Gilead and Arcus Announce Etrumadenant Plus Zimberelimab Regimen Significantly Reduced the Risk of Death in Third-line Metastatic Colorectal Cancer
Gilead Sciences and Arcus Biosciences announced significant findings from Cohort B of the ARC-9 study. The combination of etrumadenant and zimberelimab with FOLFOX chemotherapy and bevacizumab (EZFB) demonstrated a 63% reduction in the risk of death and a 73% reduction in disease progression compared to regorafenib in third-line metastatic colorectal cancer (mCRC) patients. The data showed a median overall survival of 19.7 months for EZFB, compared to 9.5 months for regorafenib. The findings will be presented at the 2024 ASCO Annual Meeting. The trial included 112 patients and showed a favorable safety profile for the EZFB regimen.
- The EZFB regimen reduced the risk of death by 63% compared to regorafenib.
- Disease progression risk was reduced by 73% with EZFB compared to regorafenib.
- Median overall survival for EZFB was 19.7 months versus 9.5 months for regorafenib.
- EZFB showed a higher objective response rate (ORR) of 17.3% compared to 2.7% for regorafenib.
- Median duration of response for EZFB was 11.5 months, with regorafenib being not evaluable.
- Lower incidence of Grade ≥3 treatment emergent adverse events (TEAEs) with EZFB (23.0%) compared to regorafenib (25.7%).
- Favorable safety profile with fewer treatment discontinuations (5% for EZFB vs 17% for regorafenib).
- Etrumadenant and zimberelimab remain investigational and are not yet approved by any regulatory authority.
- The safety and efficacy for the treatment of colorectal cancer are not yet established for the investigational molecules.
- High reliance on continued successful clinical trials for future validation and approval.
Insights
These results from the ARC-9 study are groundbreaking for third-line metastatic colorectal cancer (mCRC) treatment. The combination of etrumadenant and zimberelimab with FOLFOX chemotherapy and bevacizumab (EZFB) significantly reduced the risk of death and disease progression compared to regorafenib. Achieving a 63% reduction in mortality risk and a 73% reduction in disease progression is noteworthy, especially in a patient group that has already progressed through multiple lines of therapy. The median overall survival (OS) of 19.7 months versus 9.5 months for regorafenib is particularly impressive, setting a new benchmark for third-line treatments in mCRC.
These improvements align with the hypothesis that blocking the adenosine pathway can enhance the efficacy of immunotherapy in colorectal cancer. This study validates the potential for etrumadenant to be a critical component in treatment regimens for advanced-stage mCRC, offering new hope to patients who have exhausted other options. However, it is vital to remember that both etrumadenant and zimberelimab are investigational molecules and their safety and efficacy must be proven in larger, more comprehensive trials.
From an oncological viewpoint, these results could alter treatment protocols if further validated, emphasizing the importance of continued investment in combination therapies targeting multiple pathways in cancer treatment.
The data from ARC-9 provides compelling evidence for the efficacy of the EZFB regimen in treating third-line mCRC. The reported median progression-free survival (PFS) of 6.2 months compared to 2.1 months with regorafenib highlights the potential for this combination to delay disease progression significantly, which is important for patients with limited treatment options.
This extended PFS, coupled with a notable objective response rate (ORR) of 17.3% for EZFB versus 2.7% for regorafenib, suggests that the EZFB regimen not only stabilizes the disease but also induces meaningful tumor shrinkage in a subset of patients. The median duration of response (DOR) of 11.5 months further supports the durability of these responses, which is a substantial advancement for this patient population.
It is also important to note the safety profile of the EZFB regimen, which showed fewer treatment-emergent adverse events leading to discontinuation compared to regorafenib. The safety data implies that patients can tolerate this combination well, allowing them to stay on therapy longer and potentially see greater benefit.
Overall, these trial results underscore the promise of the EZFB regimen in improving clinical outcomes in mCRC, but regulatory approvals and further studies are needed to confirm these findings and make the treatment widely available.
For investors, the ARC-9 trial results are a significant development for both Gilead Sciences and Arcus Biosciences. Demonstrating such a pronounced improvement in survival and disease progression metrics in third-line mCRC patients could position these companies favorably in the oncology market. The potential market for successful third-line therapies is substantial, given the high unmet need in this patient population.
These results enhance the potential value of Gilead’s and Arcus's oncology pipelines. If subsequent trials validate these findings, it could lead to regulatory approvals and commercial success, driving revenue growth. Moreover, the partnership between Gilead and Arcus might yield further collaborative opportunities in developing novel cancer treatments, reinforcing their positions in the market.
