Significant Prolongation Of Progression-free Survival Research Articles

Abstract P1-13-12: Quality of life and patient-reported outcomes in US patients enrolled in the MONALEESA-2 study

Abstract Background: Improvement to and maintenance of the highest possible health-related quality of life (QoL), in addition to disease control, are key goals of treatment in patients with advanced breast cancer (ABC). Endocrine therapy is preferred as first-line therapy in ABC because of its preferable safety profile compared with chemotherapy. In the MONALEESA-2 study, the cyclin-dependent kinases 4 and 6 inhibitor ribociclib, in combination with letrozole, significantly extended progression-free survival (PFS) compared with placebo + letrozole in patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) ABC. Patient-reported outcomes demonstrated similar QoL among patients in both treatment groups. Here, we present data from US patients enrolled in the MONALEESA-2 study on overall QoL as well as individual domains. Methods: Postmenopausal women (N=668) with HR+, HER2− ABC who did not receive prior systemic treatment for ABC and had an Eastern Cooperative Oncology Group performance status score of ≤1, adequate bone marrow and organ function, and no history of active cardiac dysfunction were randomized 1:1 to receive either ribociclib (600 mg/d, 3 weeks on/1 week off) + letrozole (2.5 mg/d, continuous) or placebo + letrozole. The primary end point was locally assessed PFS. Quality of life was reported using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the EuroQol 5-domain 5 level (EQ-5D-5L) visual analog scale (VAS) of overall health, and the breast symptom score of the EORTC QLQ-Breast Cancer 23 (EORTC QLQ-BR23) module. Data cutoff in this analysis was January 29, 2016. Results: Patient characteristics and QoL survey reports were well balanced across treatment groups in US patients (n=213). The global health status/QoL scores of the EORTC QLQ-C30 were maintained between groups, and improved over time in the ribociclib group (mean ± standard deviation [SD] score at baseline, 69.1 ± 19.0; at 8 months, 71.3 ± 18.2; and at 16 months, 73.0 ± 16.0) and the placebo group (mean ± SD score at baseline, 69.9 ± 20.0; at 8 months, 75.9 ± 19.2; and at 16 months, 77.0 ± 15.0), which was consistent with scores in the overall population. At 16 months, the proportion of patients who did not experience ≥10% deterioration of all QoL scores was similar among treatment groups. Quality of Life Outcomes of US Patients in the MONALEESA-2 Study at 16 MonthsOutcomeTreatment, nPatients without ≥10% deterioration in score, % (95% CI, %)EORTC QLQ-C30 Global health status/QoLRIB + LET, 2664.0 (49.4–75.4) PBO + LET, 3550.5 (36.2–63.2)Physical functioningRIB + LET, 2175.7 (62.6–84.7) PBO + LET, 1773.1 (57.2–83.9)Emotional functioningRIB + LET, 2271.6 (58.6–81.2) PBO + LET, 3159.7 (45.7–71.2)Social functioningRIB + LET, 1780.1 (68.5–87.8) PBO + LET, 2660.2 (44.1–73.0)EORTC QLQ-BR23 breast symptom scoreRIB + LET, 888.0 (76.6–94.0) PBO + LET, 886.2 (70.6–93.9)EQ-5D-5L VAS of overall healthRIB + LET, 1386.6 (76.9–92.4) PBO + LET, 1873.4 (56.8–84.4)LET, letrozole; PBO, placebo; RIB, ribociclib. Conclusions: Addition of ribociclib to letrozole in US patients enrolled in MONALEESA-2 led to significant prolongation of PFS while maintaining QoL. Citation Format: Tolaney SM, Tan-Chiu E, Truica C, Volas-Redd G, Shtivelband M, Dalal AA, Chandiwana D, Hortobagyi G. Quality of life and patient-reported outcomes in US patients enrolled in the MONALEESA-2 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 P1-13-12.

Abstract P5-21-27: Efficacy and safety of ribociclib plus letrozole in US patients enrolled in the MONALEESA-2 study

