Arcus Biosciences and Summit Therapeutics Collaborate to Advance Novel Combination Therapy for Advanced Kidney Cancer
Arcus Biosciences, Inc., a clinical-stage global biopharmaceutical company focused on developing innovative therapies for cancer as well as inflammatory and autoimmune diseases, has entered into a clinical trial collaboration with Summit Therapeutics Inc. to investigate a promising new treatment approach for patients with clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer. The collaboration will evaluate the combination of Arcus’ investigational hypoxia-inducible factor 2-alpha (HIF-2α) inhibitor, casdatifan, with Summit’s investigational ivonescimab, a first-in-class PD-1/VEGF bispecific antibody, in patients with metastatic clear cell renal cell carcinoma, including those receiving first-line treatment.
The partnership reflects a growing trend in oncology research toward combining therapies that target multiple cancer-driving pathways simultaneously in an effort to improve clinical outcomes, extend survival, and reduce treatment-related toxicity. By bringing together two highly differentiated investigational therapies with complementary mechanisms of action, Arcus and Summit aim to explore whether this novel combination can provide a more effective treatment option for patients with advanced kidney cancer.
Addressing the Challenges of Kidney Cancer
Renal cell carcinoma accounts for approximately 90% of all kidney cancers, with clear cell renal cell carcinoma representing nearly 75% to 80% of these cases. Although therapeutic advances over the past decade have significantly improved outcomes for many patients, metastatic disease continues to present major treatment challenges. Many patients eventually develop resistance to currently available therapies, and long-term survival remains limited despite improvements in immunotherapy and targeted treatment strategies.
The treatment landscape for advanced kidney cancer has evolved rapidly with the introduction of immune checkpoint inhibitors, VEGF-targeted therapies, tyrosine kinase inhibitors (TKIs), and combination regimens. However, many currently approved combinations rely heavily on TKIs, which can be associated with chronic toxicities that affect quality of life and limit treatment duration.
Researchers continue to search for innovative treatment combinations capable of delivering deeper and more durable responses while reducing dependence on therapies associated with significant adverse effects.
Combining Two Innovative Therapeutic Platforms
The collaboration brings together two investigational medicines that target different biological mechanisms involved in kidney cancer progression.
Casdatifan is Arcus Biosciences’ oral HIF-2α inhibitor. HIF-2α has emerged as an important therapeutic target in clear cell renal cell carcinoma because alterations in the von Hippel-Lindau (VHL) tumor suppressor gene lead to persistent activation of hypoxia signaling pathways. This activation promotes tumor growth, angiogenesis, and cancer cell survival. By selectively inhibiting HIF-2α, casdatifan aims to interrupt one of the fundamental biological drivers of clear cell renal cell carcinoma.
Ivonescimab represents a different therapeutic strategy. Developed as a bispecific antibody targeting both the programmed death-1 (PD-1) immune checkpoint pathway and vascular endothelial growth factor (VEGF), ivonescimab is designed to simultaneously stimulate the body’s immune response against tumors while inhibiting tumor-associated blood vessel formation. This dual-target mechanism may offer advantages over therapies that inhibit only one pathway.
Researchers believe that combining these two investigational therapies could provide complementary anti-tumor activity by attacking kidney cancer through multiple biological mechanisms simultaneously.
Scientific Rationale Behind the Combination
The scientific rationale supporting this collaboration is based on the central role that both hypoxia signaling and angiogenesis play in kidney cancer biology.
Clear cell renal cell carcinoma is characterized by dysregulation of oxygen-sensing pathways resulting from VHL gene mutations. This leads to increased HIF-2α activity, which subsequently promotes expression of numerous genes involved in angiogenesis, metabolism, cell proliferation, and tumor survival.
At the same time, VEGF signaling plays a critical role in maintaining the extensive blood vessel network that supports tumor growth. Immune checkpoint pathways such as PD-1 further enable tumors to evade immune system surveillance.
Targeting all three pathways—HIF-2α, VEGF, and PD-1—could potentially generate stronger anti-tumor responses than inhibiting any single pathway alone.
Investigators hope the combination will not only improve tumor control but also delay or overcome resistance mechanisms that often emerge during treatment.
ARC-20 Platform Study Expansion
The combination therapy will be evaluated as a newly added cohort within Arcus’ ongoing ARC-20 platform study.
ARC-20 is designed as a flexible clinical research platform investigating casdatifan both as monotherapy and in combination with various investigational and standard treatment options across multiple patient cohorts with metastatic clear cell renal cell carcinoma.
