On October 20, 2025 Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit," "we," or the "Company") reported its financial results and provides an update on operational progress for the third quarter ended September 30, 2025.
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Planned BLA Submission for Ivonescimab in Q4 2025
Today, Summit announces that, based on the results of the HARMONi clinical trial, it plans to submit a Biologics License Application (BLA) in order to seek approval for ivonescimab plus chemotherapy for this proposed indication. We intend to submit the BLA in the fourth quarter of 2025. The positive results of the multiregional Phase III study are detailed further below. As previously noted, the FDA noted that a statistically significant overall survival benefit is necessary to support marketing authorization in this setting. After careful consideration of the safety and efficacy profile of the current FDA-approved options for patients in this setting, the positive results of the Phase III multiregional study, including regional consistency, as well as discussions with key opinion leaders and those physicians who have administered ivonescimab to patients in a clinical study setting, we believe that the safety and efficacy data generated in the HARMONi study demonstrates that patients suffering from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) in this setting can benefit from the ivonescimab regimen despite the lack of a statistically significant showing on overall survival.
Further Expansion of the Phase III Ivonescimab Clinical Development Program
In addition to the announcement HARMONi-GI3, a new global Phase III study in first-line unresectable metastatic colorectal cancer (CRC), Summit today announces its intention to expand its ivonescimab clinical development program with an additional set of Phase III clinical studies. We intend to provide additional color with respect to these Phase III studies in the first quarter of 2026.
Other Operational & Corporate Updates
Operational progress continues with ivonescimab (SMT112), an investigational, potentially first-in-class 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:
Since in-licensing ivonescimab (SMT112), from Akeso Inc. (Akeso, HKEX Code: 9926.HK) in January 2023, over 3,000 patients have been treated with ivonescimab in clinical studies globally, and over 40,000 patients when considering those treated in a commercial setting in China as noted by Akeso. Summit has rights to develop and commercialize ivonescimab in the United States, Canada, Europe, Japan, Latin America, including Mexico and all countries in Central America, South America, and the Caribbean, the Middle East, and Africa while Akeso retains development and commercialization rights for the rest of the world, including China.
Summit is developing ivonescimab in NSCLC, specifically conducting Phase III clinical trials in the following proposed indications:
HARMONi: Ivonescimab combined with chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who were previously treated with a third-generation EGFR tyrosine kinase inhibitor (TKI)
HARMONi-3: Ivonescimab combined with chemotherapy in patients with first-line metastatic NSCLC
HARMONi-7: Ivonescimab monotherapy in patients with first-line metastatic NSCLC whose tumors have high PD-L1 expression
In addition, Summit plans to start developing ivonescimab in CRC with an intention to begin a Phase III clinical study in the following proposed indication:
HARMONi-GI3: ivonescimab combined with chemotherapy in patients with first-line metastatic CRC
In September 2025, we announced detailed results from our multiregional, double-blinded, placebo-controlled, Phase III study, HARMONi, including data from the study’s prespecified primary analysis as well as results from longer-term follow up in western patients.
At the prespecified primary data analysis, ivonescimab in combination with chemotherapy demonstrated a statistically significant improvement in progression-free survival (PFS), the magnitude of which we believe to be clinically meaningful, with a hazard ratio (HR) of 0.52 (95% CI: 0.41 – 0.66; p<0.00001); median PFS was 6.8 months for those patients receiving ivonescimab plus chemotherapy compared to 4.4 months for those receiving chemotherapy. In a longer-term follow-up of PFS, which included all western patients, ivonescimab plus chemotherapy demonstrated a consistent improvement in PFS with an observed HR of 0.57 (95% CI: 0.46 – 0.71). We believe the PFS HR that was observed in both Asian and western sub-populations to be clinically meaningful. In both the primary analysis as well as longer-term follow-up analysis, consistency of the magnitude of PFS benefit was demonstrated between patients randomized in Asia and ex-Asia. PFS was assessed by blinded independent central radiology review committee (BICR) compared to placebo in combination with chemotherapy. The longer-term follow-up analysis of PFS was performed at the time of the primary overall survival (OS) analysis.