Abstract Background: Endocrine-based therapy is the standard of care for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), in whom delaying disease progression is the primary goal. In the randomized Phase 3 MONALEESA-2 study (ClinicalTrials.gov identifier, NCT01958021), first-line ribociclib (a selective inhibitor of cyclin-dependent kinases 4 and 6) + letrozole significantly prolonged progression-free survival (PFS) compared with placebo + letrozole in postmenopausal women with HR+, HER2− ABC (hazard ratio, 0.556; 95% confidence interval [CI], 0.429–0.720) at the interim analysis cutoff date. Here, we present safety and efficacy data from US patients who were enrolled in the MONALEESA-2 study. Methods: Postmenopausal women (N=668) with HR+, HER2− ABC who did not receive prior systemic treatment for ABC and had an Eastern Cooperative Oncology Group performance status score of ≤1, adequate bone marrow and organ function, and no history of active cardiac dysfunction were randomized 1:1 to receive either ribociclib (600 mg/d, 3 weeks on/1 week off) + letrozole (2.5 mg/d, continuous) or placebo + letrozole. The primary end point was locally assessed PFS. The data cutoff for this analysis was January 29, 2016. Results: Baseline demographics, patient disposition, and prior therapy were well balanced across treatment groups in the US subset (N=213; ribociclib group, n=100; placebo group, n=113). Median treatment duration was 16.3 months. In US patients, median PFS was significantly prolonged in the ribociclib group (median PFS, not reached [NR]; 95% CI, 17.1 months to NR) versus the placebo group (median PFS, 14.4 months [95% CI, 11.1–18.4 months]; hazard ratio, 0.451 [95% CI, 0.281–0.724]; P=0.000363), with a median follow-up of 11.0 months. In a subsequent preplanned analysis of overall survival, median PFS was 27.6 months in the ribociclib group versus 15.0 months in the placebo group (hazard ratio, 0.527; 95% CI, 0.351–0.793). The overall response rate (ORR) was significantly greater in the ribociclib group (ORR, 38.0%; 95% CI, 28.5–47.5%) versus the placebo group (ORR, 26.5%; 95% CI, 18.4–34.7%; P=0.040). A trend toward benefit was observed with ribociclib in all subgroups (including age, disease burden, prior therapy, and biomarker status), which was consistent with the overall population. No on-treatment deaths occurred. The most common all-grade adverse events, irrespective of causality, were neutropenia (ribociclib, 69.0%; placebo, 3.7%), nausea (ribociclib, 65.0%; placebo, 39.4%), fatigue (ribociclib, 56.0%; placebo, 46.8%), and diarrhea (ribociclib, 41.0%; placebo, 32.1%). The most common grade 3 (≥25% in either group) and grade 4 (≥10% in either group) AE was neutropenia (grade 3: ribociclib, 39.0%; placebo, 0%; grade 4: ribociclib, 14.0%; placebo, 0%). Two patients (2.0%) in the ribociclib group and none in the placebo group experienced febrile neutropenia. Conclusions: The US patients in the MONALEESA-2 study derived significant PFS benefit from ribociclib + letrozole compared with placebo + letrozole, with a 55% reduction in the relative risk of disease progression. The safety profile was consistent with and comparable to the global study population. Citation Format: Yardley DA, Hart L, Favret A, Blau S, Diab S, Richards D, Sparano J, Beck JT, Richards P, Ward P, Ramaswamy B, Tsai M, Pluard T, Tolaney S, Esteva F, Small T, Purkayastha D, Miller M, Hortobagyi G. Efficacy and safety of ribociclib plus letrozole in US patients enrolled in the MONALEESA-2 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 P5-21-27.

Abstract CT141: Longterm survival in glioblastoma patients after tumor treating fields (TTFields) therapy

Abstract Introduction: Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor and traditionally has a median survival of only 10 to 14 months, with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only 5 to 7 months with optimal therapy. Materials and Methods: Tumor treating fields (TTFields) therapy is a novel treatment technique that has recently shown significant prolonged progression free survival and overall survival innewly diagnosed GBM. This therapy is approved for the treatment of newly diagnosed and recurrent GBM and is based on the principle that low intensity, intermediate frequency alternating electric fields (100 to 300 kHz) have an anti-mitotic effect in specific cell types. The applied fields disrupt the mitotic spindle, microtubule assembly and the segregation of intracellular organelles during cell division, leading to apoptosis or mitotic arrest. Results: Our center was the first in the world to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals (10 GBM and 10 RGBM) in 2004 and 2005, and 4 of the original 20 patients are still alive today (2 GBM, 2 RGBM), in good health and no longer receiving any treatment roughly 12 years after initiating TTField therapy, with no clinical or radiological evidence of recurrence. Two of the 4 surviving patients exhibited radiological signs of tumor growth initially, before the tumor regressed in size after a median of 4 months of continuous treatment. Conclusions: Our results indicate that TTField treatment may be remarkably successful for both newly diagnosed and recurrent GBM patients. Further investigation is needed to identify any unique characteristics of these patients. We recommend that TTField treatment should be applied for a sufficient amount of time, and that initial radiologic progression following treatment initiation should not be considered a reason to discontinue treatment. Citation Format: Aaron Rulseh, Jan Šroubek, Jan Klener, Josef Vymazal. Longterm survival in glioblastoma patients after tumor treating fields (TTFields) therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT141. doi:10.1158/1538-7445.AM2017-CT141

FDA Approval Summary: TAS-102.

The FDA approved TAS-102 (Lonsurf; Taiho Oncology, Inc.) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and if RAS wild type, an anti-EGFR therapy. In an international, multicenter, double-blinded, placebo-controlled trial (TPU-TAS-102-301, herein referred to as RECOURSE), 800 patients with previously treated mCRC were randomly allocated (2:1) to receive either TAS-102 35 mg/m2 orally twice daily after meals on days 1 through 5 and 8 through 12 of each 28-day cycle (n = 534) or matching placebo (n = 266). The trial demonstrated a statistically significant improvement in overall survival for those randomized to receive TAS-102, with a median survival of 7.1 months in the TAS-102 arm [confidence interval (CI), 6.5-7.8] and 5.3 months in the placebo arm [CI, 4.6-6.0; hazard ratio (HR), 0.68; 95% CI, 0.58-0.81; P < 0.001, stratified log-rank test]. The trial also demonstrated a statistically significant prolongation of progression-free survival (HR, 0.47; 95% CI, 0.40-0.55; P < 0.001). The most common adverse reactions, in order of decreasing frequency, observed in the patients who received TAS-102 were anemia, neutropenia, asthenia/fatigue, nausea, thrombocytopenia, decreased appetite, diarrhea, vomiting, abdominal pain, and pyrexia. Adverse events led to discontinuation of TAS-102 in 3.6% of patients, and 13.7% required a dose reduction. The most common adverse reactions leading to dose reduction were neutropenia, anemia, febrile neutropenia, fatigue, and diarrhea. Clin Cancer Res; 23(12); 2924-7. ©2017 AACR.

