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Chronic lymphocytic leukaemia is the most common adult leukaemia, and a progressive incurable disease. Alth ough recent advances with chemoimmunotherapy have improved survival for patients without signifi cant medical comorbidities,1 these regimens cause striking myelosuppression and immunosuppression. These adverse eff ects can be especially severe in individuals older than 65–70 years—who are most at risk of development of chronic lymphocytic leukaemia—and the toxicities of the chemoimmunotherapy regimens may make them an intolerable therapeutic option. In the past few years, very potent kinase inhibitors that modulate downstream B-cell receptor signalling have entered the clinical setting.2 One such agent is ibrutinib, a covalent inhibitor of Bruton tyrosine kinase.3 In July, 2013, a phase 1b/2 study4 reported the results of single-agent ibrutinib in patients who had

relapsed or refractory chronic lymphocytic leukaemia, a median of four previous treatment regimens, and frequent high-risk cytogenetics (33% del17p, and 36% del11q). The study reported that 60 (71%) of 85 patients achieved an objective response, and, notably, an estimated 75% of these patients were progression-free at 26 months.

In The Lancet Oncology, Susan O’Brien and colleagues report the results5 for the previously untreated cohort of patients in the same phase 1b/2 study. 31 patients with chronic lymphocytic leukaemia who were older than 65 years and in need of fi rst-line therapy were enrolled. The primary endpoint of the study was to assess the safety of single-agent ibrutinib, and its toxicity profi le was notably good, with low myelosuppression and few infections. Even in an untreated population, this is an impressive toxicity

between countries: surveillance-based modelling using US data suggests that a third of the reduction in prostate cancer mortality is a result of screening and a further third is a result of advances in treatment.9 Some of the apparent improvement for prostate cancer survival in northern Europe might be caused by increased ad-hoc screening (with the associated risk of overdiagnosis), whereas the greater improvement in eastern Europe might primarily be a result of increased availability and use of systemic treatments.

The EUROCARE studies emphasise the importance and utility of population-based data for management of cancer, but use limited datasets. In an era of big data, and to be able to make sense of the patterns that emerge, more detailed information is needed. Registries should record more sociodemographic information and more details about investigation, staging, treatment, recurrences, and second-line treatment. Investigators should actively seek infor-mation about long-term consequences of treatment and precise information about causes of death. Immanuel Kant’s dictum applies: “out of the crooked timber of humanity, no straight thing was ever made”.10 Until more is known about the individual attributes of patients, the interpretation of the EUROCARE studies will be far from straightforward.

Alastair J MunroCancer Research Division, University of Dundee School of Medicine, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UKa.j.munro@dundee.ac.uk

I declare that I have no confl icts of interest.

1 De Angelis R, Sant M, Coleman MP, et al. Cancer survival in Europe 1999–2007 by country and age: results of EUROCARE-5—a population-based study. Lancet Oncol 2013; published online Dec 5. http://dx.doi.org/10.1016/S1470-2045(13)70546-1.

2 Gatta G, Botta L, Rossi S, et al. Childhood cancer survival in Europe 1999–2007: results of EUROCARE-5—a population-based study. Lancet Oncol 2013; published online Dec 5. http://dx.doi.org/10.1016/S1470-2045(13)70548-5.

3 Richards M. EUROCARE-4 studies bring new data on cancer survival. Lancet Oncol 2007; 8: 752–53.

4 Ellis L, Coleman MP, Rachet B. How many deaths would be avoidable if socioeconomic inequalities in cancer survival in England were eliminated? A national population-based study, 1996–2006. Eur J Cancer 2012; 48: 270–78.

5 OECD. Immigrant and foreign population. OECD Factbook 2013: Economic, Environmental and Social Statistics. OECD publishing, 2013.

6 Richards MA. The National Awareness and Early Diagnosis Initiative in England: assembling the evidence. Br J Cancer 2009; 101 (suppl 2): S1–4.

7 Eurostat. Mortality and life expectancy statistics. http://epp.eurostat.ec.europa.eu/statistics_explained/index.php/Mortality_and_life_expectancy_statistics (accessed Nov 21, 2013).

8 Gatta G, Zigon G, Aareleid T, et al. Patterns of care for European colorectal cancer patients diagnosed 1996–1998: a EUROCARE high resolution study. Acta Oncol 2010; 49: 776–83.

