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Efficacy and Safety of Platinum and Metronomic Cyclophosphamide in Triple Negative Breast Cancer
Abstracts / The Breast 36 S1 (2017) S19–S76
Conclusion: Ribociclib + EVE + EXE demonstrated encouraging signs of antitumor activity in pretreated pts with HR+, HER2– ABC, and most patients remained on treatment after 1.7 months of exposure. The study is ongoing, enrolling CDK4/6i-refractory patients; updated safety and efficacy data from this study will be presented at the meeting.
PO73 EFFICACY AND SAFETY OF PALBOCICLIB (PAL) PUS FULVESTRANT (F) BY GEOGRAPHIC REGION IN WOMEN WITH ENDOCRINERESISTANT HORMONE RECEPTOR-POSITIVE (HR+), HUMAN EPIDERMAN GROWTH FACTOR RECEPTOR 2-NEGATIVE (HER2-) ADVANCED BREAST CANCER (ABC) FROM PALOMA-3 Nadia Harbeck1, Marco Colleoni2, Angela Demichele6, Nicholas C. Turner11, Massimo Cristofanilli10, Shailendra Verma5, Bethany Sleckman3, Xin Huang7, Kathy Puyana Theall8, Eustratios Bananis9, Norikazu Masuda4, Seock-Ah Im12 1 Brustzentrum der Universitaet Muenchen (LMU), OB&GYN, Munich, Germany; 2European Institute of Oncology, Divisione di Senologia Medica, Milano, Italy; 3Mercy Clinic Oncology LLC, Oncology, St. Louis, USA; 4NHO Osaka National Hospital, Breast Oncology, Osaka, Japan; 5 Ottawa Hospital Cancer Centre, Division of Medical Oncology, Ottawa, Canada; 6Perelman School of Medicine, University of Pennsylvania, Medicine and Epidemiology, Philadelphia, USA; 7Pfizer Inc, Oncology, San Diego, USA; 8Pfizer Inc, Oncology Clinical Development, Cambridge, USA; 9Pfizer Inc, US Medical Affairs, New York, USA; 10Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, USA; 11Royal Marsden Hospital and Institute of Cancer Research, Breast Cancer, London, UK; 12Seoul National University Hospital Cancer Research Institute, Seoul National University College of Medicine, Internal Medicine, Seoul, South Korea Background: In PALOMA-3, PAL + F showed significant improvement in median progression-free survival (PFS) vs F + placebo (PBO) in patients ( pts) with endocrine-resistant HR+, HER2-ABC (cutoff date: Mar 16, 2015; 9.5 vs 4.6 mo; hazard ratio [HR], 0.46; P < 0.0001) (Cristofanilli et al. Lancet Oncol. 2016;425–39). Here, we report the efficacy and safety results by geographic region (North America [NA], Europe [EU], and Asia Pacific [AP]). Methods: Women who progressed on prior endocrine therapy regardless of menopausal status were randomized 2:1 to PAL (125 mg/d oral [3 weeks on, 1 week off]) + F (500 mg day 1 and 15 of cycle 1 and monthly thereafter) or PBO + F. One previous line of chemotherapy in ABC was allowed. This analysis was based on Oct 23, 2015 cutoff data. Results: Of 521 pts, 240 enrolled in NA, 167 in EU, and 114 in AP and were included in this analysis. Baseline demographics were similar between regions; however, AP pts were younger (median age of 53 vs 58 y in both NA and EU), and therefore more AP pts were pre/ perimenopausal (38% vs 16% in both NA and EU). In NA, more pts had visceral disease (63% vs 57% in EU and 57% in AP). PAL + F improved median PFS vs PBO + F in the overall population (11.2 [95% CI, 9.5‒12.9] vs 4.6 mo [95% CI, 3.5‒5.6]; HR, 0.50; P < 0.0001) and in NA (9.9 [95% CI, 7.4‒11.3] vs 3.5 mo [95% CI, 2.0‒5.5]; HR, 0.52; P < 0.0001), EU (13.4 [95% CI, 10.8‒15.9] vs 5.3 mo [95% CI, 3.3‒ 9.2]; HR, 0.46, P < 0.0001), and AP (12.9 mo [95% CI, 9.2‒15.5] vs 5.8 mo [95% CI, 3.6‒9.2]; HR, 0.51; P < 0.005). Objective response rate (ORR) was higher with PAL + F vs PBO + F in NA (24% [95% CI, 16.8‒32.8] vs 9% [95% CI, 3.4‒18.5]), EU (36% [95% CI, 25.6‒46.6] vs 13% [95% CI, 4.4‒28.1]), and AP (22% [95% CI, 12.1‒34.2] vs 12% [95% CI, 3.4‒28.2]). Clinical benefit response rate (CBR) was higher with PAL + F vs PBO + F in NA (58% [95% CI, 48.1‒66.5] vs 28% [95% CI, 18.0‒40.7]), EU (69% [95% CI, 58.1‒78.5] vs 42% [95% CI, 26.3‒59.2]), and AP (65% [95% CI, 51.6‒76.9] vs 45% [95% CI, 28.1‒63.6]). Treatment-emergent adverse events (AEs) for all grades occurred in