Bevacizumab counteracts VEGF-dependent resistance to erlotinib in an EGFR-mutated NSCLC xenograft model.

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), shows superior efficacy in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations (EGFR Mut+). However, almost all tumors eventually develop resistance to erlotinib. Recently, the Phase II JO25567 study reported significant prolongation of progression-free survival (PFS) by erlotinib plus bevacizumab combination compared with erlotinib in EGFR Mut+ NSCLC. Herein, we established a preclinical model which became refractory to erlotinib after long-term administration and elucidated the mode of action of this combination. In this model, tumor regrowth occurred after remarkable shrinkage by erlotinib; regrowth was successfully inhibited by erlotinib plus bevacizumab. Tumor vascular endothelial growth factor (VEGF) was greatly reduced by erlotinib in the erlotinib-sensitive phase but significantly increased in the erlotinib-refractory phase despite continued treatment with erlotinib. Although EGFR phosphorylation remained suppressed in the erlotinib-refractory phase, phosphorylated extracellular signal-regulated kinase (pERK), phosphorylated AKT, and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) were markedly higher than in the erlotinib-sensitive phase; among these, pERK was suppressed by erlotinib plus bevacizumab. MVD was decreased significantly more with erlotinib plus bevacizumab than with each drug alone. In conclusion, the erlotinib plus bevacizumab combination demonstrated promising efficacy in the B901L xenograft model of EGFR Mut+ NSCLC. Re-induction of VEGF and subsequent direct or indirect VEGF-dependent tumor growth was suggested as a major mechanism of erlotinib resistance, and erlotinib plus bevacizumab achieved remarkably prolonged antitumor activity in this model.

The role of stem cell transplant for lymphoma in 2017.

The role of stem cell transplant for lymphoma in 2017.

Efficacy and Toxicity of Metronomic Chemotherapy in Metastatic Breast Cancer: Egyptian Experience

BackgroundMetronomic chemotherapy (MC) has shown efficacy in patients with metastatic breast cancer (MBC). We therefore tested the efficacy and toxicity of MC in pretreated MBC. Patients and MethodsThis prospective phase II study included 50 patients with heavily pretreated MBC who received MC in the form of continuous oral cyclophosphamide 50 mg/day and oral methotrexate 2.5 mg twice per day on days 1 and 2 every week. The primary end point was progression-free survival (PFS), whereas the secondary end points were response rate, overall survival (OS), and safety. ResultsForty-eight patients were assessed. One patient achieved complete response and 10 patients had partial response, whereas 19 patients had stable disease. The median PFS was 5 months, whereas the median OS was 7 months. Patients with negative progesterone receptors, Eastern Cooperative Oncology Group performance status (PS) 1, achieving response, and those who developed leucopenia, neutropenia, and anemia had significant prolonged PFS, whereas patients with early stage at presentation, receiving < 5 previous treatment lines, achieving response, and experiencing anemia with MC had significant superior OS. In multivariate analysis, achieving response, PS 1, a longer time interval from initial diagnosis until starting MC, and anemia were independent prognostic factors for longer PFS. Initial stage at presentation, number of previous treatment lines, and response were independent prognostic factors for OS. ConclusionsMC is an attractive treatment approach that is effective and less toxic. There are certain groups of patients who seem to benefit more, especially those who experienced toxicity with treatment. Larger trials are warranted to assess this approach early in the course of the disease and with other more active agents.

FIRST LINE 5-FU-BASED CHEMOTHERAPY WITH/WITHOUT BEVACIZUMAB FOR METASTATIC COLORECTAL CANCER: TISSUE BIOMARKER CANDIDATES

Purpose: Colorectal cancer is the second leading cause of cancer mortality in the USA. According to Bulgarian National Statistics Institute, 2370 colon and 1664 rectal cancer cases were diagnosed in 2012 with total number of patients 29995. Adding bevacizumab to chemotherapy in patients with metastatic disease improves progression-free survival (PFS) but no predictive markers have been proven in the clinical practice. In our study we examined two tissue biomarkers that may correlate with response to bevacizumab-containing chemotherapy in patients with metastatic colorectal cancer. Patients and Methods: 54 patients with metastatic colorectal cancer were assigned to first line 5-Fu-based chemotherapy with/without bevacizumab. The primary end point was PFS, with additional determination of response and toxicity. Paraffin-embedded samples from primary tumors were collected from all 54 patients. Expression levels of two tumor biomarkers VEGFR-2 and Neuropilin 1 (NP1) were evaluated with immunohistochemistry. Results: The median PFS for the group treated with CT/Bev was 8.8 months, compared with 5.4 months for the group with chemotherapy alone (95% CI, log-rank test P =0.003). The corresponding overall response rates were 19.3% and 10.2% respectively (P < 0.05 for CT/Bev vs CT). Patients with low NP-1 had statistically significant prolongation of PFS as compared to those with high NP-1 (95% CI, log rank test p= 0.017). Patients with low NP-1 appeared to experience a larger bevacizumab treatment effect in terms of PFS (p=0,049,HR 0.333, 95% CI, 0.111 to 0.995) than patients with high NP-1. Conclusion: The addition of bevacizumab to 5-Fu based chemotherapy improves PFS for patients with metastatic colorectal cancer. Expression of tumor NP-1 is a potential biomarker candidate for prediction of clinical outcome in patients with metastatic colorectal cancer, treated with first line chemotherapy plus bevacizumab.

