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Background: First-line (1L) docetaxel+trastuzumab+pertuzumab (THP) for HER2-positive metastatic breast cancer (MBC) significantly improved progression-free survival (PFS) and overall survival in the phase III CLEOPATRA trial, and led to the approval of this regimen. PERUSE (NCT01572038) was designed to assess the safety and efficacy of investigator's choice of taxane+HP for 1L locally recurrent (LR)/MBC, and allows exploration of safety and efficacy in a larger population. Methods: PERUSE is a multicenter, single-arm phase IIIb study. Patients (pts) with Eastern Cooperative Oncology Group performance status ≤2 and no prior systemic therapy for LR/MBC (except endocrine therapy) receive T, paclitaxel (PAC), or nab-PAC plus H (8 mg/kg→6 mg/kg every 3 weeks [q3w]) and P (840 mg→420 mg q3w) until disease progression (PD) or unacceptable toxicity. The primary endpoint is safety. Secondary endpoints include best overall response (BOR) and PFS. Results: The safety/ITT population includes 1436 pts at data cutoff (1 Apr 2016). Median follow-up was 17.2 mo (range, Most pts discontinued taxanes for 'other' reasons (25%), adverse events (AEs; 16%), PD, or investigator decision (15% each); H, for PD or AEs (46% and 7%); and P, for PD or AEs (46% and 8%). Grade ≥3 treatment-emergent AEs (TEAEs) of interest are shown in table 1. Serious TEAEs were reported in 282 (36%) pts on T, 185 (31%) on PAC, and 21 (32%) on nab-PAC. Preliminary efficacy by taxane is shown in table 2. Table 1Pts, n (%)TPACNab-PAC n=775n=589n=65Neutropenia110 (14)31 (5)1 (2)Diarrhea62 (8)50 (8)4 (6)Febrile neutropenia81 (10)7 (1)0Fatigue21 (3)10 (2)1 (2)Asthenia16 (2)10 (2)0Peripheral neuropathy10 (1)15 (3)0Anemia11 (1)12 (2)2 (3)Left ventricular dysfunction1 ( Table 2 TPACNab-PACBOR, based on pts with measureable disease at baseline, n (%)n=659n=482n=53Complete72 (11)80 (17)4 (8)Partial442 (67)319 (66)38 (72)Stable disease112 (17)62 (13)8 (15)PD18 (3)12 (2)2 (4)Missing15 (2)9 (2)1 (2)PFS, ITT populationn=775n=589n=65Pts with events, n (%)439 (57)324 (55)40 (62)Median, mo (95% confidence interval)19.6 (17.4–22.6)24.8 (20.7–27.0)18.1 (11.9–34.2)25th–75th percentile, mo9.4–not reached (NR)10.2–NR7.9–NR Conclusion: The preliminary findings of this large, single-arm study suggest that safety and efficacy of 1L taxane+HP for HER2-positive LR/MBC are in keeping with the results of the phase III CLEOPATRA study. There was less febrile neutropenia with PAC/nab-PAC+HP compared with THP, and preliminary PFS was similar to that seen in the CLEOPATRA study for all taxane+HP combinations. Citation Format: Bachelot T, Puglisi F, Ciruelos E, Peretz-Yablonski T, Schneeweiss A, Easton V, Lindegger N, Restuccia E, Miles D. Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent/metastatic breast cancer (PERUSE) [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 P4-21-04.

Background: First-line (1L) docetaxel+trastuzumab+pertuzumab (THP) is approved for HER2-positive metastatic breast cancer (MBC), based on superior progression-free (PFS) and overall survival vs TH in the phase III CLEOPATRA trial. Predefined CLEOPATRA subgroup analyses suggested that THP use should not be limited by patient (pt) age: toxicity was increased but efficacy was similar in pts ≥65 vs Methods: In this multicentre, single-arm phase IIIb study, pts with ECOG PS ≤2 and no prior systemic therapy for LR/MBC (except endocrine therapy) receive investigator's choice of T, paclitaxel (PAC), or nab-PAC + H (8→6 mg/kg q3w) + P (840→420 mg q3w) until disease progression/unacceptable toxicity. The primary endpoint is safety. Secondary endpoints include PFS, estimated using the Kaplan–Meier method. Results: At data cutoff (1 Apr 2016), 1436 pts were included in the safety/ITT populations. 312 pts (22%) were aged ≥65 at study entry; they were more likely to have comorbidities than the Proportions of pts with visceral and hormone receptor-positive disease were similar (78% vs 74% and 65% vs 64%, respectively). Median duration of chemotherapy was similar but median exposure to antibodies was shorter in the ≥65 vs Interruptions/discontinuations due to treatment-emergent adverse events (TEAEs) were more common in pts ≥65 compared with pts TEAEs related to taxanes, H, and P were generally similar in pts aged ≥65 and Serious TEAE rates and most common grade ≥3 TEAEs of interest are shown in table 1. Table 1Pts, n (%) Preliminary median PFS at the time of this analysis was 23.2 mo in the Conclusion: Preliminary findings with 1L taxane+HP in this large cohort of LR/MBC pts show that pts aged ≥65 years had more comorbidities and poorer PS at study entry compared with those aged Citation Format: Miles D, Schneeweiss A, Peretz-Yablonski T, Ciruelos E, Puglisi F, Easton V, Lindegger N, Restuccia E, Bachelot T. Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy in patients ≥65 years with HER2-positive locally recurrent/metastatic breast cancer: Subgroup analyses of the PERUSE study [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 P4-21-07.

