Everolimus In Pts Research Articles

Everolimus for advanced breast cancer: Is the histological subtype important?

e13165 Background: Invasive lobular (L) breast carcinomas (BC), which account for up to 15% of all BC, had particularly histopathological characteristics: tends to be estrogen/progesterone receptor positive and HER2-neu negative and as such are treated with endocrine therapy (ET). It had been demonstrated a frequent activation of PI3K–AKT–mTOR signaling in LBCs, suggesting this pathway to be a promising therapeutic target for LBC. Interestingly, in some of these patients, the subsequent use of a mTOR inhibitor (everolimus) combined with an ET produced greater clinical benefits. Our aim is to evaluate the efficacy of everolimus in advanced BC (ABC) in the usual clinical practice, focusing on LBC. Methods: We retrospectively analyzed 147 women with ABC from four Spanish hospitals who were treated with everolimus (Ev) in second or successive lines of treatment between 2014-2023. We performed a descriptive statistical analysis of the clinicopathological variables and calculated the investigator-assessed time to treatment failure (TTF), defined as the interval from initiation of treatment to its premature discontinuation (because of progression disease (PD) or toxicity), as well as its association using Kaplan-Meier test. Survival curves were analyzed using long-rank test. Finally, we analyzed the subgroup of those with everolimus TTF (TTF2) longer than previous line TTF (TTF1) by Xi2 test. Results: With a median (m) age of 59, 21 (14%) patients (pts) were diagnosed with advanced LBC. The histopathological characteristics of the pts are shown (Table). Treatment had to be stopped in 24 pts due to toxicity (oral mucositis 21%), and the rest was due to PD or exitus. The response rate (stabilization, partial and complete response (CR)) was 49% with 4% of CR. The overall m of TTF2 was 9,1 months, while the TTF1 m was 9,5 months. Analyzing by histology, TTF2 m was 18.16 months in LBC vs 7.85 in ductal BC (p=0.01). Contrary to expectations, 40 pts (27,2%) had a longer TTF2 compared with TTF1 (p>0.001). When analyzing this subgroup we found 9 pts with LBC and 27 DBC (p>0,05). 26 pts (65%) had not received previous line with HT (p=0.005). On the other hand, when analyzing the subgroup of pts with LBC, up to 47.36% of pts had TTF2>TTF1. Conclusions: The use of everolimus in pts with LBC appears to be more effective than in DBC according to the results reported in our series and its use in initial hormonal lines may be reconsidered. However, we need more prospective studies differentiating histologies to demonstrate our results for others Pi3k inhibitors. [Table: see text]

Abstract 7196: Evaluation of nab-sirolimus in combination with fulvestrant or PI3K pathway inhibitors to overcome resistance in breast cancer cell lines

Abstract Background: Endocrine therapy (ET) is the standard of care for hormone receptor positive (HR+) breast cancer (BC), but ET resistance develops in most patients (pts). One resistance mechanism involves cross talk between the PI3K-AKT-mTOR and estrogen receptor (ER) signaling pathways, resulting in increased ER signaling and tumor proliferation. This is mitigated by mTOR inhibition as demonstrated by improved outcomes with exemestane plus the mTOR inhibitor (mTORi) everolimus in pts with HR+ advanced BC. While PI3K inhibitors (PI3Ki [e.g. alpelisib]) are efficacious in pts with HR+, PIK3CA-mutated BC, resistance can occur due to acquired genomic alterations in the PI3K-AKT-mTOR pathway. Combination therapy that targets a critical downstream node, mTOR, could delay or overcome acquired resistance due to activation of upstream components of the PI3K-AKT-mTOR pathway. nab-Sirolimus is an intravenously administered, albumin-bound nanoparticle form of the mTORi sirolimus, with significantly greater tumor accumulation, mTOR target suppression, and improved antitumor effects than oral mTORis in nonclinical tumor models. We evaluated the antiproliferative and cytotoxic effects of nab-sirolimus in combination with ET or PI3Kis in BC cell lines. Methods: HR+, PI3K-mutated BC cell lines (MCF7 or MDA-MB-361) were incubated for 5 days with increasing concentrations of nab-sirolimus and the selective ER degrader fulvestrant. MDA-MB-361 cells or HR-negative (HR−), PI3K-mutated BC cells, MDA-MD-453, were incubated for 5 days with increasing concentrations of nab-sirolimus and PI3K-AKT-mTOR pathway inhibitors gedatolisib or alpelisib. Antiproliferative/cytotoxic effects of single-agent and combination treatment were assessed via an automated trypan blue exclusion assay. Results: Addition of 20 or 80 nM nab-sirolimus to fulvestrant (12.5-500 nM) markedly decreased cell viability and nearly doubled cell death in MCF7 and MDA-MB-361 cells. Antiproliferative effects of low-dose gedatolisib (2.5-10 nM) were enhanced by 61-71% when nab-sirolimus (20 or 80 nM) was added to MDA-MB-453 cells. While low doses (2.5, 5, and 10 nM) of gedatolisib alone led to limited cytotoxicity (4.2-9.6%), up to 48.9% of cell death occurred when 20 or 80 nM nab-sirolimus was added. Results were similar with alpelisib (1 uM) plus nab-sirolimus (20 or 80 nM). Western blot showed increased p4EBP1 in response to fulvestrant or PI3Ki treatment, which was reversed with the addition of nab-sirolimus. Conclusions: nab-Sirolimus enhanced the cytotoxic effects of fulvestrant in HR+ BC cells and of PI3Kis in HR+ and HR− BC cells. Addition of nab-sirolimus to ET or other PI3K-AKT-mTOR pathway inhibitors may overcome mechanisms of resistance; further exploration is warranted to elucidate clinical relevance. Citation Format: Khine Nyein Myint, Sean Wallace, Shihe Hou, Maria Zalath, Brian McMorran, Andrew Kwon, Igor Vivanco. Evaluation of nab-sirolimus in combination with fulvestrant or PI3K pathway inhibitors to overcome resistance in breast cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7196.