Abstract P4-13-03: Updated safety from a double-blind phase 3 trial (PALOMA-3) of fulvestrant with placebo or with palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy

Abstract Background: Endocrine therapy (ET) resistance remains a major clinical problem for patients (pts) with hormone receptor (HR+) breast cancer (BC). In PALOMA-3, palbociclib (P) combined with fulvestrant (F) demonstrated significant prolongation of progression-free survival (PFS) vs F plus placebo (PLB) in pre/peri and postmenopausal women with HR+/HER2– metastatic BC (MBC) whose disease progressed on prior ET (median PFS 9.2 vs 3.8 m; HR=0.422, P=0.0001). Methods: In this double-blind phase 3 study, 521 pts with HR+/HER2– MBC were randomized 2:1 to receive P (125 mg/d orally for 3 weeks followed by 1 week off) and F (500 mg given per standard of care) or PLB plus F. Pre- and perimenopausal women also received goserelin. One previous line of chemotherapy (CT) for MBC was allowed. Safety assessments occurred at baseline and D1 of each cycle; blood counts occurred every 2 wks for the first 2 cycles and on D1 of subsequent cycles. As pts may have experienced multiple episodes of neutropenia during treatment, we analyzed all episodes in aggregate based on laboratory data per CTCAE4.0. Results: The results reported here are from the data cutoff of Dec 2014, with a median follow-up of 5.6 m. Overall rate of any grade (G) and G3/4 AEs was 98/70% of pts in P+F vs 89/18% in PLB+F. The most commonly reported AEs in P+F (≥20%) were hematologic toxicities, fatigue, nausea, and headache. Per lab data, G3/G4 neutropenia occurred in 52.2/8.2%, G3/G4 leukopenia in 39.5/1.2%, G3/G4 anemia in 20.8/2.9% and G3/G4 thrombocytopenia in 2.1/1.2% of pts on P+F. Neutropenia occurred early, with a median onset time for first episode of ≥G3 neutropenia of 15 d (13–197) and median time from first dose to the lowest absolute neutrophil count (ANC) of 29 d (13–334). The median duration of ≥G3 episode was 7 d (1–35), suggesting that most pts can resume treatment after a 1-week cycle delay. A comparable proportion of any grade neutropenia was observed in pts with or without prior CT (prior CT 88.4% vs no prior CT 85.4%). There was no difference in the rate of G3/G4 neutropenia in the older pts (&amp;gt;65 yrs, 51% vs ≤65 yrs, 57%) in P+F arm. Concurrent G≥3 infections occurred in 1% of pts with G≥3 neutropenia (2/192 pts). Febrile neutropenia occurred in 0.6% of pts in both arms. 21% of pts had dose reductions and 45% had dose interruption due to neutropenia. Dose intensity was maintained at 89.7% for P. Serious adverse events (SAEs) were reported in 9.6% of pts on P+F and in 14% of pts on PLB+F. The most common SAEs on P+F were pulmonary embolism (0.9%) and pyrexia (0.9%). Safety analyses with longer follow-up (data cut off, March 2015) are ongoing and will be presented. Conclusions: Findings suggest P+F has a favorable safety profile characterized mainly by asymptomatic hematologic toxicity. Overall SAE rates were low and comparable between the 2 arms. Palbociclib-related neutropenia differs from that seen with CT, consistent with proposed mechanism of action, in that it is not commonly associated with fever, and can be effectively managed by a dose interruption or cycle delay. Funding: Pfizer, Inc. Citation Format: Verma S, DeMichele AM, Loi S, Ro J, Colleoni M, Iwata H, Harbeck N, Stearns V, Cristofanilli M, Huang Bartlett C, Schnell P, Zhang K, Thiele A, Turner NC, Rugo HS. Updated safety from a double-blind phase 3 trial (PALOMA-3) of fulvestrant with placebo or with palbociclib in pre- and postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-03.

