Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370)

a multicentre, open-label, phase 3, randomised, controlled trial

IMblaze370 Investigators

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background: Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting. Methods: IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0–1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four)to assign patients (2:1:1)via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks)plus cobimetinib (60 mg orally once daily for days 1–21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1–21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant)and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279. Findings: Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7–13·6). Median overall survival was 8·87 months (95% CI 7·00–10·61)with atezolizumab plus cobimetinib, 7·10 months (6·05–10·05)with atezolizumab, and 8·51 months (6·41–10·71)with regorafenib; the hazard ratio was 1·00 (95% CI 0·73–1·38; p=0·99)for the combination versus regorafenib and 1·19 (0·83–1·71; p=0·34)for atezolizumab versus regorafenib. Grade 3–4 adverse events were reported in 109 (61%)of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%)of 90 in the atezolizumab group, and 46 (58%)of 80 in the regorafenib group. The most common all-cause grade 3–4 adverse events in the combination group were diarrhoea (20 [11%]of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%)of 179 patients in the combination group, 15 (17%)of 90 in the atezolizumab group, and 18 (23%)of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis)and one in the regorafenib group (intestinal perforation). Interpretation: IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer. Funding: F Hoffmann-La Roche Ltd/Genentech Inc.

Original languageEnglish
Pages (from-to)849-861
Number of pages13
JournalThe Lancet Oncology
Volume20
Issue number6
DOIs
Publication statusPublished - Jun 1 2019

Fingerprint

Colorectal Neoplasms
Randomized Controlled Trials
GDC-0973
regorafenib
MPDL3280A
Microsatellite Repeats
Immunotherapy
Survival
Intestinal Perforation
Safety
Microsatellite Instability
Creatine Kinase
Random Allocation
Patient Selection
Population
Fatigue
Disease Progression
Anemia
Diarrhea
Sepsis

ASJC Scopus subject areas

  • Oncology

Cite this

@article{b558eaf9e051474799eb7b37e90996fa,
title = "Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial",
abstract = "Background: Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting. Methods: IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0–1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four)to assign patients (2:1:1)via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks)plus cobimetinib (60 mg orally once daily for days 1–21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1–21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant)and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5{\%}. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279. Findings: Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7–13·6). Median overall survival was 8·87 months (95{\%} CI 7·00–10·61)with atezolizumab plus cobimetinib, 7·10 months (6·05–10·05)with atezolizumab, and 8·51 months (6·41–10·71)with regorafenib; the hazard ratio was 1·00 (95{\%} CI 0·73–1·38; p=0·99)for the combination versus regorafenib and 1·19 (0·83–1·71; p=0·34)for atezolizumab versus regorafenib. Grade 3–4 adverse events were reported in 109 (61{\%})of 179 patients in the atezolizumab plus cobimetinib group, 28 (31{\%})of 90 in the atezolizumab group, and 46 (58{\%})of 80 in the regorafenib group. The most common all-cause grade 3–4 adverse events in the combination group were diarrhoea (20 [11{\%}]of 179), anaemia (ten [6{\%}]), increased blood creatine phosphokinase (12 [7{\%}]), and fatigue (eight [4{\%}]). Serious adverse events were reported in 71 (40{\%})of 179 patients in the combination group, 15 (17{\%})of 90 in the atezolizumab group, and 18 (23{\%})of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis)and one in the regorafenib group (intestinal perforation). Interpretation: IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer. Funding: F Hoffmann-La Roche Ltd/Genentech Inc.",
author = "{IMblaze370 Investigators} and Cathy Eng and Kim, {Tae Won} and Johanna Bendell and Guillem Argil{\'e}s and Tebbutt, {Niall C.} and {Di Bartolomeo}, Maria and Alfredo Falcone and Marwan Fakih and M. Kozloff and Segal, {Neil H.} and Alberto Sobrero and Yibing Yan and Ilsung Chang and Anne Uyei and Louise Roberts and Fortunato Ciardiello and Ahn, {J. B.} and J. Asselah and S. Badarinath and S. Baijal and S. Begbie and S. Berry and Canon, {J. L.} and Carbone, {R. G.} and A. Cervantes and Cha, {Y. J.} and K. Chang and A. Chaudhry and E. Chmielowska and Cho, {S. H.} and D. Chu and F. Couture and J. Cultrera and D. Cunningham and {Van Cutsem}, E. and Cuyle, {P. J.} and J. Davies and S. Dowden and M. Dvorkin and V. Ganju and Garcia, {R. V.} and R. Kerr and Kim, {T. Y.} and K. King and J. Kortmansky and M. Kozloff and Lam, {K. O.} and J. Lee and Lee, {A. S.} and E. Maiello",
year = "2019",
month = "6",
day = "1",
doi = "10.1016/S1470-2045(19)30027-0",
language = "English",
volume = "20",
pages = "849--861",
journal = "The Lancet Oncology",
issn = "1470-2045",
publisher = "Lancet Publishing Group",
number = "6",

}

TY - JOUR

T1 - Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370)

T2 - a multicentre, open-label, phase 3, randomised, controlled trial

AU - IMblaze370 Investigators

AU - Eng, Cathy

AU - Kim, Tae Won

AU - Bendell, Johanna

AU - Argilés, Guillem

AU - Tebbutt, Niall C.

