Type Of Prior Therapy Research Articles

Abstract PS15-09: Imlunestrant monotherapy and in combination with abemaciclib, with or without an aromatase inhibitor, in estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC): updated results from the EMBER study

Abstract Background: Imlunestrant is an oral, brain-penetrant selective estrogen receptor degrader, designed to deliver continuous ER target inhibition, including in ESR1-mutant breast cancer. In the first-in-human dose escalation/expansion (Phase 1a/1b) study of the EMBER trial (NCT04188548), imlunestrant showed favorable safety, pharmacokinetics, and clinical benefit in pre-treated patients with ER+, HER2- aBC when administered as monotherapy (Jhaveri, ASCO 2022) or with abemaciclib ± aromatase inhibitor (AI) (Jhaveri, SABCS 2022). Here, we report updated data from Phase 1a/1b of imlunestrant monotherapy as well as from Phase 1b of imlunestrant with abemaciclib ± AI in EMBER. Methods: Phase 1a/1b enrolled patients with ER+ aBC (prior endocrine therapy (ET) sensitivity or untreated de novo aBC). Prior aBC therapy allowance was ≤3 (no restrictions on the type of prior therapies) in Phase 1a and ≤2 (only 1 prior ET) in Phase 1b for patients receiving imlunestrant monotherapy; and ≤1 (no prior CDK4/6 inhibitors) in Phase 1b for patients randomized to receive imlunestrant + abemaciclib ± AI. Key endpoints included safety and tolerability, objective response rate (ORR: complete response (CR) or partial response (PR) in patients with measurable disease), clinical benefit rate (CBR: CR or PR, or stable disease ≥24 weeks) per RECIST v1.1, and progression-free survival (PFS). Results: As of March 2023, 114 patients received imlunestrant monotherapy (200mg n=21; 400mg (RP2D) n= 51; ≥600mg n=42), and 85 patients received imlunestrant (400mg n=80; 800 mg n=5) in combination with abemaciclib ± AI (both at labeled doses). At the RP2D, the most common all-grade/Grade 3 treatment-emergent adverse events (TEAEs) with imlunestrant monotherapy were fatigue (39%/4%), nausea (39%/2%), and diarrhea (29%/2%). With the combination of imlunestrant + abemaciclib ± AI, the most common all-grade/Grade 3 TEAEs were diarrhea (88%/9%), nausea (61%/0%), fatigue (51%/5%), and neutropenia (44%/16%). No safety signals of ocular or cardiac toxicity (bradycardia/QTc prolongation) were observed. Baseline characteristics, safety, and preliminary efficacy are presented in Table 1. Combination therapy of imlunestrant and abemaciclib ± AI improved ORR and CBR. Conclusion: With longer follow-up, imlunestrant alone or in combination with abemaciclib ± AI continues to demonstrate a tolerable safety profile along with favorable preliminary efficacy in patients with ER+, HER2- aBC. Further data will be presented at the meeting. The Phase 3, EMBER-3 study is ongoing; evaluating imlunestrant, investigator’s choice ET, and imlunestrant plus abemaciclib in ET pre-treated ER+, HER2- aBC patients (NCT04975308). Table. Baseline characteristics, safety and preliminary efficacy a, in patients with available ctDNA data. Citation Format: Komal Jhaveri, Elgene Lim, Rinath Jeselsohn, Cynthia Ma, Erika Hamilton, Cynthia Osborne, Manali Bhave, Peter Kaufman, J. Thaddeus Beck, Luis Manso, Ritesh Parajuli, Hwei-Chung Wang, Jessica Tao, Ajay Dhakal, Jean-Yves Pierga, Yen-Shen Lu, Tim Larson, Yolanda Jerez Gilarranz, Roohi Ismail-Khan, Francesca Bacchion, Claudia Karacsonyi, Yujia Li, Shawn T. Estrem, Bastien Nguyen, Muralidhar Beeram. Imlunestrant monotherapy and in combination with abemaciclib, with or without an aromatase inhibitor, in estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer (aBC): updated results from the EMBER study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS15-09.

Real-World Data of Nivolumab in Classical Hodgkin Lymphoma: Results from the Italian Expanded Access Programme