Abstract P4-13-12: Everolimus plus trastuzumab and vinorelbine for trastuzumab-resistant, taxane-pretreated, HER2+ advanced breast cancer: Overall survival results from BOLERO-3

Abstract Background PI3K/AKT/mTOR pathway activation due to PTEN loss may lead to trastuzumab (TRAS) resistance. mTOR inhibition has been shown to restore TRAS sensitivity in PTEN-deficient tumors. This provided the rationale for the BOLERO-3 trial which evaluated the combination of everolimus (EVE), an mTOR inhibitor, plus TRAS and a taxane in HER2+ advanced breast cancer (ABC). The addition of EVE to TRAS plus vinorelbine (VNB) led to a statistically significant prolongation of 1.2 months in median progression free survival (PFS) vs TRAS plus VNB in patients with TRAS-resistant and taxane-pretreated, HER2+ ABC (7.0 months vs 5.78 months; hazard ratio, 0.78; p=0.0067). The final overall survival (OS) analysis from this study is presented here. Materials and methods BOLERO-3 is a randomized, double-blind, placebo-controlled, phase 3 trial. Women with HER2+ ABC progressing on prior TRAS and taxane therapy were randomized (1:1) to receive either daily EVE (5 mg) or PBO plus weekly TRAS (2 mg/kg) and VNB (25 mg/m2), in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was PFS by local investigator assessment. Overall survival was a key secondary endpoint. Results Overall, 569 patients were enrolled; 284 patients received EVE and 285 patients received PBO. As of April 1, 2015, after a median follow-up of 44.7 months, 388 deaths had occurred, 191 (67.3%) in the EVE arm and 197 (69.1%) in the PBO arm. The median OS in the EVE arm vs PBO arm was 23.5 months vs 24.1 months (HR = 0.96; 95% CI, 0.79-1.17; p = 0.3392). In the HR+ subgroup, the median OS with EVE was 23.5 months (vs 25.5 months with PBO; HR = 1.03; 95% CI, 0.79-1.35); in the HR subgroup, the median OS with EVE was 22.9 months (vs 23.1 months with PBO; HR = 0.86; 95% CI, 0.64-1.17). AEs leading to treatment discontinuation were reported in 81 (28.9%) vs 46 (16.3%) patients in the EVE vs PBO arms. Serious adverse events (SAEs) were reported in 122 (43.6%) vs 58 (20.6%) patients in the EVE vs PBO arms. Overall, 14 on-treatment deaths were observed, 7 (2.5%) in the EVE arm and 7 (2.5%) in the PBO arm; on-treatment deaths due to AEs were balanced between treatment arms (0.7% in each treatment arm). Types of post-progression therapies were balanced across both treatment arms. Conclusions In BOLERO-3, EVE showed a statistically significant prolongation of PFS. OS was similar in both treatment arms. The safety profile of EVE was comparable to that observed previously with EVE in breast cancer. (Funded by Novartis; BOLERO-3 ClinicalTrials.gov number, NCT01007942.) Citation Format: Isaacs C, O'Regan R, Xu B, Masuda N, Arena F, Yap Y-S, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Zhang Y, Jappe A, Pacaud LB, Taran T, Ozguroglu M. Everolimus plus trastuzumab and vinorelbine for trastuzumab-resistant, taxane-pretreated, HER2+ advanced breast cancer: Overall survival results from BOLERO-3. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-12.

FDA Approval Summary: Lenvatinib for Progressive, Radio-iodine-Refractory Differentiated Thyroid Cancer.

The FDA approved lenvatinib (Lenvima, Eisai Inc.) for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory (RAI-refractory) differentiated thyroid cancer (DTC). In an international, multicenter, double-blinded, placebo-controlled trial (E7080-G000-303), 392 patients with locally recurrent or metastatic RAI-refractory DTC and radiographic evidence of disease progression within 12 months prior to randomization were randomly allocated (2:1) to receive either lenvatinib 24 mg orally per day (n = 261) or matching placebo (n = 131) with the option for patients on the placebo arm to receive lenvatinib following independent radiologic confirmation of disease progression. A statistically significant prolongation of progression-free survival (PFS) as determined by independent radiology review was demonstrated [HR, 0.21; 95% confidence interval (CI), 0.16-0.28; P < 0.001, stratified log-rank test], with an estimated median PFS of 18.3 months (95% CI, 15.1, NR) in the lenvatinib arm and 3.6 months (95% CI, 2.2-3.7) in the placebo arm. The most common adverse reactions, in order of decreasing frequency, observed in the lenvatinib-treated patients were hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. Adverse reactions led to dose reductions in 68% of patients receiving lenvatinib at the 24 mg dose and 18% of patients discontinued lenvatinib for adverse reactions leading to residual uncertainty regarding the optimal dose of lenvatinib.

Profile of lanreotide autogel and its potential in the treatment of gastroenteropancreatic neuroendocrine tumors

