55% ECOG PS = ; 38% chemo-naïve for abc; 8% prior platinum; 5% CNS metastases); 287 were assigned to TALA and 44 to PCT ( TALA, 8 PCT patients were not treated). Median duration of exposure was 6. and 3.9 months, respectively; TALA had a relative dose intensity of 87%. At 62% PFS data maturity: Improved clinical benefit was seen in all subsets including those with HR+ BC (HR.47; 95% CI.32.7) and CNS metastasis (HR.32; 95% CI.5.88). There was a significant delay in the time to deterioration in global health status (GHS)/QoL for TALA vs. PCT (HR.38; 95% CI.26.55; P <.]. Grade 3 4 hematologic adverse events (AEs) occurred in 55% TALA (mainly anemia)/39% PCT (mainly 5

6 TALA PCT Hazard Ratio/ Odds Ratio PFS by BICR, mo (95% CI) OS [interim], mo (95% CI) ORR by INV, % (95% CI) DOR by INV, mo (IQR) CBR24 by INV, % (95% CI) 8.6 ( ); n = ( ); n = % ( ); n = (2.8.2); n = % ( ); n = ( ); n = ( ); n = % ( ); n = 4 3. ( ); n = 3 36.% ( ); n = 44 (P value).542 (<.).76 (.5) 4.99 (<.).43 (.5)* 4.28 (.) neutropenia). Grade 3 4 non-hematologic AEs were seen in 32% TALA/38% PCT; TALA was associated with fewer gastrointestinal disorders (5.6% vs..9%) and skin/ subcutaneous tissue disorders (.7% vs. 5.6%) than PCT. Grade 3 4 serious AEs were observed in 26% TALA/25% PCT. AEs associated with permanent study drug discontinuation occurred in 8% TALA/% PCT. AE resulting in death occurred in 2.% TALA/3.2% PCT. CONCLUSIONS: Single-agent TALA significantly prolonged PFS by BICR in HER2-negative abc patients with a gbrcamut compared to PCT; all key secondary efficacy endpoints demonstrated benefit with TALA, with a significant delay in time to deterioration in GHS/QoL. TALA was generally well tolerated with minimal non-hematologic toxicity and few AEs associated with treatment discontinuations. INV, investigator. *Not a randomized subset. 6