Introduction: Nivolumab is the first checkpoint inhibitor approved for the treatment of patients (pts) with relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL). In previous studies, agents who target the PD-1 pathway have demonstrated to show substantial and durable response rates, with encouraging survival data and acceptable safety profile in this pts population. The Expanded Access Programme (EAP) provided the opportunity to treat pts before market availability of the drug. The aim of this analysis is to provide information about nivolumab use in a real world setting as well as in pts subgroups usually excluded from clinical trials.Methods: Nivolumab was made available through the EAP conducted in Italy between July 2015 and December 2016 and treatment was delivered according to a prespecified protocol approved by ethical committees of participating centers. Pts aged ≥10 years, with histologically confirmed cHL who either failed or were not eligible for ASCT and failed brentuximab vedotin, were eligible if they had an ECOG Performance Status ≤2. Patients could have received prior allogenic transplantation if 6 or more months had lapsed since transplant and pts had no history of acute GVHD or extensive chronic GVHD. Nivolumab (3 mg/kg) was administered intravenously every 2 weeks until disease progression or unacceptable toxicity for up to 2 years. Pts included in the analysis received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events.Results: A total of 133 pts were enrolled across 40 Italian sites. Median age was 35 years (range: 15-82), 65% of pts were male and median number of previous lines of therapy was 4 (range 1-9), with 128 pts (96%) who had received prior brentuximab, 73 pts (55%) who had received prior autologous stem cell transplantation (ASCT) and 27 pts (20%) who had received prior allogenic stem cell transplantation (allo-SCT). At first tumor assessment, the objective response rate (ORR) was 68%, with 20 pts (15%) with complete response (CR), 71 (53%) with partial response (PR) and 18 (14%) with stable disease (SD). Among pts with no prior response to brentuximab (n= 74), ORR was 71%. At a median follow-up of 10.6 months (range 1-19), 1-year progression free survival (PFS) and overall survival (OS) were 61.4% and 89.0%, respectively. Overall, 68 pts (51%) discontinued treatment for the following reasons: 21 pts (13%) due to disease progression, 14 pts (10%) due to adverse events, 31 pts (23%) proceeded to transplantation (20 pts were bridged to allo-SCT and 11 pts to ASCT) and 2 pts for other reasons (physician decision). No treatment related deaths have been reported.Conclusions: To date, this is the largest clinical experience with nivolumab in a real world setting in pts with R/R cHL. Data confirm results from pivotal trial demonstrating that nivolumab is a safe and effective therapy in this pts population, regardless of number and type of prior therapies. Importantly, about one quarter of pts were bridged to transplantation further supporting that PD1-blockade can overcome resistance to prior conventional treatments. DisclosuresSantoro:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Zinzani:Celgene, Roche, Janssen, Gilead, Takeda, BMS, MSD, Servier, Sandoz, Mundipharma: Honoraria; Celgene, Janssen, Gilead, Roche, Takeda, BMS, MSD, Sandoz, Servier, Mundipharma: Speakers Bureau; Merck: Consultancy, Other: Advisory board. Corradini:Janssen: Honoraria; Roche: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Gilead: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Specchia:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

TIVO-3: Durability of response and updated overall survival of tivozanib versus sorafenib in metastatic renal cell carcinoma (mRCC).

4546 Background: Tivozanib is a potent and highly selective VEGF receptor (R) tyrosine kinase inhibitor in clinical development for mRCC. Methods: The TIVO-3 study enrolled subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI, stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized 1:1 to T or sorafenib. Tivozanib demonstrated PFS and ORR advantages over sorafenib. Here we report long term durability of response based on investigator assessment and updated overall survival. Results: There were 41 responders (23%) to tivozanib and 20 responders (11%) to sorafenib. The median duration of response (mDoR) was 20.3 months (95% CI: 9.8, 29.9) and 9.0 months (95% CI: 3.7, 16.6) for tivozanib and sorafenib, respectively. With prolonged follow up there were 270 deaths; the HR for overall survival favored tivozanib at 0.91 (95% CI: 0.716, 1.165). Clinical trial information: NCT02627963 . Conclusions: Tivozanib treatment in third and fourth line mRCC results in longer PFS, higher objective response rate and more durable responses compared to sorafenib. There is no difference in overall survival.[Table: see text]

TIVO-3: Tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib.

278 Background: Tivozanib (T) is a potent and highly selective VEGF receptor (R) tyrosine kinase inhibitor in clinical development for RCC. Axitinib is also a potent and selective VEGF-R inhibitor now commonly part of front-line aRCC treatment. The activity of T after axitinib has not been previously defined. The activity of T after prior therapy types including axitinib is of clinical relevance. Methods: The pivotal TIVO-3 study enrolled subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI, stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective of the overall trial was to compare progression free survival (PFS) by blinded independent radiological review. Patients with prior axitinib received as monotherapy in the second or third line setting and other predefined subgroups were reviewed for outcome with T. Results: Patients treated with T after prior axitinib had a PFS of 5.5 months and an ORR of 13% compared to 3.7 months and 8% for patients treated with S. Other subgroups are presented in the table below. Clinical trial information: NCT02627963 . Conclusions: Tivozanib improved PFS vs. sorafenib in patients who have progressed after multiple VEGFR-TKIs, including patients with prior second or third line axitinib treatment. These results suggest differential activity from tivozanib and axitinib despite both being potent and selective VEGF-R inhibitors. [Table: see text]

Phase Ib Trial with Dose Expansion of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, in Combination with Rituximab and Lenalidomide in Patients with Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL) and Refractory/Recurrent Secondary Central Nervous System Lymphoma (SCNSL)