Profile of lanreotide autogel and its potential in the treatment of gastroenteropancreatic neuroendocrine tumors Anja Rinke, Daniela M&uuml;ller Department of Internal Medicine, Division of Gastroenterology and Endocrinology, Philipps University, Marburg, Germany Abstract: Gastroenteropancreatic neuroendocrine tumors (GEPNETs) comprise a heterogenous group of neoplasm, and their incidence is increasing in the population. Approximately one-third of these tumors are associated with characteristic hormonal syndromes like flushing and diarrhea in carcinoid syndrome. Most GEPNETs express receptors for somatostatin. The somatostatin analogs octreotide and lanreotide constituted a major therapeutic advance in palliating hypersecretion syndromes. Lanreotide autogel is a viscous aqueous solution of lanreotide that is usually administered deep subcutaneously every 4 weeks, but extended dosing intervals have also been proposed. In recent years, increasing evidence has supported the use of somatostatin analogs (SSA) as antitumor agents. In the double-blind, placebo-controlled, Phase III CLARINET trial, lanreotide autogel 120 mg every 4 weeks was associated with a significant prolongation of progression-free survival in patients with nonfunctioning GEPNETs, with a Ki-67 of &lt;10%. This antiproliferative effect and the favorable toxicity profile make lanreotide autogel attractive for long-term treatment in patients with well-differentiated GEPNETs. Further studies are needed to evaluate the role of lanreotide autogel as a combination partner and the efficacy of high-dose lanreotide. Keywords: neuroendocrine tumor, somatostatin analogs, lanreotide, symptomatic treatment, antiproliferative treatment

Abstract 5481: Effect of genetic polymorphisms on erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer

Abstract Introduction: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor, a 150 mg daily dose of which has been shown to be effective for improving overall survival in non-small-cell lung cancer (NSCLC) patients who had failed at least 1 prior chemotherapy regimen. Furthermore, erlotinib demonstrated significant prolongation of progression-free survival versus standard chemotherapy in EGFR mutation positive NSCLC patients. However, skin rash and diarrhea often occurs, and these toxicities lead to discontinuation of therapy or dose reduction in many patients. Several population pharmacokinetics (PK) analyses have reported large interindividual variabilities in erlotinib blood exposure and its toxicities. However, none of those analyses clearly explains the determinants of these large interindividual variabilities. Here, aiming to develop a dose regimen that would maintain the clinical benefits of erlotinib while minimizing its adverse effects, we analyzed single nucleotide polymorphisms (SNPs) of PK-related genes and investigated the relationships between genotypes and interindividual variabilities in the PK and adverse effects. Methods: We performed a multicenter study of 50 patients treated with 150 mg erlotinib as a second-line or later treatment. PK and toxicity were assessed. For PK analyses, blood samples were collected from 28 patients at 5 to 18 time points, and trough blood samples were collected from 20 patients at 1 time point. SNPs in genes encoding metabolizing enzymes or efflux transporters (CYP1A1, CYP1A2, CYP2D6, CYP3A4, CYP3A5, UGT1A1, UGT2B7, GSTM1, GSTT1, ABCB1, and ABCG2) were analyzed. Population PK analyses were carried out using NONMEM. SNPs were tested as covariates in a population PK model. The effects of these SNPs and erlotinib exposure on toxicity were evaluated. Results and Discussion: A 2-compartment model with first order absorption and linear elimination described the erlotinib PK. Only the ABCB1 1236C&amp;gt;T polymorphism was a statically significant covariate for CL/F, showing a 29.4% decrease in CL/F for the TT genotype as compared with the CC and the CT genotypes. The interindividual variability in CL/F decreased by 10.6% after inclusion of the TT genotype as a covariate in the model. This result indicates that a dose reduction to 100 mg for the TT genotype group could equalize the erlotinib exposure between each genotype group. A higher incidence of adverse effects (mainly diarrhea) was observed in the TT genotype group. Conclusions: Of the 20 SNPs that are related to erlotinib PK, only ABCB1 1236C&amp;gt;T influenced the exposure of erlotinib. This SNP was suggested to be related to the risk of adverse events. Individual dosing based on ABCB1 genotype might reduce the adverse effects. Further clinical trials are needed to investigate the toxicity and the clinical outcome of this dose regimen. Citation Format: Chihiro Endo-Tsukude, Ji-ichiro Sasaki, Sho Saeki, Norihiro Iwamoto, Megumi Inaba, Sunao Ushijima, Hiroto Kishi, Shinji Fujii, Hiroshi Semba, Kosuke Kashiwabara, Yukari Tsubata, Yuki Kai, Hideyuki Saito, Takeshi Isobe, Hirotsugu Kohrogi, Akinobu Hamada. Effect of genetic polymorphisms on erlotinib pharmacokinetics and toxicity in Japanese patients with non-small-cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5481. doi:10.1158/1538-7445.AM2015-5481

Abstract 4100: Epithelial-mesenchymal transition and tumor vascular remodeling in eribulin chemotherapy for breast cancer

