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Background The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic breast cancer. Patients and methods Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life. Results The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months [95% confidence interval (CI), 7.26-9.07]} versus placebo arm (5.4 months [95% CI, 3.68-7.29]) (stratified hazard ratio [HR] 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm. Conclusion SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.

Evaluation of health-related quality of life (HR-QoL) among cancer patients has gained an increasing importance and is now a key determinant of anticancer treatments' value. HR-QoL has been assessed in trials testing cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in breast cancer (BC), using various questionnaires at different timepoints. HR-QoL reports from BC patients treated with CDK4/6i in the real-world setting are also available.We systematically reviewed the literature, searching for full-length articles, and selected conference abstracts reporting data on HR-QoL in BC patients at any stage and of any molecular subtype treated with abemaciclib, palbociclib or ribociclib.A total of 533 full-length articles and 143 abstracts were retrieved. After screening for eligibility, 38 records were included (31 clinical trials; 7 real-world reports). Assessment methods were heterogeneous across studies in terms of questionnaires, evaluation timepoints and endpoints. Overall, adding CDK4/6i to endocrine therapy did not worsen patients' HR-QoL, with a positive trend towards pain improvement. Gastrointestinal scores (diarrhea, nausea and appetite loss) statistically favored the control arm among metastatic BC patients receiving abemaciclib, whereas they were superimposable in the early setting. The combination of palbociclib and endocrine therapy showed similar HR-QoL outcomes compared with endocrine therapy alone, but determined better scores compared with chemotherapy. HR-QoL was specifically assessed in premenopausal patients treated with ribociclib, showing similar scores compared with postmenopausal patients.Despite methodological heterogeneity does not allow a proper comparison, HR-QoL was generally maintained with CDK4/6i. However, differences between abemaciclib, palbociclib and ribociclib exist and mainly rely on the distinct safety profiles of the compounds. These differences should be acknowledged and taken into account in the clinical practice.

Background Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Patients and methods Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival. Results All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9–31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9–34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0–2.2), and median overall survival was 18.0 months (95% CI 12.9–23.0). Conclusions Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. Clinical trial registration ClinicalTrials.gov, NCT02447003.

Background: The international guidelines support upfront use of endocrine therapies (HT), with or without new targeted agents (TA), in HR+ve/HER2-ve mBC. However, routine administration of regimens containing chemotherapy (CT) is still common, even in the absence of visceral crisis. Unfortunately, robust data from head-to-head direct comparisons among CT and HT-based strategies are still not available; therefore, a NMA is now the only valuable methodological approach to compare the efficacy and activity of HT- versus CT-based regimens, and to drive adequate suggestions for a potential therapeutic algorithm in 1stand 2ndline HR+ve/HER2-ve mBC. Methods: We performed a systematic literature search and selected all available phase II-III RCT published between January 2000 and December 2017, which evaluated CT or HT ± TA as 1stand/or 2nd line treatments for postmenopausal women with HR+ve/HER2-ve mBC. Primary endpoint was progression-free survival (PFS)/time to tumor progression (TTP); secondary endpoint was overall response rate (ORR). A Bayesian NMA was generated to compare posterior median hazard ratios (HR) for PFS and odds ratios (OR) for ORR. The aromatase inhibitor (AI) anastrozole (ana) was chosen as the common comparator for the overall analyses, being the most frequent treatment in the dataset. Results: A total of 137 eligible trials (48,653 patients) were included in the NMA. Among the regimens approved for clinical use, palbociclib (palbo) + letrozole (let) [HR:0.42, 95% credible intervals (CI):0.27-0.65], ribociclib (ribo) + let (HR:0.43, 95%CI:0.27-0.74), abemaciclib (abe) + ana/let (HR:0.42, 95%CI:0.25-0.71), palbo + fulvestrant (ful) (HR:0.37, 95%CI:0.25-0.55), abe + ful (HR:0.45, 95%CI:0.30-0.65), everolimus (eve) + exemestane (exe) (HR:0.37, 95%CI:0.25-0.54), and ful alone (HR:0.81, 95%CI:0.66-0.98) were significantly superior to ana in terms of PFS/TTP. Conversely, none of the CT-based regimens (i.e. paclitaxel±bevacizumab, anthracycline-based schemes, capecitabine, eribulin) was significantly superior to ana. Additionally, head-to-head comparisons among the CDK 4/6 inhibitors (CDK4/6i) combined with AI showed no significant difference (palbo + let vs. ribo + let, HR:0.98, 95%CI:0.63-1.54; palbo + let vs. abe + ana/let, HR:1.02, 95%CI:0.63-1.60; ribo + let vs. abe + ana/let, HR:1.03, 95%CI:0.62-1.73). On the other hand, CDK4/6i+AI were significantly superior to many 1stline CT, including taxane- and/or anthracycline-based regimens. Interestingly, no CT±TA regimen was significantly superior to ana or to HT+TA, in terms of ORR. Conclusions: Our analysis suggests that CT-based regimens are not significantly superior to HT-based therapies as 1st/2ndline treatments for postmenopausal HR+ve/HER2-ve mBC. Instead, HT+TA, including CDK 4/6i and eve, were significantly superior to HT alone and to many 1st/2ndline CT regimens. Moreover, the three CDK4/6i combined with AI did not differ significantly among each other. These data strongly support the combination of a CDK 4/6i along with HT as the preferred first choice of treatment for the 1stand 2ndline in HR+ve/HER2-ve mBC, as indicated in all the international guidelines. Citation Format: Schettini F, Giuliano M, Rognoni C, De Placido S, Arpino G, Milani M, Giordano A, Cristofanilli M, Jerusalem G, Bachelot T, Pistilli B, De Laurentiis M, Venturini S, Generali D. Efficacy of endocrine- versus chemotherapy-based treatments in hormone receptor-positive (HR+ve), HER2-negative (HER2-ve) postmenopausal metastatic breast cancer (mBC): A network meta-analysis (NMA) [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 P1-16-01.

