Research Spotlight

Posted September 15th 2018

Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.

Joanne L. Blum M.D.

Joanne L. Blum M.D.

Litton, J. K., H. S. Rugo, J. Ettl, S. A. Hurvitz, A. Goncalves, K. H. Lee, L. Fehrenbacher, R. Yerushalmi, L. A. Mina, M. Martin, H. Roche, Y. H. Im, R. G. W. Quek, D. Markova, I. C. Tudor, A. L. Hannah, W. Eiermann and J. L. Blum (2018). “Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.” N Engl J Med 379(8): 753-763.

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BACKGROUND: The poly(adenosine diphosphate-ribose) inhibitor talazoparib has shown antitumor activity in patients with advanced breast cancer and germline mutations in BRCA1 and BRCA2 ( BRCA1/2). METHODS: We conducted a randomized, open-label, phase 3 trial in which patients with advanced breast cancer and a germline BRCA1/2 mutation were assigned, in a 2:1 ratio, to receive talazoparib (1 mg once daily) or standard single-agent therapy of the physician’s choice (capecitabine, eribulin, gemcitabine, or vinorelbine in continuous 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 431 patients who underwent randomization, 287 were assigned to receive talazoparib and 144 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the talazoparib group than in the standard-therapy group (8.6 months vs. 5.6 months; hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.41 to 0.71; P<0.001). The interim median hazard ratio for death was 0.76 (95% CI, 0.55 to 1.06; P=0.11 [57% of projected events]). The objective response rate was higher in the talazoparib group than in the standard-therapy group (62.6% vs. 27.2%; odds ratio, 5.0; 95% CI, 2.9 to 8.8; P<0.001). Hematologic grade 3-4 adverse events (primarily anemia) occurred in 55% of the patients who received talazoparib and in 38% of the patients who received standard therapy; nonhematologic grade 3 adverse events occurred in 32% and 38% of the patients, respectively. Patient-reported outcomes favored talazoparib; significant overall improvements and significant delays in the time to clinically meaningful deterioration according to both the global health status-quality-of-life and breast symptoms scales were observed. CONCLUSIONS: Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single-agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression-free survival. Patient-reported outcomes were superior with talazoparib. (Funded by Medivation [Pfizer]; EMBRACA ClinicalTrials.gov number, NCT01945775 .).


Posted September 15th 2018

Semaglutide and GLP-1 analogues as weight-loss agents.

Peter McCullough M.D.

Peter McCullough M.D.

Kluger, A. Y. and P. A. McCullough (2018). “Semaglutide and GLP-1 analogues as weight-loss agents.” Lancet 392(10148): 615-616.

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The increasing global frequency of obesity and its resultant health effects are well documented. Drug development for obesity has been hampered by concerns over cardiovascular safety and a paucity of significant efficacy. One possible pharmaceutical solution to promote weight loss lies in the glucagon-like peptide-1 (GLP-1) analogue class of drugs, one of which is semaglutide and is approved with a dosing schedule of once per a week for the treatment of type 2 diabetes. Reported in The Lancet, Patrick O’Neil and colleagues’ Article5 presents a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial of daily subcutaneous semaglutide (doses ranging from 0·05 mg to 0·4 mg) versus liraglutide (3·0 mg per day) and matched placebo for the treatment of non-diabetic obesity over a 52-week period. The primary endpoint was percentage weight loss at week 52. O’Neil and colleagues found that all semaglutide doses were relatively well tolerated and were associated with reductions in bodyweight from baseline compared with placebo. Placebo was associated with a 2·48 kg weight loss from a baseline of 114·2 kg (estimated mean weight loss of −2·3%), whereas the semaglutide 0·05 mg per day dose was associated with a 6·66 kg weight loss from a baseline of 111·3 kg (estimated mean weight loss of −6·0%), the 0·1 mg per day dose with a 9·34 kg weight loss from a baseline of 111·3 kg (−8·6%), the 0·2 mg per day dose with a 12·30 kg weight loss from a baseline of 114·5 kg (−11·6%), the 0·3 mg per day dose with a 12·45 kg weight loss from a baseline of 111·5 kg (−11·2%), and the 0·4 mg/day dose with a 15·15 kg weight loss from a baseline of 113·2 kg (−13·8%). These treatment differences for all the semaglutide doses versus placebo were significant. (Excerpt from this commentary on O’Neal et al., Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial, Lancet, Volume 392, Issue 10148, 25–31 August 2018, Pages 637-649.)


