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Background: Several randomized clinical trials clearly demonstrated that adding palbociclib (P) to endocrine therapies (ET), such as letrozole (LT) or fulvestrant (FLV), significantly improves outcome both in first-line/endocrine sensitive and second-line/endocrine resistant hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2) metastatic breast cancer (MBC) patients (pts). The aims of the present study were to assess efficacy, activity and toxicity of P combined with either LT or FLV in a real world setting, and to study the efficacy and activity of treatments administered after progression to P + ET. Methods: Records of 245 consecutive HR+/HER2- MBC patients from 14 Italian cancer centers were reviewed in this observational study. Primary end-point was progression-free survival (PFS) obtained with P+ET; secondary end-points were overall response rates (ORR) and clinical benefit rate (CBR) obtained with P+ET and with post-progression treatments, as well as overall survival (OS), PFS to subsequent treatment lines and post-progression survival (PPS). Results: Overall 245 pts were treated with P+ET from April 2014. Of them, 116 (47%) received it in first-line setting, 70 (28%) in second-line and the rest (68 pts, 25%) in subsequent lines. Median age was 60 (35-80) years and median ECOG performance status was 0. Seventy-three pts (30%) had more than two metastatic sites and 75 (31%) had visceral metastasis. Ninenty-one (37%) pts received P+LT and 92 (37%) were treated with P+FLV. For 15 (6%) premenopausal pts an LHRH analogue was added to P+ET. In 77 (41%) patients a biopsy of a metastatic lesion was performed. Among the 116 pts treated in first-line setting, median PFS was 14.7 (95% CI 12.0-17.3) and 15.1 (95%CI 8.6-21.6) months for pts receiving P+LT and P+FLV, respectively. ORR was 48% (95% CI: 39-57%) and CBR was 75% (95% CI, 66-82%). Four (3%) complete responses (CR), 52 (45%) partial responses (PR), 31 (27%) stable disease (SD) and 11 (9%) progression disease (PD) were observed as best response; 18 pts were not yet evaluable. Among the 70 pts treated in second-line setting, median PFS was 10.8 (95%CI 0-24.3) and 7.9 (95%CI 3.3-12.5) months, for pts receiving P+LT and P+FLV, respectively. The ORR was 26% (95% CI: 16-38) and the CBR was 66% (95% CI, 53-76). One CR (1%), 17 PR (24%), 28 SD (40%) and 13 PD (18.5%) were observed as best response, while 9 were not yet evaluable. Best response was achieved after a median of 5 cycle. At time of the current analysis, 50 pts experienced PD during P+ET. Of them, 38 (76%) received chemotherapy (capecitabine, eribulin, nab-paclitaxel, paclitaxel+bevacizumab, vinoreline) and 12 (24%) ET. To date, only 5 pts progressed during these therapies, preventing us for evaluating secondary end-points regarding efficacy and activity. The most frequent adverse event (AE) was grade 3-4 neutropenia (31%), with febrile neutropenia reported in 5 (2%) cases. Main non-hematological AEs were fatigue and gastrointestinal symptoms (diarrhea and stypsis). Conclusions: Our findings confirm the efficacy and safety of P+ET as first/second-line treatment for HR+/HER2- MBC pts, even in a non-selected, real world population. Since data regarding the efficacy and activity of post-progression therapies were not mature at the time of the current analysis, they will be subsequently presented. Citation Format: Alessandra Fabi, Michelangelo Russillo, Mariangela Ciccarese, Simone Scagnoli, Francesco Schettini, Giuseppe Buono, Vito Lo Russo, Grazia Arpino, Rosalba Rossella, Giuseppina Sarobba, Marianna Giampaglia, Patrizia Pellegrini, Simonetta Stani, Michela Palleschi, Vincenzo Adamo, Francesca Morelli, Maria Agnese Fabbri, Cecilia Nistico, Gianluigi Ferretti, Giovanna Catania, Simona Pisegna, Diana Giannarelli, Francesco Cognetti. Real-world evidence of efficacy and activity of palbociclib plus endocrine therapy and post-progression treatments in HR+/HER2- metastatic breast cancer patients: The PALPract study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-11-18.

Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). Results: Patients who received a first-line pertuzumab-based regimen showed better PFS ( p < 0.0001) and OS ( p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine ( p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine ( p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 ( p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs ( p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. Conclusion: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

Background: Despite the sequential E therapy is recognized as the preferred approach for HR+/HER2- MBC, no data from clinical trials support the choice between the different sequential strategies. Methods: In this retrospective study descriptive statistics are reported using the median (Interquartile range, IQR) or frequency. Progression Free Survival (PFS) curves were estimated with the Kaplan-Meier method and compared with the log-rank test. Analysis were performed by SPSS version 21.0 (SPSS Inc., Chicago, IL). Results: From January 2006 to December 2017, 240 patients (pts) with HR+/HER2- MBC receiving at least two consecutive E therapies as first approach were selected from 12 italian cancer centers. The median age at the time of metastasis onset was 63.5 (IQR: 55-72.5) years; 184 (76.7%) pts were in menopausal status; 38 (16%) had de novo stage IV disease and the remaining 202 (84%) had recurrent BC with a median time of 78 months (5-396 months). At the beginning of MBC diagnosis, 148 (62%) pts had a single site of distant disease, 108 (45%) of whom had bone only disease and 45 (18.8%) presented visceral involvement too. The aromatase inhibitor (AI) was chosen as I-line therapy in 146 (60.9%) pts, followed by Fulvestrant (F) in 62 (25.8%) pts; the alternative I-line options were everolimus-exemestane (Eve-Exe), tamoxifene (T), Palbociclib (P)+AI and F+AI in 13 (5.4%), 14 (5.8%), 1 (0.4%) and 4 (1.7%) pts, respectively. The most favourite II-line option resulted F for 111 (46.2%) pts while the Eve-Exe combination was chosen in 70 (29.2%) pts, AI in 30 (12.5%) pts; T, AI+F, P+F and antiprogestincwere administered in 4 (1.7%), 4 (1.7%), 19 (7.9%) and 2 (0.8%) pts, respectively. For I and II-line, the AI followed by F (40%) and F followed by Eve-Exe (18%) were the most common sequential therapeutic approaches; the several alternative options were scanty used (in less than 10%). The median Progression-Free Survival (PFS) from first and second-line E therapies resulted 15.7 (95% CI 13.3-18.1) and 10.3 months (95% CI 8.7-11.9), respectively. Among 194 pts with disease progression after second-line E therapy, 87 (44.8%) received further E therapies with a median PFS 9.4 months (95% CI 7.9-10.9). The remaining 70 (29.2%) pts was treated with palliative chemotherapy. Interestingly, the median Overall Survival (OS) was even longer for pts receiving more lines of E therapies compared to the group with earlier introduction of chemotherapy (204.3 vs 92.8; p=0.007). Finally, in the subgroup analyses a longer PFS benefit was observed in pts with disease recurrence over 12 months from initial diagnosis (38.1 vs 30.3 months p=0.04) and limited sites of disease involvement at the time of MBC diagnosis (37.6 vs 28.3 months, p=0.03) Conclusions: The sequential use in first and second-line setting of E therapies for HR+/HER2- MBC improves median PFS up to 32.3 months. According to real practice experience the optimal sequences could be AIs followed by F and F followed by Eve-Exe. A role for these compounds should be redefined in the light of recently introduction of CDK 4/6 inhibitors in combination with AIs or F for the first or later lines. Citation Format: Fabi A, Giannarelli D, Botticelli A, Scagnoli S, Pellegrino A, Fabbri A, Corsi D, Magri V, Pizzuti L, Paris I, Bruni V, Pace R, Lanzetta G, Stani S, Moscetti L, Marchetti P, Piesco G, Cognetti F, Rossi V. SEQUERPLUS: A multicenter real practice observational study investigating the endocrine-based (E) therapies sequential approach in hormonal receptor positive (HR+) HER2 negative (-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-07.

Background We reported the results of an Italian large retrospective analysis that evaluated the effectiveness and safety of T-DM1 in ‘field-practice’ breast cancer patients. We performed a sub-analysis to investigate the clinical activity of T-DM1 in patients with brain metastases (BMs). Methods The records of 87 adult women with HER2-positive breast cancer and BMs treated with T-DM1 were reviewed. Their clinical outcomes were compared with those of 216 patients without central nervous system (CNS) involvement. Results Response to T-DM1 treatment in BMs was available for 53 patients in the BM group (60.9%): two patients reported a complete response (3.8%), 11 patients obtained partial response (20.7%; overall response rate: 24.5%), 16 patients had a stable disease (30.1%). Regarding extracranial disease, a total of 77 and 191 patients were evaluable for response in BM group and non-BM group, respectively. The overall response rate was 35.1% in the BM group and 38.3% in the non-BM group; disease control rate was 53.3% and 66.6%, respectively. At a median follow-up of 16 months (range: 1–55), median cumulative progression-free survival (PFS) was 7 months (95% CI: 5.4–8.6) in the BM group and 8 months (95% CI: 5.7–10.3) in the non-BM group. In the second-line setting, PFS was 5 (95% CI: 3.1–6.9) versus 11 (95% CI: 7.1–14.9) months (p = 0.01). Overall survival was 14 months (95% CI: 12.2–15.8) in the BM group and 32 months (95% CI: 24.4–39.6) in the non-BM group (p Conclusions T-DM1 is active in breast cancer patients with BMs.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (mBC). The aim of this ‘field-practice’ study was to investigate the efficacy and safety of T-DM1, focusing on treatment line, previous lapatinib treatment and patterns of metastasis. Three hundred and three patients with HER2-positive mBC who received T-DM1 were identified by reviewing the medical records of 24 Italian Institutions. One hundred fourty-nine (49%) and 264 (87%) had received prior hormonal treatment and/or anti-HER2 targeted therapy, respectively. Particularly, 149 patients had been previously treated with lapatinib. The objective response rate (ORR) was 36.2%, and 44.5% when T-DM1 was administrated as second-line therapy. Considering only patients with liver metastases, the ORR was 44.4%. The median progression-free survival (PFS) was 7.0 months in the overall population, but it reached 9.0 and 12.0 months when TDM-1 was administered as second- and third-line treatment, respectively. In conclusion, in this ‘real-word’ study evaluating the effects of T-DM1 in patients with HER2-positive mBC who progressed on prior anti-HER2 therapies, we observed a clinically-relevant benefit in those who had received T-DM1 in early metastatic treatment-line and in subjects previously treated with lapatinib.