Background: At present, there is no standard second-line chemotherapy-based treatment in patients with HER2-negative MBC. Continued VEGF inhibition with bevacizumab is a new potential option in patients progressing to first line bevacizumab and chemotherapy. Eribulin is a non-taxane microtubule dynamics inhibitor, with a unique mechanism of action and suggested beneficial effects on tumor microenvironment and neoangiogenesis. This study evaluated efficacy and safety of eribulin plus bevacizumab as a novel second-line chemotherapy scheme, in patients progressing after first line paclitaxel and bevacizumab. Methods: This is a multicenter, single-arm, Simon's two-stage, Phase II study. Patients with HER2-negative MBC progressing to paclitaxel and bevacizumab received eribulin (1.23 mg/m2 intravenously on Days 1 and 8 of every 21-day cycle) plus bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks intravenously), as second-line chemotherapy. The primary endpoint was the overall response rate (ORR), considered as sum of partial (PR) and complete response (CR), basing on the best overall response. The present safety and efficacy analyses, as planned per study design, refer to six cycles of treatment (18 weeks). Results: Among the 61 patients enrolled in the study, 55 (90,2% ) were evaluable for efficacy. ORR (PR/CR) was 9.1% [95% confidence intervals (C.I.) 3.0 to 19.9]; stable disease (SD) rate was 63.6% [95% C.I. 49.6 to 76.2]; clinical benefit rate (CR/PR/SD) at 24 weeks was 35% [95% C.I. 22.0 to 49.1]. The median progression free survival was 6.3 months [95% C.I. 4.1 to 7.8 months]. Drugs-related adverse events (AEs) were: 49.5% related to eribulin, 7.7% related to bevacizumab, and 11.8% related to both the study drugs. The most common AEs were fatigue (9.9% of all AEs), paresthesia (6.5% of all AEs) and neutropenia (6.2% of all AEs). Quality of life was well preserved among the majority of patients. Conclusions: The results of our trial suggest that continuing bevacizumab in combination with eribulin, beyond first line treatment with bevacizumab and paclitaxel, offers a reasonable therapeutic option for patients with HER2-negative MBC, without detrimentally affecting quality of life. Citation Format: De Placido S, De Laurentiis M, Bruzzese D, Bernardo A, Baldini EE, Montesarchio V, Fabi A, Gamucci T, De Placido P, Russo S, Lauria R, De Santo I, De Angelis C, Del Mastro L, Giuliano M, Arpino G. A phase II single arm trial evaluating the efficacy and safety of eribulin in combination with bevacizumab for second-line treatment of human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC) progressing after first-line therapy with bevacizumab and paclitaxel [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 P6-21-13.