BACKGROUND: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single-agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). We hypothesize that combing ibrutinib with the immunomodulatory imide lenalidomide and theanti-CD20 antibody rituximab would be adding clinical efficacy. In this phase 1b trial, we investigate the toxicity of ibrutinib in combination with rituximab and lenalidomide in r/r PCNSL/SCNSL. METHODS: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. Enrollment followed the 3+3 design. Ibrutinib was dosed at 560mg daily (dose level 1) and 840mg (level 2, 3, 4); lenalidomide was dosed at 10mg daily (day 1-21) (level 1, 2), 15mg daily (day 1-21) (level 3) and 20mg daily (day 1-21) (level 4); rituximab was dosed at 500mg/m2 (all dose levels). Rituximab was given for 6 cycles, lenalidomide for 12 cycles, and ibrutinib ongoing. RESULTS: Fifteen patients have been enrolled; 3 at dose level 1-3 and 6 at level 4. Median age was 69 years (range 56-82); 4 were women. Median ECOG was 1 (0: 5, 1: 7, 2: 3). Eleven had r/r PCNSL. Eleven had recurrent parenchymal disease; two had additional cerebrospinal fluid (CSF) involvement; two had both. Nine patients had recurrent and 6 refractory disease. No DLT occurred. One grade 4 lymphopenia was observed. The following grade 3 events occurred: rash (in 3 patients); lymphopenia (in 2); AST, ALT, lung infection, and elevated aPTT (in 1). The most common adverse events were thrombocytopenia, lymphopenia, and rash. No Aspergillosis infection was observed. After a median follow-up of 6.9 months, 14/15 were evaluated for response with 13/15 (73%) showing a response: 4 CR, 7 PR, and 2 SD, 1 PD. Median PFS was 3.03 months; not yet reached for Dose level 4 (only 1/6 has developed progression with a median follow up of 5 months). CONCLUSION: Patients with CNS lymphoma tolerate the combination of rituximab, lenalidomide and ibrutinib well. No dose limiting toxicities were observed. No Aspergillosis infection occurred with this combination regimen. Continued enrollment is ongoing. Disclosures Grommes: BTG: Consultancy; Ono: Consultancy; Kite: Consultancy. Schaff:Debiopharm: Consultancy.

TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC).

5062 Background: Tivozanib (T) is a potent and highly selective VEGFR inhibitor. TIVO-3 is a phase 3 study designed to compare the efficacy and safety of T with those of sorafenib (S) as 3rd and 4th line therapy in patients with metastatic RCC. Methods: Subjects with RCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint inhibitor (CPI); TKI plus other) then randomized in a 1:1 ratio to T or S. Results: The 2 arms were well balanced for demographics and prior cancer history. 60% of subjects had 2 prior lines of therapy and 40% had 3 prior lines. 26% had prior treatment with a CPI. Patients treated with T demonstrated PFS superiority compared to S, 5.6 (95% CI 7.3 - 5.3) v. 3.9 mos (95% CI 5.6 – 3.7; HR 0.73; p=0.02). ORR was 18% for T compared to 8% for S (p=0.02). 44% of T treated subjects experienced a grade 3 treatment-related adverse event compared to 55% for S. The predefined, interim analysis for OS performed two years after enrollment was closed had a HR of 0.99 based on 227 events. The final analysis will be presented based on an estimate of 263 events. Conclusions: T is superior to S as measured by PFS; 2-year PFS, and ORR in this heavily-treated/relapsed or refractory RCC population and is better tolerated than S. Final OS data will be updated prior to presentation. Clinical trial information: 02627963 .

Selpercatinib (LOXO-292) in patients with RET-fusion+ non-small cell lung cancer.

3584 Background: Selpercatinib (LOXO-292) is a highly selective and potent small molecule RET kinase inhibitor. Here we report an update on the efficacy and safety of selpercatinib in RET-fusion+ non-small-cell lung cancer (NSCLC). Methods: Patients with RET-fusion+ NSCLC were enrolled to the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a global, multicenter trial (16 countries, 89 sites). Following the Phase 1 dose escalation portion of the trial, patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. Per health authority agreement, the primary analysis set was defined as the first 105 consecutively enrolled patients previously treated with platinum-based chemotherapy. Treatment-naïve patients were analyzed separately. All analyses were based on a 16-Dec-2019 data cutoff date. Results: In the primary analysis set of platinum-treated patients (median of 3 prior systemic regimens; range 1-15), the ORR by investigator assessment was 70% (95% CI 59.8–78.1, n = 73/105). Responses did not differ by fusion partner or number or type of prior therapies, including anti-PD-1/PD-L1 agents and off-label multikinase inhibitor use. The median DoR was 20.3 months (95% CI 15.6–24.0) with 45 of 73 (62%) responders censored at a median follow-up of 14.8 months. Among 39 treatment-naïve patients, the ORR by investigator assessment was 90% (95% CI 75.8–97.1, n = 35/39, including 2 responses pending confirmation). Median DoR was not reached with 27 of 33 (82%) confirmed responses ongoing at a median follow-up of 7.4 months. In the safety analysis set consisting of all selpercatinib dosed patients (N = 702), the most common treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were dry mouth (33.3%), increased AST (24.5%), increased ALT (23.8%), hypertension (23.2%), diarrhea (19.7%), and fatigue (16.8%). Only 2% (14 of 702) of patients discontinued selpercatinib for TRAEs. Conclusions: Selpercatinib achieved marked and durable antitumor activity in patients with RET-fusion+ NSCLC. Selpercatinib was well tolerated. Efficacy data assessed by independent review committee based on the 16-Dec-2019 data cutoff date will be presented. Clinical trial information: NCT03157128 .