Adding ivonescimab to the study expands the scientific scope of ARC-20 and enables researchers to evaluate another promising combination while leveraging the efficiencies of a platform trial design.
Platform studies have become increasingly important in oncology because they allow multiple treatment strategies to be investigated under a unified clinical infrastructure, accelerating development timelines and improving operational efficiency.
Roles and Responsibilities
Under the collaboration agreement, Summit Therapeutics will provide ivonescimab for the study, while Arcus Biosciences will sponsor and conduct the clinical trial.
Both companies will share study costs while maintaining independent ownership of their respective investigational therapies. Each organization will retain worldwide development and commercialization rights for its own product.
This collaborative structure allows both companies to explore potential clinical benefits without altering existing intellectual property ownership or commercial strategies.
Leadership Perspective
Terry Rosen, Ph.D., Chief Executive Officer of Arcus Biosciences, emphasized the strategic importance of establishing casdatifan as a foundational treatment option across multiple stages of kidney cancer care.
He noted that combining a potent HIF-2α inhibitor with one of the most advanced PD-1/VEGF bispecific antibodies represents an opportunity to develop a treatment regimen that could deliver meaningful clinical benefit while reducing reliance on tyrosine kinase inhibitors. According to Rosen, Arcus envisions casdatifan serving as a backbone therapy capable of supporting combination strategies throughout various lines of treatment for renal cell carcinoma.
The collaboration aligns with Arcus’ broader development strategy of maximizing the therapeutic potential of casdatifan through scientifically driven combination approaches.
Summit Therapeutics’ View
Dr. Maky Zanganeh, President and Co-Chief Executive Officer of Summit Therapeutics, highlighted ivonescimab’s dual-target mechanism as particularly well suited for kidney cancer.
She explained that both immune checkpoint signaling and VEGF-mediated angiogenesis are well-established contributors to disease progression in renal cell carcinoma. Simultaneously targeting these pathways could provide enhanced anti-tumor activity compared with conventional approaches.
Dr. Zanganeh also emphasized the continued unmet medical need within advanced kidney cancer despite recent therapeutic advances.
Although modern immunotherapy combinations have improved outcomes for many patients, long-term survival remains limited, particularly in metastatic disease. She expressed optimism that combining ivonescimab with casdatifan may ultimately provide patients with more durable treatment responses.
Potential Advantages of a TKI-Sparing Strategy
One particularly attractive aspect of the collaboration is its focus on developing a potential TKI-sparing treatment regimen.
Current first-line therapies for advanced renal cell carcinoma frequently incorporate tyrosine kinase inhibitors alongside immune checkpoint inhibitors. While effective, prolonged TKI therapy is commonly associated with adverse events including fatigue, hypertension, diarrhea, hand-foot syndrome, and liver toxicity.
Reducing or eliminating dependence on TKIs could potentially improve treatment tolerability while preserving anti-cancer efficacy.
If successful, the casdatifan and ivonescimab combination may offer physicians an additional treatment option capable of balancing effectiveness with improved patient quality of life.
Future Development Timeline
Enrollment into the newly added ARC-20 cohort is expected to begin following study activation.
Initial clinical data from the collaboration are anticipated by mid-2027, providing the first indication of the combination’s safety profile and preliminary anti-tumor activity in patients with metastatic clear cell renal cell carcinoma.
The findings will help determine whether further clinical development, including larger randomized studies, is warranted.
Positive results could ultimately support broader evaluation across additional patient populations and potentially establish a new treatment option within the evolving kidney cancer landscape.
Continuing Innovation in Renal Cell Carcinoma
The collaboration between Arcus Biosciences and Summit Therapeutics underscores the industry’s continued commitment to developing next-generation therapies that move beyond traditional treatment paradigms.
Rather than relying solely on incremental improvements, researchers are increasingly pursuing rational combinations that simultaneously target multiple biological drivers of cancer. Such strategies have the potential to enhance efficacy, delay resistance, and improve patient outcomes.
As understanding of kidney cancer biology continues to deepen, precision-based therapeutic combinations like casdatifan plus ivonescimab may represent an important step toward more personalized and durable treatment approaches.
With the launch of this clinical collaboration, both companies aim to generate evidence supporting a novel combination that could eventually expand therapeutic options for patients living with metastatic clear cell renal cell carcinoma, a disease that continues to require more effective and better-tolerated treatment solutions.
