- Presented today at the ASCO Gastrointestinal Cancers Symposium, 23-25 January in San Francisco, results of 2 phase 3 clinical studies co-authored by VHIO investigators point to new standard-of-care options for patients with metastatic colorectal cancer (mCRC) who have a determined genetic alteration in their tumor.
- Data from the BREAKWATER clinical trial, co-led by VHIO’s Director Josep Tabernero and Scott Kopetz of the University of Texas MD Anderson Cancer Center, support a new frontline treatment approach for BRAF V600E-mutant mCRC. Results of this study published simultaneously in Nature Medicine.
- Co-authored by Elena Élez, Head of VHIO’s Colorectal Cancer Group, latest results of the CheckMate 8HW study show that dual immunotherapy improves clinical outcomes across all lines of therapy in patients with high-level microsatellite instability or deficient mismatch repair (MSI-H/dMMR) mCRC compared with single-agent immunotherapy. Results of this study publishen simultaneously in The Lancet.
The American Society of Clinical Oncology’s annual Gastrointestinal Cancers Symposium (ASCO GI) offers the latest innovative science, solution-focused strategies, and multidisciplinary approaches in GI cancer treatment, research, and care. Celebrated in San Francisco, January 23-25, this year’s meeting is themed Breaking Boundaries to Enhance Patient-Centered Care.
Among the various studies (co) led by investigators at the Vall d’Hebron Institute of Oncology (VHIO) and Vall d’Hebron University Hospital (HUVH), potentially practice-changing data from two open-label, multicenter, randomized phase 3 studies point to new standard-of-care options for the first-line treatment of patients with metastatic colorectal cancer (mCRC) who have a determined genetic alteration in their tumor.
BREAKWATER: supporting a new standard of care for the first-line treatment of patients with BRAF V600E-mutant mCRC.
BRAF V600E mutations occur in 8% to 12% of mCRC and associate with a poor prognosis. In 2019, results from the BEACON study led by Josep Tabernero, Head of the Medical Oncology Department at Vall d’Hebron and VHIO’s Director, demonstrated that targeted therapy including BRAF (encorafenib) and EGFR (cetuximab) inhibitors significantly prolonged overall survival and improved response rates compared with standard-of-care in patients with previously treated mCRC.
“Based on these results, the combination of encorafenib plus cetuximab was approved in most countries for BRAF V600E-mutant metastatic colorectal cancer in second-and later-line settings. First-line strategies have had limited efficacy in the treatment of these patients,” said Josep Tabernero, co-Principal Investigator of the BREAKWATER study along with Scott Kopetz, Professor of Gastrointestinal Medical Oncology at the University of Texas MD Anderson Cancer Center in the U.S., who presented results of this study today at ASCO GI 2025(1).
“BREAKWATER is a phase 3 study evaluating the combination of cetuximab and encorafenib, with or without the mFOLFOX6 regimen with fluorouracil, leucovorin, and oxaliplatin, versus standard-of-care in previously untreated BRAF V600E-mutant CRC,” said Elena Élez, Medical Oncologist at Vall d’Hebron, Head of VHIO’s Colorectal Cancer Group, and BREAKWATER study coordinator at HUVH as one of the main recruitment sites for this study.
Results show a statistically significant and clinically meaningful benefit in overall response rate with the combination of encorafenib plus mFOLFOX6 compared with standard therapy (61% versus 40%). At six months, a superior objective response rate was observed in 68.7% of patients assigned to this novel combination compared with 34,1% of patients assigned to standard therapy. Prolonged response of over 12 months was observed in 22.4% of patients who received the combination of encorafenib and mFOLFOX6. Data showed a potential improvement in overall survival, although more follow-up is needed. Follow-up is ongoing, with planned additional interim and final analyses by the study investigators.
“While follow-up analysis considering other indicators including mature overall survival and progression-free survival is required, results from this first analysis have supported the FDA accelerated approval of this novel combination for the treatment of patients with BRAFV600-mutant metastatic colorectal cancer,” concluded Tabernero, Senior Investigator of this present study, results of which published simultaneously today in Nature Medicine(2).