EvERA Breast Cancer (BC): Phase III study of giredestrant + everolimus vs exemestane + everolimus in patients (pts) with estrogen receptor-positive, HER2-negative locally advanced or metastatic BC (ER+, HER2– LA/mBC).

TPS1119 Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard of care in pts with ER+, HER2– mBC in the first-line setting. Fulvestrant ± a CDK4/6i, and everolimus + exemestane are the current approved second-line regimens. However, therapeutic resistance to some ETs, such as aromatase inhibitors, can arise from ESR1 mutations (m) driving estrogen-independent transcription and proliferation. Current post-CDK4/6i treatment options are suboptimal. New therapy options are therefore needed to reduce this risk and to improve outcomes, tolerability, quality of life, and adherence to treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD) that achieves robust ER occupancy and is active regardless of ESR1-mut status. While Phase I SERD combination data in the post-CDK4/6i setting are encouraging, there are no randomized combination data. Combining giredestrant and everolimus may improve outcomes after CDK4/6is and in pts with ESR1m tumors. Methods: evERA BC (NCT05306340), a Phase III, global, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant + everolimus vs. exemestane + everolimus in pts with ER+, HER2– LA/mBC who had previous treatment with a CDK4/6i and ET in the LA/mBC or adjuvant setting. Pts will be randomized to either giredestrant (30 mg) + everolimus (10 mg) by mouth (PO) every day (QD), or exemestane (25 mg) + everolimus (10 mg) PO QD. Pts will receive treatment until disease progression or unacceptable toxicity. Pts will use a dexamethasone mouth rinse 4 times QD for 8 weeks concurrently with study treatment. Eligibility: Female/male pts ≥ 18 years with ER+, HER2– LA/mBC and disease progression ≥ 6 months (mo) after initiating ET + CDK4/6i in the LA/mBC setting (and ≥ 4 mo on most recent ET, if ET + CDK4/6i was not the most recent therapy received), or relapsed either while taking or within 12 mo of exposure to combination adjuvant ET (≥ 12 mo) + CDK4/6i (≥ 6 mo), and available blood sample for circulating tumor DNA central testing for ESR1m status. Men and pre-/perimenopausal women will receive a LHRH. Co-primary endpoints: Investigator-assessed progression-free survival (per RECIST v1.1) in the intent-to-treat and ESR1m populations. Secondary endpoints: Overall survival; objective response rate; duration of response; clinical benefit rate; pt-reported outcomes; safety; pharmacokinetics. Co-primary endpoint analyses will use a two-sided stratified log-rank test at an overall 0.05 significance level. An independent data monitoring committee will be in place for safety. Target enrollment is 320 pts, and this study is currently recruiting. Encore from SABCS 2022 (OT2-01-07). Clinical trial information: NCT05306340 .

256TiP TACTIVE-E: Phase Ib study of ARV-471, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, in combination with everolimus in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer

ARV-471 is an oral PROTAC ER degrader that binds to and degrades both wild-type ER and ESR1 mutants. ARV-471 was well tolerated and showed clinical activity in a phase I/II study in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR), is approved with exemestane for pts with ER+/HER2- breast cancer after progression on aromatase inhibitors and has shown clinical activity after cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor treatment. In pts with prior CDK4/6 inhibitor therapy, the combination of ARV-471 and everolimus may offer additional advantages as ARV-471 can degrade mutant forms of ER, and ESR1 mutations are enriched in this setting. Preclinical studies in ER-expressing breast cancer cell lines showed evidence of cell growth inhibition with ARV-471 plus everolimus, including in cells expressing Y537S or D538G ESR1 mutations. ARV-471 plus everolimus demonstrated greater tumor growth inhibition in a xenograft breast cancer model than either monotherapy. Here we describe the open-label, phase Ib TACTIVE-E study (NCT05501769) of ARV-471 plus everolimus in pts with ER+/HER2- advanced breast cancer. Eligible pts (aged ≥18 years) have histologically or cytologically confirmed ER+/HER2- metastatic, recurrent, or unresectable breast cancer; received 1–3 prior lines systemic therapy in the advanced/metastatic setting, including ≥1 endocrine therapy and ≤1 chemotherapy; and progression on or intolerance to a CDK4/6 inhibitor. Pts may not have received prior ARV-471 or an mTOR-targeting therapy. ARV-471 combined with everolimus is administered orally in 28-day cycles. The primary endpoints are dose-limiting toxicities to determine the recommended phase II dose for ARV-471 in combination with everolimus, and type, frequency, and severity of adverse events and laboratory abnormalities. Secondary endpoints are preliminary antitumor activity (overall response rate, clinical benefit rate, and duration of response) and pharmacokinetic parameters of ARV-471 plus everolimus. NCT05501769. Medical writing support: Justine Lempart, PhD, of Apollo Medical Communications, and funded by Arvinas Operations, Inc. Arvinas Estrogen Receptor, Inc.

