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Background RECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients. Methods RECORD-4 enrolled patients with clear cell mRCC into 3 cohorts based on prior first-line therapy: sunitinib, other anti-VEGF (sorafenib, bevacizumab, pazopanib, other), or cytokines. Patients received everolimus 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was progression-free survival per investigator review. Data cutoff was Sept 1, 2014. Results Among Asian (n = 55) versus non-Asian (n = 79) patients, 98% versus 84% had good/intermediate MSKCC prognosis; 73% versus 65% were men, and 85% versus 73% were

Patients with intermediate-risk advanced renal cell carcinoma are a heterogeneous population, having either 1 or 2 risk factors. It is unclear whether all patients in this risk category should be treated similarly. A secondary analysis of the PRINCIPAL study of pazopanib found that patients can be stratified by number of risk factors and Eastern Cooperative Oncology Group performance status to more accurately predict outcomes. Introduction: The objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778). Patients and Methods: Patients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients. Results: Three hundred sixty three and 343 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS >= 2 (vs. PS = 2) to more accurately predict outcomes. (C) 2019 Published by Elsevier Inc.

Background PALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of pazopanib in aSTS. Methods PALETTE compared pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory. Results A total of 246 patients received pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged

This post hoc analysis of the COMPARZ study (pazopanib, n = 557; sunitinib, n = 553) supported similar efficacy of first-line pazopanib and first-line sunitinib treatment in advanced renal cell carcinoma. Patients who required dose modifications because of toxicity received higher cumulative doses with longer time of treatment and had significantly better objective response rate, progression-free survival, and overall survival than patients with minimal toxicity. Background: The phase III COMPARZ study showed noninferior efficacy of pazopanib versus sunitinib in advanced renal cell carcinoma. In this COMPARZ post hoc analysis we characterized pazopanib responders, patient subgroups with better outcomes, and the effect of dose modification on efficacy and safety. Patients and Methods: Patients were randomized to pazopanib 800 mg/d (n = 557) or sunitinib 50 mg/d, 4 weeks on/2 weeks off (n = 553). Secondary end points included time to complete response (CR)/partial response (PR); the proportion of patients with CR/PR ≥10 months and progression-free survival (PFS) ≥10 months; efficacy in patients with baseline metastasis; and logistic regression analyses of patient characteristics associated with CR/PR ≥10 months. Median PFS, objective response rate (ORR), and safety were evaluated in patients with or without dose reductions or interruptions lasting ≥7 days. Results: Median time to response was numerically shorter for patients treated with pazopanib versus sunitinib (11.9 vs. 17.4 weeks). Similar percentages of pazopanib and sunitinib patients had CR/PR ≥10 months (14% and 13%, respectively), and PFS ≥10 months (31% and 34%, respectively). For patients without versus with adverse event (AE)-related dose reductions, median PFS, median overall survival, and ORR were 7.3 versus 12.5 months, 21.7 versus 36.8 months, and 22% versus 42% (all P < .0001) for pazopanib, and 5.5 versus 13.8 months, 18.1 versus 38.0 months, and 16% versus 34% (all P < .0001) for sunitinib; results were similar for dose interruptions. Conclusion: Dose modifications when required because of AEs were associated with improved efficacy, suggesting that AEs might be used as a surrogate marker of adequate dosing for individual patients.