In the prespecified primary analysis, a positive trend in OS was observed without achieving a statistically significant benefit with an HR of 0.79 (95% CI: 0.62 – 1.01; p=0.057). Median OS was 16.8 months for those patients administered ivonescimab plus chemotherapy vs. 14.0 months for those receiving placebo plus chemotherapy. Analysis from longer-term follow-up in western patients, resulted in an OS HR consistent with the primary analysis with an improved nominal p-value (HR=0.78; 95% CI: 0.62 – 0.98; nominal p=0.0332). Median OS in the longer-term follow-up analysis remained the same in both arms from the primary analysis, 17.0 months in western patients receiving ivonescimab compared to 14.0 months for those receiving placebo (HR=0.84). Median OS in North American patients, specifically, had not yet been reached in the ivonescimab arm compared to 14.0 months in the placebo arm (HR=0.70). The HRs for western patients in totality, as well as patients from the North American and European regions individually, improved from the primary OS analysis to the analysis with longer-term follow-up of western patients. Consistent benefit was observed across pre-defined subgroups, with both Asian and North American patients demonstrating a positive trend in OS.
These trends provide further support for ivonescimab’s use in 2L+ EGFRm NSCLC, a setting where high unmet need continues to exist with limited approved options in the United States and other western territories. Currently there are no FDA-approved regimens that have demonstrated a statistically significant OS benefit in this patient setting. The results of the primary and longer-term follow up analysis in this multiregional study were consistent with that of the single-region HARMONi-A study, which demonstrated an OS HR of 0.80 at 52% data maturity in a similar patient population.
The dual primary endpoints were allocated separate alpha levels and tested individually. The alpha was recycled from the PFS to the OS analysis upon the successful achievement of the PFS endpoint.
Observed overall response rates (ORR) were 45% in the ivonescimab arm vs. 34% in the placebo arm; median duration of response (DoR) was longer in those patients administered ivonescimab plus chemotherapy (7.6 months) compared to those receiving placebo and chemotherapy (4.2 months).
The safety profile of ivonescimab in combination with chemotherapy was acceptable and manageable in the context of the observed clinical benefit, with comparable rates of discontinuation and death between both arms. There were 16 patients (7.3%) who discontinued ivonescimab due to treatment-related adverse events (TRAEs) compared to 11 patients (5.0%) who discontinued placebo due to TRAEs. There were four patients (1.8%) in the ivonescimab plus chemotherapy arm and five patients (2.3%) in the chemotherapy alone arm who died as a result of TRAEs. In the ivonescimab plus chemotherapy arm, 50.0% of patients experienced Grade 3 or higher TRAEs compared to 42.2% in the chemotherapy arm. Of note, 0.9% of patients in the ivonescimab plus chemotherapy arm experienced Grade 3 or higher hemorrhage (bleeding) events.
Last week, we announced the expansion of our Phase III clinical development program into CRC with the planned initiation of the global Phase III HARMONi-GI3 trial. The trial will evaluate ivonescimab plus chemotherapy compared to bevacizumab plus chemotherapy as first line therapy in patients with unresectable metastatic CRC. Clinical trial sites for HARMONi-GI3 are planned to begin activating in the United States prior to the end of the year. The study intends to enroll 600 patients in this multiregional study. The primary endpoint for this study is PFS.
Each year, approximately 48,000 patients are estimated to be diagnosed with or have unresectable recurrent metastatic microsatellite stable (MSS) CRC (also known as mismatch repair-proficient colorectal cancer, or pMMR CRC). 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 first-line metastatic MSS CRC.
In April 2025, Akeso announced that HARMONi-6, which evaluated ivonescimab combined with platinum-based chemotherapy vs. tislelizumab, a PD-1 inhibitor, with the same chemotherapy in patients with locally advanced or metastatic squamous NSCLC, regardless of PD-L1 expression, met its primary endpoint of PFS. Yesterday, additional HARMONi-6 data were presented as part of the Presidential Symposium at the European Society for Medical Oncology 2025 Congress (ESMO 2025) and featured in a manuscript published in The Lancet simultaneously. The presentation and publication are based on the results of HARMONi-6, a single region, multi-center, Phase III study conducted in China sponsored by Akeso, Inc., with data generated and analyzed by Akeso.
In the HARMONi-6 planned interim analysis of progression-free survival (PFS), ivonescimab in combination with chemotherapy demonstrated a statistically significant improvement in the primary endpoint, PFS, by Independent Radiologic Review Committee (IRRC), when compared to tislelizumab in combination with chemotherapy, achieving a hazard ratio (HR) of 0.60 (95% CI: 0.46, 0.78; p<0.0001). A clinically meaningful benefit was demonstrated across clinical subgroups, including those with either PD-L1 negative or positive expression.