Abstract OT2-01-07: evERA Breast Cancer: A phase III study of giredestrant (GDC-9545) + everolimus vs exemestane + everolimus in patients with estrogen receptor+, HER2– locally advanced or metastatic breast cancer

Abstract BACKGROUND Endocrine therapy (ET) modulates estrogen synthesis and/or estrogen receptor (ER) activity and is the mainstay of ER+ breast cancer (BC) treatment. ET + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is the standard of care in patients (pts) with ER+, HER2– metastatic BC (mBC) in the first-line setting. Fulvestrant ± a CDK4/6i, and everolimus + exemestane, are the current regimens approved for use in the second-line setting. However, therapeutic resistance to some ETs, such as aromatase inhibitors, can arise from ESR1 mutations driving estrogen-independent transcription and proliferation. Current post-CDK4/6i treatment options are suboptimal. New therapy options are therefore needed to reduce this risk and to improve outcomes, tolerability, quality of life, and adherence to treatment. Giredestrant is a highly potent, nonsteroidal oral selective ER antagonist and degrader (SERD) that achieves robust ER occupancy and is active regardless of ESR1 mutation status. While phase I SERD combination data in the post CDK4/6 setting is encouraging, there is no randomized combination data. Combining giredestrant and everolimus may potentially improve outcomes after CDK4/6is and in pts with ESR1-mutated tumors; evERA BC is investigating this combination to address the unmet need in the post-CDK4/6i setting. TRIAL DESIGN This phase III, global, randomized, open-label, multicenter study will evaluate the efficacy and safety of giredestrant + everolimus vs exemestane + everolimus in pts with ER+/HER2– locally advanced (LA)/mBC who had previous treatment with a CDK4/6i and ET in the LABC/mBC or adjuvant setting. Pts will be randomized to either giredestrant (30 mg) + everolimus (10 mg) by mouth (PO) every day (QD) on Days 1–28 of each 28-day cycle, or exemestane (25 mg) + everolimus (10 mg) PO QD on Days 1–28 of each 28-day cycle. Pts will receive treatment until disease progression or unacceptable toxicity. Pts will use a dexamethasone mouth rinse four times QD for 8 weeks, started concurrently with study treatment. ELIGIBILITY Female/male pts ≥18 years with ER+/HER2– LA/mBC, an Eastern Cooperative Oncology Group Performance Status of 0–1, measurable disease defined per RECIST v.1.1 (or evaluable bone metastases with at least one predominantly lytic bone lesion confirmed by computed tomography or magnetic resonance imaging), disease progression ≥6 months after initiating ET + CDK4/6i in the LABC/mBC setting (and ≥4 months on most recent ET, if ET + a CDK4/6i was not the most recent therapy received), or relapsed either while taking or within 12 months of exposure to combination adjuvant ET (≥12 months) and a CDK4/6i (≥6 months). Availability of a baseline blood sample to determine ESR1 mutation status by circulating tumor DNA assay for testing at a central laboratory. Men and pre-/perimenopausal women will receive a luteinizing hormone-releasing hormone agonist on Day 1 of each 28-day cycle. AIMS Primary endpoint: investigator-assessed progression-free survival (PFS; per RECIST v1.1). Secondary endpoints: investigator-assessed PFS in pts with detectable ESR1-mutated tumors in circulating tumor DNA at baseline; overall survival; objective response rate; duration of response; clinical benefit rate; patient-reported outcomes; safety; pharmacokinetics. STATISTICAL METHODS The primary endpoint analysis will use a stratified log-rank test at an overall 0.05 significance level (two-sided). An independent data monitoring committee will be in place for safety. ACCRUAL Target enrollment is 224 pts globally, and this study is currently recruiting. CONTACT INFORMATION For more information or to refer a patient, email global.rochegenentechtrials@roche.com or call 1-888-662-6728 (USA only). Clinicaltrials.gov number NCT05306340. Citation Format: Erica L. Mayer, Sara Tolaney, Adam M. Brufsky, William Gradishar, Komal Jhaveri, Miguel Martín, Luca Moscetti, Gregory Vidal, Patricia Cortazar, Merilin Feldman, Bann-mo Day, Hope Rugo. evERA Breast Cancer: A phase III study of giredestrant (GDC-9545) + everolimus vs exemestane + everolimus in patients with estrogen receptor+, HER2– locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-01-07.

673P Cabozantinib-nivolumab (CN) vs. nivolumab-cabozantinib (NC) in patients (pts) with metastatic clear cell renal cell carcinoma (mRCC) following one prior VEGFR tyrosine kinase inhibitor (TKI): The CABIR multicentric matching-adjusted study

N and C are two approved agents after a prior TKI in mRCC pts. However, the optimal sequence, CN or NC, is still unknown. The superiority of C over everolimus in pts with prior anti-PD-1 (HR 0.22) in the METEOR trial suggests a sensitizing role of N. We conducted the CABIR study to identify the optimal sequence between CN and NC after one prior TKI.

A phase II trial of LEE011 in combination with everolimus in the treatment of advanced well differentiated neuroendocrine tumors of foregut origin.

TPS546 Background: Changes in the retinoblastoma (Rb) tumor suppressor pathway are believed to contribute to the development of well differentiated neuroendocrine tumors (WDNETs). In the pre-clinical setting, loss or downregulation of proteins that normally inhibit the cyclin dependent kinases Cdk4 and Cdk6 have contributed to NET development. Separately, rigorous investigation of everolimus in WDNETs has demonstrated a survival benefit in this patient (pt) population. Pre-clinical data suggests that the Cdk4/Cdk6 inhibitor LEE011 is synergistically active with everolimus. The aim of this study is to evaluate the efficacy and safety of LEE011 in combination with everolimus in pts with advanced WDNETs of foregut origin (thymic, bronchopulmonary, gastric, duodenal, pancreatic). Methods: This study is a multicenter, non-randomized, open-label phase II clinical trial using a Simon two stage optimal design. Main inclusion criteria include: adult patients with WDNET of foregut origin, low to intermediate grade, unresectable and/or metastatic, disease progression ≤ 12 months prior to enrollment, ECOG 0-1. Between 15 and 43 patients will be enrolled from three sites across the US. LEE011 300mg daily, 3 weeks on and 1 week off, in combination with everolimus 2.5mg daily (final dosing based on phase 1b clinical trial performed in metastatic breast cancer; LEE011X2106) will be administered orally until disease progression, unacceptable toxicity, investigator decision, or pt withdrawal. All enrolled pts will be followed by telephone contact for overall survival until death or consent withdrawal. The primary endpoint, progression free survival, will be assessed based on radiographic review by RECISTv1.1. Main secondary endpoints include establishing the safety of this drug combination in this patient population, objective response rate, clinical benefit rate, and overall survival. Correlative objectives include exploring the effect of this drug combination on biomarkers related to the Rb pathway and/or WDNET pathogenesis. This trial began enrollment in 2/27/2017, with 10 patients enrolled to date. Clinical trial information: NCT03070301.