About Kidney Cancer
According to the American Cancer Society, kidney cancer is among the top 10 most commonly diagnosed forms of cancer among both men and women in the U.S., and an estimated 80,450 Americans will be diagnosed with kidney cancer in 2026.1 ccRCC is the most common type of kidney cancer in adults.2 If detected in its early stages, the five-year survival rate for kidney cancer is high; for patients with advanced or late-stage metastatic kidney cancer, however, the five-year survival rate is only 19%.3 For metastatic kidney cancer, targeted drug therapies are one of the main treatment options.4
About Casdatifan (AB521)
Casdatifan is a small-molecule inhibitor of hypoxia-inducible factor 2-alpha (HIF-2α), a master switch that turns on hundreds of genes in response to low oxygen levels. In a majority of people with the most common form of kidney cancer (clear cell renal cell carcinoma), genetic anomalies result in the dysregulation of this master switch and transformation of normal kidney cells into cancerous ones.
Casdatifan was designed to provide deep and durable inhibition of the HIF-2α pathway. Early clinical studies have shown high response rates and a low primary progression rate relative to clinical benchmarks, warranting further investigation in late-stage studies. Casdatifan, which is administered in pill form once daily, has a safety profile that allows it to be investigated in combination with other treatments.
The casdatifan development strategy is designed to generate evidence needed to establish casdatifan as a backbone therapy so that every patient has the opportunity to benefit from casdatifan across each line of therapy. In addition to partner-operationalized studies, Arcus is investigating casdatifan across multiple cohorts in the ARC-20 platform study, alone and in combination with other potential new treatment options, including in the:
- First-line setting with cohorts evaluating casdatifan plus zimberelimab, an anti-PD-1 (ongoing); casdatifan plus zimberelimab and ipilimumab, an anti-CTLA-4 (ongoing); and casdatifan plus ivonescimab, an anti-PD-1/VEGF bispecific (planned)
- Second-line setting with a cohort evaluating casdatifan plus cabozantinib, a TKI, in immunotherapy-experienced patients (ongoing)
- Late-line setting with a cohort evaluating casdatifan plus tivozanib, a TKI, in HIF-2α inhibitor-experienced patients (planned)
Arcus is also enrolling PEAK-1, the global Phase 3 study evaluating casdatifan plus cabozantinib versus cabozantinib in immunotherapy-experienced metastatic ccRCC. Arcus expects to complete enrollment in PEAK-1 and to initiate a Phase 3 study in the first-line metastatic ccRCC setting by year-end 2026.
Casdatifan is an investigational molecule. Approval from any regulatory authority for its use has not been received, and its safety and efficacy have not been established. Taiho has development and commercial rights in Japan and other countries in Asia, excluding China. Arcus Biosciences holds full rights to casdatifan everywhere else globally.
About Ivonescimab
Ivonescimab, known as SMT112 in Summit’s license territories, North America, South America, Europe, the Middle East, Africa, and Japan, and as AK112 outside of Summit’s license territories, is a novel, potential first-in-class investigational bispecific antibody combining the effects of immunotherapy via a blockade of PD-1 with the anti-angiogenesis effects associated with blocking VEGF into a single molecule. By design, ivonescimab displays unique cooperative binding to each of its intended targets with multifold higher affinity to PD-1 when in the presence of VEGF.
This design is intended to differentiate ivonescimab as there is potentially higher expression (presence) of both PD-1 and VEGF in tumor tissue and the tumor microenvironment (TME) as compared to normal tissue in the body. Summit believes ivonescimab’s specifically engineered tetravalent structure (four binding sites) enables higher avidity (accumulated strength of multiple binding interactions) in the TME (Zhong, et al, iScience, 2025).
This tetravalent structure, the intentional novel design of the molecule, and bringing these two targets into a single bispecific antibody with cooperative binding qualities have the potential to direct ivonescimab to the tumor tissue versus healthy tissue. The intent of this design, together with a half-life of 6 to 7 days after the first dose (Zhong, et al, iScience, 2025) increasing to approximately 10 days at steady state dosing, is to improve upon previously established efficacy thresholds, side effects, and safety profiles associated with prior approved drugs to these targets.
Ivonescimab was engineered by Akeso Inc. (HKEX Code: 9926.HK) and is currently utilized in multiple Phase III clinical trials. Over 4,000 patients have been treated with ivonescimab in clinical studies globally, and over 70,000 patients when considering those treated in a commercial setting in China, as noted by Akeso.
