On October 17, 2025 Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit," "we," or the "Company") reported the expansion of its Phase III clinical development program of the novel, potential first-in-class investigational bispecific antibody, ivonescimab, into colorectal cancer (CRC) with the initiation of the global Phase III HARMONi-GI3 trial.
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Summit is starting a Phase III clinical study, HARMONi-GI3, to evaluate ivonescimab plus chemotherapy compared to bevacizumab plus chemotherapy as first line therapy in patients with unresectable metastatic colorectal cancer (CRC).
Clinical trial sites for HARMONi-GI3 are planned to begin activating in the United States prior to the end of the year. The multiregional study intends to enroll approximately 600 patients. The primary endpoint for this study is progression-free survival.
Each year, approximately 48,000 patients are estimated to be diagnosed with or have unresectable recurrent metastatic MSS CRC (also known as mismatch repair-proficient colorectal cancer, or pMMR CRC).1 There have been limited options approved in the United States in the last 20 years for those first-line patients whose tumors are not positive for certain biomarkers or other activating mutations.
MSS CRC is a setting where monoclonal PD-1 inhibitors such as pembrolizumab and nivolumab have failed to show a clinically meaningful benefit. Anti-VEGF therapy (e.g., bevacizumab) plus chemotherapy is the standard of care for many patients with 1L metastatic MSS CRC.
At the 2024 Annual Congress of the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) (ESMO 2024), Akeso Inc. (Akeso) presented encouraging Phase II data of ivonescimab in combination with FOLFOXIRI chemotherapy demonstrating an objective response rate (ORR) of 81.8% (95% CI: 59.7% – 94.8%) and a disease control rate (DCR) of 100% (95% CI: 84.6% – 100.0%) in 22 patients. This Phase II study, AK112-206, was conducted in China and sponsored by Akeso with all relevant data exclusively generated, managed, and analyzed by Akeso. In the ivonescimab plus FOLFOXIRI chemotherapy arm, there were no treatment emergent adverse events that led to permanent discontinuation of ivonescimab as of the data cutoff from the ESMO (Free ESMO Whitepaper) 2024 presentation.
Subsequently, AK112-206 was expanded to include additional patients from the United States and China to study ivonescimab in combination with FOLFOX chemotherapy. FOLFOX in combination with a monoclonal antibody such as bevacizumab represents a preferred treatment regimen for physicians treating patients in the United States and other western territories. The data from the initial patient cohort presented at ESMO (Free ESMO Whitepaper) 2024 have continued to mature, in addition to the global Phase II data generated in combination with FOLFOX in the United States and China, which support the Phase III HARMONi-GI3 study design using FOLFOX.
"As promised earlier in the year, we sought to expand the ivonescimab clinical development program beyond non-small cell lung cancer in order to continue to explore the potential benefits of its specifically-engineered, novel design and mechanism of action, including its cooperative binding attributes," stated Robert W. Duggan and Dr. Maky Zanganeh, Co-Chief Executive Officers of Summit. "Microsatellite stable colorectal cancer represents a global unmet need whereby ivonescimab has the potential to bring the benefits of immunotherapy to solid tumors where PD-1 monoclonal antibodies have not been able to successfully improve upon existing standards of care. We are thrilled by the potential of ivonescimab to make a significant difference to these patients with few front-line options available today."
Conference Call
Summit Therapeutics Inc. will host a conference call and live webcast to discuss recent updates related to ivonescimab, including data released at ESMO (Free ESMO Whitepaper), on Monday, October 20, 2025, at 8:00am ET. Conference call and webcast information will be accessible through our website www.smmttx.com.
An archived edition of the webcast will be available on our website later in the day on Monday.
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 in China and Australia, 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. Ivonescimab displays unique cooperative binding to each of its intended targets with multi-fold higher affinity to PD-1 when in the presence of VEGF.
This could 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. Ivonescimab’s specifically engineered tetravalent structure (four binding sites) enables higher avidity (accumulated strength of multiple binding interactions) in the TME (Zhong, et al., SITC (Free SITC Whitepaper), 2023). 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., SITC (Free SITC Whitepaper), 2023) increasing to approximately 10 days at steady state dosing, is to improve upon previously established efficacy thresholds, in addition to side effects and safety profiles associated with these targets.
Ivonescimab was engineered by Akeso Inc. (HKEX Code: 9926.HK) and is currently engaged in multiple Phase III clinical trials. Over 3,000 patients have been treated with ivonescimab in clinical studies globally.
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 early 2025, the Company began enrolling patients in the United States for HARMONi-7. Summit intends to open clinical trial sites in the United States for the Phase III study in colorectal cancer (CRC) by the end of 2025.
HARMONi is a Phase III clinical trial which intends to evaluate 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 3rd generation EGFR TKI (e.g., osimertinib). Enrollment in HARMONi was completed in the second half of 2024, top-line results were announced in May of 2025, with detailed results provided in September 2025.
HARMONi-3 is a Phase III clinical trial which is intended to evaluate 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.
HARMONi-7 is a Phase III clinical trial which is intended to evaluate ivonescimab monotherapy compared to pembrolizumab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression.
HARMONi-GI3 is a planned Phase III clinical trial evaluating ivonescimab in combination with chemotherapy compared with bevacizumab plus chemotherapy in patients with first-line unresectable metastatic CRC.
In addition, Akeso has recently had positive read-outs in three single-region (China), randomized Phase III clinical trials for ivonescimab in NSCLC: HARMONi-A, HARMONi-2, and HARMONi-6.
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, colorectal cancer, breast cancer, pancreatic cancer, small cell lung cancer, and head and neck 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. Ivonescimab was granted Fast Track designation by the US Food & Drug Administration (FDA) for the HARMONi clinical trial setting.
(Press release, Summit Therapeutics, OCT 17, 2025, View Source [SID1234656762])