Background: The cyclin-dependent kinase (CDK)4/6 inhibitor RIBO is approved in combination with an aromatase inhibitor (AI) for HR+, HER2– ABC in postmenopausal women with no prior therapy for ABC, based on the MONALEESA-2 trial (Hortobagyi et al. NEJM 2016). Although a high proportion of patients with HR+, HER2– ABC are >65 years of age, older patients are often under-represented in clinical trials. Furthermore, treatment decisions may be complicated by comorbidities, functional status, and concurrent medications. Here, we report early safety results for patients ≥65 years of age enrolled in CompLEEment-1, an open-label, phase 3b trial evaluating RIBO+LET as first-line endocrine-based therapy in an expanded patient population. Methods: Patients with HR+, HER2– ABC, ≤1 line of prior chemotherapy (CT), and no prior endocrine therapy for ABC received RIBO (600 mg/day, 3 weeks on/1 week off) + LET (2.5 mg/day); men and premenopausal women received concomitant goserelin (3.6-mg subcutaneous implant every 28 days). The primary outcome was safety and tolerability. A pre-planned interim analysis was conducted ˜15 months after first patient first visit. Results: Of the first 1,008 patients enrolled who completed 56 days of follow-up or discontinued before the data cut-off date, 377 were ≥65 years of age. Of these, 157 (41.6%) were 65- Conclusions: Initial safety results from CompLEEment-1, from the first 56 days of follow-up, demonstrate the tolerability of RIBO+LET in older patients, consistent with the overall patient population. NCT02941926. Citation Format: Ring A, Borstnar S, Ferreira A, Azim HA, Cottu P, Lu J, Martin M, Zamagni C, Beck JT, Zhou K, Wu J, Menon L, De Laurentiis M. Ribociclib (RIBO) + letrozole (LET) in older patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC): Preliminary subgroup results from the phase 3b CompLEEment-1 trial [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 P6-18-16.

This abstract was not presented at the conference. Citation Format: Cazzaniga ME, Blasi L, Pronzato P, Giordano M, Garrone O, Donadio M, Del Mastro L, Livi L, Natoli C, Michelotti A, Turletti A, Riccardi F, De Laurentiis M, Marchetti P, Montemurro F, Romagnoli E, De Placido S, Biganzoli L, Bologna A, Bria E, Mustacchi G. Not presented [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 P4-13-04.

Abundant preclinical evidences indicate that stress-induced autophagy in tumor cells is predominantly cytoprotective and that inhibition of autophagy can enhance tumor cell death by diverse anticancer therapies. A major negative regulator of autophagy is the mammalian target of rapamycin (mTOR), activated downstream of PI3KAKT pathway. mTOR inhibitors, including rapamycin, have been shown to induce autophagy in tumor cells, while the combination of PI3K-AKT/mTOR and autophagy inhibitors shown synergistic effect on increased apoptosis and reduced autophagy (Takeuchi H. 2005). This project aimed to characterize the role of autophagy in Breast Cancer models exposed to new potent Genentech PI3K/AKT inhibitors GDC0068 (Ipatasertib) and GDC0032 (Taselisib) currently in phase III clinical trials on TNBC and ER+ patients. However, the efficacy of PI3K/AKT inhibitors may be limited by resistance mechanisms that result in minimal cell death in tumor cells. In order to investigate the role of autophagy as possible mechanisms of resistance, Ipatasertib and Taselisib have been evaluated in breast cancer cell lines characterized by different receptors profile: TNBC, HER2/c-erb-2 and luminal A cell lines. Our results showed that both drugs are able to induce G1/S cell cycle block and increase of autophagy signaling measured by p62 level and LC3 II/LC3 I ratio and by the percentage of cells exhibiting LC3 positive puncta. In addition, apoptosis increase was also evaluated by measuring positive annexin V staining, by flow cytometry technique, and apoptosis markers, such as PARP and cleaved caspase 3, by immunoblot assay. Furthermore, the supplement of pharmacologic inhibitors of autophagy, such as hydroxichloroquine, were able to reduce cell viability evaluated by both short- and long-term assays in cell lines exposed to Ipatasertib and Taselisib. 3D breast cancer models are ongoing to confirm the synergic effect of PI3K/AKT inhibitors and hydroxychloroquine, in order to provide a new therapeutic combinatorial approach potentially translatable to patients. Citation Format: Cocco S, Leone A, Buonfanti G, Sisalli MJ, Budillon A, De Laurentiis M. Role played by autophagy in breast cancer models exposed to new PI3K/AKT inhibitors, GDC-0068 and GDC-0032 [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 P4-07-09.