PURPOSE: The ENEST1st sub-analysis presents data based on Philadelphia chromosome (Ph) status, i.e., Ph+ and Ph-/BCR-ABL1 + chronic myeloid leukemia.METHODS: Patients received nilotinib 300 mg twice daily, up to 24 months.RESULTS: At screening, 983 patients were identified as Ph+ and 30 patients as Ph-/BCR-ABL + based on cytogenetic and RT-PCR assessment; 76 patients had unknown karyotype (excluded from this sub-analysis). In the Ph-/BCR-ABL1 + subgroup, no additional chromosomal aberrations were reported. In the Ph+ subgroup, 952 patients had safety and molecular assessments. In the Ph-/BCR-ABL1 + subgroup, 30 patients had safety assessments and 28 were followed up for molecular assessments. At 18 months, the molecular response (MR) 4 rate [MR4; BCR-ABL1 ≤0.01% on International Scale (IS)] was similar in the Ph-/BCR-ABL1+ (39.3%) and Ph+ subgroups (38.1%). By 24 months, the cumulative rates of major molecular response (BCR-ABL1IS≤0.1%;), MR4, and MR4.5(BCR-ABL1IS≤0.0032%) were 85.7, 60.7, and 50.0%, respectively, in the Ph-/BCR-ABL1 + subgroup, and 80.3, 54.7, and 38.3%, respectively, in the Ph+ subgroup. In both Ph-/BCR-ABL1 + and Ph+ subgroups, rash (20 and 22%), pruritus (16.7 and 16.7%), nasopharyngitis (13.3 and 10.4%), fatigue (10 and 14.2%), headache (10 and 15.8%), and nausea (6.7 vs 11.4%) were frequent non-hematologic adverse events, whereas hypophosphatemia (23.3 and 6.8%), anemia (10 and 6.5%), and thrombocytopenia (3.3 and 10.2%) were the common hematologic/biochemical laboratory events.CONCLUSION: Based on similar molecular response and safety results in both subgroups, we conclude that Ph-/BCR-ABL1 + patients benefit from nilotinib in the same way as Ph+ patients.

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR4 (BCR-ABL1less than or equal to0.01% on the International Scale or undetectable BCR-ABL1 with greater than or equal to10?000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and less than or equal to3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR4 at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.

4574Background: PRINCIPAL (NCT01649778) was the largest prospective real-world effectiveness and safety study of pazopanib (PAZ) in patients (pts) with renal cell carcinoma (RCC). Methods: Pts with...

4561Background: Although pazopanib (PAZ) has been evaluated in clinical trials of patients (pts) with renal cell carcinoma (RCC), limited real-world data on the effectiveness and safety of PAZ exis...

648 Background: EVE following failure of sorafenib or sunitinib for RCC was first approved by the FDA in 2009. CATChEz (NCT01545817) was designed to test the activity of EVE following first-line PAZ in pts with advanced or metastatic RCC who had not received prior systemic therapy. Methods: From 2012 to 2016, pts received first-line PAZ followed by EVE until progressive disease (PD), death, unacceptable toxicity, consent withdrawal, or study termination. Pts with PD during or within 6 months of stopping PAZ were eligible for EVE. Pts off study treatment were evaluated for PD, survival, and updates on anticancer treatment every 8 weeks until death or end of study. The primary efficacy endpoint was median progression-free survival (mPFS) for the second-line EVE treatment period; secondary endpoints included other survival measures, and safety evaluations were for second-line EVE and grade 3/4 toxicities attributable to PAZ and EVE. Results: Of 74 pts who started first-line PAZ, 38 received ≥1 dose of second-line EVE. The primary endpoint of mPFS from the start of second-line EVE and the secondary endpoint of mPFS with first-line PAZ (Table) were consistent with previous reports; no unexpected adverse events (AEs) were reported. All pts had ≥1 treatment-emergent AE, 83.8% had grade ≥3 AEs, and 71.6% had serious AEs. Of 34 total deaths, 29 were due to PD and 5 were due to AEs (2 related to EVE [lower respiratory tract infection; pulmonary sepsis]; 3 unrelated to study treatment). Conclusions: Efficacy and safety outcomes were consistent with published phase III data. The CATChEz study supports sequential first-line use of PAZ followed by EVE for the treatment of pts with advanced or metastatic RCC. Clinical trial information: NCT01545817. [Table: see text]