Posted September 15th 2018

Final results of a randomized multicenter phase II study of alvocidib, cytarabine, and mitoxantrone versus cytarabine and daunorubicin (7 + 3) in newly diagnosed high-risk acute myeloid leukemia (AML).

Moshe Y. Levy M.D.

Moshe Y. Levy M.D.

Zeidner, J. F., M. C. Foster, A. L. Blackford, M. R. Litzow, L. E. Morris, S. A. Strickland, J. E. Lancet, P. Bose, M. Y. Levy, R. Tibes, I. Gojo, C. D. Gocke, G. L. Rosner, R. F. Little, J. J. Wright, L. A. Doyle, B. D. Smith and J. E. Karp (2018). “Final results of a randomized multicenter phase II study of alvocidib, cytarabine, and mitoxantrone versus cytarabine and daunorubicin (7 + 3) in newly diagnosed high-risk acute myeloid leukemia (AML).” Leuk Res 72: 92-95.

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Despite recent advances in the management of subpopulations of AML, overall outcomes remain unsatisfactory. Encouraging results were seen with alvocidib (formerly known as flavopiridol), a CDK9 inhibitor with pan-cyclin-dependent kinase (CDK) activity, followed by cytarabine and mitoxantrone (FLAM) in serial phase I-II studies in newly diagnosed AML patients. Therefore, we conducted a randomized phase II clinical trial comparing FLAM to cytarabine and daunorubicin (7 + 3) in newly diagnosed AML patients 18–70 years of age with non-favorable risk cytogenetics. We previously published results of this trial revealing no significant differences in overall survival (OS) between FLAM and 7 + 3 despite significantly higher complete remission (CR) rates with FLAM. It is imperative to analyze long-term OS on this study as a secondary endpoint. Furthermore, we hypothesized that the survival trends may change with longer follow-up. We report the final long-term OS results of this trial. This study randomized 165 patients between FLAM (n = 109) and 7 + 3 (n = 56) with a median age of 59 years (range: 19–70 years) across 10 institutions. Overall, 41% of patients had adverse-risk features based on 2010 European Leukemia Net Guidelines. The primary endpoint of this trial was the rate of CR (including CR with incomplete hematologic recovery: CRi) with FLAM and 7 + 3. FLAM led to significantly increased CR rates when compared with 7 + 3 with 1 or 2 cycles of treatment (70% vs. 47%, p = 0.003, and 70% vs. 57%, p = 0.08, respectively). Despite the improvement in CR rates with FLAM, our earlier published results did not reveal significant differences in overall survival (OS) and event-free survival (EFS) between the arms, with median follow-up 811 days (range: 1–1217 days) by reverse Kaplan-Meier methodology . . . Our final analysis reveals that FLAM leads to higher CR rates compared with 1 or 2 cycles of 7 + 3 induction in newly diagnosed AML patients 18–70 years with non-favorable cytogenetics but no significant difference was seen in OS or EFS. Subset analyses suggest that younger patients are more likely to achieve CR on FLAM compared with 7 + 3. Ongoing trials of alvocidib will provide further direction for its role in the current treatment armamentarium for AML. (Excerpt from text, p. 92, 94; no abstract available.)


Posted September 15th 2018

The regulatory role of APE1 in epithelial-to-mesenchymal transition and in determining EGFR-TKI responsiveness in non-small-cell lung cancer.

Laura Baugh D.O.

Laura Baugh D.O.