Background:Previous studies suggested a link between obesity, insulin-resistance and breast cancer outcome. The aim of the present prospective observational study was to investigate the role of metabolic syndrome (MetS) and its components on early breast cancer (EBC) patients' outcome. Methods: MetS was defined by the presence of 3 to 5 of the following components: waist circumference (WC) > 88 cm, blood pressure ≥ 130/≥85 mmHg, serum levels of triglycerides (TG) ≥ 150 mg/dL, high-density lipoprotein (HDL) < 50 mg/dL and fasting glucose (FG) ≥ 110 mg/ dL (National Cholesterol Education Program Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults - NCEP-ATPIII criteria). Overall, 955 EBC patients were prospectively enrolled between January 2009 and December 2013 at University Hospital Federico II and National Cancer Institute G.Pascale, Naples, Italy. Clinical and tumor characteristics were collected for all the patients. A total of 494 patients (51.7%) had complete data on all the components of MetS at first diagnosis and thus were included in the current analysis. Study population was divided into 2 main groups: (1) patients with less than 3 components (No MetS); (2) patients with 3-5 components (MetS). Categorical variables were analyzed by the chi-square test and survival data by the log-rank test and Cox proportional hazards regression model. Results: Overall 366 (74.1%) and 128 (25.9%) women were categorized as No MetS and MetS, respectively. MetS patients were more likely to be older and postmenopausal compared to No MetS patients. In detail, 46% vs 38% were older than 55 yrs (p Conclusions: MetS is correlated with poor outcome in EBC patients. Among patients without full criteria for MetS diagnosis, the presence of 1 or 2 components of the syndrome may predict for worse survival. Testing for components of MetS in BC patients is recomended to predict outcome and to eventually suggest lifestyle changes, exercise and diet. Citation Format: Buono G, Crispo A, Giuliano M, Rea CG, Forestieri V, Lauria R, De Placido P, De Laurentiis M, Pacilio C, Grimaldi M, Nocerino F, Montella M, De Placido S, Arpino G. Metabolic syndrome and early-stage breast cancer outcome: Results from a prospective observational study [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 P2-08-15.

BACKGROUND: Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months). PATIENTS AND METHODS: This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2- ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling). RESULTS: Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) [hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90]. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug-drug interaction between ribociclib and fulvestrant or new safety signals were observed. CONCLUSIONS: This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2- ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy. ispartof: ANNALS OF ONCOLOGY vol:32 issue:8 pages:1015-1024 ispartof: location:England status: published

Background The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. Patients and methods We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian ‘real-world’ setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. Results Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095). Conclusions Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials., Highlights • This is the first study comparing pertuzumab + trastuzumab + taxane (P + T + taxane) with T-DM1 in early-relapsing HER2+ MBC. • The majority of early-relapsing HER2+ MBC have high-grade, node-positive, large primary tumors. • First-line T-DM1 compared with P + T + taxane is associated with worse progression-free survival. • First-line T-DM1 compared with P + T + taxane is associated with worse overall survival. • Post-progression survival does not differ between the two treatments cohorts.