Abstract OT2-01-11: A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in human epidermal growth factor receptor 2–negative, hormone receptor–positive breast cancer patients with bone metastases

Abstract Background: Radium-223 dichloride (Ra-223), a first-in-class α-emitter with a potent, targeted antitumor effect on bone metastases (mets), was well tolerated and reduced baseline bone biomarker levels in a phase 2 study in metastatic breast cancer (MBC) patients (pts) with bone-dominant disease (Coleman et al. Breast Cancer Res Treat 2014). Adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) versus EXE alone in human epidermal growth factor receptor 2–negative (HER2-), hormone receptor–positive (HR+) MBC pts with advanced disease. This trial will evaluate efficacy and safety of Ra-223 with EXE and EVE in pts with HER2-, HR+ breast cancer and bone mets (NCT02258451). Trial design: Pts scheduled to receive EXE (25 mg PO once daily) and EVE (10 mg PO once daily) will be randomized 1:1 to Ra-223 (50 kBq/kg IV) or placebo × 6 cycles q4wk. EXE and EVE treatment (tx) will continue until disease progression, unacceptable toxicity, or the pt can no longer travel to the clinic to receive study medication. Stratification will be by geographic region, previous lines of hormone therapy, and presence of visceral disease. Safety and efficacy will be assessed at each 4-week clinic visit during tx. Long-term safety will be assessed until study termination (ie, pt death, pt loss to follow-up, or pt reaching required number of events). Main eligibility criteria: Eligible pts are pre- or postmenopausal with estrogen receptor–positive and HER2- bone lesion–related asymptomatic or mildly symptomatic MBC not amenable to cure by surgery or radiotherapy, and with ≥2 bone mets visible on bone scan. Pts must have measurable disease per RECIST v1.1, ≥1 prior line of hormonal therapy in the metastatic setting, and 1-2 skeletal related events before study entry; be on bisphosphonates or denosumab for ≥1 mo before study entry; and have ECOG performance status of 0-1, adequate hematologic, renal, and liver function, and life expectancy ≥6 mo. Pts may not have prior or current need for chemotherapy in the metastatic setting, unresolved spinal cord compression, and prior or current EVE tx. Specific aims: The primary endpoint is symptomatic skeletal event (SSE)–free survival. Secondary endpoints are overall survival, time to opiate use for cancer pain, time to pain progression, time to cytotoxic chemotherapy, radiologic PFS (rPFS), and acute and long-term safety. Exploratory endpoints include time to first on-study SSE, time to bone alkaline phosphatase (bALP) progression, bALP response at wk 12 and end of tx, bone-specific rPFS, resource utilization, biomarker assessments, and time to visceral mets onset. Statistical methods: Assuming a one-sided α of 0.1, power of 90%, ∼160 SSEs will be required at the time of analysis. A stratified log-rank test will be used to analyze efficacy (intent-to-treat population). Safety analysis will be descriptive. Present and target accrual: This trial is now enrolling pts. Target accrual is 311. Citation Format: Rugo HS, Huang L, Petrenciuc O, Zaccarini P, Coleman RE. A phase 2 randomized, double-blind, placebo-controlled trial of radium-223 dichloride with exemestane and everolimus in human epidermal growth factor receptor 2–negative, hormone receptor–positive breast cancer patients with bone metastases. [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 OT2-01-11.

RECORD-4 multicenter phase II trial of second-line everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC): Anti-VEGF cohort subanalysis.

611 Background: RECORD-4 assessed EVE in pts with mRCC who progressed after only 1 prior therapy and enrolled pts into 3 cohorts based on first-line sunitinib (cohort 1), other anti-VEGF agents (cohort 2) or cytokines (cohort 3) (J Clin Oncol2015;abstr 4518). Median PFS in cohort 2 was 7.8 mo (95% CI, 5.7-11). This RECORD-4 subanalysis assessed EVE outcomes after individual first-line anti-VEGF agents in cohort 2. Methods: Pts received EVE 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was PFS per investigator review. Data cutoff was Sept 1, 2014. In this analysis, efficacy and safety were analyzed for pts in cohort 2 (n=62) who received sorafenib (Sor, n=23), bevacizumab (Bev, n=16), pazopanib (Paz, n=13), tivozanib (Tiv, n=5), or axitinib (Ax, n=3); missing information for 2 pts. Results: In groups Sor/Bev/Paz/Tiv/Ax, respectively, 96/81/100/80/33% of pts had good/intermediate MSKCC prognosis, 30/94/54/100/100% were white, 70/0/38/0/0% were Asian, and 83/75/77/100/67% were <65 years of age. Median duration of exposure in groups Sor/Bev/Paz/Tiv/Ax, respectively, was 5.5/6.7/6.2/8.1/11 mo. Median PFS (95% CI) was 5.7 (3.6-11.3) mo in group Sor, 9.2 (2.2-NE) mo in group Bev, and 9.2 (1.9-18.0) mo in group Paz. Overall rate of grade 3/4 adverse events (AEs), rates of discontinuation due to AEs, and rates of dose adjustments due to AEs are presented in the table. Conclusions: Results of this RECORD-4 subanalysis demonstrated a favorable benefit-risk profile of second-line EVE in pts whose disease progressed during or after first-line anti-VEGF therapies. Results should be interpreted with caution due to small patient numbers. Clinical trial information: NCT01491672. [Table: see text]

RECORD-4 phase 2 trial of second-line everolimus (EVE) in patients (pts) with metastatic renal cell carcinoma (mRCC): Final OS analysis.