Abstract Purpose: Eribulin mesylate (eribulin) is a promising chemotherapeutic agent to treat locally advanced or metastatic breast cancer (MBC). Not only its cytotoxic efficacy, but its unique mechanisms to suppress epithelial-mesenchymal transition (EMT) of the cancer cells, or to promote tumor vascular remodeling attracted attention in basic models. In this study, we investigated markers of EMT and hypoxia in sets of clinical specimens before and after treatment of eribulin in an aim to verify its profound mechanisms. Experimental Design: A series of 20 sets of the tissue specimens of MBC obtained before and after chemotherapy from patients treated either with eribulin (n = 10), or with paclitaxel (n = 10) were immunohistochemically investigated with the expression of E-cadherin, N-cadherin, Vimentin, and CA9. The cut-off for E-cadherin positivity was &amp;gt;30% positive tumor cells with membrane staining. The cut-off for N-cadherin and Vimentin positivity were &amp;gt;10% positive tumor cells with cytoplasm staining. And, the cut-off for CA9 positivity was &amp;gt;10% positive tumor cells with membrane staining. Results: Looking at the relation between the transition in this protein expression and therapeutic effect, cases observed with positive conversion in E-cadherin expression and cases observed with negative conversion in CA9 expression had significantly high response rate (RR) (p = 0.004, p = 0.024). Among high RR cases, E-cadherin expression was remarkably increased, the N-cadherin, Vimentin and CA9 expression were reduced. A significant prolongation of progression-free survival (PFS) was observed in patients with tumor showed E-cadherin positive-conversion (p = 0.041, log-rank). Significantly longer periods of time to treatment-failure (TTF) were achieved in patients with tumors showed E-cadherin positive-conversion (p = 0.018, log-rank) or showed CA9 negative-conversion (p = 0.038, log-rank). There was no difference in over-all survival (OS) of the patients when stratified with the expression of and change in EMT markers. No difference was observed either in PFS, TTF, or OS of the patients according to the expressions of and change in N-cadherin and Vimentin.Conclusions: Increased expression of E-cadherin was observed along with reduced expression of N-cadherin, Vimentin, and CA9, EMT suppression was caused by eribulin chemotherapy, and further, it was suggested that vascular remodeling may have been induced. Citation Format: Kashiwagi Shinichiro, Yuka Asano, Yukie Tauchi, Tokumoto Mao, Tamami Morisaki, Satoru Noda, Hidemi Kawajiri, Tsutomu Takashima, Naoyoshi Onoda, Kosei Hirakawa. Epithelial-mesenchymal transition and tumor vascular remodeling in eribulin chemotherapy for breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4100. doi:10.1158/1538-7445.AM2015-4100

BIM Gene Polymorphism Lowers the Efficacy of EGFR-TKIs in Advanced Nonsmall Cell Lung Cancer With Sensitive EGFR Mutations: A Systematic Review and Meta-Analysis.

The strong association between bcl-2-like 11 (BIM) triggered apoptosis and the presence of epidermal growth factor receptor (EGFR) mutations has been proven in nonsmall cell lung cancer (NSCLC). However, the relationship between EGFR-tyrosine kinase inhibitor's (TKI's) efficacy and BIM polymorphism in NSCLC EGFR is still unclear.Electronic databases were searched for eligible literatures. Data on objective response rates (ORRs), disease control rates (DCRs), and progression-free survival (PFS) stratified by BIM polymorphism status were extracted and synthesized based on random-effect model. Subgroup and sensitivity analyses were conducted.A total of 6 studies that involved a total of 773 EGFR mutant advanced NSCLC patients after EGFR-TKI treatment were included. In overall, non-BIM polymorphism patients were associated with significant prolonged PFS (hazard ratio 0.63, 0.47–0.83, P = 0.001) compared to patients with BIM polymorphism. However, only marginal improvements without statistical significance in ORR (odds ratio [OR] 1.71, 0.91–3.24, P = 0.097) and DCR (OR 1.56, 0.85–2.89, P = 0.153) were observed. Subgroup analyses showed that the benefits of PFS in non-BIM polymorphism group were predominantly presented in pooled results of studies involving chemotherapy-naive and the others, and retrospective studies. Additionally, we failed to observe any significant benefit from patients without BIM polymorphism in every subgroup for ORR and DCR.For advanced NSCLC EGFR mutant patients, non-BIM polymorphism ones are associated with longer PFS than those with BIM polymorphism after EGFR-TKIs treatment. BIM polymorphism status should be considered an essential factor in studies regarding EGFR-targeted agents toward EGFR mutant patients.

Abstract A01: Exploring phosphatase and tensin homolog (PTEN) loss as a potential predictive marker for response to everolimus in patients with pancreatic neuroendocrine tumors (PNETs)

Abstract Introduction: Identification of patients with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to activation of phosphatidylinositol 3-kinase/Akt and mammalian target of rapamycin (mTOR) signaling. The RADIANT-3 trial of everolimus in advanced PNETs demonstrated a significant prolongation of progression-free survival (PFS) from 4.6 months with placebo versus 11 months with everolimus. Despite the improvement in PFS, the response rate was only 5% among patients receiving everolimus. The index case for our study was an exceptional responder who had a significant radiological response as well as a PFS of 24 months, which were both better than expected from the literature. This led to the hypothesis that there may be mutational changes in genes affecting the mTOR pathway that could predict sensitivity to mTOR inhibitors. In this study, we specifically explored the role of PTEN loss as a potential predictive marker. Methods and Materials: Between 2010 and 2014, patients with well-differentiated unresectable and metastatic PNETs treated at the University of Miami/Sylvester Comprehensive Cancer Center and Jackson Memorial Hospital with everolimus were identified. Eight patients had pathology specimens available for testing. PTEN loss detected by Fluorescence In Situ Hybridization (FISH) was carried out using a commercially available probe for cytoband 10q23. Patients' response to everolimus was evaluated through June 2014. The primary outcome was PFS. PTEN expression by immunohistochemistry (IHC) will also be performed and the results will be compared to those obtained by FISH. Results: The median age was 60 years (range 45-78). 50% of the patients were females and 50% were males. Two patients had gastrinomas, 1 patient had an insulinoma, and five patients had non-functional PNETs. All patients had unresectable metastases to the liver. In addition to sandostatin LAR, the patients received everolimus starting at a dose of 10mg daily. Three patients were found to have deletion of PTEN. Of those, one patient did not tolerate everolimus and the PFS for the other two was 8 and 24 months respectively. Detection of PTEN loss by FISH yielded no results in 2 patients due to insufficient tumor left in the specimen. PFS in these 2 patients was 24 and 4 months respectively. Testing is ongoing in the last 3 patients and the PFS for these patients is 3, 10 and 13 months. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusion: The index case for this study had a PTEN deletion and had a partial response to treatment and prolonged disease control for 2 years with everolimus. Testing is ongoing in additional cases to determine if there is a consistent correlation between PTEN loss by FISH and PFS. Citation Format: Moh'd Khushman, Joyce Slingerland, Yao-Shan Fan, Monica Garcia-Buitrago, Ernesto Bustinza, Maria Restrepo, Daniel Sussman, Caio Rocha-Lima, Peter Hosein. Exploring phosphatase and tensin homolog (PTEN) loss as a potential predictive marker for response to everolimus in patients with pancreatic neuroendocrine tumors (PNETs). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr A01.