Background In the phase III IMpassion130 trial, combining atezolizumab with first-line nanoparticle albumin-bound-paclitaxel for advanced triple-negative breast cancer (aTNBC) showed a statistically significant progression-free survival (PFS) benefit in the intention-to-treat (ITT) and programmed death-ligand 1 (PD-L1)-positive populations, and a clinically meaningful overall survival (OS) effect in PD-L1-positive aTNBC. The phase III KEYNOTE-355 trial adding pembrolizumab to chemotherapy for aTNBC showed similar PFS effects. IMpassion131 evaluated first-line atezolizumab–paclitaxel in aTNBC. Patients and methods Eligible patients [no prior systemic therapy or ≥12 months since (neo)adjuvant chemotherapy] were randomised 2:1 to atezolizumab 840 mg or placebo (days 1, 15), both with paclitaxel 90 mg/m2 (days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. Stratification factors were tumour PD-L1 status, prior taxane, liver metastases and geographical region. The primary endpoint was investigator-assessed PFS, tested hierarchically first in the PD-L1-positive [immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay] population, and then in the ITT population. OS was a secondary endpoint. Results Of 651 randomised patients, 45% had PD-L1-positive aTNBC. At the primary PFS analysis, adding atezolizumab to paclitaxel did not improve investigator-assessed PFS in the PD-L1-positive population [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.60-1.12; P = 0.20; median PFS 6.0 months with atezolizumab–paclitaxel versus 5.7 months with placebo–paclitaxel]. In the PD-L1-positive population, atezolizumab–paclitaxel was associated with more favourable unconfirmed best overall response rate (63% versus 55% with placebo–paclitaxel) and median duration of response (7.2 versus 5.5 months, respectively). Final OS results showed no difference between arms (HR 1.11, 95% CI 0.76-1.64; median 22.1 months with atezolizumab–paclitaxel versus 28.3 months with placebo–paclitaxel in the PD-L1-positive population). Results in the ITT population were consistent with the PD-L1-positive population. The safety profile was consistent with known effects of each study drug. Conclusion Combining atezolizumab with paclitaxel did not improve PFS or OS versus paclitaxel alone. ClinicalTrials.gov NCT03125902.

Background We evaluated the efficacy and safety of the nontaxane microtubule dynamics inhibitor eribulin plus the humanized anti-VEGF monoclonal antibody bevacizumab in a novel second-line chemotherapy scheme in HER2-negative metastatic breast cancer (MBC) patients progressing after first-line paclitaxel and bevacizumab. Patients and methods This is a multicenter, single-arm, Simon's two-stage, phase II study. The primary endpoint was the overall response rate, considered as the sum of partial and complete response based on the best overall response rate (BORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and clinical benefit rate. Results A total of 58 of the 61 patients enrolled in the study were evaluable for efficacy. The BORR was 24.6% (95% CI 14.5-37.3). The clinical benefit rate was 32.8% (95% CI 21.3-46.0). The median PFS was 6.2 months (95% CI 4.0-7.8), and median OS was 14.8 months (95% CI 12.6-22.8). Overall, adverse events (AEs) were clinically manageable and the most common AEs were fatigue, paresthesia, and neutropenia. Quality of life was well preserved in most patients. Conclusions The results of this study suggest that second-line therapy with bevacizumab in combination with eribulin has a meaningful clinical activity and may represent a potential therapeutic option for patients with HER2-negative MBC., Highlights • Bevacizumab + chemotherapy improved progression-free survival in HER2-negative metastatic breast cancer (MBC) patients. • Eribulin monotherapy improved overall survival in patients with anthracycline- and taxane-pretreated MBC. • The GIM11-BERGI trial assessed the efficacy and safety of eribulin + bevacizumab as second-line treatment for HER2-MBC. • Eribulin + bevacizumab showed to be a safe and active treatment after progression to first-line paclitaxel + bevacizumab.