CheckMate-8HW: first-line dual immunotherapy improves clinical outcomes over single-agent immunotherapy in patients with MSI-H/dMMR mCRC
4% to 7% of patients with metastatic colorectal cancer (mCRC) have tumors which are characterized by defects in DNA mismatch repair (dMMR) resulting in microsatellite instability (MSI-H), and are correlated with poor outcomes with standard chemotherapy with or without targeted therapies.
Presented at the same ASCO GI oral abstract session(1) by first author Thierry André, of Sorbonne University and Saint-Antoine Hospital, in France, first results from the second dual primary endpoint of the CheckMate 8HW study evaluating progression-free survival for dual immunotherapy with nivolumab plus ipilimumab versus nivolumab monotherapy across all lines of therapy in patients with MSI-H/dMMR mCRC, support the use of nivolumab with ipilimumab as a new standard-of-care treatment in this setting.
This part of the study included a total of 707 patients who were randomly assigned to receive nivolumab with ipilimumab or single-agent nivolumab. The investigators observed that patients treated with the immunotherapy combination had a 38% lower risk of disease progression or death. Objective response rate was 71% in patients assigned to dual immunotherapy compared with 58% in patients who received nivolumab alone.
“Our results show that nivolumab and ipilimumab work together to boost the immune system to recognize and destroy tumor cells more effectively over single-agent nivolumab,” said Elena Élez, Head of VHIO’s Colorectal Cancer Group and a co-author of this present study, results of which published simultaneously today in The Lancet(3)
“As part of this study, the next step will be to analyze these results specifically in the first-line setting,” added Élez.
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References
- 2025 ASCO Gastrointestinal Cancers Symposium corresponding session details
Oral Abstract Session C: Cancers of the Colon, Rectum, and Anus
Track: Colorectal Cancer | Anal Cancer
Type: Oral Abstract Session
Date: 25 January, 2025
Time: 13:00h – 14:45h GMT-8
Chairs: Ann Raldow -University of California Los Angeles, Sara Lonardi- Veneto Institute of Oncology IOV-IRCCS
BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer.
Scott Kopetz, Takayuki Yoshino, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet S. Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S. Maughan, Elena Beyzarov, Xiaoxi Zhang, Graham Ferrier, Xiaosong Zhang, Josep Tabernero.
Abstract #:16
First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW.
Thierry Andre, Elena Elez, Heinz-Josef Lenz, Lars Henrik Jensen, Yann Touchefeu, Eric Van Cutsem, Rocio Garcia-Carbonero, David Tougeron, Guillermo Mendez, Michael Schenker, Christelle De La Fouchardiere, Maria Luisa Limon, Takayuki Yoshino, Jin Li, Francine Aubin, Elvis Cela, Tian Chen, Ming Lei, Lixian Jin, Sara Lonardi.
Abstract #: LBA143
(2)Kopetz S, Yoshino T, Van Cutsem E, Eng C, Kim TW, Wasan HS, Desai J, Ciardiello F, Yaeger R, Maughan TS, Beyzarov E, Zhang X, Ferrier G, Zhang X, Tabernero J. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025 Jan 25. doi: 10.1038/s41591-024-03443-3. Epub ahead of print.
(3)Thierry Andre, Elena Elez, Heinz-Josef Lenz, Lars Henrik Jensen, Yann Touchefeu, Eric Van Cutsem, Rocio Garcia-Carbonero, David Tougeron, Guillermo Mendez, Michael Schenker, Christelle De La Fouchardiere, Maria Luisa Limon, Takayuki Yoshino, Jin Li, Francine Aubin, Elvis Cela, Tian Chen, Ming Lei, Lixian Jin, and Sara Lonardi. First results of nivolumab (NIVO) plus ipilimumab (IPI) vs NIVO monotherapy for microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) from CheckMate 8HW. The Lancet.