Both the overall response rate (ORR) measured according to RECIST v1.1 criteria, as well as the duration of response (DoR) were higher in patients treated with ivonescimab plus chemotherapy compared to those treated with tislelizumab plus chemotherapy.
Ivonescimab demonstrated an acceptable and manageable safety profile in the HARMONi-6 study, which was consistent with previous Phase III studies conducted studying ivonescimab. In squamous NSCLC, VEGF-A monoclonal antibodies have not been approved by health authorities including the FDA and have had limited clinical development based on historical early phase clinical trials, primarily due to significant risks of toxicity, including hemorrhage and other life-threatening, bleeding-related complications. The results of this study further validate the unique mechanism of action of ivonescimab, including key differences as compared to separately administering an anti-PD-1 monoclonal antibody and an anti-VEGF monoclonal antibody.
In this Phase III study, there were nine patients (3.4%) who discontinued ivonescimab plus chemotherapy due to treatment-related adverse events (TRAEs) compared to 11 patients (4.2%) who discontinued tislelizumab plus chemotherapy due to TRAEs. There were eight patients (3.0%) in the ivonescimab plus chemotherapy arm and 10 patients (3.8%) in the tislelizumab plus chemotherapy arm who died as a result of TRAEs in this Phase III study. The most frequent TRAEs for ivonescimab treatment in combination with chemotherapy were common chemotherapy-related AEs, including alopecia, anemia, and various laboratory abnormalities, including neutrophil, white blood cell, and platelet count decreases. Grade 3 or higher immune-related adverse events occurred in 9.0% of patients receiving ivonescimab in combination with chemotherapy and 10.2% of patients receiving tislelizumab in combination with chemotherapy. Grade 3 or higher adverse events that were possibly VEGF-related in the ivonescimab plus chemotherapy arm were 7.5% vs. 2.3% for tislelizumab plus chemotherapy. Most of the possibly VEGF-related adverse events occurring in the ivonescimab plus chemotherapy arm were classified as Grade 1 or 2. Of note, Grade 3 or higher hemorrhage events were observed in five patients in the ivonescimab plus chemotherapy arm compared to two patients in the tislelizumab plus chemotherapy arm in this study.
This marks the first known Phase III trial in NSCLC to show significant improvement over PD-(L)1 inhibitor therapy combined with chemotherapy in a head-to-head setting. Following the success of Akeso’s HARMONi-2 study in China, this is the second instance where ivonescimab-based regimens have demonstrated a statistically significant benefit compared to standard-of-care PD-(L)1 inhibitor-based regimens in a Phase III trial.
Yesterday, we announced an update to our HARMONi-3 Phase III clinical trial evaluating ivonescimab combined with chemotherapy compared to pembrolizumab, a PD-1 inhibitor, combined with chemotherapy in patients with first-line metastatic, squamous and non-squamous NSCLC. The primary endpoints for this study are PFS and OS.
Summit has amended the protocol for the HARMONi-3 study in order to separate the statistical analysis (i.e., the outcome) of the primary endpoints by histology. Therefore, there will be separate analyses conducted to evaluate ivonescimab plus chemotherapy compared to pembrolizumab plus chemotherapy in patients with squamous NSCLC and in patients with non-squamous NSCLC.
As a result of having two separate intention-to-treat analyses within the HARMONi-3 study, the analyses for squamous tumors and non-squamous tumors may be conducted at separate times, as each analysis will be conducted upon the prespecified numbers of events being reached in the separate cohorts.
Summit currently expects to complete enrollment in the squamous cohort of HARMONi-3 in the first half of 2026 and expects to reach the prespecified number of events for the PFS primary endpoint analysis for this cohort in the second half of 2026. An interim analysis for overall survival may be conducted at a similar time.
At present time, Summit expects to complete enrollment in the non-squamous cohort of HARMONi-3 in the second half of 2026 and expects to reach the prespecified number of events for the PFS primary endpoint analysis for this cohort in the first half of 2027. An interim analysis for overall survival is planned to be conducted based upon reaching a prespecified number of events.
In order to sufficiently power each of the dual primary endpoints in both cohorts of this study, Summit plans to enroll 600 patients with squamous NSCLC and 1,000 patients with non-squamous NSCLC.