Introduction The clinical trial “DECLARE-TIMI 58” (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), demonstrated that dapagliflozin, a Sodium glucose cotransporter 2 inhibitor, reduces the composite end point of cardiovascular death/hospitalization for heart failure in a broad population of patients with type 2 diabetes mellitus. Purpose We aimed to study if dapagliflozin could exerts cardioprotective effects in doxorubicin and trastuzumab-induced cardiotoxicity through the analysis of multiple biochemical mechanisms. Methods HL-1 adult cardiomyocytes were exposed to subclinical concentration of doxorubicin and trastuzumab (100 nM) alone or in combination with dapagliflozin at 50 nM. Determination of cell viability was performed through analysis of mitochondrial dehydrogenase activity and the study of lipid peroxidation (quantifying cellular Malondialdehyde and 4-hydroxynonenal), and of intracellular Ca2+ homeostasis by spectrophotometric methods. Moreover, anti-inflammatory studies were also performed (activation of NLRP3 inflammasome; expression of TLR4/MyD88; transcriptional activation of p65/NF-κB and secretion of cytokines involved in cardiotoxicity (Interleukins 1β, 8 and 6). Moreover, mTORC1 /Fox01/3a expression studies were performed through western blot and confocal laser microscope methods. Results Dapagliflozin increases significantly the cardiomyocytes viability during exposure to doxorubicin and trastuzumab. Its cardioprotective properties are explainable by the reduction of intracellular Ca2+ overload (−47,6% vs cells treated only to anticancer drugs; p Conclusion Dapagliflozin demonstrated for the first time cardioprotective properties during doxorubicin and trastuzumab exposure. The main biochemical effects of dapagliflozin are related to MYD88, NLRP3 complex, Leukotrienes/Interleukin 6 axis and mTORC1 /Fox01/3a mediated apoptosis. This study provides the proof of concept for translational studies designed to investigate the cardioprotective use of dapagliflozin in preclinical models of cardio-oncology. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was funded by the “Ricerca Corrente” grant from the Italian Ministry of Health

Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs.To develop recommendations for the diagnosis and management of DIILD in cancer patients.Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events.The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis.These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD.

Background: Ado-trastuzumab emtansine (T-DM1) is a drug-antibody conjugate whose activity has been confirmed in HER2+ advanced breast cancer (BC) patients by the phase 3 EMILIA trial (Verma et al, NEJM 2012). Within the 991 patients enrolled in this trial, about 10% were affected with brain metastases (BM); in this subgroup, safety and efficacy of T-DM1 were confirmed although without any PFS improvement. Patients and methods: In an Italian, multicenter, retrospective analysis involving 303 patients with advanced BC treated with T-DM1 (Fabi et al, Oncotarget 2017), we analyzed 87 patients with BM (BM-group). The study wanted to evaluate the efficacy of T-DM1 on BM; furthermore we compared BM-group with the remaining 216 patients without BM (nBM-group) in order to study outcome of disease. MRI was used as assessment imaging. The number of extracranial metastatic sites in the BM-group and in the nBM-group was 1 for 10 (11.5%) and for 74 patients (34.3%), 2 for 23 (26.4%) and 93 (43%) patients, 3 for 25 (28.7% and 38 (17.6%) and 4 or more for 29 (33%) and 11 (5%), respectively. In the BM-group, 5 patients (5.7%) had received surgery alone as local treatment for brain metastases, 13 (14.9%) surgery plus stereotactic radio-surgery (SRS), 4 (4.7%) surgery plus whole-brain radiotherapy (WBRT), 23 (26.5%) SRS alone, 40 (45.9%)WBRT alone and 2 (2.3%) WBRT followed by SRS. Twenty-eight patients (32.9%) and 89 (42.4%) in the BM-group and nBM-group, respectively, received T-DM1 as second line, 24 (28.2%) and 49 (23.3%) as third line and 33 (38.8%) and 72 (34.3%) as fourth line. Mean number of cycles was 6 in both groups. Results:Among BM-group, 53 patients (60.9%) were evaluable for response. Two (3.8%) obtained brain complete response, 14 (26.4%) partial response and 13 (24.5%) stable disease [brain disease control rate: 54.7%); 24 (45.3%) progressed during T-DM1. Regarding extracranial metastases, overall response rate was 35.1% in the BM-group and 38.3% in the nBM-group; 6 months-clinical benefit was 50.6% and 52.3%, respectively. Median PFS was 7 months in the BM-group and 8 months in the nBM-group; when T-DM1 was given as second line, median PFS was 5 months in the BM-group and 11 months in nBM-group (p=0.01) while as third, line in which 76% of patients received lapatinib/capacitabine before TDM1, median PFS was 12 and 13 months (p=NS), respectively. Conclusions: T-DM1 showed a good activity on BM in BC patients. A better outcome was shown in patients previously treated with lapatinib. The identification of clinical and biological prognostic factors could be needed to better select more responder patients with BM to T-DM1. Citation Format: Fabi A, Alesini D, Valle E, Carbognin L, Arpino G, Montemurro F, Ciccarese M, Cannita K, Paris I, Cursano MC, Moscetti L, Ferretti G, De Laurentiis M, Zambelli A, La Verde N, Nisticò C, Gasparro S, Giannarelli D, Cognetti F. Ado-trastuzumab emtansine (TDM-1) treatment and brain metastases in HER2 positive metastatic breast cancer patients: Final analysis of an italian multicenter study [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 P1-17-02.