9 Etzioni R, Durand-Zaleski I, Lansdorp-Vogelaar I. Evaluation of new technologies for cancer control based on population trends in disease incidence and mortality. J Natl Cancer Inst Monogr 2013; 2013: 117–23.

10 Kant I. 6th Proposition. In: Beck LW, trans. Idea for a universal history from a cosmopolitan point of view. Bobbs-Merrill Co, 1784.

A new era of treatment for chronic lymphocytic leukaemia?Published OnlineDecember 10, 2013http://dx.doi.org/10.1016/S1470-2045(13)70558-8

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4 www.thelancet.com/oncology Vol 15 January 2014

profi le, and makes ibrutinib potentially very appealing as a therapeutic option, especially for elderly patients. However, the effi cacy of the regimen was perhaps even more impressive: 96·3% (95% CI 76·5–99·5) of patients were progression-free after a median follow-up of 22·1 months (IQR 18·4–23·2). These results are the best reported outcomes for an upfront therapy in this population of patients. However, a couple of caveats should be mentioned. First, the study was quite small, with only 31 patients, and 22 months median follow-up is short. In addition, enrolled patients showed low risk, likely treatment responsive disease, because very few patients had high-risk cytogenetic abnormalities or bulky lymphadenopathy. 55% had advanced Rai stage disease, but the indications for therapy for the remainder are somewhat unclear. Even with these caveats, however, the results are impressive.

An interesting feature of ibrutinib activity is that most patients have prolonged stable partial remissions (ie, persistent disease, rather than complete remissions). The stability of the disease in this setting might relate to the capacity of ibrutinib to induce quiescence of chronic lymphocytic leukaemia cells.6 Nonetheless, this persistence of disease does raise the concern that resistant clones can emerge over time. Such clones have been reported in patients relapsing on ibrutinib therapy.7 An additional concern is the early suggestion that Richter’s transformation, specifi cally the transformation of chronic lymphocytic leukaemia to an aggressive lymphoma, might be unexpectedly

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common in patients relapsing after ibrutinib. The one patient who relapsed and died on this study5 showed Richter’s transformation, as did seven of 11 relapsing patients in the previous report.4 All studies to date have been small, so larger studies will be needed to clarify the extent of this risk. Whether and how these relapsing patients can be best salvaged is unknown at present.

These concerns emphasise some of the questions that remain about how best to use ibrutinib, and in particular whether ibrutinib might be better used in combinations that could result in deeper remissions, and potentially increased progression-free survival. The only drug to date that has shown an early defi nitive overall survival benefi t in chronic lymphocytic leukaemia is the anti-CD20 antibody rituximab,1 which is also reasonably well-tolerated. Thus, combining ibrutinib with anti-CD20 antibody is very appealing even for older patients, and studies are assessing these regimens.8

In view of the number of small molecule inhibitors becoming available for chronic lymphocytic leukaemia, particularly the phosphatidylinositol 3 kinase (PI3K) δ inhibitors such as idelalisib9 and BCL-2 inhibitors such as ABT-199,10 key questions arise as to how best to use these drugs: will they be most benefi cial given sequentially as single agents, or as combined therapy? It is possible that combinations of several agents might reduce the risk of resistant clonal outgrowth. In either case, treatment of this cancer seems to be on the cusp of transformation, as amply shown by the safety and activity of ibrutinib in this study. Although the unanswered questions might be as abundant as the answers, these extremely active novel agents, led by ibrutinib, hold the promise of striking benefi t for patients in the coming years.

Jennifer R BrownDana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USAjbrown2@partners.org

JB has consulted for Pharmacyclics, Genentech, Emergent, Onyx, Sanofi , Vertex, Novartis, Celgene, Boehringer, Gilead, and GlaxoSmithKline, and received research funding from Celgene.

1 Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fl udarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 1164–74.

2 Davids MS, Brown JR. Targeting the B cell receptor pathway in chronic lymphocytic leukemia. Leuk Lymphoma 2012; 53: 2362–70.

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3 Honigberg LA, Smith AM, Sirisawad M, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is effi cacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci USA 2010; 107: 13075–80.

4 Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42.

5 O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 2013; published online Dec 10. http://dx.doi.org/10.1016/S1470-2045(13)70513-8.