Yang, X., Y. Peng, X. Jiang, X. Lu, W. Duan, S. Zhang, N. Dai, J. Shan, Y. Feng, X. Li, Y. Cheng, Y. Yang, L. Baugh, G. Tell, D. Wang and M. Li (2018). “The regulatory role of APE1 in epithelial-to-mesenchymal transition and in determining EGFR-TKI responsiveness in non-small-cell lung cancer.” Cancer Med. 7(9): 4406-4419.

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BACKGROUND: Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC). Our previous study revealed that in osteosarcoma, human apurinic/apyrimidinic endonuclease 1 (APE1) regulates transforming growth factor-beta (TGF-beta), an important player in EMT. We therefore hypothesized a link between APE1 and EGFR-TKI responsiveness in NSCLC. METHODS: The protein levels of APE1 were analyzed in tumors of NSCLC patients receiving EGFR-TKI treatment. The correlation between APE1 expression and progression-free survival (PFS), overall survival (OS), or response rate were analyzed. The impact of APE1 on the response to EGFR-TKIs was measured by exogenous manipulation of APE1 in EGFR-TKI-sensitive and EGFR-TKI-resistant cells. RESULTS: We indicate that low expression of APE1 in tumors is associated with a significantly longer PFS (20.8 months vs 8.4 months, P = 0.008) and a preferential OS (39.0 months vs 17.0 months, P = 0.001), with no difference in initial response rate to EGFR-TKIs. We observed that APE1 protein level was significantly increased in EGFR-TKI-resistant cells and was associated with downregulated E-cadherin and upregulated vimentin. The EMT phenotype, as well as the levels of TGF-beta, was suppressed in APE1 knockdown HCC827/IR and PC-9/ER cells, while the EMT phenotype was promoted in APE1-overexpressed HCC827 and PC-9 cells. Furthermore, a specific APE1 redox inhibitor (ie, E3330) effectively reversed the EMT phenotype and further sensitized the cells to EGFR-TKIs. CONCLUSION: This study revealed a significant role of APE1 in EGFR-TKI resistance via novel regulatory effects on the EMT phenotype in NSCLC.


Posted September 15th 2018

Proliferative glomerulonephritis with monoclonal IgG deposits in children and young adults.

Xin J. Zhou M.D.

Xin J. Zhou M.D.

Xing, G., R. Gillespie, B. Bedri, A. Quan, P. Zhang and X. J. Zhou (2018). “Proliferative glomerulonephritis with monoclonal IgG deposits in children and young adults.” Pediatr Nephrol 33(9): 1531-1538.

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BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) has been recognized as a distinct entity in recent years. To the best of our knowledge, all patients with PGNMID reported thus far were older than 20 years of age. We now report five cases of PGNMID in patients under 20 years of age. METHODS: The clinical database was searched for patients with native kidney biopsies from 9/2011 to 8/2017, and cases with a diagnosis of PGNMID were retrieved. Light microscopy specimens and immunofluorescence and electron microscopy images were revisited. Clinical data and kidney biopsy findings for patients under the age of 20 were recorded. RESULTS: Five (0.78%) of a total of 637 patients younger than 20 with native renal biopsies had a diagnosis of PGNMID, including three males and two females with an average age of 14 years old (range 10-19). All five patients presented with microscopic hematuria and proteinuria. Three patients were nephrotic and their C3 levels were low. All five cases showed a membranoproliferative pattern with abundant mesangial and subendothelial monoclonal IgG3 deposits (3 kappa and 2 lambda light chain, respectively). The patients were followed up to 56 months. Two patients had re-biopsies 28 and 18 months after initial diagnosis and both showed similar morphologic changes. Various treatments were attempted including prednisone, mycophenolate mofetil, tacrolimus, rituximab, and eculizmab, with mixed responses. CONCLUSIONS: PGNMID does occur in children and young adults. Membranoproliferative glomerulonephritis pattern with monoclonal IgG3 deposits is a common feature. Despite various immunosuppressive treatments, the disease appears slowly progressive.