560 Background: The phase 2 RECORD-4 study assessed EVE in pts with mRCC who progressed after 1 prior anti-VEGF or cytokine (J Clin Oncol 2015;abstr 4518). At primary analysis, median progression-free survival (PFS, primary end point) in the overall population was 7.8 months (95% CI, 5.7-11.0). Here we present results of the final updated primary PFS and final overall survival (OS) analysis. Methods: RECORD-4 enrolled 134 pts with clear cell mRCC into 1 of 3 cohorts based on prior first-line therapy: sunitinib (cohort 1, n=58), other anti-VEGF (cohort 2, n=62: 23 sorafenib, 16 bevacizumab, 13 pazopanib, 10 other), or cytokines (cohort 3, n=14). Pts received EVE 10 mg/d until progression of disease (PD; RECIST, v1.0) or intolerance. Database lock for final analysis was June 26, 2015. Results: Demographics were balanced among cohorts; overall most pts were men (68%) and most had good/intermediate MSKCC prognosis (90%); median age was 59 yrs. Median duration of exposure was 5.8 mo. At the time of final analysis, study discontinuation was primarily due to disease progression (61%). In the overall population, median PFS (95% CI) was 7.4 (5.6-10.5) mo and median OS (95% CI) was 23.8 (17.0-not evaluable [NE]) mo (Table). Overall rate of grade 3 or 4 adverse events (AEs) was 56%. There were 13 on-treatment deaths; primary causes were disease progression, multi-organ failure, and respiratory failure (2.3% each). Conclusions: RECORD-4 final OS analysis supports EVE as a second-line option after sunitinib and other first-line therapies. EVE safety profile was consistent with previous experience. Clinical trial information: NCT01491672. [Table: see text]

1BA The impact of pathological factors on long-term local control in the EORTC boost no-boost trial

patients (pts) with advanced renal cell carcinoma (RCC), treatment with cabozantinib was associated with encouraging clinical activity. The objective of the METEOR trial was to evaluate the efficacy and safety of cabozantinib compared to everolimus in pts with clear cell RCC and disease progression following treatment with one or more VEGFR tyrosine kinase inhibitors (TKIs). Methods: In this open-label phase 3 trial (NCT01865747), pts were randomized 1:1 to receive cabozantinib (60mg QD) or everolimus (10mg QD). Pts had measurable disease per RECIST 1.1, KPS 70%, and were stratified by MSKCC prognostic criteria and number of prior VEGFR TKIs. Patients must have progressed within 6 months of their prior VEGFR TKI. The primary endpoint was progression-free survival (PFS) per independent radiology committee (IRC). The trial was designed for an event-driven analysis of PFS events among the first 375 randomized pts to provide 90% power to detect a hazard ratio of 0.667 with a 2-sided 0.05 level of significance using a stratified log-rank test. Secondary efficacy endpoints include objective response rate (ORR) and overall survival (OS) among all randomized pts. Results: A total of 658 pts were randomized between Aug 2013 and Nov 2014. 71% pts had 1 and 29% pts 2 or more prior VEGFR TKIs. 46% pts were favorable, 41% intermediate, and 13% poor risk by MSKCC criteria. The study met the primary endpoint. The estimated median PFS among the first 375 randomized pts was 7.4 months for pts receiving cabozantinib, and 3.8 months for patients receiving everolimus, HR 0.58 (95% CI 0.45 to 0.75), p < 0.001. Prespecified subgroup analyses for PFS will be presented. The ORR in the PFS population was 21% with cabozantinib compared to 5% with everolimus (P < 0.001). At the interim analysis of OS (49% information fraction) among all 658 pts, the hazard ratio was 0.67 (95% CI 0.51 to 0.89), p = 0.0050, in favor of cabozantinib, not meeting the criteria for early rejection of H0 (p 0.0019). Medians for OS could not yet be estimated. The most common serious adverse events for pts receiving cabozantinib were abdominal pain (3%), pleural effusion (2.7%), diarrhoea (2.1%), and for pts receiving everolimus were anemia (3.7%), dyspnoea (3.7%), pneumonia (3.7%). Treatment discontinuation for adverse events occurred in 9.1% for cabozantinib and 10% for everolimus. Conclusions: Cabozantinib demonstrated improvement in PFS and ORR compared with everolimus in VEGFR TKI pretreated pts with advanced clear cell RCC. A trend of improved survival for pts receiving cabozantinib was observed at the interim analysis. The incidence of serious adverse events was similar in both arms. Conflict of interest: Ownership: Stock ownership: Anne Borgman-Hagey, Colin Hessel, Christian Scheffold, Gisela Schwab. Advisory Board: Tannir, Powles, Escudier. Corporate-sponsored Research:. Tannir, Roth, Motzer, Heng, Hammers, Choueiri. Other Substantive Relationships: Honoraria: Tannir, Escudier.

Exploring phosphatase and tensin homolog (PTEN) loss via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) as a potential predictive marker for response to everolimus in patients (pts) with neuroendocrine tumors (NET).