Abstract A031: Association of tumor DNA in circulation with clinical characteristics and treatment response in HR+/HER2− advanced breast cancer

Abstract Background: The sensitivity of plasma-based oncological assays is influenced by the amount of tumor DNA shed into the circulation (ctDNA fraction). Higher ctDNA fraction has been shown to correlate with later-stage cancers and poorer overall survival (Bettegowda C, et al. Sci Transl Med. 2014; Dawson SJ, et al. N Engl J Med. 2014). Other factors affecting ctDNA fraction are poorly understood. We present results from three large Phase III breast cancer studies (MONALEESA-2, -3, and -7) to evaluate correlations between ctDNA fraction and clinical characteristics and impact on progression-free survival (PFS) and best overall tumor response. Methods: Baseline plasma samples were collected from patients (pts) in the MONALEESA-2, -3, and -7 studies, which are Phase III registration trials testing ribociclib, a cyclin-dependent kinase 4/6 inhibitor, in hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer. For each trial, cell-free DNA was extracted from plasma and sequenced using a validated next-generation sequencing assay targeting approximately 550 genes. ctDNA fraction was estimated by analyzing short-read sequences using PureCN (Riester M, et al. Source Code Biol Med. 2016) and tested for correlations with various tumor characteristics (size at baseline, Ki67 expression, number and type of metastatic sites, hormone receptor status) and pt characteristics (type of prior therapy, line of therapy, ECOG performance status, age, body mass index, race, histological grade, menopausal status). We also evaluated the prognostic value of ctDNA fraction on PFS and best overall response. To evaluate the prognostic effect on PFS, ctDNA fraction was binned into 3 categories (not detectable; low, 0.5%-10%; high, > 10%). Results: Higher ctDNA fractions were observed in pts with more metastatic sites (P < 0.0001), larger tumor diameter (P < 0.0001), higher Ki67 expression (P = 0.0001), higher lactate dehydrogenase levels (P < 0.0001), higher-grade tumors (P = 0.0004), worse ECOG performance status (P < 0.0001), progesterone receptor–negative tumors (P = 0.01), presence of liver metastases (P < 0.0001), and shorter disease-free intervals (P < 0.0001). ctDNA fractions were also higher in younger pts (continuous variable; P < 0.0001) and pts with lower BMI (P = 0.0003), prior chemotherapy (P = 0.002), and prior endocrine therapy (P = 0.01). Lower ctDNA fractions were observed in pts with better overall response (P < 0.0001), with median ctDNA fractions lowest in pts with complete responses followed by partial response, stable disease, and progressive disease. Pts with low (0.5%-10%) ctDNA fractions had longer PFS than pts with high (> 10%) ctDNA fractions (HR [95% CI], 0.63 [0.48-0.82], 0.64 [0.51-0.80], and 0.67 [0.52-0.86] in the MONALEESA-2, -3, and -7 trials, respectively). A more pronounced effect on PFS was observed in pts with undetectable levels of ctDNA vs pts with higher ctDNA fractions (HR [95% CI], 0.35 [0.23-0.52], 0.34 [0.21-0.55], and 0.31 [0.21-0.47] in the MONALEESA-2, -3, and -7 trials, respectively). Conclusions: Generally, higher ctDNA fraction was associated with more aggressive tumor characteristics and prior exposure to therapy. Lower ctDNA fraction was associated with longer PFS and better overall response. Together these data suggest that ctDNA fraction is a robust prognostic factor. Citation Format: Nadia Solovieff, Faye Su, Rebecca Leary, Alejandro Balbin, Arunava Chakravartty, Karen Rodriguez Lorenc, Tetiana Taran, Naveen Babbar. Association of tumor DNA in circulation with clinical characteristics and treatment response in HR+/HER2− advanced breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A031. doi:10.1158/1535-7163.TARG-19-A031

TIVO-3: A Phase 3, Randomised, Open-Label Study Comparing Tivozanib to Sorafenib in Patients with Advanced Renal Cell Carcinoma

Background: Treatment for renal cell carcinoma (RCC) has been revolutionised by vascular endothelial growth factor receptor (VEGFR) inhibitors. TIVO-3 was designed to compare the efficacy and safety of tivozanib (a potent and selective VEGFR inhibitor) versus sorafenib as third- or fourth-line therapy for metastatic RCC. Methods: Patients with metastatic RCC with at least two prior systemic treatments, including at least one prior VEGFR inhibitor, were stratified by IMDC risk category and type of prior therapy, then randomised 1:1 to either tivozanib 1·5 mg orally once daily in 4-week cycles (21 days on treatment followed by 7 days off treatment) or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival; key secondary endpoints were objective response rate, overall survival, and safety. Findings: 350 patients were randomly assigned to tivozanib or sorafenib. Median progression-free survival was significantly longer for tivozanib (5·6 months) than sorafenib (3·9 months; hazard ratio [HR] 0·73 [95% CI 0·56-0·94], p=0·0165). Objective response rate was higher for tivozanib than sorafenib (18% vs 8%; p=0·0168). At the time of this analysis, preliminary overall survival was not significantly different (HR 1·12 [95% CI 0·84-1·51], p=0·437). The most common treatment-related adverse events were hypertension (36%), diarrhoea (33%), and fatigue (29%) for tivozanib and diarrhoea (50%), palmar-plantar erythrodysesthesia syndrome (38%), and hypertension (25%) for sorafenib. Adverse events led to fewer dose interruptions (48% vs 63%, p=0·007) and reductions (24% vs 38%, p=0·005) for tivozanib versus sorafenib. No treatment-related deaths were reported. Interpretation: Tivozanib demonstrated improved progression-free survival versus sorafenib as third- or fourth-line therapy for metastatic RCC. Tivozanib was better tolerated than sorafenib, with fewer dose reductions and interruptions, and is the first to demonstrate clinical benefit in a third-line or later setting in RCC. Trial Registration: This trial is registered with ClinicalTrials.gov, NCT02627963. Funding Statement: This study was sponsored by AVEO Oncology. Declaration of Interests: BIR has received research funding from Peloton, and research funding and and honoraria from AVEO, Pfizer, Bristol-Myers Squibb, and Merck. SKP has received honoraria from and served as a consultant to Pfizer, Novartis, AVEO, Genentech, Exelixis, Bristol-Myers Squibb, Astellas, Eisai, Roche, and Ipsen. BJE has received research funding from AVEO, Bristol-Myers Squibb and Novartis, and honoraria from Bristol-Myers Squibb, Roche, Pfizer, Oncorena, AVEO, and Ipsen. MBA has served as an advisor to and received honoraria from AVEO, Merck, Bristol-Myers Squibb, Eisai, Pfizer, Exelixis, Roche, Novartis, and Arrowhead. TEH has served as an advisor to Pfizer, Exelexis, Bristol-Myers Squibb, AVEO, and Janssen. CP has served as a consultant to and on the speakers’ bureaus of EUSA, Bristol-Myers Squibb, MSD, Pfizer, Ipsen, Eisai, AstraZeneca, Janssen, Novartis, and General Electrics, and honoraria from Roche. EV has served as an advisor to and on the speakers’ bureaus of Eusa Pharma, Pfizer, Novartis, Bristol-Myers Squibb, Merck, and Ipsen. MNN is an employee of AVEO. DFM has served as an consultant to Array BioPharm, Genentech, Alkermes, Inc., Jounce Therapeutics, Peloton, EMD Serono and Eli Lilly, received research funding from X4 Pharma, Prometheus, Genentech and Alkermes, and has served as a consultant to and received research funding from Bristol-Myers Squibb, Pfizer, Merck, Novartis, and Exelius. Ethics Approval Statement: This trial was approved by the institutional review board or ethics committee at every centre and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws. All patients provided written informed consent before any trial procedure.