4574 Background: COMPARZ was a randomized, controlled, open-label, phase 3 trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in patients (pts) with mRCC (NEJM 2013;369:722). We evaluated the relationship between dosing, safety, and efficacy in PAZ- and SUN-treated pts who did or did not undergo dose reduction or interruption resulting from adverse events (AEs) and other reasons. Methods: The AEs and median progression-free survival (mPFS) of PAZ and SUN were evaluated for pts with no, any, 1, and ≥2 dose reductions or dose interruptions lasting ≥7 days. Results: Similar percentages of pts in the PAZ and SUN groups had a dose interruption (44% vs 49%, respectively) or reduction (44% and 51%, respectively). The incidence of AEs in pts from the PAZ and SUN groups with dose modifications was higher compared to those with no dose modifications. Longer mPFS was observed in pts with dose modification (Table). Pts treated with PAZ or SUN with no dose reductions had mPFS of 7.3 months (mos) and 5.5 mos, respectively, whereas pts with any dose reduction had mPFS of 12.5 mos and 13.8 mos, respectively. Similarly, pts treated with PAZ or SUN with no dose interruptions lasting ≥7 days had mPFS of 8.2 mos and 5.6 mos, respectively, whereas those with any dose interruption lasting ≥7 days had mPFS of 12.6 mos and 13.8 mos, respectively. Pts with 2 or more dose interruptions or reductions had mPFS > 16 mos with both SUN and PAZ. Conclusions: Consistent with previous data for SUN, the current analyses showed longer mPFS with PAZ and SUN when dose modification is required to manage toxicity, suggesting that pts are not disadvantaged by such dose reductions or interruptions. Pts not requiring dose modification may have sub-optimal therapeutic drug exposure. Clinical trial information: NCT00720941. [Table: see text]

4572 Background: COMPARZ (NCT00720941) was a phase 3, randomized, controlled, open-label trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in 1110 patients with mRCC (NEJM 2013;369:722). The objectives of this study were to identify patients from COMPARZ who exhibited a long-term response (LTR) to PAZ and SUN, determine time to response, and describe the clinical characteristics of patients who achieved LTR. Methods: Patients in the intention-to-treat population of COMPARZ were analyzed for differences in LTR (≥10 months [mos]) as measured by responder rate with either complete response or partial response (CR/PR) and PFS rate, and time to response. We also compared the clinical characteristics between long-term and shorter-term responders within and between each treatment arm. Results: The overall percentage of long-term responders with CR/PR (PAZ = 14%, SUN = 13%) and PFS (PAZ = 31.4%, SUN = 33.6%) in the PAZ and SUN groups were similar. This similarity was observed regardless of the cut-off for long-term duration of response. However, a shorter time to achieve CR/PR was observed in the overall population with PAZ (11.9 weeks [95% CI, 11.3–12.1] vs 17.4 weeks; [95% CI, 12.7–18.0]). Analysis conducted to identify baseline clinical characteristics that may be related to LTR will be reported. Conclusions: These exploratory subanalyses in long-term responders support the overall efficacy results with PAZ and SUN, which were reported in the COMPARZ trial. However, the results here demonstrate that the time to response was shorter with PAZ versus SUN. Clinical trial information: NCT00720941.

Background Cell fusion induced by polyethylene glycol (PEG) is an efficient but poorly controlled procedure for obtaining somatic cell hybrids used in gene mapping, monoclonal antibody production, and tumour immunotherapy. Genetic selection techniques and fluorescent cell sorting are usually employed to isolate cell fusion products, but both procedures have several drawbacks. Results Here we describe a simple improvement in PEG-mediated cell fusion that was obtained by modifying the standard single-step procedure. We found that the use of two PEG undertreatments obtains a better yield of cell fusion products than the standard method, and most of these products are bi- or trinucleated polykaryocytes. Fusion rate was quantified using fluorescent cell staining microscopy. We used this improved cell fusion and cell isolation method to compare giant cells obtained in vitro and giant cells obtained in vivo from patients with Hodgkin's disease and erythroleukemia. Conclusions In the present study we show how to improve PEG-mediated cell fusion and that cell separation by velocity sedimentation offers a simple alternative for the efficient purification of cell fusion products and to investigate giant cell formation in tumor development.