Juan W Valle
Department of Medical Oncology, University of Manchester and Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK [email protected]
I have received grants from AstraZeneca, personal fees from Sirtex, grants and personal fees from Celgene, and non-ﬁnancial support from Merck, all unrelated to the submitted work.
Malka D, Cervera P, Foulon S, et al, for the BINGO investigators. Gemcitabine and oxaliplatin with or without cetuximab in advanced biliary-tract cancer (BINGO): a randomised, open-label, non-comparative phase 2 trial. Lancet Oncol 2014; published online May 20. http://dx.doi.org/10.1016/S1470-2045(14)70212-8. Gruenberger B, Schueller J, Heubrandtner U, et al. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol 2010; 11: 1142–48. Glimelius B, Hoﬀman K, Sjoden PO, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol 1996; 7: 593–600.
Sharma A, Dwary AD, Mohanti BK, et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer: a randomized controlled study. J Clin Oncol 2010; 28: 4581–86. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 2010; 362: 1273–81. Eckel F, Schmid RM. Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials. Br J Cancer 2007; 96: 896–902. Sotelo MJ, Garcia-Paredes B, Aguado C, Sastre J, Diaz-Rubio E. Role of cetuximab in ﬁrst-line treatment of metastatic colorectal cancer. World J Gastroenterol 2014; 20: 4208–19. Lamarca A, Hubner RA, Ryder, WD, Valle JW. Second-line chemotherapy in advanced biliary cancer: a systematic review. Ann Oncol 2014; published online April 25. DOI:10.1093/annonc/mdu162. Chen L-T, Chen J-S, Chao Y, et al. KRAS mutation status-stratiﬁed randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): the TCOG T1210 trial. Proc Am Soc Clin Oncol 2013; 31 (suppl): 4018 (abstr). Lee J, Park SH, Chang HM, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2012; 13: 181–88.
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Chemoimmunotherapy: still waiting for the magic to happen
Published Online June 20, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70267-0 See Articles page 829
Over the past 10 years, there has been mainstream acceptance that some chemotherapies can be combined with immunotherapy in murine models, combining synergistically to lead to an improved outcome. What has proven more diﬃcult is translating that knowledge to positive, practice-changing clinical trials. The TeloVac investigators did a large three-arm randomised phase 3 trial, investigating a telomerase peptide vaccine plus granulocyte-macrophage colony-stimulating factor (GM-CSF) in combination with sequential or simultaneous gemcitabine plus capecitabine compared with chemotherapy alone in locally advanced or metastatic pancreatic cancer.1 This trial also had the potential to answer important questions of scheduling and immunomonitoring. The study was built on a platform of phase 2 data proving both safety and immune responses to the vaccine, with a signal for better survival outcomes in immune responders and the largest proportion of immune responders at the chosen dose.2 Preclinical data had shown independently that gemcitabine and ﬂuoropyrimidines, at least separately, were immunogenic adjuncts to immunotherapy.3–5 But unfortunately, no such beneﬁt was seen in this trial: median overall survival was not signiﬁcantly diﬀerent in the chemotherapy group compared with the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1–8·8] vs 6·9 months [6·4–7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97–1·48, p=0·05), nor the concurrent chemoimmunotherapy group (8·4 months
[95% CI 7·3–9·7], HR 1·05, 98·25% CI 0·85–1·29, p=0·64, with an overall log-rank of χ22df= 4·3; p=0·11). The question of scheduling of chemoimmunotherapy combinations is crucial for investigators in this ﬁeld, and the TeloVac investigators should be commended for including two experimental groups to explore the outcomes of concurrent versus sequential chemoimmunotherapy. Previous work in mice had shown that the eﬃcacy of such combinations could be very schedule dependent.3,6,7 This situation might also occur for chemoimmunotherapy in human beings, but to directly extrapolate from murine data has proven diﬃcult. Murine experiments run on a tight timeline. Experimental tumours often grow to a size requiring euthanasia over a few weeks. Chemotherapy is given as single or a few doses, with schedules that barely resemble what is used in the clinic. Furthermore, we cannot easily use human tumour xenografts or human peptide vaccines in immunologically intact mice, limiting the utility of murine testing of clinically relevant immunochemotherapy combinations. Finding the best schedule for chemoimmunotherapy within the model system might not necessarily help us select the most appropriate schedule for clinical trials in human beings. Hence, investigators in chemoimmunotherapy trials need to do as the TeloVac investigators did, and build in scheduling questions to the study design. Nevertheless, the study does give us a salutary reminder that compromising any aspect of conventional www.thelancet.com/oncology Vol 15 July 2014
