TY - JOUR
T1 - Phase II single-arm study of durvalumab and tremelimumab with concurrent radiotherapy in patients with mismatch repair-proficient metastatic colorectal cancer
AU - Segal, Neil H.
AU - Cercek, Andrea
AU - Ku, Geoffrey
AU - Wu, Abraham J.
AU - Rimner, Andreas
AU - Khalil, Danny N.
AU - Reidy-Lagunes, Diane
AU - Cuaron, John
AU - Yang, T. Jonathan
AU - Weiser, Martin R.
AU - Romesser, Paul B.
AU - Stadler, Zsofia K.
AU - Varghese, Anna M.
AU - Ganesh, Karuna
AU - Yaeger, Rona
AU - Connell, Louise C.
AU - Faleck, David
AU - Abou-Alfa, Ghassan K.
AU - Mcauliffe, Kathleen C.
AU - Vaiskauskas, Pamela
AU - Solter, Mark L.
AU - Ogle, Martinique
AU - Adamow, Matthew J.
AU - Holland, Aliya
AU - Vedantam, Pallavi
AU - Wong, Phillip
AU - Merghoub, Taha
AU - Vakiani, Efsevia
AU - Hollmann, Travis J.
AU - Juluru, Krishna
AU - Chou, Joanne F.
AU - Capanu, Marinela
AU - Erinjeri, Joseph
AU - Solomon, Stephen
AU - Yamada, Yoshiya
AU - Kemeny, Nancy
AU - Crane, Christopher H.
AU - Saltz, Leonard B.
N1 - Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/4
Y1 - 2021/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85104326667&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-2474
DO - 10.1158/1078-0432.CCR-20-2474
M3 - Article
C2 - 33504552
AN - SCOPUS:85104326667
SN - 1078-0432
VL - 27
SP - 2200
EP - 2208
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -