TY - JOUR
T1 - Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM)
AU - Hurwitz, Herbert I.
AU - Tan, Benjamin R.
AU - Reeves, James A.
AU - Xiong, Henry
AU - Somer, Brad
AU - Lenz, Heinz Josef
AU - Hochster, Howard S.
AU - Scappaticci, Frank
AU - Palma, John F.
AU - Price, Richard
AU - Lee, John J.
AU - Nicholas, Alan
AU - Sommer, Nicolas
AU - Bendell, Johanna
N1 - Funding Information:
The concept of aggressive induction for the treatment of mCRC is supported by the TRIBE study [12, 13]. The use of multiple anticancer agents with distinct mechanisms of action may help prevent the development of resistant clones and provide longer disease control [20]. Our findings suggest that cFOLFOXIRI-BEV and sFOLFOXIRI-BEV are active and well tolerated in patients with mCRC, consistent with prior data from TRIBE and OLIVIA, as well as several recent meta-analyses [21, 22]. cFOLFOXIRI-BEV conferred either statistically significant or strong trends for improvements in both ORR and PFS compared with FOLFOX-BEV, benefits that appeared largely independent of the molecular characteristics or sidedness of the tumor. To further optimize the first-line FOLFOXIRI-BEV treatment strategy, the randomized, phase III TRIBE-2 trial will directly assess whether the use of concurrent FOLFOXIRI-BEV improves survival relative to sequential FOLFOXIRI-BEV [23]. Taken together, these data support the use of concurrent or sequential FOLFOXIRI-BEV as potential first-line treatment options for patients with mCRC who can tolerate these treatment regimens.
Funding Information:
This study was funded by F. Hoffmann-La Roche, Ltd. Support for third-party writing assistance was provided by Sabrina Hom, Ph.D., of CodonMedical, an Ashfield Company, part of UDG Healthcare Plc, and was funded by F. Hoffmann-La Roche, Ltd./Genentech, Inc. H.I.H. is currently affiliated with Genentech, Inc., South San Francisco, CA. These data were presented in part as the following abstracts: Bendell JC, Tan BR, Reeves JA et al. Overall response rate (ORR) in STEAM, a randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for the first-line (1 L) treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC). American Association of Clinical Oncology Gastrointestinal Cancers Symposium; January 21?23, 2016; San Francisco, CA; Abstract 492. Hurwitz H, Tan BR, Reeves JA et al. Updated efficacy, safety, and biomarker analyses of STEAM, a randomized, open-label, phase II trial of sequential (s) and concurrent (c) FOLFOXIRI-bevacizumab (BV) vs FOLFOX-BV for first-line (1 L) treatment (tx) of patients with metastatic colorectal cancer (mCRC). American Association of Clinical Oncology Gastrointestinal Cancers Symposium; January 19?21, 2017; San Francisco, CA; Abstract 657.
Publisher Copyright:
© AlphaMed Press 2018
PY - 2019/7
Y1 - 2019/7
N2 - Background: First-line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI-BEV) or sequentially (sFOLFOXIRI-BEV, FOLFOX-BEV alternating with FOLFIRI-BEV), versus FOLFOX-BEV for mCRC. Patients and Methods: Patients with previously untreated mCRC (n = 280) were randomized 1:1:1 to cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, or FOLFOX-BEV and treated with 4–6-month induction followed by maintenance. Coprimary objectives were overall response rate (ORR; first-line cFOLFOXIRI-BEV vs. FOLFOX-BEV) and progression-free survival (PFS; pooled first-line cFOLFOXIRI-BEV and sFOLFOXIRI-BEV vs. FOLFOX-BEV). Secondary/exploratory objectives included overall survival (OS), liver resection rates, biomarker analyses, and safety. Results: ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, and FOLFOX-BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI-BEV and FOLFOX-BEV did not significantly differ (p =.132); thus, the primary ORR endpoint was not met. cFOLFOXIRI-BEV and sFOLFOXIRI-BEV numerically improved ORR and PFS, regardless of RAS status. Median PFS was higher with pooled concurrent and sequential FOLFOXIRI-BEV versus FOLFOX-BEV (11.7 vs. 9.5 months; hazard ratio, 0.7; 90% confidence interval, 0.5–0.9; p <.01). Liver resection rates were 17.2% (cFOLFOXIRI-BEV), 9.8% (sFOLFOXIRI-BEV), and 8.4% (FOLFOX-BEV). Grade ≥ 3 treatment-emergent adverse events (TEAEs) were observed in 91.2% (cFOLFOXIRI-BEV), 86.7% (sFOLFOXIRI-BEV), and 85.6% (FOLFOX-BEV) of patients, with no increase in serious chemotherapy-associated TEAEs. Conclusion: cFOLFOXIRI-BEV and sFOLFOXIRI-BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX-BEV, supporting triplet chemotherapy plus BEV as a first-line treatment option for mCRC. Implications for Practice: The combination of first-line FOLFIRI with FOLFOX and bevacizumab (concurrent FOLFOXIRI-BEV) improves clinical outcomes in patients with metastatic colorectal cancer (mCRC) relative to FOLFIRI-BEV or FOLFOX-BEV, but it is thought to be associated with increased toxicity. Alternating treatment of FOLFOX and FOLFIRI (sequential FOLFOXIRI-BEV) could improve tolerability. In the phase II STEAM trial, which is the largest study of FOLFOXIRI-BEV in patients in the U.S., it was found that both concurrent and sequential FOLFOXIRI-BEV are active and well tolerated in patients with previously untreated mCRC, supporting the use of these regimens as potential first-line treatment options for this population.
AB - Background: First-line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI-BEV) or sequentially (sFOLFOXIRI-BEV, FOLFOX-BEV alternating with FOLFIRI-BEV), versus FOLFOX-BEV for mCRC. Patients and Methods: Patients with previously untreated mCRC (n = 280) were randomized 1:1:1 to cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, or FOLFOX-BEV and treated with 4–6-month induction followed by maintenance. Coprimary objectives were overall response rate (ORR; first-line cFOLFOXIRI-BEV vs. FOLFOX-BEV) and progression-free survival (PFS; pooled first-line cFOLFOXIRI-BEV and sFOLFOXIRI-BEV vs. FOLFOX-BEV). Secondary/exploratory objectives included overall survival (OS), liver resection rates, biomarker analyses, and safety. Results: ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, and FOLFOX-BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI-BEV and FOLFOX-BEV did not significantly differ (p =.132); thus, the primary ORR endpoint was not met. cFOLFOXIRI-BEV and sFOLFOXIRI-BEV numerically improved ORR and PFS, regardless of RAS status. Median PFS was higher with pooled concurrent and sequential FOLFOXIRI-BEV versus FOLFOX-BEV (11.7 vs. 9.5 months; hazard ratio, 0.7; 90% confidence interval, 0.5–0.9; p <.01). Liver resection rates were 17.2% (cFOLFOXIRI-BEV), 9.8% (sFOLFOXIRI-BEV), and 8.4% (FOLFOX-BEV). Grade ≥ 3 treatment-emergent adverse events (TEAEs) were observed in 91.2% (cFOLFOXIRI-BEV), 86.7% (sFOLFOXIRI-BEV), and 85.6% (FOLFOX-BEV) of patients, with no increase in serious chemotherapy-associated TEAEs. Conclusion: cFOLFOXIRI-BEV and sFOLFOXIRI-BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX-BEV, supporting triplet chemotherapy plus BEV as a first-line treatment option for mCRC. Implications for Practice: The combination of first-line FOLFIRI with FOLFOX and bevacizumab (concurrent FOLFOXIRI-BEV) improves clinical outcomes in patients with metastatic colorectal cancer (mCRC) relative to FOLFIRI-BEV or FOLFOX-BEV, but it is thought to be associated with increased toxicity. Alternating treatment of FOLFOX and FOLFIRI (sequential FOLFOXIRI-BEV) could improve tolerability. In the phase II STEAM trial, which is the largest study of FOLFOXIRI-BEV in patients in the U.S., it was found that both concurrent and sequential FOLFOXIRI-BEV are active and well tolerated in patients with previously untreated mCRC, supporting the use of these regimens as potential first-line treatment options for this population.
KW - Bevacizumab
KW - Concurrent FOLFOXIRI
KW - FOLFOX
KW - Metastatic colorectal cancer
KW - Sequential FOLFOXIRI
UR - http://www.scopus.com/inward/record.url?scp=85058644723&partnerID=8YFLogxK
U2 - 10.1634/theoncologist.2018-0344
DO - 10.1634/theoncologist.2018-0344
M3 - Article
C2 - 30552157
AN - SCOPUS:85058644723
SN - 1083-7159
VL - 24
SP - 921
EP - 932
JO - Oncologist
JF - Oncologist
IS - 7
ER -