Advertisement

Current Oncology Reports

, 16:363 | Cite as

Palliative Treatment of Metastatic Colorectal Cancer: What is the Optimal Approach?

  • John H. StricklerEmail author
  • Herbert I. Hurwitz
Gastrointestinal Cancers (B Czito, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Gastrointestinal Cancers

Abstract

Worldwide, colorectal cancer (CRC) is responsible for over 600,000 deaths annually and remains a significant public health concern. Because of therapeutic advancements over the past two decades, patients with metastatic CRC are living longer with an improved quality of life. This review will highlight recent trial evidence that improves outcomes for patients with metastatic disease. Topics will include the optimal use of first-line combination chemotherapy, bevacizumab in patients with advanced age or comorbidities, maintenance chemotherapy, first-line use of anti-EGFR therapies, first-line cetuximab versus bevacizumab, anti-angiogenic therapies past progression, and management of treatment-refractory disease. Clinical trial evidence will be presented, along with guidance on how to integrate recent evidence into clinical practice. Finally, this review will examine innovative drug development strategies, and will discuss potentially actionable targets identified by molecular testing.

Keywords

Metastatic colorectal cancer Bevacizumab Cetuximab Panitumumab Maintenance chemotherapy Palliative chemotherapy FOLFOX FOLFIRI FOLFOXIRI Bevacizumab in the elderly Ziv-aflibercept Regorafenib HER2 c-MET 

Notes

Compliance with Ethics Guidelines

Conflict of Interest

John H. Strickler is on an advisory board for Amgen and has received payment for CME lectures supported by Lily USA, LLC for The Academy for Healthcare Learning.