333 Background: Identification of pts with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Exceptional responders to everolimus in NET including pancreatic (PNET) were observed in our cohort of pts. PTEN is a key negative regulator of the phosphatidylinositol 3-kinase(PI3K)/Akt and mammalian target of rapamycin (mTOR) pathway. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to PI3K/Akt/mTOR pathway activation. Inthis study, we explored the role of PTEN as a potential predictive marker of everolimus in pts with NET including PNET. Methods: Between 2010 and 2014, pts with well-differentiated unresectable and metastatic gastrointestinal NET treated at our institution with everolimus were identified. 17 patients had pathology specimens available for testing. PTEN loss detection by FISH was carried out using a commercially available probe for cytoband 10q23, and by IHC using a commercially available antibody. Patients’ response to everolimus was evaluated through August 2014. The primary outcome was PFS and PTEN status was correlated with PFS for any potential association. Results: The median age was 59 years (range 45-78); 7 were male; 8 had PNET (2 gastrinomas, 1 insulinoma and 5 non-functional); 7 had small bowel NET and 2 unknown primary. All pts received everolimus starting at 10mg daily and octreotide LAR. Of the pts with PNETs, 3 had PTEN loss by FISH. Of those, one did not tolerate everolimus. The PFS for the other two pts was 8 and 24 months respectively. Among the 4 pts with intact PTEN; PFS was 14, 26, 3 and 12 months. 1 patient had insufficient tumor for testing. PTEN FISH is ongoing in the 9 non-pancreatic NET pts. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusions: Testing for PTEN loss by FISH is feasible. Due to the small sample size, the role of PTEN loss could not be defined as a predictive marker in PNET. Testing on additional cases is ongoing and will be presented at the meeting.

Efficacy and safety of everolimus in patients with advanced low- or intermediate-grade pancreatic neuroendocrine tumors previously treated with chemotherapy: RADIANT-3 subgroup analysis.

224 Background: In the phase 3 RADIANT-3 trial, everolimus (EVE) demonstrated significantly improved median progression-free survival (PFS) versus placebo (PBO) (11.0 vs 4.6 months; HR=0.35, p &lt; 0.0001) in patients (pts) with pancreatic neuroendocrine tumors (pNET) (Yao et al, NEJM, 2011). Here we present a planned exploratory analysis by prior chemotherapy (chemo) use. Methods: Pts with progressive low- or intermediate-grade pNET were prospectively stratified by prior chemo use and randomized (1:1) to EVE 10 mg/d (n = 207) or PBO (n = 203) plus best supportive care. Results: Of the 410 pts, 206 (50%) had received prior chemo and 204 (50%) were chemo naive. Baseline characteristics (age, sex, race, tumor type, histologic grade) and baseline tumor biomarker levels were similar for pts with/without prior chemo. More chemo-naive pts were newly diagnosed (time since initial diagnosis ≤ 6 mo: 50 [25%] vs. 7 [3%] pts with prior chemo). A lower proportion of chemo-naive pts received prior somatostatin therapy (45% vs. 54% prior chemo). EVE significantly prolonged median PFS regardless of prior chemo use (with prior chemo: 11.0 vs. 3.2 months; HR = 0.35, 95% CI 0.25-0.49, p &lt; 0.001; chemo naive: 11.4 vs. 5.4 months; HR = 0.42, 95% CI 0.29-0.60; p &lt; 0.001). Stable disease was the best overall response in 73% of EVE-treated pts irrespective of prior chemo use. The benefit from EVE irrespective of prior chemo was further demonstrated by disease stabilization or minor tumor shrinkage and in the lower incidence of progressive disease in waterfall plots. Safety of EVE was consistent regardless of prior chemo use. The most common drug-related adverse events (chemo vs chemo naive) included rash (53% vs. 52%), stomatitis (52% vs. 56%), diarrhea (41% vs. 52%), and fatigue (37% vs. 51%). Conclusions: This planned subgroup analysis demonstrated the beneficial effects of EVE in pts with pNET regardless of prior chemo use. These findings support the possible first-line use of EVE for pts with pNET.

879 - Treatment of Patients with Metastatic Kidney Cancer During Haemodialysis with mTOR Inhibitors

ABSTRACT Background On the basis of a few published data, sunitinib and sorafenib can be administered safely to patients (pts) with metastatic renal cell carcinoma (mRCC) and end-stage renal disease on haemodialysis (HD). Aim of this study was to investigate the safety and efficacy of temsirolimus and everolimus in pts with mRCC on HD. Patients and methods between September 2007 and February 2012, 13 pts with mRCC undergoing HD were treated with temsirolimus and everolimus in 6 Italian Institutions. We retrospectively reviewed the medical records of these pts to evaluate the doses of mTOR inihibitors administered, the tolerability and the activity of the treatment. Results Gender: 9 males/4 females; median age: 63 years (range 47–79). All pts were undergoing HD, in 7 cases for bilateral nephrectomy; the time interval between the start of HD and the start of mTOR inhibitors treatment was 37 months. Everolimus was administered at 10 mg daily in 5 pts and at 5 mg in one patient; 7 pts received temsirolimus at 25 mg weekly. Everolimus was administered as second-line treatment in 4 pts, as third and fourth-line in two pts; temsirolimus was given as first-line treatment to 4 pts, as second-line to one patient and as third-line to 2 pts. No unexpected adverse event (AE) and no grade 4 haematological or non-haematological toxicity were reported. The most common grade 1–2 non-haematological treatment-related AEs were fatigue (9/13 pts), dyslipidemia (4/13 pts), oral mucositis in 2/13 pts. A grade 3 dyspnea due to interstitial pneumonia led to treatment discontinuation. The most frequent grade 1–2 haematologic toxicity was anemia (10/13 pts). None of the patients had to change the number of dialysis sessions during mTOR inhibitors treatment. None of the pts experienced an objective response while a disease stabilization was observed in 7 pts. At the time of the analysis, 7 pts had died due to disease progression. The estimated median progression-free survival (PFS) of this cohort of pts was 6.1 months. Conclusions In this small retrospective series of pts the incidence of AEs was as expected, and a prolonged PFS was observed. The use of temsirolimus and everolimus is not contraindicated in pts with mRCC and severe renal impairment on HD. Disclosure All authors have declared no conflicts of interest.

