Research Spotlight

Posted November 15th 2019

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.

Charles L. Cowey M.D.
Charles L. Cowey M.D.

Larkin, J., V. Chiarion-Sileni, R. Gonzalez, J. J. Grob, P. Rutkowski, C. D. Lao, C. L. Cowey, D. Schadendorf, J. Wagstaff, R. Dummer, P. F. Ferrucci, M. Smylie, D. Hogg, A. Hill, I. Marquez-Rodas, J. Haanen, M. Guidoboni, M. Maio, P. Schoffski, M. S. Carlino, C. Lebbe, G. McArthur, P. A. Ascierto, G. A. Daniels, G. V. Long, L. Bastholt, J. I. Rizzo, A. Balogh, A. Moshyk, F. S. Hodi and J. D. Wolchok (2019). “Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma.” New England Journal of Medicine 381(16): 1535-1546.

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BACKGROUND: Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS: We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS: At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS: Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).


Posted November 15th 2019

The Changing Paradigm of Ethics in Uterus Transplantation: A Systematic Review.

Liza Johannesson, M.D.
Liza Johannesson, M.D.

Ngaage, L. M., S. Ike, A. Elegbede, C. J. Vercler, S. Gebran, F. Liang, E. M. Rada, C. Cooney, G. Brandacher, R. J. Redett, L. Johannesson and Y. M. Rasko (2019). “The Changing Paradigm of Ethics in Uterus Transplantation: A Systematic Review.” Transplant International Nov 1. [Epub ahead of print].

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BACKGROUND: The first uterus transplantation was performed in 2000. As key milestones are reached (longlasting graft survival in 2011, and first birth from a transplanted womb in 2014), the ethical debate around uterus transplant evolves. METHODS: We performed a systematic review of articles on uterus transplantation. Ethical themes were extracted and categorised according to four bioethical principles. Papers were divided into time periods separated by key events in uterus transplant history: Phase I (first technical achievement, 2002-11), Phase II (clinical achievement, 2012-14), and Phase III (after the first childbirth, 2015-18). RESULTS: Eighty-one articles were included. The majority of ethics papers were published in Phase III (65%, p<0.0001), i.e. after the first birth. 80% of papers discussed non-maleficence making it the most discussed principle. The first birth acted as a pivotal point: non-maleficence was discussed by a lower proportion of articles (p=0.0073), as was beneficence (p=0.0309). However, discussion of justice increased to become the most discussed principle of the time period (p=0.0085). CONCLUSIONS: The ethical debate surrounding uterus transplantation has evolved around landmark events that signify scientific progress. As safety and efficacy become evident, the focus of ethical debate shifts from clinical equipoise to socioeconomic challenges and equitable access to uterus transplantation.


Posted November 15th 2019

Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial.

Joyce O'Shaughnessy M.D.
Joyce O’Shaughnessy M.D.

Tan, A. R., G. S. Wright, A. R. Thummala, M. A. Danso, L. Popovic, T. J. Pluard, H. S. Han, Z. Vojnovic, N. Vasev, L. Ma, D. A. Richards, S. T. Wilks, D. Milenkovic, Z. Yang, J. M. Antal, S. R. Morris and J. O’Shaughnessy (2019). “Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial.” Lancet Oncology 20(11): 1587-1601.