treatment can be risky when testing new combinations. A fundamental strategy of combined modality therapy has been to advance incrementally by aiming to achieve the full dose of each modality, retreating when we reach a therapeutic or toxicity ceiling. The TeloVac trial substantially shortened the duration of chemotherapy in the sequential group, despite modest evidence for single-agent eﬃcacy of the vaccine2 and an accepted standard of care which recommends chemotherapy to remain ongoing until disease progression, or occurrence of toxic eﬀects.8 Unfortunately, this decision seems to have compromised the eﬃcacy of the sequential group, and does not allow a meaningful comparison between sequential and concurrent administration of the vaccine. We also need to consider some of the possible reasons why this combination failed to provide any survival beneﬁt.9 Immune responses were noted in fewer patients in this trial than in the phase 2 study.2 If two cytotoxic drugs are immunogenic alone, will they be as immunogenic—or better—when combined? Or can they ameliorate the complex balance of beneﬁcial and detrimental eﬀects on the immune response? Testing the immunological eﬀects of chemotherapy combinations in murine studies might not provide all the answers, but perhaps it should be a simple precursor to strengthen the scientiﬁc rationale of a large and costly clinical trial. Similarly, a case could be made for randomised phase 2 trials to guide scheduling and immunomonitoring before embarking on phase 3 studies, albeit knowing that endless combinations and schedules could potentially be tested. Does chemotherapy need to cause more cell death? Indeed, gemcitabine lost its immunogenicity in animal models of mesothelioma where chemoresistant cell lines were used and apoptosis did not occur.10 Gemcitabine as a single agent in pancreatic cancer was originally approved on the basis of clinical beneﬁt response that included minimal radiological response, and the combination with capecitabine adds little to overall radiological response.8 Perhaps there is just not enough cell death to enhance responses to immunotherapy; would FOLFIRINOX be a better partner, if the study were designed today? Finally, was the right immunotherapy used? Peptide vaccines have not yet transitioned to regulatory approval in any solid tumour, despite decades of investigation and clear evidence of human immune responses on laboratory monitoring; use of one antigen www.thelancet.com/oncology Vol 15 July 2014
can allow immune escape, and peptide vaccines rely on the quality of the adjuvant used. Checkpoint blockade inhibitors have made this crucial step over less than 10 years of clinical trials. Perhaps this is simply the wrong immunotherapy. This study is an important negative trial, designed on the basis of preclinical and clinical supporting data, and well conducted. It reminds us all how crucial it is to change only one parameter when investigating diﬀerent schedules, and perhaps that we should try to generate preclinical data that examine what we actually want to do. Most importantly, it reminds us that bringing chemotherapy and immunotherapy together in the clinic is not necessarily going to be easy, but we need to keep trying until magic happens. *Anna K Nowak, Willem J Lesterhuis School of Medicine and Pharmacology University of Western Australia, Crawley 6009, WA, Australia (AKN, WJL); National Research Centre for Asbestos Related Diseases, University of Western Australia, Crawley, WA, Australia (AKN, WJL); and Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia (AKN) [email protected]
We declare no competing interests. 1
Middleton G, Silcocks P, Cox T, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. Lancet Oncol 2014; published online June 24. http://dx.doi.org/10.1016/S1470-2045(14)70236-0. Bernhardt SL, Gjertsen MK, Trachsel S, et al. Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br J Cancer 2006; 95: 1474–82. Nowak AK, Robinson BW, Lake RA. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res 2003; 63: 4490–96. Bergmann-Leitner ES, Abrams SI. Treatment of human colon carcinoma cell lines with anti-neoplastic agents enhances their lytic sensitivity to antigen-speciﬁc CD8+ cytotoxic T lymphocytes. Cancer Immunol Immunother 2001; 50: 445–55. Correale P, Del Vecchio MT, Di Genova G, et al. 5-ﬂuorouracil-based chemotherapy enhances the antitumor activity of a thymidylate synthase-directed polyepitopic peptide vaccine. J Nat Cancer Inst 2005; 97: 1437–45. Kedar E, Ben-Aziz R, Epstein E, Leshem B. Chemo-immunotherapy of murine tumors using interleukin-2 (IL-2) and cyclophosphamide. IL-2 can facilitate or inhibit tumor growth depending on the sequence of treatment and the tumor type. Cancer Immunol Immunother 1989; 29: 74–78. Lesterhuis WJ, Salmons J, Nowak AK, et al. Synergistic eﬀect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity. PloS One 2013; 8: e61895. Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009; 27: 5513–18. Lake RA, Robinson BW. Immunotherapy and chemotherapy—a practical partnership. Nat Rev Cancer 2005; 5: 397–405. Nowak AK, Lake RA, Marzo AL, et al. Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-speciﬁc CD8 T cells. J Immunol 2003; 170: 4905–13.