Background: BELLE-2 (NCT01610284) met its primary endpoint of a statistically significant improvement in progression-free survival (PFS) with the pan-phosphoinositide 3-kinase (PI3K) inhibitor BUP+FUL compared with PBO+FUL in postmenopausal pts with HR+, HER2– ABC (Baselga et al. Lancet Oncol 2017). Here, we report the final results for OS. Methods: Postmenopausal women with HR+, HER2– ABC refractory to aromatase inhibitors were enrolled in this randomized, double-blind, placebo-controlled, Phase III study. Pts were randomized (1:1) to receive either oral BUP (100 mg/day) or PBO plus intramuscular FUL (500 mg per standard of care). Randomization was stratified by PI3K pathway status in archival tumor tissue (activated [PIK3CA mutation or loss of phosphatase and tensin homolog expression], non-activated or unknown) and visceral disease status (present or absent). Baseline PIK3CA mutation status in circulating tumor (ct) DNA was assessed in a subset of pts. The key secondary endpoint was OS, defined as time from randomization to date of death due to any cause, in the full population (PI3K pathway activated, non-activated and unknown), main study cohort (PI3K pathway activated and non-activated) and PI3K pathway-activated subpopulation. Other secondary endpoints included safety. OS by PIK3CA status in ctDNA was also investigated. Results: 1147 pts received BUP+FUL or PBO+FUL. In the full population and main cohort, OS results trended in favor of BUP+FUL vs PBO+FUL, but were not statistically significant (Table). Post-treatment use of antineoplastic medications was balanced between both arms. In pts with PI3K pathway-activated status, OS improved by approximately 6 months (Table). In pts with mutant PIK3CA ctDNA status, there was a slight trend in favor of BUP+FUL vs PBO+FUL (Table). Median OS, monthsHR (95% CI)P valueFull population N=1147BUP+FUL n=57633.20.87 (0.74–1.02)0.045* PBO+FUL n=57130.4 Main cohort n=851BUP+FUL n=42730.90.91 (0.75–1.09)0.144* PBO+FUL n=42428.9 PI3K pathway activated n=372BUP+FUL n=18833.60.81 (0.61–1.08)0.075** PBO+FUL n=18427.5 ctDNA PIK3CA mutant n=200BUP+FUL n=8726.00.81 (0.56–1.17)0.127** PBO+FUL n=11324.8 ctDNA PIK3CA non-mutant n=387BUP+FUL n=19931.41.12 (0.83–1.50)0.774** PBO+FUL n=18836.8 *One-sided P value. **Nominal P value. The safety profile of BUP+FUL was consistent with that previously reported, with no new safety concerns. Grade 3/4 adverse events with at least 5% difference between BUP+FUL vs PBO+FUL, respectively, were increased alanine aminotransferase (25.7% vs 1.1%), increased aspartate aminotransferase (18.0% vs 2.8%), hyperglycemia (15.4% vs 0.2%) and rash (8.0% vs 0.0%). Conclusions: The BELLE-2 OS results showed a trend in favor of BUP+FUL, but did not meet statistical significance. More selective PI3K inhibition may improve treatment benefit and safety compared with pan-PI3K inhibition. Further assessment of the predictive benefit of ctDNA-confirmed PIK3CA mutations in this setting is required. Citation Format: Campone M, Im S-A, Iwata H, Clemons M, Ito Y, Awada A, Chia S, Jagiełło-Gruszfeld A, Pistilli B, Tseng L-M, Hurvitz S, Masuda N, Cortés J, De Laurentiis M, Arteaga CL, Jiang Z, Jonat W, Sellami D, El-Hashimy M, Le Mouhaër S, Sankaran B, Bourdeau L, Baselga J. Buparlisib (BUP) or placebo (PBO) plus fulvestrant (FUL) in postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC): Overall survival (OS) results from BELLE-2, a randomized, phase III study [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 PD5-12.