Herbert I. Hurwitz is a consultant for from Genetech, Roche, Pfizer, Sanofi, Regeneron, BMS, Lilly, GSK, Threshold, Tracon, and Amgen; has grants pending from Genetech, Roche, Pfizer, Sanofi, Regeneron, BMS, Lilly, GSK, Threshold, Tracon, and Amgen; and has received honoraria from Roche.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Ferlay J, Shin H, Bray F, et al.: GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010. Available at http://globocan.iarc.fr. Accessed August 26, 2013.
  2. 2.
    NCCN Clinical Practice Guidelines in Oncology: Colon Cancer, version 1.2014. Available at http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed September 24, 2013.
  3. 3.
    Cassidy J, Clarke S, Diaz-Rubio E, et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol. 2008;26(12):2006–12.PubMedCrossRefGoogle Scholar
  4. 4.
    Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008;26(21):3523–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale. J Clin Oncol. 2005;23(22):4866–75.PubMedCrossRefGoogle Scholar
  6. 6.
    Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22(2):229–37.PubMedCrossRefGoogle Scholar
  7. 7.
    Bajetta E, Di Bartolomeo M, Mariani L, et al. Randomized multicenter Phase II trial of two different schedules of irinotecan combined with capecitabine as first-line treatment in metastatic colorectal carcinoma. Cancer. 2004;100(2):279–87.PubMedCrossRefGoogle Scholar
  8. 8.
    Borner MM, Bernhard J, Dietrich D, et al. A randomized phase II trial of capecitabine and two different schedules of irinotecan in first-line treatment of metastatic colorectal cancer: efficacy, quality-of-life and toxicity. Ann Oncol. 2005;16(2):282–8.PubMedCrossRefGoogle Scholar
  9. 9.
    Kohne CH, De Greve J, Hartmann JT, et al. Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol. 2008;19(5):920–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Patt YZ, Lee FC, Liebmann JE, et al. Capecitabine plus 3-weekly irinotecan (XELIRI regimen) as first-line chemotherapy for metastatic colorectal cancer: phase II trial results. Am J Clin Oncol. 2007;30(4):350–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Rea DW, Nortier JW, Ten Bokkel Huinink WW, et al. A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer. Ann Oncol. 2005;16(7):1123–32.PubMedCrossRefGoogle Scholar
  12. 12.
    Hess GP, Wang PF, Quach D, et al. Systemic Therapy for Metastatic Colorectal Cancer: Patterns of Chemotherapy and Biologic Therapy Use in US Medical Oncology Practice. J Oncol Pract. 2010;6(6):301–7.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Cheeseman SL, Joel SP, Chester JD, et al. A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002;87(4):393–9.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    • Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42. This study demonstrated the survival advantage of bevacizumab in the first-line treatment of metastatic CRC.PubMedCrossRefGoogle Scholar
  15. 15.
    Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25(30):4779–86.PubMedCrossRefGoogle Scholar
  16. 16.
    • Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26(12):2013–9. This study demonstrated the PFS advantage of bevacizumab with oxaliplatin-based chemotherapy.PubMedCrossRefGoogle Scholar
  17. 17.
    Falcone A, Cremolini C, Masi G, et al.: FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group. J Clin Oncol 2013, 31(suppl; abstr 3505).Google Scholar
  18. 18.
    Cassidy J, Saltz LB, Giantonio BJ, et al. Effect of bevacizumab in older patients with metastatic colorectal cancer: pooled analysis of four randomized studies. J Cancer Res Clin Oncol. 2010;136(5):737–43.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol. 2003;21(1):60–5.PubMedCrossRefGoogle Scholar
  20. 20.
    Kabbinavar FF, Hambleton J, Mass RD, et al. Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol. 2005;23(16):3706–12.PubMedCrossRefGoogle Scholar
  21. 21.
    Kabbinavar FF, Hurwitz HI, Yi J, et al. Addition of bevacizumab to fluorouracil-based first-line treatment of metastatic colorectal cancer: pooled analysis of cohorts of older patients from two randomized clinical trials. J Clin Oncol. 2009;27(2):199–205.PubMedCrossRefGoogle Scholar
  22. 22.
    Kozloff M, Bekaii-Saab TS, Bendell JC, et al.: Effectiveness of first- or second-line bevacizumab (BV) treatment (tx) in elderly patients (pts) with metastatic colorectal cancer (mCRC) in ARIES, an observational cohort study (OCS). J Clin Oncol 29: 2011 (suppl; abstr 3625).Google Scholar
  23. 23.
    Kozloff MF, Berlin J, Flynn PJ, et al. Clinical outcomes in elderly patients with metastatic colorectal cancer receiving bevacizumab and chemotherapy: results from the BRiTE observational cohort study. Oncology. 2010;78(5–6):329–39.PubMedCrossRefGoogle Scholar
  24. 24.
    • Cunningham D, Lang I, Marcuello E, et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly patients with previously untreated metastatic colorectal cancer (AVEX): an open-label, randomised phase 3 trial. Lancet Oncol. 2013;14(11):1077–85. This study established the safety and clinical activity of bevacizumab in patients aged 70 years or older.PubMedCrossRefGoogle Scholar
  25. 25.
    Tebbutt NC, Wilson K, Gebski VJ, et al. Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group Randomized Phase III MAX Study. J Clin Oncol. 2010;28(19):3191–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer–a GERCOR study. J Clin Oncol. 2006;24(3):394–400.PubMedCrossRefGoogle Scholar
  27. 27.
    • Koopman M, Simkens LHJ, Tije AJT, et al.: Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 2013, 31(suppl; abstr 3502). This study established the clinical activity and tolerability of maintenance capecitabine and bevacizumab. Google Scholar
  28. 28.
    Diaz-Rubio E, Gomez-Espana A, Massuti B, et al. First-line XELOX plus bevacizumab followed by XELOX plus bevacizumab or single-agent bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: the phase III MACRO TTD study. Oncologist. 2012;17(1):15–25.PubMedCrossRefGoogle Scholar
  29. 29.
    Tournigand C, Scheithauer W, Samson B, et al.: Induction treatment in first-line with chemotherapy + bevacizumab (bev) in metastatic colorectal cancer: Results from the gercor-DREAM phase III study. J Clin Oncol 2012, 30(suppl 34; abstr 457).Google Scholar
  30. 30.
    Koeberle D, Betticher DC, Moos RV, et al.: Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06). J Clin Oncol 2013, 31(suppl; abstr 3503).Google Scholar
  31. 31.
    Berry SR, Cosby R, Asmis TR, et al.: Randomized controlled trials (RCTs) examining continuous (CS) versus intermittent strategies (IS) of delivering systemic treatment (Tx) for untreated metastatic colorectal cancer (mCRC): A meta-analysis from the Cancer Care Ontario program in evidence-based care. J Clin Oncol 2013, 31(suppl; abstr 3534).Google Scholar