TIVO-3: Subgroup analysis of progression-free survival of tivozanib compared to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC).

4572 Background: Tivozanib (T) is a biochemically potent and highly selective VEGF tyrosine kinase receptor inhibitor in clinical development in RCC. The TIVO-3 trial in 3rd and 4th line subjects with metastatic (m) RCC showed a median progression free survival (mPFS) of 5.6 months (mos) for T compared to 3.9 mos for sorafenib (S) (p = 0.017, HR = 0.73). Methods: Subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective was to compare PFS by blinded independent radiological review. Pre-specified subgroups included prior treatment, IMDC prognostic group, and demographic characteristics. Results: Tivozanib demonstrated PFS benefit in all subgroups including men, women, patients over 65, and under 65. The hazard ratio was the same for patients enrolled in North America and the EU. Patients with ECOG performance status (PS) of 0 had a lower HR than patients with ECOG PS of 1. There was an increase in HR from IMDC favorable vs IMDC intermediate vs IMDC poor. PFS favored tivozanib in patients who had two prior lines of therapy, those treated with three prior lines, those with a prior checkpoint inhibitor, or with two prior VEGFR TKIs. Conclusions: Tivozanib improved PFS vs. sorafenib across several subgroups in TIVO-3. Patients with favorable and intermediate IMDC risk and ECOG PS 0 seemed to derive the most benefit. Patients treated with a prior checkpoint inhibitor or two VEGFR-TKIs had a longer PFS than patients treated on sorafenib. Clinical trial information: NCT02627963. [Table: see text]

Expert Panel Consensus Statement for Proper Evaluation of First Relapse in Multiple Myeloma.

A working group of six expert physicians convened to assess the spectrum of multiple myeloma relapse presentations, discussed the features that can define the disease as aggressive and not aggressive, and established whether this information could help in selecting treatment together with the characteristics of disease and of patients and type of prior therapy. The working group agreed that relapse should be distinguished between biochemical and clinical according to IMWG. Moreover, the expert panel defined "aggressive disease" as a clinical condition that requires therapy able to induce a rapid and as deep as possible response to release symptoms and to avoid impending danger of new events. According to this definition, relapse was considered aggressive if it presents with at least one of the following features: doubling of M protein rate over 2months, renal insufficiency, hypercalcemia, extramedullary disease, elevated LDH, high plasma cell proliferative index, presence of plasma cells in peripheral blood, or skeletal-related complications. Moreover, the panel agreed that this classification can be useful to choose therapy in first relapse together with other patient, disease, and prior therapy characteristics. So, this item was included in a new therapeutic algorithm. The treatment choice in MM at relapse is wider than in the past with the availability of many new therapeutic regimens leading to increased diversity of approaches and relevant risk of inappropriate treatment decisions. A practical classification of relapses into aggressive or non-aggressive, included in a decisional algorithm on MM management at first relapse, could help to make the appropriate treatment decisions.

A phase 2, randomized trial evaluating the combination of dalantercept plus axitinib in patients with advanced clear cell renal cell carcinoma

In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8months vs 5.6months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P=.670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P=.349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group. Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.

TIVO-3: A phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC).

