Srinivas K. Tantravahi

Impact of Bone and Liver Metastases on Patients with Renal Cell Carcinoma Treated with Targeted Therapy

BACKGROUND The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC). OBJECTIVE To analyze outcomes based on the presence of bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy. DESIGN, SETTING, AND PARTICIPANTS We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression. RESULTS AND LIMITATIONS The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively (p<0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) (p=0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval [CI], 1.22-1.62) for BMs, 1.42 (95% CI, 1.17-1.73) for LMs, and 1.82 (95% CI, 1.47-2.26) for both BMs and LMs compared with other metastatic sites (p<0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p<0.0001). Data in this analysis were collected retrospectively. CONCLUSIONS The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.

Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia

Mutations in the BCR-ABL1 kinase domain are an established mechanism of tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive leukemia, but fail to explain many cases of clinical TKI failure. In contrast, it is largely unknown why some patients fail TKI therapy despite continued suppression of BCR-ABL1 kinase activity, a situation termed BCR-ABL1 kinase-independent TKI resistance. Here, we identified activation of signal transducer and activator of transcription 3 (STAT3) by extrinsic or intrinsic mechanisms as an essential feature of BCR-ABL1 kinase-independent TKI resistance. By combining synthetic chemistry, in vitro reporter assays, and molecular dynamics-guided rational inhibitor design and high-throughput screening, we discovered BP-5-087, a potent and selective STAT3 SH2 domain inhibitor that reduces STAT3 phosphorylation and nuclear transactivation. Computational simulations, fluorescence polarization assays and hydrogen–deuterium exchange assays establish direct engagement of STAT3 by BP-5-087 and provide a high-resolution view of the STAT3 SH2 domain/BP-5-087 interface. In primary cells from chronic myeloid leukemia (CML) patients with BCR-ABL1 kinase-independent TKI resistance, BP-5-087 (1.0 μM) restored TKI sensitivity to therapy-resistant CML progenitor cells, including leukemic stem cells. Our findings implicate STAT3 as a critical signaling node in BCR-ABL1 kinase-independent TKI resistance, and suggest that BP-5-087 has clinical utility for treating malignancies characterized by STAT3 activation.

Age-related mutations and chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a hematologic malignancy nearly confined to the elderly. Previous studies to determine incidence and prognostic significance of somatic mutations in CMML have relied on candidate gene sequencing, although an unbiased mutational search has not been conducted. As many of the genes commonly mutated in CMML were recently associated with age-related clonal hematopoiesis (ARCH) and aged hematopoiesis is characterized by a myelomonocytic differentiation bias, we hypothesized that CMML and aged hematopoiesis may be closely related. We initially established the somatic mutation landscape of CMML by whole exome sequencing followed by gene-targeted validation. Genes mutated in ⩾10% of patients were SRSF2, TET2, ASXL1, RUNX1, SETBP1, KRAS, EZH2, CBL and NRAS, as well as the novel CMML genes FAT4, ARIH1, DNAH2 and CSMD1. Most CMML patients (71%) had mutations in ⩾2 ARCH genes and 52% had ⩾7 mutations overall. Higher mutation burden was associated with shorter survival. Age-adjusted population incidence and reported ARCH mutation rates are consistent with a model in which clinical CMML ensues when a sufficient number of stochastically acquired age-related mutations has accumulated, suggesting that CMML represents the leukemic conversion of the myelomonocytic-lineage-biased aged hematopoietic system.

Six-month progression-free survival as the primary endpoint to evaluate the activity of new agents as second-line therapy for advanced urothelial carcinoma.

OBJECTIVE Second-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents. METHODS Ten second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction. RESULTS In the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R(2) = 0.55, Pearson correlation = 0.66) and individual levels (82%, Қ = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Қ = 0.36), and the trial level association was not statistically significant (R(2) = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Қ = 0.44) appeared stronger than the correlation of response (76%, Қ = 0.17) with OS12 in the external validation dataset. CONCLUSIONS PFS6 is strongly associated with OS12 and appears more optimal than RR to identify active second-line agents for advanced UC.