Introduction T-DM1 treatment significantly improved overall survival and had a lower incidence of grade ≥3 adverse events (AEs) vs capecitabine plus lapatinib in patients (pts) with HER2-positive advanced breast cancer (BC) in the EMILIA study, including pts with treated, asymptomatic CNS metastases (mets). KAMILLA is an ongoing, single-arm, open-label, phase 3b global safety study of T-DM1 in pts with HER2-positive locally-advanced or metastatic BC (target n=2220). In this interim analysis we describe clinical characteristics, safety, and efficacy in pts with stable CNS mets at baseline (BL). Methods Eligible pts received prior HER2-directed therapy and chemotherapy and progressed on or after most recent treatment for advanced BC, or within 6 months of completing adjuvant therapy. Pts with asymptomatic CNS mets were eligible, including pts with stable CNS disease with prior radiation therapy. Pts received T-DM1 3.6 mg/kg every 3 weeks until unacceptable toxicity, withdrawal of consent, or disease progression. This exploratory analysis describes pts with BL CNS mets. Median progression-free survival (PFS) was estimated using the Kaplan-Meier method. Results As of April 4, 2016, data were available for 2017 treated pts, of whom 399 (20%) had BL CNS mets, with a median follow-up of 33 months. Table 1 presents demographic and BL characteristics. The incidence of AEs was similar between pts with and without BL CNS mets. Serious AEs (SAEs) occurred in 112 pts with BL CNS mets (28%) vs 311 of 1618 pts without BL CNS mets (19%), and the frequency of SAEs was comparable to that observed in EMILIA. However, nervous system disorder SAEs, such as seizure, epilepsy, and brain edema, occurred more frequently in pts with BL CNS mets (30 pts [8%]) vs 18 pts [1%] with no BL CNS mets. Mean T-DM1 treatment duration was 8.0 months (median 8 cycles; range 1–55) in pts with BL CNS mets and 9.4 months (median 9 cycles; range 1–57) in pts with no BL CNS mets. Median PFS was 5.5 months in pts with BL CNS mets vs 7.9 months in pts with no BL CNS mets. A decrease in the size of brain target lesions was observed during T-DM1 treatment in 84 of 126 pts with measurable CNS lesions. Table 1. BL characteristics CNS mets at BL (n=399)No BL CNS mets (n=1618)Median age, yrs (range)52 (28–83)55 (26–88)ECOG performance status, n (%) 0193 (48)929 (57)1174 (44)605 (37)232 (8)83 (5)Hormone receptor status, n (%) ER and/or PR positive246 (62)992 (61)ER and PR negative149 (37)593 (37)Median time since initial BC diagnosis, yrs (range)4.8 (0–28)5.0 (0–53)Median time since first metastasis, yrs (range)2.4 (0–25)2.6 (0–35)Median number of prior therapies for metastatic BC (range)3 (0–>10)2 (0–>10) Conclusions This subgroup analysis of KAMILLA is the largest reported cohort of pts with CNS mets treated with T-DM1. The overall safety profile of T-DM1 in pts with BL CNS mets was comparable to that of pts without CNS mets. As might be expected in pts with CNS disease, serious neurological AEs occurred more frequently in pts with BL CNS mets vs those without. Response to T-DM1 was seen in the CNS in pts with BL CNS mets, however, median PFS was lower in pts with BL CNS mets vs those without BL CNS mets. Citation Format: Montemurro F, Ellis P, Delaloge S, Wuerstlein R, Anton A, Button P, Lindegger N, Barrios C. Safety and efficacy of trastuzumab emtansine (T-DM1) in 399 patients with central nervous system metastases: Exploratory subgroup analysis from the KAMILLA study [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 P1-12-10.

Background Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8mg/kg loading dose, then 6mg/kg every 3weeks (q3w)] and pertuzumab (840mg loading dose, then 420mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54years; 29% had received prior trastuzumab. Median treatment duration was 16months for pertuzumab and trastuzumab and 4months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Conclusions Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. ClinicalTrials.gov NCT01572038.