541 Background: Tivozanib (T) is a biochemically potent and highly selective VEGF tyrosine kinase receptor inhibitor in clinical development in RCC. The TIVO-1 trial in treatment naïve or prior cytokine-treated subjects with metastatic (m) RCC showed a median progression free survival (mPFS) of 11.9 months (mos) for T compared to 9.1 mos for sorafenib (S) (p = 0.042, HR = 0.797). However, overall survival (OS) favored sorafenib, likely due to imbalanced crossover to active treatments. TIVO-3 was conducted to confirm the PFS results from TIVO-1. Methods: Subjects with mRCC who failed 2 or 3 prior systemic regimens, one of which included a VEGFR TKI other than S or T, were stratified by IMDC risk category and type of prior therapy (two TKIs; TKI plus checkpoint; TKI + other) then randomized in a 1:1 ratio to T or S. The primary objective was to compare PFS by blinded independent radiological review. 350 subjects were enrolled to yield 244 events with ~88% power to detect a difference of 6 mos vs. 4 mos with a two-sided p-value of 0.05 by the log-rank test. Secondary endpoints were OS, safety, objective response rate (ORR), and duration of response. Results: The two arms were well balanced for demographics and prior cancer history.60% of subjects had 2 prior lines of therapy and 40% had 3 prior lines. 28% had prior treatment with a checkpoint inhibitor. T demonstrated a statistically significant improvement in mPFS compared to S, 5.6 (95% CI 7.3-5.3) v. 3.9 mos (95% CI 5.6-3.7; HR 0.73; p=0.02). PFS rate at 2 years was 18% for T compared to 5% for S. ORR was 18% for T compared to 8% for S. 44% of T treated subjects experienced a grade 3 treatment-related adverse event compared to 55% for S. Subjects on T were less likely to require a dose reduction (24% v. 38%), interruption (48% v. 63%), or discontinuation (21% v. 29%) due to an adverse event than subjects on S. Conclusions: T is superior to S as measured by PFS; 2-year PFS, and ORR in this pre-treated population and is better tolerated than S. OS data will be updated prior to presentation. Clinical trial information: NCT02627963.

Phase 1B of ibrutinib and high-dose methotrexate for recurrent/refractory CNS lymphoma.

7533 Background: Primary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Outcome and treatment options for patients with recurrent/refractory (r/r) disease are poor. We have observed promising efficacy of single agent ibrutinib in r/r PCNSL and secondary CNS lymphoma (SCNSL). In this phase 1B trial, we investigate the toxicity of ibrutinib in combination with high-dose methotrexate (HD-MTX) in r/r PCNSL/SCNSL. Methods: Eligible patients had r/r PCNSL/SCNSL or newly diagnosed SCNSL, age≥18, ECOG≤2, normal end-organ function, and with any number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. HD-MTX was given at 3.5g/m2 every 2 weeks for a total of 8 doses. To minimize adverse events, ibrutinib was stopped on days of HD-MTX infusion and was restarted 5 days after MTX infusion or after completion of MTX-clearance, if clearance of MTX required more than 5 days. Ibrutinib was continued daily after completion of 8 doses of MTX. Results: Six patients have been enrolled; 3 received 560mg and 3 received 840mg ibrutinib in combination with HD-MTX. Median age was 62 (range 43-74); median ECOG 1 (0:2; 1:3; 2:1). Two had r/r PCNSL and 4 SCNSL. Three had brain disease, one isolated cerebrospinal fluid (CSF) involvement and two parenchymal and CSF involvement. Three patients had recurrent (2 PCNSL; 1 SCNSL), two refractory (both SCNSL), and one newly diagnosed disease (SCNSL). There were no grade 4 adverse events. Grade 3 events were observed in 5 patients (lymphopenia in 3, ALT elevation in 2, diarrhea in 1, electrolyte changes in 1, hypertension in 1). The most common adverse events were hypokalemia, low WBC, hyperglycemia, ALT and AST elevation. There was no dose reduction of methotrexate or ibrutinib in any patient. After a median follow-up of 130 days, all patients were evaluated for response after 4 doses of HD-MTX, with 4/6 (67%) showing a response: 2 CR, 2 PR, and 1 SD, 1 PD; both non-responders were refractory SCNSL. Ibrutinib concentrations were measured in plasma and CSF. Conclusions: Patients with CNS lymphoma tolerate the combination of HD-MTX and Ibrutinib (at 560 and 840mg) well. Continued enrollment into a combination arm that includes rituximab, methotrexate and ibrutinib is ongoing. Clinical trial information: NCT02315326.

Is the tenofovir based therapy almighty for previous treatment failure in chronic hepatitis B?

Is the tenofovir based therapy almighty for previous treatment failure in chronic hepatitis B?

Phase I study of single agent ibrutinib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL).

2046Background: PCNSL is an aggressive primary brain tumor. Outcome and treatment options are poor for patients with recurrent/refractory disease. Response rates range between 30-60% with a progression free survival (PFS) of 2-6 months. Ibrutinib has shown promising clinical response in some B-cell malignancies. This phase I trial investigates ibrutinib in patients with recurrent/refractory (r/r) PCNSL and secondary CNS lymphoma (SCNSL). Methods: Eligible patients had r/r PCNSL or SCNSL, age ≥ 18, KPS ≥ 50, normal end-organ function, and unrestricted number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent. Results: Ten patients were enrolled (3 at 560 mg; 7 at 840 mg). Median age was 70 (range 21-80); 7 were women. Median ECOG was 1 (0: 1, 1: 5, 2: 4). 70% had PCNSL and 30% SCNSL. Six had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 1 both. Patients were highly pretreated: 2 (both SCNSL) had prior stem cell transplant; 3 (2 PCNS...