  32. 32.
    Cetuximab [package insert]. Available at http://packageinserts.bms.com/pi/pi_erbitux.pdf. Accessed September 29, 2013.
  33. 33.
    Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28(31):4697–705.PubMedCrossRefGoogle Scholar
  35. 35.
    O'Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007;25(24):3644–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–34.PubMedCrossRefGoogle Scholar
  37. 37.
    Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27(5):663–71.PubMedCrossRefGoogle Scholar
  38. 38.
    Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–65.PubMedCrossRefGoogle Scholar
  39. 39.
    Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360(14):1408–17.PubMedCrossRefGoogle Scholar
  40. 40.
    •• Douillard JY, Oliner KS, Siena S, et al. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–34. This study expanded the definition ofRAS mutationto KRAS and NRAS exons 2, 3, and 4. With this expanded definition, FOLFOX plus panitumumab had a statistically significant survival benefit compared to FOLFOX alone.PubMedCrossRefGoogle Scholar
  41. 41.
    Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet. 2011;377(9783):2103–14.PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Ye LC, Liu TS, Ren L, et al. Randomized Controlled Trial of Cetuximab Plus Chemotherapy for Patients With KRAS Wild-Type Unresectable Colorectal Liver-Limited Metastases. J Clin Oncol. 2013;31(16):1931–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Primrose JN, Falk S, Finch-Jones M, et al.: A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study. J Clin Oncol 2013, 31(suppl; abstr 3504).Google Scholar
  44. 44.
    •• Heinemann VVW, L. F., Decker T, Kiani A, et al.: Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). J Clin Oncol 2013, 31(suppl; abstr LBA3506). This study demonstrated superior survival for FOFIRI plus cetuximab compared to FOLFIRI plus bevaicizumab. Google Scholar
  45. 45.
    Schwartzberg LS, Rivera F, Karthaus M, et al.: Analysis of KRAS/NRAS mutations in PEAK: A randomized phase II study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC). J Clin Oncol 2013, 31(suppl; abstr 3631).Google Scholar
  46. 46.
    Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25(12):1539–44.PubMedCrossRefGoogle Scholar
  47. 47.
    Cohn AL, Bekaii-Saab T, Bendell JC, et al.: Clinical outcomes in bevacizumab (BV)-treated patients (pts) with metastatic colorectal cancer (mCRC): Results from ARIES observational cohort study (OCS) and confirmation of BRiTE data on BV beyond progression (BBP). J Clin Oncol 2010, 28:15s(suppl; abstr 3596).Google Scholar
  48. 48.
    Grothey A, Sugrue MM, Purdie DM, et al. Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: results from a large observational cohort study (BRiTE). J Clin Oncol. 2008;26(33):5326–34.PubMedCrossRefGoogle Scholar
  49. 49.
    • Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14(1):29–37. This study established the survival advantage of second-line bevacizumab past progression.PubMedCrossRefGoogle Scholar
  50. 50.
    Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002;99(17):11393–8.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012;30(28):3499–506.PubMedCrossRefGoogle Scholar
  52. 52.
    Wilhelm SM, Dumas J, Adnane L, et al. Regorafenib (BAY 73–4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129(1):245–55.PubMedCrossRefGoogle Scholar
  53. 53.
    Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303–12.PubMedCrossRefGoogle Scholar
  54. 54.
    • Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7. This study provided comprehensive molecular characterization of 276 human colon and rectal tumor specimens.CrossRefGoogle Scholar
  55. 55.
    Richman SD, Seymour MT, Chambers P, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009;27(35):5931–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Bokemeyer C, Cutsem EV, Rougier P, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48(10):1466–75.PubMedCrossRefGoogle Scholar
  57. 57.
    Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Kopetz S, Desai J, Chan E, et al.: PLX4032 in metastatic colorectal cancer patients with mutant BRAF tumors. J Clin Oncol 2010, 28(15s): (suppl; abstr 3534).Google Scholar
  59. 59.
    Yang H, Higgins B, Kolinsky K, et al. Antitumor activity of BRAF inhibitor vemurafenib in preclinical models of BRAF-mutant colorectal cancer. Cancer Res. 2012;72(3):779–89.PubMedCrossRefGoogle Scholar
  60. 60.
    Corcoran RB, Ebi H, Turke AB, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2(3):227–35.PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Corcoran RB, Falchook GS, Infante JR, et al.: Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer (CRC). J Clin Oncol 2013, 31(suppl; abstr 3507).Google Scholar
  62. 62.
    Marsoni S, Bertotti A, Sartore-Bianchi A, et al.: Dual anti-HER2 treatment of patients with HER2-positive metastatic colorectal cancer: The HERACLES trial (HER2 Amplification for Colo-rectaL Cancer Enhanced Stratification). J Clin Oncol 2013, 31(suppl; abstr TPS3648).Google Scholar
  63. 63.
    Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337–45.PubMedCrossRefGoogle Scholar
  64. 64.
    Diehl F, Li M, Dressman D, et al. Detection and quantification of mutations in the plasma of patients with colorectal tumors. Proc Natl Acad Sci U S A. 2005;102(45):16368–73.PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    • Diaz Jr LA, Williams RT, Wu J, et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature. 2012;486(7404):537–40. This study utilized circulating tumor DNA obtained from peripheral blood to describe a proposed mechanism of acquired resistance to EGFR blockade.PubMedCentralPubMedGoogle Scholar
  66. 66.
    Palma NA, Palmer GA, Ali SM, et al.: Frequency of MET amplification determined by comprehensive next-generation sequencing (NGS) in multiple solid tumors and implications for use of MET inhibitors. J Clin Oncol 2013, 31(suppl; abstr 11068).Google Scholar
  67. 67.
    Bardelli A, Corso S, Bertotti A, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Discov. 2013;3(6):658–73.PubMedCrossRefGoogle Scholar
  68. 68.
    Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122–33.PubMedCrossRefGoogle Scholar
  69. 69.
    Lipson EJ, Sharfman WH, Drake CG, et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res. 2013;19(2):462–8.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Medicine, Division of Medical OncologyDuke University Medical CenterDurhamUSA

Personalised recommendations