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99%/99% of pts (PAL + F/PBO + F) in NA, 97%/84% in EU, and 100%/ 92% in AP. With PAL + F, the most common AE in each region (all grade/grade ≥3) was neutropenia, (78%/62% in NA, 83%/59% in EU, and 95%/91% in AP). In general, regardless of treatment, pts from EU had lower incidences of fatigue, infections, nausea, stomatitis, alopecia, diarrhea, and rash vs pts from NA or AP. Conclusions: In all geographic regions analyzed (NA, EU, and AP), PAL + F demonstrated improvement in PFS, ORR, and CBR vs PBO + F in pts with HR+, HER2-ABC; the magnitude of benefit was comparable between regions. The safety profile of PAL + F was similar to previous results; neutropenia was the most commonly reported AE.
PO74 EFFICACY AND SAFETY OF PLATINUM AND METRONOMIC CYCLOPHOSPHAMIDE IN TRIPLE NEGATIVE BREAST CANCER Giulia Viale, Marzia Locatelli, Carmen Criscitiello, Dario Trapani, Giuseppe Curigliano European Institute of Oncology, Division of Early Drug Development, Milan, Italy Background: Triple negative breast cancer (TNBC) accounts for approximately 15–20% of breast carcinomas and is associated with poor prognosis. Platinum-based regimens showed efficacy in this tumor subtype, particularly in cases with defective BRCA DNA repair pathways. Cyclophosphamide administered at low metronomic doses has the potential of downregulating regulatory T cells. Methods: Our aim was to evaluate the efficacy and safety of a combination of cisplatin and metronomic cyclophosphamide in patients with advanced TNBC. Cisplatin was administered at the dose of 60 mg/mq every 3 weeks up to 6–8 cycles; cyclophosphamide was given orally (50 mg daily) in a continuous regimen both concomitant and as maintenance therapy after cisplatin. Data on toxicity were reported according to Common Terminology Criteria for Adverse Events Version 4.0. Results: A total of 47 patients with advanced TNBC were treated in our Institute from October 2011 to September 2015. Patients with uncontrolled brain metastases or leptomeningeal disease were excluded. A fair number of patients (36% of the cohort) was largely pretreated, with ≥3 lines of chemotherapy received in the metastatic setting. The treatment was generally well tolerated. The most common adverse event (AE) was G1-G2 hematologic toxicity, but the incidence of G3 anemia and leukopenia was 2% and 9.4% respectively. Only one case of G4 febrile neutropenia was reported. Other observed AEs were nausea, vomiting, neurotoxicityand fatigue, commonly of grade 1–2; although 1% G3 fatigue was reported and one case of G3 transaminase elevation. Severe adverse events occurred in 3 patients (2 thromboembolic events and 1 case of pulmonary edema). Hematologic toxicity was managed with cisplatin dose delay (23% of patients) or dose reduction (28% of patients) in the majority of cases, but 3 patients definitively interrupted treatment with cisplatin due to persistent hematologic toxicity. An additional 10% of cisplatin dose reduction was due to other causes, as neurotoxicity or elevation of transaminases. Although no dose reductions were made for cyclophosphamide, 4 patients temporary suspended treatment due to persistent neutropenia. Data on efficacy were available for 43 patients: Objective response rate was 23.3% and clinical benefit – defined as partial/ complete response or stable disease at 6 months after treatment– was 57.9%. No significant correlation between response to treatment and age, extent and site of disease, or time after surgery has been observed. Conclusion: The combination of cisplatin and metronomic cyclophosphamide showed efficacy with a favorable toxicity profile in patients with advanced TNBC. This regimen could represent a potential therapeutic option with a biologic rationale in TNBC.