There are currently 15 Phase III clinical studies that are either announced, ongoing, or have been completed studying ivonescimab, four of which are Summit-sponsored global studies, one of which is a multiregional study sponsored by a cooperative group, and 10 of which are being or have been conducted in China by Akeso. Summit began its clinical development of ivonescimab in non-small cell lung cancer (NSCLC), commencing enrollment in 2023 in two multiregional Phase III clinical trials, HARMONi and HARMONi-3. In 2025, Summit began enrolling patients in HARMONi-7. Summit expanded its Phase III clinical development program into colorectal cancer (CRC) in the fourth quarter of 2025 by initiating enrollment in HARMONi-GI3.
HARMONi is a Phase III clinical trial evaluating ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who were previously treated with a third-generation EGFR TKI (e.g., osimertinib). Detailed results of the study were provided in September 2025, and a Biologics License Application (BLA) was submitted to the United States Food and Drug Administration (FDA) for marketing authorization, which the FDA accepted for filing in January 2026; the goal Prescription Drug User Fee Act (PDUFA) date is November 14, 2026.
HARMONi-3 is a Phase III clinical trial evaluating ivonescimab combined with chemotherapy compared to pembrolizumab combined with chemotherapy in patients with first-line metastatic, squamous or non-squamous NSCLC, irrespective of PD-L1 expression. The clinical trial is evaluating the two histologies as individual, separately powered cohorts with independent statistical powering.
HARMONi-7 is a Phase III clinical trial evaluating ivonescimab monotherapy compared to pembrolizumab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression.
HARMONi-GI3 is a Phase III clinical trial evaluating ivonescimab in combination with chemotherapy compared with bevacizumab plus chemotherapy in patients with first-line unresectable metastatic CRC.
ILLUMINE is a Phase III study being conducted by GORTEC, a cooperative group dedicated to Head and Neck Oncology, in recurrent / metastatic head and neck squamous cell carcinoma (r/m HNSCC). ILLUMINE is a three-arm Phase III clinical trial designed to evaluate ivonescimab monotherapy, as well as ivonescimab in combination with ligufalimab, Akeso’s proprietary anti-CD47 monoclonal antibody, compared to monotherapy pembrolizumab in patients with PD-L1 positive r/m HNSCC.
In addition, Akeso has recently had positive read-outs in three single-region (China), randomized Phase III clinical trials, HARMONi-A, HARMONi-2, and HARMONi-6, for ivonescimab in NSCLC, including a statistically significant overall survival benefit in both the HARMONi-A and HARMONi-6 studies, and a manageable safety profile in each study.
HARMONi-A was a Phase III clinical trial which evaluated ivonescimab combined with chemotherapy compared to placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with an EGFR TKI.
HARMONi-2 is a Phase III clinical trial evaluating monotherapy ivonescimab against monotherapy pembrolizumab in patients with locally advanced or metastatic NSCLC whose tumors have positive PD-L1 expression.
HARMONi-6 is a Phase III clinical trial evaluating ivonescimab in combination with platinum-based chemotherapy compared with tislelizumab, an anti-PD-1 antibody, in combination with platinum-based chemotherapy in patients with locally advanced or metastatic squamous NSCLC, irrespective of PD-L1 expression.
Akeso is actively conducting multiple Phase III clinical studies in settings outside of NSCLC, including biliary-tract cancer, triple-negative breast cancer, head and neck squamous cell carcinoma, small cell lung cancer, colorectal cancer, and pancreatic cancer.
Ivonescimab is an investigational therapy that is not approved by any regulatory authority in Summit’s license territories, including the United States and Europe. Ivonescimab was initially approved for marketing authorization in China in May 2024.
About Arcus Biosciences
Arcus Biosciences is a clinical-stage, global biopharmaceutical company focused on developing differentiated molecules for the treatment of cancer and inflammatory and autoimmune diseases. In partnership with industry collaborators, patients and physicians around the world, Arcus is expediting the development of its late-stage portfolio of first- and/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 advanced multiple investigational medicines into registrational clinical trials including casdatifan, a HIF-2α inhibitor for clear cell renal cell carcinoma, and quemliclustat, a small-molecule CD73 inhibitor for pancreatic cancer. For more information about Arcus Biosciences’ clinical and preclinical programs, please visit www.arcusbio.com.
About Summit Therapeutics Inc.
Summit Therapeutics Inc. is a biopharmaceutical oncology company focused on the discovery, development, and commercialization of patient-, physician-, caregiver- and societal-friendly medicinal therapies intended to improve quality of life, increase potential duration of life, and resolve serious unmet medical needs.
Summit was founded in 2003 and the company’s shares are listed on the Nasdaq Global Market (symbol “SMMT”). Summit is headquartered in Miami, Florida, with additional offices in Palo Alto, California, Princeton, New Jersey, Dublin, Ireland, and Oxford, UK.