RAMSETE: A single-arm, multicenter, single-stage phase II trial of RAD001 (everolimus) in advanced and metastatic silent neuro-endocrine tumours in Europe.

4122 Background: The mammalian target of rapamycin (mTOR) signaling pathway is involved in the pathogenesis of neuroendocrine tumors (NET). Everolimus (RAD001), an oral mTOR inhibitor, has antitumor activity in patients (pts) with advanced NET. In this open-label, multicenter, phase II study (RAMSETE), the safety and efficacy of everolimus monotherapy was evaluated in pts with advanced nonsyndromic, nonpancreatic NET. Methods: Pts with advanced (unresectable or metastatic), progressive, nonsyndromic, nonpancreatic NET received everolimus (10 mg/day) as monotherapy. The primary endpoint was objective response rate (proportion of pts with best overall complete response [CR] or partial response [PR] per RECIST v1.0) by central radiologic review. A secondary endpoint included progression-free survival (PFS). Results: By database soft lock (December 1, 2011), 73 pts from 16 European clinics received everolimus (median duration of treatment: 193 days). Fifty-five (75%) pts discontinued; reasons included disease progression (n=23), adverse events (AEs [n=23]), withdrawal of consent (n=4), death (n=3), and protocol deviation (n=2). In the per protocol population (N=60), 32 (53%) pts received prior antineoplastic therapy. The best response by central review was stable disease in 55%. By local review, 3 (5%) pts had a PR, with SD in 39 (65%) pts. Median PFS by central review was 185 days (95% CI: 158-255). Median PFS by local investigator review was 285 days (95% CI: 231-not estimable). 69 (95%) pts reported treatment-related AEs of any grade, including rash (n=28; 38%), diarrhea (n=20; 27%), mucosal inflammation (n=18; 25%), and decreased appetite (n=17; 23%). Treatment-related grades 3 and 4 AEs and serious AEs were reported by 27 (37%) and 18 (25%) pts, respectively. Conclusions: In this open-label trial of everolimus in pts with advanced, nonsyndromic, extrapancreatic NET, a high rate of disease stabilization was achieved after prior tumor progression with favorable median PFS. This study further supports efficacy of everolimus in types of NET other than those studied in RADIANT-3 (pancreatic NET) and RADIANT-2 (NET associated with carcinoid syndrome).

Final results of a phase II study of everolimus (RAD001) in metastatic transitional cell carcinoma (TCC) of the urothelium.

4606 Background: Second-line chemotherapy has limited activity in advanced TCC with a median progression free survival (PFS) of 2-3 months. We have previously demonstrated the over-expression of activated mTOR pathway markers in invasive TCC specimens (BJU Int. 2010 Jul 26). Everolimus selectively inhibits mTOR, a central regulator of cell growth, proliferation, survival, and angiogenesis. This trial was designed to assess the efficacy of everolimus in patients (pts) with advanced TCC. Methods: The primary objectives of this single institution phase II trial of everolimus in pts with TCC who have failed prior chemotherapy are: 1) to measure PFS as determined by RECIST; and 2) to evaluate toxicity. Prior therapy is restricted to ≤ 4 chemotherapy drugs. Pts receive everolimus 10 mg oral daily continuously (1 cycle = 4 weeks). A Simon 2-stage design requires ≥13 of 23 pts to be progression free at 2 months to proceed to maximal accrual of 37. Results: 45 pts (31 M, 14 F) with a median age of 66 yrs (32-84) and median KPS of 90 (70-100) were enrolled between 02/17/2009 and 11/8/2010. Primary tumor sites include bladder (32 pts) and ureter/renal pelvis (13 pts). Prior therapy included 30 pts with 2 drugs, 13 with 3, and 2 with 4. 36 pts have visceral metastases including lung (23), liver (19), and bone (6), and 9 pts have lymph node only disease. The median PFS for 37 evaluable pts is 3.3 months (95% CI 2.1, 3.7). 2 partial responses in nodal metastases have been seen. The median OS for the 37 evaluable pts is 10.5 months (95% CI 7.8, NR). The most common grade 3-4 toxicities at least possibly related to everolimus include: anemia (7), infection (6), hyperglycemia (5), lymphopenia (4), hypophosphatemia (4), fatigue (4), hyponatremia (3), mucositis (3), dehydration (2), renal (2), and liver (2). Conclusions: Everolimus has clinical activity in pts with advanced TCC. An analysis of pre-treatment tumor tissue specimens for markers of activated mTOR pathway correlated with PFS will be presented.

Phase II study of everolimus (RAD001) in metastatic transitional cell carcinoma (TCC) of the urothelium.

245 Background: Second-line chemotherapy has limited activity in advanced TCC with a median progression free survival (PFS) of 2-3 months. We have previously demonstrated the overexpression of activated mTOR pathway markers in invasive TCC specimens (BJU Int. 2010 Jul 26). Everolimus selectively inhibits mTOR, a central regulator of cell growth, proliferation, survival, and angiogenesis. This trial was designed to assess the efficacy of everolimus in patients (pts) with advanced TCC. Methods: The primary objectives of this single-institution phase II trial of everolimus in pts with TCC who have failed prior chemotherapy are 1) to measure PFS as determined by RECIST and 2) to evaluate toxicity. Prior therapy is restricted to ≤ 4 chemotherapy drugs. Pts receive everolimus 10 mg oral daily continuously (1 cycle = 4 weeks). A Simon 2-stage design requires ≥13 of 23 pts to be progression free at 2 months to proceed to maximal accrual of 37. Results: 43 pts (31 M, 12 F) with a median age of 65 yrs (32-84) and median KPS of 90 (70-90) were enrolled between 02/16/2009 and 09/30/2010. Primary tumor sites include bladder (32 pts) and ureter/renal pelvis (11 pts). Prior therapy included 28 pts with 2 drugs, 13 with 3 and 2 with 4. 34 pts have visceral metastases including lung (21), liver (19), and bone (5), and 9 pts have lymph node only disease. 8 pts who received ≤ 1 cycle secondary to rapid progression or toxicity unrelated to everolimus were deemed inevaluable for PFS endpoint and were replaced. To date, 33 pts are evaluable for the primary PFS endpoint; 2 pts are too early for PFS assessment. 22 of 33 pts are progression-free at 2 months. The median PFS for 33 evaluable pts is 2.9 months (1.4-9). One partial response has been seen. The most common grade 3-4 toxicities at least possibly related to everolimus include: anemia (7), infection (6), hyperglycemia (5), lymphopenia (4), hypophosphatemia (4), fatigue (3), hyponatremia (3), mucositis (2), dehydration (2), renal (2) and liver (2). Conclusions: Everolimus has clinical activity in pts with advanced TCC. An ongoing analysis of pretreatment tumor tissue specimens for markers of activated mTOR pathway will be correlated with PFS. [Table: see text]