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BACKGROUND: Trilaciclib is an intravenous cell-cycle inhibitor that transiently maintains immune cells and haemopoietic stem and progenitor cells in G1 arrest. By protecting the immune cells and bone marrow from chemotherapy-induced damage, trilaciclib has the potential to optimise antitumour activity while minimising myelotoxicity. We report safety and activity data for trilaciclib plus gemcitabine and carboplatin chemotherapy in patients with metastatic triple-negative breast cancer. METHODS: In this randomised, open-label, multicentre, phase 2 study, adult patients (aged >/=18 years) with evaluable, biopsy-confirmed, locally recurrent or metastatic triple-negative breast cancer who had no more than two previous lines of chemotherapy were recruited from 26 sites in the USA, three in Serbia, two in North Macedonia, one in Croatia, and one in Bulgaria; sites were academic and community hospitals. Availability of diagnostic samples of tumour tissue confirming triple-negative breast cancer was a prerequisite for enrolment. Eligible patients were randomly assigned (1:1:1) by an interactive web-response system, stratified by number of previous lines of systemic therapy and the presence of liver metastases, to receive intravenous gemcitabine 1000 mg/m(2) and intravenous carboplatin (area under the concentration-time curve 2 mug x h/mL) on days 1 and 8 (group 1), gemcitabine and carboplatin plus intravenous trilaciclib 240 mg/m(2) on days 1 and 8 (group 2), or gemcitabine and carboplatin on days 2 and 9 plus trilaciclib on days 1, 2, 8, and 9 (group 3) of 21-day cycles. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal of consent, or discontinuation by the investigator. The primary objective was to assess the safety and tolerability of combining trilaciclib with gemcitabine and carboplatin chemotherapy. The primary endpoints were duration of severe neutropenia during cycle 1 and the occurrence of severe neutropenia during the treatment period. Overall survival was included as a key secondary endpoint. Analyses were in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with EudraCT, 2016-004466-26, and ClinicalTrials.gov, NCT02978716, and is ongoing but closed to accrual. FINDINGS: Between Feb 7, 2017, and May 15, 2018, 142 patients were assessed for eligibility and 102 were randomly assigned to group 1 (n=34), group 2 (n=33), or group 3 (n=35). Of all patients, 38 (37%) had received one or two lines of previous chemotherapy in the metastatic setting. Median follow-up was 8.4 months (IQR 3.8-13.6) for group 1, 12.7 months (5.5-17.4) for group 2, and 12.9 months (6.7-16.8) for group 3. Data cutoff for myelosuppression endpoints was July 30, 2018, and for antitumour activity endpoints was May 17, 2019. During cycle 1, mean duration of severe neutropenia was 0.8 day (SD 2.4) in group 1, 1.5 days (3.5) in group 2, and 1.0 day (2.6) in group 3 (group 3 vs group 1 one-sided adjusted p=0.70). Severe neutropenia occurred in nine (26%) of 34 patients in group 1, 12 (36%) of 33 patients in group 2, and eight (23%) of 35 patients in group 3 (p=0.70). Overall survival was 12.6 months (IQR 5.8-15.6) in group 1, 20.1 months (9.4-not reached) in group 2, and 17.8 months (8.8-not reached) in group 3 (group 3 vs group 1 two-sided p=0.0023). The most common treatment-emergent adverse events were anaemia (22 [73%] of 34), neutropenia (21 [70%]), and thrombocytopenia (18 [60%]) in group 1; neutropenia (27 [82%] of 33), thrombocytopenia (18 [55%]) and anaemia (17 [52%]) in group 2; and neutropenia (23 [66%] of 35), thrombocytopenia (22 [63%]), and nausea (17 [49%]) in group 3. There were no treatment-related deaths. INTERPRETATION: No significant differences were observed in myelosuppression endpoints with trilaciclib plus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer; however, the regimen was generally well tolerated and overall survival results were encouraging. Further studies of trilaciclib in this setting are warranted. FUNDING: G1 Therapeutics.


Posted November 15th 2019

Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients.

Joyce O'Shaughnessy M.D.
Joyce O’Shaughnessy M.D.

Paul, D., S. J. Vukelja, F. Ann Holmes, J. L. Blum, K. J. McIntyre, D. L. Lindquist, C. R. Osborne, I. J. Sanchez, J. H. Goldschmidt, Y. Wang, L. Asmar, L. Strauss and J. O’Shaughnessy (2019). “Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients.” NPJ Breast Cancer Nov 5: 8(21). [Epub 2019 Oct 18].

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The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0-1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease >/=6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58-83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52-77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.


Posted November 15th 2019

Chronic constipation: new insights, better outcomes?

Lawrence R. Schiller M.D.

Schiller, L. R. (2019). “Chronic constipation: new insights, better outcomes?” Lancet: Gastroenterology and Hepatology 4(11): 873-882.

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Constipation is a symptom that affects around 11-20% of the adult population yearly. Most physicians consider infrequency of defecation as a hallmark of constipation. However, most patients view excessive straining as the biggest component of constipation and only a minority of patients with constipation have infrequent bowel movements. Constipation might be due to many different medical conditions or occur as a side-effect of drug therapy. When these medical conditions or drug therapies are not present, a diagnosis of functional constipation, chronic idiopathic constipation, or irritable bowel syndrome with constipation is often made. In all patients with constipation, rectal outlet dysfunction should be excluded by physical examination because this condition occurs in approximately 25% of patients diagnosed with idiopathic constipation and can be improved with different therapeutic approaches than administration of laxatives. Because of the availability of over-the-counter laxatives, most patients consider themselves able to self-manage constipation, and patients have often tried many different treatments before seeking professional help. The physician must carefully assess these previous efforts of self-treatment, optimise them, and strategically use the increasing list of prescription medications for management.