Clinical trial collaborations and investigator sponsored trials with leading organizations, including MD Anderson, the Memorial Sloan Kettering Cancer Center, and the Dana Farber Cancer Institute, among others, continue to progress and expand evaluating ivonescimab in solid tumor settings outside of metastatic NSCLC.
In June 2025, we announced a clinical collaboration with Revolution Medicines to evaluate ivonescimab in combination with three RAS(ON) inhibitors, including the multi-selective inhibitor daraxonrasib (RMC-6236), G12D-selective inhibitor zoldonrasib (RMC-9805), and G12C-selective inhibitor elironrasib (RMC-6291), in solid tumor settings with RAS mutations. We expect that clinical trials associated with this collaboration will begin in early 2026.
Enrollment continues in Summit’s global Phase III trials, HARMONi-3 and HARMONi-7. In addition to the enrollment in multiregional studies conducted and sponsored by Summit, our partners at Akeso are also enrolling several single-region Phase III studies exclusively in China in multiple indications, including biliary-tract cancer, triple-negative breast cancer, head and neck squamous cell carcinoma, colorectal cancer, and pancreatic cancer.
Financial Highlights
Cash and Cash Equivalents and Short-term Investments
Aggregate cash and cash equivalents and short-term investments were $238.6 million and $412.3 million at September 30, 2025 and December 31, 2024, respectively.
GAAP and Non-GAAP Operating Expenses
GAAP operating expenses were $234.2 million for the third quarter of 2025, compared to $58.4 million for the same period of the prior year. The increase in GAAP operating expenses was due to the increase in stock-based compensation expense of $111.4 million primarily related to modification to our performance-based stock option awards which occurred earlier during the current fiscal year.
Non-GAAP operating expenses were $103.4 million for the third quarter of 2025, compared to $39.0 million for the same period of the prior year. The increase in Non-GAAP operating expenses due to expansion of clinical studies and development costs related to ivonescimab.
GAAP and Non-GAAP Research and Development (R&D) Expenses
GAAP R&D expenses were $131.1 million for the third quarter of 2025, compared to $37.7 million for the same period of the prior year. The increase was due to the increase in stock-based compensation expense of $34.8 million primarily related to modification to our performance-based stock option awards which occurred earlier during the current fiscal year.
Non-GAAP R&D expenses were $90.5 million for the third quarter of 2025, compared to $31.9 million for the same period of the prior year. The increase is primarily related due to expansion of clinical studies and development costs related to ivonescimab.
GAAP and Non-GAAP General and Administrative (G&A) Expenses
GAAP G&A expenses were $103.1 million for the third quarter of 2025, compared to $20.7 million for the same period of the prior year. The increase was due to the increase in stock-based compensation expense of $76.6 million primarily related to modification to our performance-based stock option awards which occurred earlier during the current fiscal year.
Non-GAAP G&A expenses were $12.9 million for the third quarter of 2025, compared to $7.1 million for the same period of the prior year. The increase is related to building our infrastructure to support the development of ivonescimab.
GAAP and Non-GAAP Net Loss
GAAP net loss in the third quarter of 2025 and 2024 was $231.8 million or $(0.31) per basic and diluted share, and $56.3 million or $(0.08) per basic and diluted share, respectively.
Non-GAAP net loss in the third quarter of 2025 and 2024 was $101.0 million or $(0.13) per basic and diluted share, and $36.9 million or $(0.05) per basic and diluted share, respectively.
Use of Non-GAAP Financial Measures
This release includes measures that are not in accordance with U.S. generally accepted accounting principles ("Non-GAAP measures"). These Non-GAAP measures should be viewed in addition to, and not as a substitute for, Summit’s reported GAAP results, and may be different from Non-GAAP measures used by other companies. In addition, these Non-GAAP measures are not based on any comprehensive set of accounting rules or principles. Summit management uses these Non-GAAP measures for internal budgeting and forecasting purposes and to evaluate Summit’s financial performance. Summit management believes the presentation of these Non-GAAP measures is useful to investors for comparing prior periods and analyzing ongoing business trends and operating results. For further information regarding these Non-GAAP measures, please refer to the tables presenting reconciliations of our Non-GAAP results to our U.S. GAAP results and the "Notes on our Non-GAAP Financial Information" that accompany this press release.
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 multifold 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, and over 40,000 treated in a commercial setting in China as noted by Akeso.
Summit began its clinical development of ivonescimab in 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 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, and 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 20, 2025, View Source [SID1234656845])