A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1)

This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination. Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS). Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191). Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.

Innovation leads the future: the prospect for the treatment of lymphoma from the 56th American Society of Hematology annual meeting

The annually American Society of Hematology(ASH)annual meeting is the biggest feast in this area. The 56th ASH annual meeting showed many important data related with lymphoma. Applied brentuximab vedotin as maintenance therapy after autologous stem cell transplantion, Hodgkin lymphoma(HL)patients acquired significant prolonged progression free survival(PFS). A phase I study demonstrated that PD-1 inhibitor, nivolumab, has a high response in heavily treated HL, with ORR 87 %, which has acquired the approval from FDA. BTK inhibitor, PI3K inhibitor, new CD20 antibodies, bcl-2 inhibitor and lenalidomide all are effective in relapsed or refractory chronic lympholytic leukemia(CLL)and non-Hodgkin's lymphoma(NHL), but how to apply these new targeted drugs appropriately and combined with current chemotherapy regimens are quite difficult. CAR-T cells targeting CD19, CD20, CD30 or CD138 positive lymphomas are a kind of new cellular therapy, which has showed excellent efficacy. Key words: Lymphoma; Molecular targeted therapy; Cellular immunotherapy; American Society of Hematology annual meeting

Long-Term Everolimus Treatment of Patients with Pancreatic Neuroendocrine Tumors

Background/Aims: Based on the significant prolongation of progression-free survival in a randomized phase III trial, RADIANT-3 (RAD001 in Advanced Neuroendocrine Tumors, Third Trial), everolimus has been approved for the management of advanced, progressive pancreatic neuroendocrine tumors (pNET). Here, we describe 15 participants in RADIANT-3 who were treated with everolimus at our study center. We report the long-term survival of a subset of patients. Methods: Patients with advanced, progressive pNET were randomly assigned to the everolimus arm of RADIANT-3 or received everolimus as open-label treatment after experiencing progression on placebo or during the unblinded phase. Results: Five patients on everolimus (5-10 mg/day) had stable disease for >43 to >76 months after initiating treatment. Three patients achieved stable disease for 19-25 months, but died of progressive malignancy thereafter. Seven patients had stable disease for ≤11 months after initiating everolimus therapy. Conclusion: Patients with advanced, progressive pNET can obtain long-term benefit from daily oral treatment with everolimus.

Outcome of salvage treatment for recurrent glioblastoma

Most glioblastoma (GBM) cases recur within a year and almost all cases recur at some point. Standard treatment for recurrent GBM has not yet been established. We investigated the outcome of various salvage treatments for recurrent GBM. Retrospective analysis was undertaken in 144 patients who received salvage treatment at the time of first progression after maximum debulking surgery followed by concomitant chemoradiotherapy and adjuvant temozolomide (TMZ) chemotherapy. The median follow-up period was 18.2months. We grouped these patients into five groups according to the salvage modalities: Gamma Knife radiosurgery (GKS) group (n=29), TMZ group (n=31), GKS+TMZ group (n=28), reoperation group (n=38) and “other treatment” group (n=18). The median time to first progression from initial diagnosis was 8.8months. The median overall survival (OS) of the five different treatment groups; GKS, TMZ, GKS+TMZ, reoperation, and “other treatment”, was 9.2, 5.6, 15.5, 13.2, and 8.0months, respectively. Median progression-free survival (PFS) was 3.6, 2.3, 6.0, 4.3, and 2.6months, respectively. Pairwise comparison of OS of the GKS+TMZ group with the other groups showed that the OS of the GKS+TMZ group was significantly better than all others except the reoperation group. Statistically significant prolongation of PFS was observed in the GKS+TMZ group compared with the TMZ group and the “other treatment” group. GKS followed by TMZ salvage treatment was a good prognostic factor for both PFS and OS in multivariate analysis. Retrospectively, GKS+TMZ as a salvage treatment, tended to provide a superior survival benefit at the time of recurrence.