Ublituximab + TGR-1202 Demonstrates Activity and a Favorable Safety Profile in Relapsed/Refractory B-Cell NHL and High-Risk CLL: Phase I Results

Introduction: Ublituximab (UTX) is a novel anti-CD20 mAb that has been glycoengineered for enhanced ADCC. TGR-1202 is a novel once daily oral PI3Kδ inhibitor with clinical activity in B-cell lymphoma and a notably differentiated tolerability profile compared to similar agents. The combination of UTX + TGR-1202 showed strong synergistic activity in-vitro (Lugano 2013). Herein we report the results from the Phase 1 (dose-escalation) and updated results from the Phase Ib (dose-expansion) evaluating the safety and efficacy of the combination of UTX + TGR-1202 in patients (pts) with heavily pre-treated rel/ref NHL and CLL.Methods: A 3+3 design was utilized with rel/ref NHL and CLL pts accruing independently and no limit on the number or type of prior therapies. Patients refractory to prior PI3K or BTK inhibitors were eligible. UTX was administered D1, 8, 15 of Cyc 1 & 2, followed by D1 of Cyc 4, 6, 9 & 12. TGR-1202 was administered orally once-daily starting on D1 of Cyc 1. Primary endpoints: Safety and dose limiting toxicities (DLT). Secondary endpoints: Efficacy (ORR, CR rate).Results: 56 patients have been enrolled to date and are evaluable for safety: 16 CLL/SLL, 16 FL, 16 DLBCL, 5 MZL, 2 MCL and 1 Richter's transformation. Med age 64 yo (range 29-86); 37 M/19 F; median # prior treatment regimens = 3 (range 1-9). Day 1 infusion reactions (2% G 3/4), neutropenia (23% G 3/4), diarrhea (2% G 3/4), and nausea (0% G 3/4) were the most commonly reported adverse events considered at least possibly related to either study drug. One patient (CLL cohort 1) with baseline Gr 3 neutropenia at study entry worsened to Gr 4 resulting in a dose delay which necessitated enrollment of an additional 3 pts at that dose level. Dose escalation continued into all planned subsequent NHL and CLL cohorts (up to 1200 mg). No MTD was observed in the Phase I portion and subtype specific expansion cohorts (Phase Ib) with 800 and 1200 mg dose of micronized TGR-1202 followed. Activity was observed at all dose levels; however a possible dose-response relationship was observed with TGR-1202 at higher doses compared to the lower doses. Of the 37 evaluable pts treated at the higher doses of TGR-1202 (1200 mg original formulation or > 600 mg micronized), overall response was as follows: CLL/SLL (5/7); FL/MZL (10/15); DLBCL (5/12); MCL (0/2) and Richter's (1/1). No CLL pts progressed at the first efficacy assessment, despite 4/5 having high-risk cytogenetics. Two CLL pts with SD include a 17p del, ibrutinib refractory patient who eventually progressed on treatment and the other remains on study awaiting future assessments. Of interest, 7 of the DLBCL pts were GCB subtype of which 71% were rituximab refractory, with 3/7 achieving an objective response, 2 remaining in stable disease (4+ and 5+ mos each), and 2 having progressed to date (avg time on study 7 mos, range 2 - 16+ mos).Conclusions: The combination of UTX + TGR-1202 is active and well tolerated in pts with both indolent and aggressive rel/ref NHL and CLL. The Phase I portion is complete and enrollment remains open in expansion cohorts for CLL, FL/MZL and DLBCL pts evaluating TGR-1202 micronized doses at 800 to 1200 mg in combination with UTX. Given the favorable safety profile and clinical activity observed, Phase 3 programs are planned with UTX + TGR-1202. DisclosuresLunning:BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy. Vose:Seattle Genetics, Inc.: Honoraria, Research Funding. Nastoupil:Genentech: Honoraria; Celgene: Honoraria; TG Therapeutics: Research Funding; AbbVie: Research Funding; Janssen: Research Funding. Burger:Pharmacyclics LLC, an AbbVie Company: Research Funding. Schreeder:TG Therapeutics, Inc: Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; Pharmacyclics/Jannsen: Speakers Bureau; Kite pharma: Other: attended advisory board meeting. Flowers:Seattle Genetics: Consultancy; Millennium/Takeda: Research Funding; OptumRx: Consultancy; Millennium/Takeda: Research Funding; Infinity Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Research Funding; AbbVie: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; Gilead Sciences: Research Funding; Celegene: Other: Unpaid consultant, Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; OptumRx: Consultancy; Spectrum: Research Funding; Onyx Pharmaceuticals: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Genentech: Research Funding; Seattle Genetics: Consultancy; Janssen: Research Funding; Infinity Pharmaceuticals: Research Funding; Celegene: Other: Unpaid consultant, Research Funding. Cutter:Clearview Cancer Center: Employment. Pauli:Clearview Cancer Institute: Employment; TG Therapeutics, Inc.: Consultancy, Research Funding. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership.

Phase I Study of Single Agent Ibrutinib in Recurrent/Refractory Primary and Secondary CNS Lymphoma