Efficacy and safety of everolimus in elderly patients (pts) with metastatic renal cell carcinoma (mRCC).

4608 Background: The randomized, double-blind, placebo (PLB)-controlled phase 3 RECORD-1 study (NCT00410124) demonstrated the efficacy and safety of the mTOR inhibitor everolimus (EVE) in mRCC pts after failure of VEGFr-TKIs. EVE significantly benefitted all pt subgroups analyzed, including age, MSKCC risk group, previous VEGFr-TKI treatment, sex, and region. Efficacy and safety in elderly RECORD-1 pts were examined. Methods: Pts (N=416) with clear cell mRCC that progressed ≤6 months of stopping VEGFr-TKI therapy were randomized to receive EVE 10 mg/day + best supportive care (BSC) or PLB + BSC. Planned analysis of pt subsets included patients ≥65 years (y) and an extended analysis also examined patients ≥70 y. Results: 153 pts ≥65 y were enrolled (112 in the EVE arm; 41 in the PLB arm); 73 of those were pts ≥70 y (53 in the EVE arm, 20 in the PLB arm). For the general pt population, median progression-free survival (PFS) by central review was 4.9 months for EVE versus 1.9 months with PLB. Risk of disease progression was decreased by 67% (P<.001; hazard ratio [HR]=0.33; 95% confidence interval [CI], 0.25-0.43) by EVE. In pts ≥65 y, median PFS by central review was 5.36 months with EVE and 2.23 months with PLB; in pts ≥70 y, median PFS by central review was 5.13 and 1.91 months, respectively (P<.001; HR=0.19; 95% CI, 0.09-0.37). Most common adverse events (AEs) observed with EVE in pts ≥65 y were stomatitis and anemia. Most common grade (gr) 3/4 AEs in pts ≥65 y were anemia (14.4%) and infections (10.8%); 2 pts (1.8%) receiving EVE had gr 3 pneumonitis. Most frequent gr 3/4 biochemical and hematologic abnormalities with EVE in pts ≥65 y were decreased lymphocytes (20.7%), low hemoglobin (18.0%), elevated glucose (15.3%), and low phosphate (7.2%). AEs did not differ greatly for pts ≥70 y. Conclusions: EVE demonstrated significant efficacy in elderly mRCC pts after failure on VEGFr-TKIs, similar to the general pt population. AEs were observed in these pts more frequently than in the overall RECORD-1 population, as expected with older pts. Gr 3/4 AEs were uncommon in both the elderly and general RECORD-1 populations. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AVEO, Bayer, Bayer Schering, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Wyeth Bayer, Bayer Schering, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Wyeth Bayer, Bayer Schering, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Wyeth Novartis, Pfizer

Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors (NET).

e14597 Background: Sorafenib and everolimus independently have been shown to have activity in NET. In light of potential synergy between VEGF pathway and mTOR inhibitors in this disease, we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in pts with advanced NET. Methods: Two cohorts of 3 or 6 patients (pts) with metastatic or inoperable NET were treated with oral everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg BID; dose level 2: 200 mg in the morning, 400 mg in the evening) using a standard phase I dose escalation design. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Results: All 9 enrolled pts were evaluable for toxicity. Enrolled pts had the following characteristics: M:F = 4:5; median age 56 (range 49-68); ECOG PS 0/1 = 5/4. All 9 pts had low-intermediate grade NETs (midgut n = 6; bronchial n = 2; gastric n = 1). Pts have received a median of 2 cycles of treatment (range 1-6). One pt in Cohort 1 experienced protocol- defined DLT (grade 3 skin rash); the cohort was expanded to 6 pts with no further observed DLT in the cohort. Other ≥ grade 3 treatment-related adverse events at dose level 1 included grade 3 thrombocytopenia (n = 2), grade 3 hypokalemia (n = 2), grade 3 hypophosphatemia (n = 1), grade 4 hypophosphatemia (n = 1), grade 4 hypocalcemia (n = 1). One pt treated at dose level 1 with gastric carcinoid tumor experienced fatal gastric perforation that occurred following the first cycle of therapy and therefore was not considered DLT. In the absence of additional DLT at dose level 1, enrollment to dose level 2 was initiated. All 3 pts in Cohort 2 experienced DLT (grade 3 thrombocytopenia requiring holding treatment for > 14 days, grade 3 hand-foot skin reaction, grade 3 skin rash/allergic reaction). Grade 3 hypophosphatemia (n = 1) was also observed at dose level 2. Independently-reviewed best objective responses in 5 evaluable pts in Cohort 1 revealed stable disease in all 5 pts. Conclusions: Sorafenib 200 mg po BID in combination with everolimus 10 mg po QD has been established as the MTD in pts with advanced NET. Further enrollment to evaluate safety and antitumor efficacy at this dose level is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer/Onyx, Novartis