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Background Introduction of PH (2012) and K (2013) in the US changed the standard-of-care for HER2-positive mBC. RW studies reported decreased K effectiveness in pts with PH pre-tx. We studied whether timing of PH and K availability in clinical practice could introduce selection bias (i.e. pts with K after PH in early yrs of availability may have to have had rapid progression during PH tx to be included in RW analyses). Methods Using de-identified data from the US-based Flatiron electronic health record-derived database, we selected pts diagnosed with mBC on/after 1 Jan 2011 and initiating K between 1 Feb 2013 and 31 Jul 2018. Primary analysis included all pts receiving K (any tx line). Subgroup analysis focused on pts with 2nd-line K tx after PH tx. Time from index date to next tx/death (TTNT) was used as a proxy for progression-free survival. Results Primary cohort (N = 533) demographics were generally consistent across yrs (2013–18); median age was 61 yrs; 89% had prior HER2-targeted tx; 23% had brain metastases (mets); 68% had visceral mets. In pts with (n = 231) vs without (n = 79) prior PH, median age was 61 vs 65 yrs, mean time from mBC diagnosis was 16 vs 18 months, 27% vs 20% had brain mets, 74% vs 58% had visceral mets. Additional findings are shown (Table). Prevalence of prior PH exposure almost doubled over the yrs. In 2nd-line K treated pts with prior PH, time from mBC to K increased over the yrs, paralleled by a numerical increase in median TTNT. Table . 356P 2013 2014 2015 2016 2017 2018 Primary cohort (N = 533) N 51 77 108 106 117 74 Prior PH, n (%) 18 (35.3%) 35 (45.5%) 72 (66.7%) 80 (75.5%) 77 (65.8%) 53 (71.6%) TTNT, median months (95% CI) 6.8 (4.9–14.2) 6.5 (4.2–9.2) 7.6 (4.7–9.8) 6.3 (5.1–8.4) 8.4 (6.4–10.3) Data not yet mature % Censored 13.7% 10.4% 9.3% 17.0% 36.8% Subgroup analysis (N = 231) Pts with 2nd-line K use after PH, N 13 25 56 51 52 34 mBC to K initiation in pts with 2nd-line K use after PH, mean months (SD) 12.7 (6.9) 13.1 (8.5) 13.0 (8.0) 16.0 (12.9) 17.9 (12.5) 18.6 (11.6) TTNT in pts with 2nd-line K use after PH, median months (95% CI) 5.1 (3.0–7.5) 7.2 (4.6–11.7) 6.6 (4.5–8.4) 10.3 (5.6–12.8) Data not yet mature % Censored 7.9% 8.9% 15.7% 40.4% CI, confidence internal; SD, standard deviation. Conclusions Prevalence of PH pre-tx increased, yet K effectiveness remained consistent across yrs. With PH launched shortly before K, the initial pts receiving K were possibly selected due to shorter benefit from prior PH. This selection bias may explain reports of lower K effectiveness in pts with prior PH tx. This illustrates the challenges of assessing tx sequence effectiveness shortly after tx approval. Editorial acknowledgement Writing assistance was provided by Meredith Kalish, MD, of Ashfield Healthcare Communications (a UDG Healthcare plc company), and funded by F. Hoffmann-La Roche Ltd. Legal entity responsible for the study F. Hoffmann-La Roche Ltd. Funding F. Hoffmann-La Roche Ltd. Disclosure T. Sanglier: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. C. Flores: Full / Part-time employment: Genesis Research. E. Flahavan: Shareholder / Stockholder / Stock options: Eli Lilly; Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. N. Lindegger: Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche; Shareholder / Stockholder / Stock options: Novartis; Shareholder / Stockholder / Stock options: Idorsia; Shareholder / Stockholder / Stock options: JJ Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Ely Lilly; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche. All other authors have declared no conflicts of interest.

Long QT syndrome variant 3 (LQT-3) is a channelopathy in which mutations in SCN5A, the gene coding for the primary heart Na(+) channel alpha subunit, disrupt inactivation to elevate the risk of mutation carriers for arrhythmias that are thought to be calcium (Ca(2+))-dependent. Spontaneous arrhythmogenic diastolic activity has been reported in myocytes isolated from mice harboring the well-characterized Delta KPQ LQT-3 mutation but the link to altered Ca(2+) cycling related to mutant Na(+) channel activity has not previously been demonstrated. Here we have investigated the relationship between elevated sarcoplasmic reticulum (SR) Ca(2+) load and induction of spontaneous diastolic inward current (I(TI)) in myocytes expressing Delta KPQ Na(+) channels, and tested the sensitivity of both to the antianginal compound ranolazine. We combined whole-cell patch clamp measurements, imaging of intracellular Ca(2+), and measurement of SR Ca(2+) content using a caffeine dump methodology. We compared the Ca(2+) content of Delta KPQ(+/-) myocytes displaying I(TI) to those without spontaneous diastolic activity and found that I(TI) induction correlates with higher sarcoplasmic reticulum (SR) Ca(2+). Both spontaneous diastolic I(TI) and underlying Ca(2+) waves are inhibited by ranolazine at concentrations that preferentially target I(NaL) during prolonged depolarization. Furthermore, ranolazine I(TI) inhibition is accompanied by a small but significant decrease in SR Ca(2+) content. Our results provide the first direct evidence that induction of diastolic transient inward current (I(TI)) in Delta KPQ(+/-) myocytes occurs under conditions of elevated SR Ca(2+) load.