Background: T-DM1 showed remarkable activity in metastatic HER-2 positive breast cancer (mBC) and it was recently approved for clinical use in patients (pts) who previously failed Trastuzumab- and Taxanes-based therapies. Currently, little is known on the performance of T-DM1 in a “real life” scenario. Therefore, we investigated effectiveness and safety of T-DM1 in Italian daily practice. Methods: Pts baseline characteristics and clinical outcome of pts with HER-2 positive mBC treated with T-DM1 between 2013 and 2015 at 20 Italian Institutions were retrospectively collected and analyzed. Results: 300 pts were included in our analysis. Median age was 51 years (27-78); visceral metastases were present in 204 (68%) pts and brain metastases in 86 (29%). It is noteworthy that 111 (37%) pts received T-DM1 as pure second line, 83 (28%) as third line and 96 (32%) as further lines. Moreover 10 (3%) pts had T-DM1 as first line because disease recurrence occurred during or adjuvant trastuzumab of within 6 months of its completion. The overall response rate (ORR) was 40%, global disease control rate (gDCR) 64%, median progression-free survival (PFS) 7.0 months (C.I.95%: 5.6-8.4) and overall survival (OS) at 2 years 63%. Pts with 1, 2 and 3 or more metastatic site had OS at 2 years of 87%, 67% and 46%, respectively (p Conclusions: To our knowledge, this is the first real life, multicenter retrospective analysis evaluating efficacy and safety of T-DM1 in pretreated HER-2 positive mBC pts. We observed remarkable results in terms of PFS and OS, especially when T-DM1 was given early in the course of metastatic disease. Shortened PFS in patients progressing after pertuzumab suggest further analyses to better define possible molecular mechanisms of cross-resistences between two molecules. As a whole there was no evidence of significant or unexpected toxicities. Although these findings should be taken with caution due to the retrospective analysis and the different lines of previous treatment considered, we confirmed the potential therapeutic role of T-DM1 across a heterogeneous population of HER-2 positive mBC patients. The final analysis will be presented to the meeting. Citation Format: Fabi A, De Laurentiis M, Caruso M, Valle E, Moscetti L, Santini D, Cannita K, Carbognin L, Ciccarese M, Rossello R, Arpino G, Leonardi V, Montemurro F, La Verde N, Generali DG, Zambelli A, Scandurra G, Russillo M, Paris I, D'Ottavio AM, Filippelli G, Giampaglia M, Stani S, Fabbri A, Alesini D, Giannarelli D, Cognetti F. T-DM1 in HER2 positive advanced breast cancer patients: Real world practice from a multicenter observational 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 P4-21-11.

e12019Background: T-DM1 showed remarkable activity in metastatic (m) HER-2 positive breast cancer (BC) and it recently was approved for clinical use in patients (pts) who previously failed trastuzumab and taxanes. The impact of drug prescription in real life compared with the findings reported in clinical trials exerting a strict accrual criteria has been rarely assessed. We investigated use and effectiveness of T-DM1 in daily practice. Methods: We included all pts with HER2-positive mBC, diagnosed in 12 Italian oncology hospitals between 2013 and 2015. Our aim was to assess the actual use of T-DM1 in HER2 positive mBC pts and its efficacy in clinical practice. Results: The data of 119 pts were retrospectively collected. The median age was 49 years (28-78), visceral metastases were present in 91 pts (77%) and brain metastases in 44 (37%). It is noteworthy that 29 pts (24%) received T-DM1 as second-line, 42 (35%) as third-line, and 43 (36%) as fourth- or further-line option. Moreover, 4 pts had TDM-1 as fi...