A Population-Based Overview of Sequences of Targeted Therapy in Metastatic Renal Cell Carcinoma

BACKGROUND Several TTs are available to treat mRCC; however, the optimal sequence of therapy remains unknown. PATIENTS AND METHODS Consecutive population-based samples of patients with mRCC treated with TT were collected from 12 cancer centers via the International Metastatic Renal Cell Carcinoma Database Consortium. Patient characteristics, first-line and second-line progression-free survival rates and overall survival data were collected based on sequencing of TT. Multivariable analysis was performed when there were significant differences on univariable analysis. RESULTS A total of 2106 patients were included with a median follow-up of 36 months; 907 (43%) and 318 (15%) patients received subsequent second-line and third-line TT, respectively. Baseline characteristics were well matched among different sequences apart from more patients with non-clear-cell histology in the vascular endothelial growth factor (VEGF) to mammalian target of rapamycin (mTOR) group compared with the VEGF to VEGF group sequence. When adjusting for the Heng risk criteria and non-clear-cell histology, the hazard ratio for death for the VEGF to mTOR group versus the VEGF to VEGF group was 0.833 (95% confidence interval [CI], 0.669-1.037; P = .1016). More specifically, the adjusted hazard ratio for death for the sunitinib to everolimus versus sunitinib to temsirolimus sequences was 0.774 (95% CI, 0.52-1.153; P = .2086). CONCLUSION In this large multicenter analysis evaluating different sequences of TT in mRCC, no substantial effect on outcome based on sequence of TT was identified.

shRNA library screening identifies nucleocytoplasmic transport as a mediator of BCR-ABL1 kinase-independent resistance

The mechanisms underlying tyrosine kinase inhibitor (TKI) resistance in chronic myeloid leukemia (CML) patients lacking explanatory BCR-ABL1 kinase domain mutations are incompletely understood. To identify mechanisms of TKI resistance that are independent of BCR-ABL1 kinase activity, we introduced a lentiviral short hairpin RNA (shRNA) library targeting ∼5000 cell signaling genes into K562(R), a CML cell line with BCR-ABL1 kinase-independent TKI resistance expressing exclusively native BCR-ABL1. A customized algorithm identified genes whose shRNA-mediated knockdown markedly impaired growth of K562(R) cells compared with TKI-sensitive controls. Among the top candidates were 2 components of the nucleocytoplasmic transport complex, RAN and XPO1 (CRM1). shRNA-mediated RAN inhibition or treatment of cells with the XPO1 inhibitor, KPT-330 (Selinexor), increased the imatinib sensitivity of CML cell lines with kinase-independent TKI resistance. Inhibition of either RAN or XPO1 impaired colony formation of CD34(+) cells from newly diagnosed and TKI-resistant CML patients in the presence of imatinib, without effects on CD34(+) cells from normal cord blood or from a patient harboring the BCR-ABL1(T315I) mutant. These data implicate RAN in BCR-ABL1 kinase-independent imatinib resistance and show that shRNA library screens are useful to identify alternative pathways critical to drug resistance in CML.

Everolimus Versus Temsirolimus in Metastatic Renal Cell Carcinoma After Progression With Previous Systemic Therapies

BACKGROUND Everolimus is an approved agent for use after disease progression with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. With recently published trials showing efficacy of nivolumab and cabozantinib in the second-line therapy setting, the use of everolimus will likely move to the third- or fourth-line therapy setting. Temsirolimus has occasionally been used instead of everolimus for many reasons, including financial considerations, assurance of patient compliance given its intravenous administration, its toxicity profile, patient performance status, and patient or physician preference. However, efficacy of everolimus and temsirolimus in this setting have not been compared in a randomized trial. The results from retrospective studies have been inconsistent. MATERIALS AND METHODS We identified patients treated with a first-line VEGFR-TKI for metastatic renal cell carcinoma and then treated with either everolimus or temsirolimus on progression from the databases of 2 large academic cancer centers. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of second-line treatment using the Kaplan-Meier method. RESULTS A total of 90 patients received either everolimus (n = 59; 66%) or temsirolimus (n = 31; 34%) after progression during first-line VEGFR-TKI therapy. The patient and disease characteristics were similar in both groups. The median PFS was not different, but OS was superior with everolimus compared with temsirolimus (24.2 months vs. 12.1 months; hazard ratio, 0.58; P = .047). CONCLUSION Our results bolster existing guidelines supporting everolimus over temsirolimus as salvage therapy after previous systemic therapies.