Background: Patients with previously untreated mTNBC typically receive cytotoxic chemotherapy as first-line therapy for metastatic disease. However, efficacy and safety are suboptimal. KEYNOTE-086 (NCT02447003) is a multicohort, single-arm, phase 2 study of pembrolizumab monotherapy for mTNBC. In cohort B, we assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Methods: Key eligibility criteria for cohort B were age ≥18 y, centrally confirmed TNBC, no prior systemic anticancer therapy for metastatic disease, ECOG performance status 0-1, measurable disease per RECIST v1.1 by central review, no radiographic evidence of brain metastases, and a tumor PD-L1 combined positive score (CPS) ≥1. Pembrolizumab 200 mg was given once every 3 wk for 24 mo or until disease progression, intolerable toxicity, or investigator or patient decision. Tumor imaging was performed every 9 wk for 12 mo and every 12 wk thereafter. Clinically stable patients with radiologic progression could remain on pembrolizumab until progression was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, duration of response, and PFS (all RECIST v1.1 by central review) and OS. Results: Of the 206 patients with tumors evaluable for PD-L1 expression, 128 (62%) had PD-L1 CPS ≥1. Of these, 84 met all eligibility criteria and enrolled. All patients were women, median age was 52.5 y, 29 (35%) had ECOG PS 1, 40 (48%) had elevated LDH, 55 (65%) had visceral ± nonvisceral metastases, and 73 (87%) received prior (neo)adjuvant therapy. All patients received ≥1 pembrolizumab dose, and after median follow-up of 10.6 mo, 18 (21%) remained on pembrolizumab. Treatment-related AEs occurred in 53 (63%) patients and were of grade 3-4 severity in 7 (8%); no patients died or discontinued pembrolizumab because of treatment-related AEs. The most common treatment-related AEs were fatigue (26%), nausea (13%), and diarrhea (12%). No grade 3-4 treatment-related AE occurred in >1 patient. The most common immune-mediated AE was hypothyroidism (10%). Three patients had complete response and 16 had partial response for an ORR of 23% (95% CI 15-33). Of the 11 patients with a best response of stable disease, 1 had stable disease for ≥24 wk, leading to a disease control rate of 24% (95% CI 16-34). 12 of 19 (63%) responses were ongoing at data cutoff, and median duration of response was 8.4 mo (range 2.1+ to 13.9+). Median PFS was 2.1 mo (95% CI 2.0-2.2), with an estimated 6-mo PFS rate of 26%. Median OS was 16.1 mo (95% CI 11.3-NR), with an estimated 6-mo OS rate of 83%. Conclusions: Pembrolizumab monotherapy continues to demonstrate a favorable safety profile and robust, durable antitumor activity in patients with PD-L1-positive, previously untreated mTNBC. Citation Format: Adams S, Loi S, Toppmeyer DL, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong AC, Liu MC, Iwata H, Ryvo L, Wimberger P, Rugo HS, Tan A, D'Aquanno C, Ding Y, Karantza V, Schmid P. KEYNOTE-086 cohort B: Pembrolizumab monotherapy for PD-L1–positive, previously untreated, metastatic triple-negative breast cancer (mTNBC) [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 PD6-10.