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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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p=0·38). An explanation for the diff erent eff ects with concurrent and sequential therapy is not apparent since most patients had responsive disease when enrolled on START. Moreover, median survival for the concurrent chemoradiotherapy plus placebo cohort was lower than was reported in other contemporary studies, including for patients who received standard-dose chemoradiotherapy in the RTOG 0617 trial (28·7 months [95% CI 22·0–not reached).1 The diff erences in these fi ndings might simply be a result of the lower use of 18F-fl uorodeoxyglucose PET staging in START, but it raises the question of whether a benefi t from adjuvant therapy should be proven in the context of standardised state-of-the-art staging and therapy.

Although immunotherapy might theoretically miti-gate the eff ect of specifi c mutations and histological variation,2 perhaps personalised therapy should not be dismissed. Although tecemotide did not seem to confer a benefi t in stage IV disease,4 other vaccine trials have suggested improved outcomes in some subpopulations of patients. Belagenpumatucel-L, a vaccine that transfects cells with a TGFB2 antisense gene, underwent phase 3 testing for locally advanced or metastatic non-small-cell lung cancer, although 490 (92%) of 532 patients had stage IIIB/IV disease.6 Similar to START, an improvement in median survival was only reported in predefi ned subsets, with particular effi cacy in the cohort of patients with stage IIIB/IV non-adenocarcinoma randomly assigned to belagenpumatucel-L within 12 weeks of chemotherapy (19·9 months with belagenpumatucel-L vs 12·3 months with placebo; HR 0·55; p=0·036). Patients who had received previous radiation also had improved median survival with the vaccine (40·1 months with belagenpumatucel-L vs 10·3 months with placebo; HR 0·45; p=0·014), which might be a result of improved effi cacy in patients with a lower tumour burden.

The eff ects of immunotherapy on earlier stage non-small-cell lung cancer have also been studied, and although a vaccine directed against MAGEA3 did not signifi cantly improve survival in patients with resected MAGEA3-positive stage IB/II non-small-cell lung cancer, a trend towards improved survival was reported with the vaccine.7 Results of a confi rmatory phase 3 trial are awaited, and assessment of a gene-expression signature that might predict benefi t from the MAGEA3 vaccine is a key secondary endpoint.7,8

Thus, the theme within vaccine trials for non-small-cell lung cancer is a trend towards benefi t but a general inability to achieve primary endpoints. These results suggest that work needs to be done to better identify patients that might benefi t from treatment. The results of prospective trials in progress in Asia (NCT01015443) and the USA (NCT00828009) will add to the scientifi c literature, but are unlikely to provide defi nitive answers as to the usefulness of tecemotide. Perhaps the next phase of development should focus on the achievement of greater knowledge about the importance of MUC1 in non-small-cell lung cancer, and the identifi cation of biomarkers that predict tecemotide effi cacy.9 With greater understanding, future studies can hopefully bring the questions raised by START to a fi nish.

*Jeff rey A Bogart, Ajeet GajraDepartment of Radiation Oncology (JAB), and Department of Medicine (AG), State University of New York Upstate Medical University, Syracuse, NY 13210, USAbogartj@upstate.edu

We declare that we have no confl icts of interest.

1 Bradley JD, Paulus R, Komaki R, et al. A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: results on radiation dose in RTOG 0617. Proc Am Soc Clin Oncol 2013; 31 (suppl 15): abstr 7501.

2 Forde PM, Reiss KA, Zeidan AM, Brahmer JR. What lies within: novel strategies in immunotherapy for non-small cell lung cancer. Oncologist 2013; 18: 1203–13.

3 Hall RD, Gray JE, Chiappori AA. Beyond the standard of care: a review of novel immunotherapy trials for the treatment of lung cancer. Cancer Control 2013; 20: 22–31.

4 Butts C, Maksymiuk A, Goss G, et al. Updated survival analysis in patients with stage IIIB or IV non-small-cell lung cancer receiving BLP25 liposome vaccine (L-BLP24): phase IIB randomized, multicenter, open-label trial. Cancer Res Clin Oncol 2011; 137: 1337–42.

5 Butts C, Socinski MA, Mitchell PL, et al, for the START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol 2013; published online Dec 9. http://dx.doi.org/10.1016/S1470-2045(13)70510-2.

6 European Society for Medical Oncology. FDA backs continued study of belagenpumatucel-L for subgroups of patients based on data from phase III STOP trial—Sep 28, 2013. http://www.esmo.org/conferences/european-cancer-congress-2013/news/belagenpumatucel-l-therapeutic-tumour-cell-vaccine-for-non-small-cell-lung-cancer (accessed Nov 11, 2013).

7 Vansteenkiste J, Zielinski M, Linder A, et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: phase II randomized study results. J Clin Oncol 2013; 19: 2396–403.

8 Tyagi P, Mirakhur B. MAGRIT: the largest-ever phase III lung cancer trial aims to establish a novel tumor-specifi c approach to therapy. Clin Lung Cancer 2009; 10: 371–74.

9 Situ D, Wang J, Ma Y, et al. Expression and prognostic relevance of MUC1 in stage IB non-small cell lung cancer. Med Oncol 2011; 28 (suppl 1): S596–604.