AU - Di Bartolomeo, Maria

AU - Falcone, Alfredo

AU - Fakih, Marwan

AU - Kozloff, M.

AU - Segal, Neil H.

AU - Sobrero, Alberto

AU - Yan, Yibing

AU - Chang, Ilsung

AU - Uyei, Anne

AU - Roberts, Louise

AU - Ciardiello, Fortunato

AU - Ahn, J. B.

AU - Asselah, J.

AU - Badarinath, S.

AU - Baijal, S.

AU - Begbie, S.

AU - Berry, S.

AU - Canon, J. L.

AU - Carbone, R. G.

AU - Cervantes, A.

AU - Cha, Y. J.

AU - Chang, K.

AU - Chaudhry, A.

AU - Chmielowska, E.

AU - Cho, S. H.

AU - Chu, D.

AU - Couture, F.

AU - Cultrera, J.

AU - Cunningham, D.

AU - Van Cutsem, E.

AU - Cuyle, P. J.

AU - Davies, J.

AU - Dowden, S.

AU - Dvorkin, M.

AU - Ganju, V.

AU - Garcia, R. V.

AU - Kerr, R.

AU - Kim, T. Y.

AU - King, K.

AU - Kortmansky, J.

AU - Kozloff, M.

AU - Lam, K. O.

AU - Lee, J.

AU - Lee, A. S.

AU - Maiello, E.

PY - 2019/6/1

Y1 - 2019/6/1

N2 - Background: Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting. Methods: IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0–1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four)to assign patients (2:1:1)via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks)plus cobimetinib (60 mg orally once daily for days 1–21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1–21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant)and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279. Findings: Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7–13·6). Median overall survival was 8·87 months (95% CI 7·00–10·61)with atezolizumab plus cobimetinib, 7·10 months (6·05–10·05)with atezolizumab, and 8·51 months (6·41–10·71)with regorafenib; the hazard ratio was 1·00 (95% CI 0·73–1·38; p=0·99)for the combination versus regorafenib and 1·19 (0·83–1·71; p=0·34)for atezolizumab versus regorafenib. Grade 3–4 adverse events were reported in 109 (61%)of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%)of 90 in the atezolizumab group, and 46 (58%)of 80 in the regorafenib group. The most common all-cause grade 3–4 adverse events in the combination group were diarrhoea (20 [11%]of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%)of 179 patients in the combination group, 15 (17%)of 90 in the atezolizumab group, and 18 (23%)of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis)and one in the regorafenib group (intestinal perforation). Interpretation: IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer. Funding: F Hoffmann-La Roche Ltd/Genentech Inc.

AB - Background: Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting. Methods: IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0–1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four)to assign patients (2:1:1)via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks)plus cobimetinib (60 mg orally once daily for days 1–21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1–21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant)and time since diagnosis of first metastasis (<18 months vs ≥18 months). Recruitment of patients with high microsatellite instability was capped at 5%. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. IMblaze370 is ongoing and is registered with ClinicalTrials.gov, number NCT02788279. Findings: Between July 27, 2016, and Jan 19, 2017, 363 patients were enrolled (183 patients in the atezolizumab plus cobimetinib group, 90 in the atezolizumab group, and 90 in the regorafenib group). At data cutoff (March 9, 2018), median follow-up was 7·3 months (IQR 3·7–13·6). Median overall survival was 8·87 months (95% CI 7·00–10·61)with atezolizumab plus cobimetinib, 7·10 months (6·05–10·05)with atezolizumab, and 8·51 months (6·41–10·71)with regorafenib; the hazard ratio was 1·00 (95% CI 0·73–1·38; p=0·99)for the combination versus regorafenib and 1·19 (0·83–1·71; p=0·34)for atezolizumab versus regorafenib. Grade 3–4 adverse events were reported in 109 (61%)of 179 patients in the atezolizumab plus cobimetinib group, 28 (31%)of 90 in the atezolizumab group, and 46 (58%)of 80 in the regorafenib group. The most common all-cause grade 3–4 adverse events in the combination group were diarrhoea (20 [11%]of 179), anaemia (ten [6%]), increased blood creatine phosphokinase (12 [7%]), and fatigue (eight [4%]). Serious adverse events were reported in 71 (40%)of 179 patients in the combination group, 15 (17%)of 90 in the atezolizumab group, and 18 (23%)of 80 in the regorafenib group. Two treatment-related deaths occurred in the combination group (sepsis)and one in the regorafenib group (intestinal perforation). Interpretation: IMblaze370 did not meet its primary endpoint of improved overall survival with atezolizumab plus cobimetinib or atezolizumab versus regorafenib. The safety of atezolizumab plus cobimetinib was consistent with those of the individual drugs. These results underscore the challenge of expanding the benefit of immunotherapy to patients whose tumours have lower baseline levels of immune inflammation, such as those with microsatellite-stable metastatic colorectal cancer. Funding: F Hoffmann-La Roche Ltd/Genentech Inc.

UR - http://www.scopus.com/inward/record.url?scp=85066145160&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066145160&partnerID=8YFLogxK

U2 - 10.1016/S1470-2045(19)30027-0

DO - 10.1016/S1470-2045(19)30027-0

M3 - Article

VL - 20

SP - 849

EP - 861

JO - The Lancet Oncology

JF - The Lancet Oncology

SN - 1470-2045

IS - 6

ER -