Phase II single-arm study of durvalumab and tremelimumab with concurrent radiotherapy in patients with mismatch repair-proficient metastatic colorectal cancer Journal Article


Authors: Segal, N. H.; Cercek, A.; Ku, G.; Wu, A. J.; Rimner, A.; Khalil, D. N.; Reidy-Lagunes, D.; Cuaron, J.; Yang, T. J.; Weiser, M. R.; Romesser, P. B.; Stadler, Z. K.; Varghese, A. M.; Ganesh, K.; Yaeger, R.; Connell, L. C.; Faleck, D.; Abou-Alfa, G. K.; McAuliffe, K. C.; Vaiskauskas, P.; Solter, M. L.; Ogle, M.; Adamow, M. J.; Holland, A.; Vedantam, P.; Wong, P.; Merghoub, T.; Vakiani, E.; Hollmann, T. J.; Juluru, K.; Chou, J. F.; Capanu, M.; Erinjeri, J.; Solomon, S.; Yamada, Y.; Kemeny, N.; Crane, C. H.; Saltz, L. B.
Article Title: Phase II single-arm study of durvalumab and tremelimumab with concurrent radiotherapy in patients with mismatch repair-proficient metastatic colorectal cancer
Abstract: PURPOSE: Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models. PATIENTS AND METHODS: In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles. RESULTS: We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9-26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0-27.0]. The median progression-free survival was 1.8 (95% CI, 1.7-1.9) months, median overall survival was 11.4 (95% CI, 10.1-17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. CONCLUSIONS: This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted. ©2021 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 27
Issue: 8
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2021-04-15
Start Page: 2200
End Page: 2208
Language: English
DOI: 10.1158/1078-0432.Ccr-20-2474
PUBMED: 33504552
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 3 May 2021 -- Source: Scopus
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MSK Authors
  1. Joanne Fu-Lou Chou
    232 Chou
  2. Leonard B Saltz
    702 Saltz
  3. Taha Merghoub
    285 Merghoub
  4. Neil Howard Segal
    156 Segal
  5. Yoshiya Yamada
    407 Yamada
  6. Geoffrey Yuyat Ku
    146 Ku
  7. Ghassan Abou-Alfa
    373 Abou-Alfa
  8. Zsofia Kinga Stadler
    245 Stadler
  9. Phillip Wong
    54 Wong
  10. Marinela Capanu
    294 Capanu
  11. Diane Lauren Reidy
    224 Reidy
  12. Martin R Weiser
    403 Weiser
  13. Rona Denit Yaeger
    157 Yaeger
  14. Andreas Rimner
    356 Rimner
  15. Abraham Jing-Ching Wu
    272 Wu
  16. Stephen Solomon
    332 Solomon
  17. Joseph Patrick Erinjeri
    122 Erinjeri
  18. Efsevia Vakiani
    204 Vakiani
  19. Nancy Kemeny
    470 Kemeny
  20. T. Jonathan Yang
    100 Yang
  21. Matthew J Adamow
    14 Adamow
  22. Danny Nejad Khalil
    28 Khalil
  23. John Jacob Cuaron
    61 Cuaron
  24. Pam Joan Raasch
    5 Raasch
  25. Krishna   Juluru
    17 Juluru
  26. Karuna   Ganesh
    33 Ganesh
  27. Louise Catherine Connell
    24 Connell
  28. Christopher   Crane
    88 Crane
  29. David M. Faleck
    12 Faleck
  30. Martinique M. Ogle
    1 Ogle
  31. Mark Larry Solter
    1 Solter