Conclusion: Ribociclib + EVE + EXE demonstrated encouraging signs of antitumor activity in pretreated pts with HR+, HER2– ABC, and most patients remained on treatment after 1.7 months of exposure. The study is ongoing, enrolling CDK4/6i-refractory patients; updated safety and efficacy data from this study will be presented at the meeting.
PO73 EFFICACY AND SAFETY OF PALBOCICLIB (PAL) PUS FULVESTRANT (F) BY GEOGRAPHIC REGION IN WOMEN WITH ENDOCRINERESISTANT HORMONE RECEPTOR-POSITIVE (HR+), HUMAN EPIDERMAN GROWTH FACTOR RECEPTOR 2-NEGATIVE (HER2-) ADVANCED BREAST CANCER (ABC) FROM PALOMA-3 Nadia Harbeck1, Marco Colleoni2, Angela Demichele6, Nicholas C. Turner11, Massimo Cristofanilli10, Shailendra Verma5, Bethany Sleckman3, Xin Huang7, Kathy Puyana Theall8, Eustratios Bananis9, Norikazu Masuda4, Seock-Ah Im12 1 Brustzentrum der Universitaet Muenchen (LMU), OB&GYN, Munich, Germany; 2European Institute of Oncology, Divisione di Senologia Medica, Milano, Italy; 3Mercy Clinic Oncology LLC, Oncology, St. Louis, USA; 4NHO Osaka National Hospital, Breast Oncology, Osaka, Japan; 5 Ottawa Hospital Cancer Centre, Division of Medical Oncology, Ottawa, Canada; 6Perelman School of Medicine, University of Pennsylvania, Medicine and Epidemiology, Philadelphia, USA; 7Pfizer Inc, Oncology, San Diego, USA; 8Pfizer Inc, Oncology Clinical Development, Cambridge, USA; 9Pfizer Inc, US Medical Affairs, New York, USA; 10Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Chicago, USA; 11Royal Marsden Hospital and Institute of Cancer Research, Breast Cancer, London, UK; 12Seoul National University Hospital Cancer Research Institute, Seoul National University College of Medicine, Internal Medicine, Seoul, South Korea Background: In PALOMA-3, PAL + F showed significant improvement in median progression-free survival (PFS) vs F + placebo (PBO) in patients ( pts) with endocrine-resistant HR+, HER2-ABC (cutoff date: Mar 16, 2015; 9.5 vs 4.6 mo; hazard ratio [HR], 0.46; P < 0.0001) (Cristofanilli et al. Lancet Oncol. 2016;425–39). Here, we report the efficacy and safety results by geographic region (North America [NA], Europe [EU], and Asia Pacific [AP]). Methods: Women who progressed on prior endocrine therapy regardless of menopausal status were randomized 2:1 to PAL (125 mg/d oral [3 weeks on, 1 week off]) + F (500 mg day 1 and 15 of cycle 1 and monthly thereafter) or PBO + F. One previous line of chemotherapy in ABC was allowed. This analysis was based on Oct 23, 2015 cutoff data. Results: Of 521 pts, 240 enrolled in NA, 167 in EU, and 114 in AP and were included in this analysis. Baseline demographics were similar between regions; however, AP pts were younger (median age of 53 vs 58 y in both NA and EU), and therefore more AP pts were pre/ perimenopausal (38% vs 16% in both NA and EU). In NA, more pts had visceral disease (63% vs 57% in EU and 57% in AP). PAL + F improved median PFS vs PBO + F in the overall population (11.2 [95% CI, 9.5‒12.9] vs 4.6 mo [95% CI, 3.5‒5.6]; HR, 0.50; P < 0.0001) and in NA (9.9 [95% CI, 7.4‒11.3] vs 3.5 mo [95% CI, 2.0‒5.5]; HR, 0.52; P < 0.0001), EU (13.4 [95% CI, 10.8‒15.9] vs 5.3 mo [95% CI, 3.3‒ 9.2]; HR, 0.46, P < 0.0001), and AP (12.9 mo [95% CI, 9.2‒15.5] vs 5.8 mo [95% CI, 3.6‒9.2]; HR, 0.51; P < 0.005). Objective response rate (ORR) was higher with PAL + F vs PBO + F in NA (24% [95% CI, 16.8‒32.8] vs 9% [95% CI, 3.4‒18.5]), EU (36% [95% CI, 25.6‒46.6] vs 13% [95% CI, 4.4‒28.1]), and AP (22% [95% CI, 12.1‒34.2] vs 12% [95% CI, 3.4‒28.2]). Clinical benefit response rate (CBR) was higher with PAL + F vs PBO + F in NA (58% [95% CI, 48.1‒66.5] vs 28% [95% CI, 18.0‒40.7]), EU (69% [95% CI, 58.1‒78.5] vs 42% [95% CI, 26.3‒59.2]), and AP (65% [95% CI, 51.6‒76.9] vs 45% [95% CI, 28.1‒63.6]). Treatment-emergent adverse events (AEs) for all grades occurred in