However, investors should be cautious about the inherent risks associated with the development of investigational drugs. While the data is promising, these molecules are not yet approved and the path to regulatory clearance can be fraught with challenges. Therefore, while the immediate reaction might be positive, long-term investment decisions should consider the broader context of ongoing trials and regulatory milestones.
In summary, this development is a positive indicator for Gilead and Arcus, suggesting potential for significant future returns if the progress continues as expected.
– In Cohort B of the ARC-9 mCRC Study, Etrumadenant Plus Zimberelimab, FOLFOX Chemotherapy and Bevacizumab Significantly Reduced the Risk of Death by
– Results will be Presented Today During an Oral Session at the ASCO Annual Meeting –
“ARC-9 is the first randomized Phase 2 study to show that combining an adenosine receptor blocker with anti-PD-1, anti-VEGF and chemotherapy can meaningfully improve clinical outcomes for people with metastatic colorectal cancer who have progressed on at least two prior therapies,” said Dr. Wainberg. “19.7 months is the longest median overall survival reported in third-line mCRC and warrants further investigation of an etrumadenant-based regimen as a potential treatment option in CRC.”
Cohort B of ARC-9 randomized 112 patients with comparable baseline characteristics between two arms: EZFB or regorafenib. At the time of data cut-off (November 13, 2023) median follow-up was 20.4 months. Patient baseline characteristics were similar to those of third-line patients who have progressed on oxaliplatin- and irinotecan-based regimens in mCRC. OS and PFS were consistently longer in the EZFB arm versus regorafenib, in all sub-groups analyzed, including in patients with liver metastases.
Summary of efficacy results:
|
EZFB* n=75 |
regorafenib n=37 |
Median OS, months |
19.7 |
9.5 |
Hazard Ratio ( |
HR 0.37
p=0.0003 |
|
Median PFS, months |
6.2 |
2.1 |
Hazard Ratio ( |
HR 0.27
p<0.0001 |
|
Confirmed ORR |
13 ( |
1 ( |
Median DOR, months |
11.5 |
NE |
CI: confidence interval
|
|
|
The EZFB regimen had a safety profile consistent with the known safety profiles of each individual molecule to date, without unexpected toxicities. A higher percentage of patients treated with regorafenib (
Etrumadenant and zimberelimab are investigational molecules. Neither Gilead nor Arcus has received approval from any regulatory authority for any use of these molecules, and their safety and efficacy for the treatment of colorectal cancer have not been established.
About the ARC-9 Study
ARC-9 (NCT04660812) is a Phase 1b/2 trial evaluating the safety and efficacy of etrumadenant (E), a dual A2a/A2b adenosine receptor antagonist, plus anti-PD-1 antibody zimberelimab (Z), FOLFOX and bevacizumab (if not contraindicated) in three cohorts of patients with mCRC. The primary endpoint is PFS per RECIST 1.1, and OS is a key secondary endpoint. Cohort B enrolled patients who previously progressed on both oxaliplatin- and irinotecan-containing chemotherapy in combination with anti-VEGF (R) therapy or anti-EGFR. Patients were randomized 2:1 to the etrumadenant plus zimberelimab regimen: E (150 mg orally [PO] once daily [QD]) + Z (240 mg intravenous [IV] once every 2 weeks [Q2W]) + mFOLFOX-6 + bevacizumab (5 mg/kg IV Q2W), or regorafenib (administered at a starting dose of 80 mg/day for the first week, followed by a dose escalation of 40 mg every week to 120 mg/day for the second week and 160 mg/day for the third week during Cycle 1 followed by 160 mg/day on Days 1-21 of each subsequent 28-day cycle). Patients who progressed on regorafenib were allowed to crossover to the etrumadenant plus zimberelimab regimen.
ARC-9 is a multi-cohort study in mCRC including Cohort A, which enrolled patients who previously progressed on FOLFOX/FOLFIRI in combination with anti-VEGF(R) or anti-EGFR. Patients were randomized 2:1 to the etrumadenant plus zimberelimab regimen, or FOLFOX-6 + bevacizumab. Data from Cohort A will be presented when they are mature.
About Etrumadenant
Etrumadenant is an investigational small molecule, selective dual antagonist of the A2a and A2b receptors designed to prevent adenosine-mediated immunosuppression. Adenosine elicits its immunosuppressive effects within the tumor microenvironment by binding and activating adenosine-specific receptors expressed on the surface of tumor-infiltrating immune cells, which can help cancer cells evade host antitumor immunity. Once etrumadenant binds to the A2a and A2b receptors and blocks the immunosuppressive effects of adenosine, activation of antitumor immune cells may be restored, which could result in tumor cell death.