6 Herman SEM, Farooqui M, Bezabhie R, Aue G, Wiestner A. In vivo eff ects of ibrutinib on BCR signaling, tumor cell activation and proliferation in blood and tissue-resident cells of chronic lymphocytic leukemia patients. Blood 2012; 120: abstr 185.

7 Chang BY, Furman RR, Zapatka M, et al. Use of tumor genomic profi ling to reveal mechanisms of resistance to the BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL). Proc Am Soc Clin Oncol 2013; 31 (suppl): abstr 7014.

8 Burger JA, Keating MJ, Wierda WG, et al. The Btk inhibitor ibrutinib (PCI-32765) in combination with rituximab is well tolerated and displays profound activity in high-risk chronic lymphocytic leukemia (CLL) patients. Blood 2012; 120: 187.

9 Brown JR, Furman RR, Flinn I, et al. Final results of a phase I study of idelalisib (GSE1101) a selective inhibitor of PI3Kδ, in patients with relapsed or refractory CLL. Proc Am Soc Clin Oncol 2013; 31 (suppl): abstr 7003.

10 Seymour JF, Davids MS, Anderson MA, et al. The BCL-2-specifi c BH3-mimetic ABT-199 (GDC-0199) is active and well-tolerated in patients with relapsed/refractory chronic lymphocytic leukemia: interim results of a phase I fi rst-in-human study. Blood 2012; 120: abstr 3923.

Immunotherapy in non-small-cell lung cancer: a good start?The quest to develop improved treatments for patients with locally advanced non-small-cell lung cancer has been generally unfulfi lling, despite sizable advances in radiotherapy technology and substantial progress in the understanding of tumour biology. Results from the recently reported phase 3 US Intergroup Trial (Radiation Therapy Oncology Group [RTOG] 0617)1 of standard-dose versus high-dose conformal chemoradiotherapy with or without cetuximab are particularly defl ating: the addition of cetuximab did not improve survival outcomes, and patients who received higher radiotherapy doses fared worse than those treated with standard doses. Results of this study provide further evidence to refute the notion that the addition of more cytotoxic therapy improves outcomes in stage III non-small-cell lung cancer, and is a clear signal to explore alternative options. Modulation of the immune system, via vaccination, or immunity checkpoint inhibition, has gained interest as a potential treatment pathway for non-small-cell lung cancer, particularly in view of successes with immunotherapy in melanoma and castration-resistant prostate cancer.2,3

Tecemotide is a vaccine that targets the MUC1 glycoprotein antigen. In a phase 2B study, tecemotide was associated with prolonged survival in locoregional stage IIIB non-small-cell lung cancer, but not with more advanced disease.4 In The Lancet Oncology, Charles Butts and colleagues report the mixed results of the START trial,5 restricted to stage III non-small-cell lung cancer. The modifi ed intention-to-treat population included 829 patients randomly assigned

to tecemotide, and 410 randomly assigned to placebo; no signifi cant diff erence in median survival was noted between the two treatment groups (25·6 months [95% CI 22·5–29·2] with tecemotide vs 22·3 months [19·6–25·5] with placebo; HR 0·88, 0·75–1·03; p=0·123). However, a predefi ned subgroup analysis of patients who had received initial concurrent chemoradiotherapy showed that the patients assigned to tecemotide had signifi cantly longer median survival than those assigned to placebo (30·8 months [95% CI 25·6–36·8] vs 20·6 months [17·4–23·9]; HR 0·78, 0·64–0·95; p=0·016), leaving unanswered questions about tecemotide’s potential effi cacy.

START enrolled patients after completion of chemoradiotherapy, with the assumption that appli cation of rational stratifi cation factors would minimise imbalances between the cohorts. Although the extent to which the fi ne details of initial therapy might aff ect survival is unclear, preliminary analysis of RTOG 0617 suggests radiation dose, normal tissue contouring, gross tumour target volume, and treatment-related toxicity might signifi cantly aff ect outcomes.1 As such, the absence of standardisation and quality assurances for both radiotherapy and chemotherapy administration in the START trial needs to be considered, because they might aff ect the results. Results for patients in the sequential therapy cohort provide further food for thought, because patients assigned to tecemotide had (non-signifi cantly) lower median survival (19·4 months [95% CI 17·6–23·1]) than did patients assigned to placebo (24·6 months [18·8–33·0]; HR 1·12, 0·87–1·44;

Published OnlineDecember 9, 2013http://dx.doi.org/10.1016/S1470-2045(13)70572-2

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