BACKGROUNDPrimary CNS Lymphoma (PCNSL) is an aggressive primary brain tumor. Standard treatment of PCNSL may include radiation, methotrexate-based therapy, and anti-CD20 antibody therapy (rituximab) and is associated with substantial morbidity and treatment recurrence. Outcome and treatment options for patients with recurrent/refractory disease are poor. There is only limited use of targeted agents in this patient population. Ibrutinib has shown promising clinical response in some B-cell malignancies. This phase I trial investigates the maximal tolerated dose of ibrutinib in patients with recurrent/refractory PCNSL and secondary CNS lymphoma (SCNSL). METHODSEligible patients had a recurrent or refractory PCNSL or SCNSL, age≥18, KPS≥50, normal end-organ function, and unrestricted number and type of prior therapies. In patients with SCNSL disease, systemic disease needed to be absent or not requiring any active treatment. RESULTSThree patients have been enrolled at dose level 1 (560 mg daily) and one patient at dose level 2 (840mg daily) of whom three were women with a median age of 70 years (range 21-80). Three had recurrent PCNSL and 1 recurrent SCNSL. Two patients presented with parenchymal and two with leptomeningeal relapse. Treatment was generally well tolerated. There was one drug-related grade 4 toxicity (neutropenia) that resolved after the drug was held for 4 days. No drug related grade 3 toxicities have been observed to date. Most common grade 2 toxicities were decreased neutrophil count and hyperglycemia. All patients continue on study at a median follow up of 87 days. Three out of four patient were evaluated for response so far. There were two responses: one complete (in the CSF) and one partial, both in recurrent/refractory PCNSL as well as one stable disease in the patient with recurrent SCNSL. The patient with partial response had failed multiple prior treatment regimens including methotrexate-based chemotherapy, radiation, and rituximab/temozolomide. Serum and CSF pharmacokinetic analysis is initiated. Dose level 2 (840mg) is accruing. CONCLUSIONPatients with CNS lymphoma tolerate Ibrutinib at 560 and 840mg well. Dose escalation will continue. Targeted agents might be an alternative therapeutic approach to be investigated for refractory/recurrent CNS lymphoma patients. DisclosuresNo relevant conflicts of interest to declare.

Comparison of high-risk histopathological features in eyes with primary or secondary enucleation for retinoblastoma

AimsTo compare high-risk histopathology of eyes with primary versus secondary enucleation from patients with retinoblastoma.Patients and methodsA retrospective histopathology review identified 207 eyes enucleated from 202 patients between March 1997...

Ofatumumab (OFA) Maintenance Prolongs PFS in Relapsed CLL: Prolong Study Interim Analysis Results

▪Background: Despite encouraging progress in treatment results, CLL remains incurable and patients (pts) eventually relapse. Currently, the effects of maintenance therapy are unknown for CLL. OFA, a human anti-CD20 monoclonal antibody, has proven efficacy as a monotherapy in refractory CLL. PROLONG is an open-label, two-arm randomized study of OFA versus observation (obs) for pts in remission after induction treatment for relapsed CLL. Here, we report interim analysis results for the key primary and secondary endpoints of the study.Methods: Pts in CR or PR after 2nd or 3rd line treatment for CLL were randomized 1:1 to receive OFA (300 mg followed 1 week later by 1000 mg every 8 weeks for up to 2 years) or observation. Pts on OFA received premedication with acetaminophen, antihistamine and glucocorticoid. Pts were stratified by number and type of prior therapy, and remission status (CR or PR) after induction treatment. The primary endpoint was progression free survival (PFS) from randomization as assessed by investigator. The predefined interim analysis of efficacy occurred at 2/3 study events (minimum 187), with a p<0.001 required for a positive analysis. The interim analysis was reviewed by an Independent Data Monitoring Committee. Secondary endpoints included duration of response, OS, and safety.Results: 474 pts were randomized prior to the interim analysis. Baseline characteristics were similar between arms (Table 1). The median duration of OFA treatment was 12.5 months. The median follow-up was 26.1 months for OFA and 24.0 months for obs. The median PFS was 28.6 months for OFA and 15.2 months for obs (HR=0.48; p<0.0001) (Figure 1). Time to start of next therapy was significantly longer in the OFA arm compared to the obs arm (median 38.0 vs. 27.4 months, HR=0.63; p=0.0076). At this time, there is no differences in OS (HR=0.92, p=0.74).Adverse events (AEs) during the study occurred in 87% OFA pts vs. 75% obs pts. OFA pts had 25% Grade 3-4 AEs vs. 17% obs pts. Grade3-4 infections were 18% OFA vs. 13% obs. The most common (>5% of all pts) grade 3-4 AEs that occurred were neutropenia (22% OFA vs. 9% obs) and pneumonia (7% OFA vs. 4% obs). Death rate was similar in both arms (14%). AEs that lead to permanent discontinuation of treatment occurred in 8% OFA pts.Conclusions: OFA maintenance provided significant clinical benefit for pts with relapsed CLL. OFA was well-tolerated with no unexpected toxicities. Additional data analyses are ongoing and efficacy outcomes according to patient subgroups will be presented.Acknowledgments: The authors thank the patients for their participation in the study, the other PROLONG investigators, and the HOVON Committee. [Display omitted] [Display omitted] Disclosuresvan Oers:Roche: Consultancy. Off Label Use: Ofatumumab is a human anti-CD20 monoclonal antibody that has proven efficacy as monotherapy in refractory CLL. The purpose of its use in this clinical trial is to investigate its use in a maintenance setting for CLL. . Smolej:GlaxoSmithKline: Consultancy, Honoraria, Travel funds Other; Roche: Consultancy, Honoraria, Travel funds, Travel funds Other; Sanofi: Consultancy, Honoraria, Travel funds, Travel funds Other; Janssen: Consultancy, Honoraria, Travel funds, Travel funds Other. Gupta:GlaxoSmithKline: Employment. Phillips:GlaxoSmithKline: Employment. Williams:GlaxoSmithKline: Employment. Lisby:Genmab: Employment. Geisler:Roche: Consultancy; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Janssen: Consultancy.