Etrumadenant is being evaluated in combination with other cancer immunotherapies, including the investigational Fc-silent anti-TIGIT monoclonal antibody domvanalimab and anti-PD-1 monoclonal antibody zimberelimab, in certain types of non-small cell lung and colorectal cancers.
About Zimberelimab
Zimberelimab is an anti-programmed cell death protein-1 (PD-1) monoclonal antibody that binds PD-1, with the goal of restoring the antitumor activity of T cells. Zimberelimab has demonstrated high affinity, selectivity and potency in various tumor types.
Zimberelimab is being evaluated in the
Guangzhou Gloria Biosciences Co. Ltd., which holds commercialization rights for zimberelimab in greater
About Arcus Biosciences
Arcus Biosciences is a clinical-stage, global biopharmaceutical company developing differentiated molecules and combination medicines for people with cancer. In partnership with industry collaborators, patients and physicians around the world, Arcus is expediting the development of first- or best-in-class medicines against well-characterized biological targets and pathways and studying novel, biology-driven combinations that have the potential to help people with cancer live longer. Founded in 2015, the company has expedited the development of multiple investigational medicines into clinical studies, including new combination approaches that target TIGIT, PD-1, the adenosine axis (CD73 and dual A2a/A2b receptor), HIF-2a, CD39 and AXL. For more information about Arcus Biosciences’ clinical and preclinical programs, please visit www.arcusbio.com.
About Gilead Sciences
Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in
Arcus Forward-Looking Statements
This press release contains forward-looking statements. All statements regarding events or results to occur in the future contained herein are forward-looking statements reflecting the current beliefs and expectations of management made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, the statements in Dr. Wainberg quote and statements regarding: whether data and results from the ARC-9 study validate our pipeline or support further development of etrumadenant and/or zimberelimab. All forward-looking statements involve known and unknown risks and uncertainties and other important factors that may cause Arcus’s actual results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Factors that could cause or contribute to such differences include, but are not limited to risks associated with: interim data changing as patient enrollment continues and more patient data becomes available; interim data not being replicated in future studies evaluating the same investigational molecules or regimen; the unexpected emergence of adverse events or other undesirable side effects in Arcus’s investigational products; Arcus’s dependence on the collaboration with Gilead for the successful development and commercialization of its optioned molecules; difficulties associated with the management of the collaboration activities with our strategic partners or expanded clinical programs; changes in the competitive landscape for Arcus’s programs; and the inherent uncertainty associated with pharmaceutical product development and clinical trials. Risks and uncertainties facing Arcus are described more fully in the “Risk Factors” section of Arcus’s most recent periodic report filed with the
Gilead Forward-Looking Statements
This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress or complete clinical trials within currently anticipated timelines or at all, and the possibility of unfavorable results from ongoing or additional clinical trials, including those involving etrumadenant and zimberelimab (such as the ARC-9 study); uncertainties relating to regulatory applications and related filing and approval timelines, and the risk that any such approvals, if granted, may be subject to significant limitations on use; the possibility that Gilead may make a strategic decision to discontinue development of etrumadenant and zimberelimab for indications that are currently under evaluation and, as a result, these programs may never be successfully commercialized for such indications; the risk that Gilead may not realize the potential benefits of its collaboration with Arcus or its other investments in oncology; difficulties or unanticipated expenses in connection with the collaboration and the potential effects on Gilead’s revenues and earnings; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and other factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2024, as filed with the
Gilead and the Gilead logo are trademarks of Gilead Sciences, Inc., or its related companies.
Arcus name and logo are trademarks of Arcus Biosciences, Inc.
For more information about Gilead, please visit the company’s website at www.gilead.com, follow Gilead on X/Twitter (@Gilead Sciences) and LinkedIn (@Gilead-Sciences).
View source version on businesswire.com: https://www.businesswire.com/news/home/20240602384134/en/
Meaghan Smith, Gilead Media
public_affairs@gilead.com
Jacquie Ross, Gilead Investors
investor_relations@gilead.com
Pia Eaves, Arcus Investors
peaves@arcusbio.com, (617) 459-2006
Holli Kolkey, Arcus Media
hkolkey@arcusbio.com, (650) 922-1269
Source: Arcus Biosciences
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