First-line Mammalian target of rapamycin inhibition in metastatic renal cell carcinoma: an analysis of practice patterns from the International Metastatic Renal Cell Carcinoma Database Consortium.

INTRODUCTION/BACKGROUND Approval of the mTOR inhibitors for the treatment of mRCC was based on efficacy in poor-risk patients in the first-line setting for temsirolimus and in vascular endothelial growth factor inhibitor-refractory patients for everolimus. We strove to characterize temsirolimus and everolimus use and effectiveness in the first-line setting. PATIENTS AND METHODS We performed a retrospective database analysis of mRCC patients who received mTOR inhibitors as first-line targeted therapy. The Kaplan-Meier product-limit method was used to estimate the distribution of progression-free survival (PFS) and overall survival (OS). RESULTS We identified 127 mRCC patients who had received a first-line mTOR inhibitor. Temsirolimus was administered in 93 patients (73%) and everolimus in 34 patients (27%). The main reasons for choice of temsirolimus were poor-risk disease (38%), non-clear cell histology (27%), and clinical trial availability (15%), whereas clinical trial (82%) and non-clear cell histology (6%) drove everolimus selection. Of the temsirolimus and everolimus patients, 58% and 32% were poor-risk according to the International mRCC Database Consortium criteria, respectively. The median PFS and OS were 3.4 and 12.5 months and 4.8 and 15.9 months with temsirolimus and everolimus, respectively. Although limited by small numbers, this study characterizes a real-world, international experience with the use of mTOR inhibition in treatment-naive mRCC patients. CONCLUSION Poor-risk RCC, non-clear cell histology, and clinical trials were the predominant reasons for mTOR inhibitor selection in the front-line setting. Because of the different patient populations in which they were administered, direct comparisons of the front-line efficacy of temsirolimus and everolimus cannot be made.

A phase II study of the efficacy, safety, and determinants of response to 5-azacitidine (Vidaza®) in patients with chronic myelomonocytic leukemia.

Srinivas K. Tantravahi, Philippe Szankasi, Jamshid S. Khorashad, Kim-Hien Dao, Tibor Kovacsovics, Todd W. Kelley and Michael W. Deininger Division of Hematology and Hematologic Malignancies, Huntsman Cancer Hospital, The University of Utah, Salt Lake City, UT, USA; Department of Pathology, The University of Utah and ARUP Laboratories, Salt Lake City, UT, USA; Oregon Health & Science University, Knight Cancer Institute, OR, USA

Incidence of severe nephrotoxicity with cisplatin based on renal function eligibility criteria: Indirect comparison meta-analysis

Background:The objective of this meta-analysis was to indirectly compare incidence of nephrotoxicity in trials using cisplatin (CIS) for treatment of solid tumors when renal function was assessed using serum creatinine (SCr) or creatinine clearance (CrCl) for eligibility criteria. Methods:Randomized trials comparing CIS-containing with non-CIS-containing chemotherapy regimens were identified in PubMed. Included studies were performed from 1990 to 2010, used SCr or CrCl as an eligibility criterion, and reported incidence of grade ≥3 nephrotoxicity for both treatment arms using World Health Organization (WHO) or National Cancer Institute (NCI) toxicity criteria. The relative risk (RR) of grade ≥3 nephrotoxicity associated with CIS versus non-CIS regimens was examined. Subgroup analyses, adjusted indirect comparison, and metaregression were used to compare SCr and CrCl. Results:The literature search identified 2359 studies, 42 studies met all the inclusion criteria (N=9521 patients). SCr was used as an eligibility criterion in 20 studies (N=4704), CrCl was used in 9 studies (N=1650), and either was used in 13 studies (N=3167). The overall RR for developing nephrotoxicity with CIS versus non-CIS treatment was 1.75 (P=0.005). Subgroup analyses showed an increased risk when SCr was used (RR=2.60, P=0.005) but not when CrCl was used (RR=1.50, P=0.19). Both the adjusted indirect comparison and metaregression showed a nonsignificantly reduced risk of nephrotoxicity when CrCl was used. Conclusions:CIS-based therapy was associated with a significant increase in severe nephrotoxicity. The risk of severe nephrotoxicity appears to be lower when CrCl was used to determine whether people should be treated with CIS.