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99%/99% of pts (PAL + F/PBO + F) in NA, 97%/84% in EU, and 100%/ 92% in AP. With PAL + F, the most common AE in each region (all grade/grade ≥3) was neutropenia, (78%/62% in NA, 83%/59% in EU, and 95%/91% in AP). In general, regardless of treatment, pts from EU had lower incidences of fatigue, infections, nausea, stomatitis, alopecia, diarrhea, and rash vs pts from NA or AP. Conclusions: In all geographic regions analyzed (NA, EU, and AP), PAL + F demonstrated improvement in PFS, ORR, and CBR vs PBO + F in pts with HR+, HER2-ABC; the magnitude of benefit was comparable between regions. The safety profile of PAL + F was similar to previous results; neutropenia was the most commonly reported AE.
PO74 EFFICACY AND SAFETY OF PLATINUM AND METRONOMIC CYCLOPHOSPHAMIDE IN TRIPLE NEGATIVE BREAST CANCER Giulia Viale, Marzia Locatelli, Carmen Criscitiello, Dario Trapani, Giuseppe Curigliano European Institute of Oncology, Division of Early Drug Development, Milan, Italy Background: Triple negative breast cancer (TNBC) accounts for approximately 15–20% of breast carcinomas and is associated with poor prognosis. Platinum-based regimens showed efficacy in this tumor subtype, particularly in cases with defective BRCA DNA repair pathways. Cyclophosphamide administered at low metronomic doses has the potential of downregulating regulatory T cells. Methods: Our aim was to evaluate the efficacy and safety of a combination of cisplatin and metronomic cyclophosphamide in patients with advanced TNBC. Cisplatin was administered at the dose of 60 mg/mq every 3 weeks up to 6–8 cycles; cyclophosphamide was given orally (50 mg daily) in a continuous regimen both concomitant and as maintenance therapy after cisplatin. Data on toxicity were reported according to Common Terminology Criteria for Adverse Events Version 4.0. Results: A total of 47 patients with advanced TNBC were treated in our Institute from October 2011 to September 2015. Patients with uncontrolled brain metastases or leptomeningeal disease were excluded. A fair number of patients (36% of the cohort) was largely pretreated, with ≥3 lines of chemotherapy received in the metastatic setting. The treatment was generally well tolerated. The most common adverse event (AE) was G1-G2 hematologic toxicity, but the incidence of G3 anemia and leukopenia was 2% and 9.4% respectively. Only one case of G4 febrile neutropenia was reported. Other observed AEs were nausea, vomiting, neurotoxicityand fatigue, commonly of grade 1–2; although 1% G3 fatigue was reported and one case of G3 transaminase elevation. Severe adverse events occurred in 3 patients (2 thromboembolic events and 1 case of pulmonary edema). Hematologic toxicity was managed with cisplatin dose delay (23% of patients) or dose reduction (28% of patients) in the majority of cases, but 3 patients definitively interrupted treatment with cisplatin due to persistent hematologic toxicity. An additional 10% of cisplatin dose reduction was due to other causes, as neurotoxicity or elevation of transaminases. Although no dose reductions were made for cyclophosphamide, 4 patients temporary suspended treatment due to persistent neutropenia. Data on efficacy were available for 43 patients: Objective response rate was 23.3% and clinical benefit – defined as partial/ complete response or stable disease at 6 months after treatment– was 57.9%. No significant correlation between response to treatment and age, extent and site of disease, or time after surgery has been observed. Conclusion: The combination of cisplatin and metronomic cyclophosphamide showed efficacy with a favorable toxicity profile in patients with advanced TNBC. This regimen could represent a potential therapeutic option with a biologic rationale in TNBC.