On May 31, 2025 Immatics N.V. (NASDAQ: IMTX, "Immatics" or the "Company"), a clinical-stage biopharmaceutical company active in the discovery and development of T cell-redirecting cancer immunotherapies, reported the presentation of expanded data from the ongoing Phase 1b clinical trial evaluating IMA203 PRAME cell therapy in heavily pretreated patients with metastatic melanoma (Press release, Immatics, MAY 31, 2025, View Source [SID1234653545]). The longer follow-up of patients demonstrates a consistent and favorable tolerability profile as well as durable responses with a confirmed ORR of 56%. In addition, the Company provided details from a Trial in Progress poster on SUPRAME, the ongoing Phase 3 clinical trial evaluating IMA203 in patients with unresectable or metastatic cutaneous melanoma who have received prior treatment with a checkpoint inhibitor.

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The data from the ongoing Phase 1b trial will be presented on Saturday, May 31, 2025, during an oral presentation by Martin Wermke, M.D. The Trial in Progress poster (TiP) will be presented at the conference on Monday, June 2, 2025, by Jason Luke, M.D., FACP, FASCO. The IMA203 slides, including the ASCO (Free ASCO Whitepaper) data and additional data, are accessible in the ‘Events & Presentations’ section of the Investor & Media section of the Company’s website.

"Patients with advanced melanoma post-failure of checkpoint inhibition are left to face frequent and often rapid disease progression and limited long-term survival. These individuals are in urgent need of new treatments that deliver deeper and more durable responses," said Cedrik Britten, M.D., Chief Medical Officer at Immatics. "We believe the data presented today emphasize the strength, durability and tangible therapeutic potential of our one-time infusion PRAME cell therapy, IMA203, in this patient population. These positive results reinforce our commitment to actively advance IMA203 through the ongoing Phase 3 SUPRAME trial to bring this PRAME therapy to the market as soon as possible."

"PRAME is a highly prevalent target that is expressed in more than 50 cancers. This, combined with the data presented at ASCO (Free ASCO Whitepaper), further strengthens our position as the global leader in precision targeting of PRAME. We view our progress in melanoma as a critical step in our journey to building the broadest PRAME franchise with the most indications and modalities and delivering novel PRAME immunotherapies to cancer patients with high unmet medical needs," said Harpreet Singh, Ph.D., Chief Executive Officer and Co-Founder at Immatics.

Oral Presentation Summary – IMA203 Phase 1b Trial

Patient Population: Heavily pretreated patients with metastatic melanoma

As of April 7, 2025, 33 heavily pretreated patients with metastatic melanoma were administered a one-time infusion of IMA203 at the recommended Phase 2 dose (RP2D, 1 to 10 billion total TCR T cells) in the Phase 1b dose expansion. The treated patient population consisted of cutaneous melanoma (n=14), uveal melanoma (n=16), mucosal melanoma (n=2) and melanoma of unknown primary (n=1). Patients had a median of 2 lines of prior systemic treatments. The subgroup of patients with cutaneous melanoma had a median of 2.5 lines of prior systemic treatments, thereof a median of 2 lines of prior immune checkpoint inhibitors.

Safety: Favorable tolerability

The safety population included 74 patients combined from the Phase 1a dose escalation and Phase 1b dose expansion across all dose levels and all tumor types. IMA203 has maintained a favorable tolerability profile.

The most frequent treatment-emergent adverse events were anticipated cytopenias associated with lymphodepletion. Expected and manageable cytokine release syndrome (CRS) was mostly Grades 1 and 2, which is consistent with the mechanism of action (Grade 1: 37%, Grade 2: 47%, Grade 3: 11%, Grade 4: 0%). No patients experienced long-term CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred infrequently, was manageable and mostly mild (Grade 1: 5%, Grade 2: 4%, Grade 3: 4%, Grade 4: 0%). No IMA203-related Grade 5 events were observed.

Tolerability in the Phase 1b melanoma subset was generally consistent with the full IMA203 tolerability profile.

Anti-tumor activity and durability: Encouraging anti-tumor activity of IMA203 PRAME cell therapy, including durable responses up to >2.5 years with longer follow-up

All melanoma1,2
(n=33) Cutaneous melanoma
(n=14) Uveal melanoma2
(n=16)

cORR 56% (18/32) 50% (7/14) 67% (10/15)
ORR 64% (21/33) 57% (8/14) 69% (11/16)
DCR 91% (30/33) 93% (13/14) 88% (14/16)
mDOR (range) / mFU [mo] 12.1 (1.8+, 32.6+) / 13.4 NR3 (4.2, 32.6+) / 16.7 11.0 (1.8+, 31.6) / 13.4
mPFS (range) / mFU [mo] 6.1 (1.4, 34.0+) / 14.4 6.0 (1.4, 34.0+) / 14.4 8.5 (1.4, 32.9) / 8.7
mOS (range) / mFU [mo]

15.9 (2.4, 34.2+) / 14.4 13.9 (2.4, 34.0+) / 14.4 16.2 (3.2+, 34.2+) / 14.5
The PFS rate was 53% at six months and 27% at 12 months. The overall survival rate was 61% at 12 months. In addition, 42% (14/33) of patients had a deep response (≥50% tumor reduction) with a mPFS of 12.9 months.

Translational analyses demonstrated that treatment with IMA203 resulted in the shrinkage of metastatic target lesions throughout the body. This included reductions in difficult-to-treat metastases, such as liver, lung, lymph node, abdomen/peritoneum, skin and others. Some individual lesions had a complete resolution (-100%). All patients (n=3) who had a best overall response of progressive disease according to RECIST 1.1 experienced shrinkage of individual lesions.

The positive Phase 1b data and high PRAME prevalence (~90-95% in melanoma) reinforce the potential of IMA203, which is currently being evaluated in the ongoing SUPRAME Phase 3 trial in previously treated advanced or metastatic cutaneous melanoma, as well as the continued Phase 1b expansion into uveal melanoma.

Trial-in-Progress Poster Summary – IMA203 SUPRAME Phase 3 Trial

Based on the positive clinical data and supported by the FDA RMAT designation4, Immatics advanced its PRAME cell therapy, IMA203, into the randomized-controlled Phase 3 SUPRAME trial (NCT06743126).

SUPRAME is a prospective, multicenter, open-label, randomized, actively controlled Phase 3 clinical trial evaluating the efficacy, safety and tolerability of IMA203 vs. investigator’s choice in ~360 patients with unresectable or metastatic cutaneous melanoma who have received prior treatment with a checkpoint inhibitor. Patient eligibility is determined by protocol inclusion/exclusion criteria, including HLA screening. If patients are HLA-A*02:01 positive and meet the eligibility criteria, they will undergo leukapheresis and be randomized 1:1. Patients in the IMA203 arm will undergo lymphodepletion with cyclophosphamide (500 mg/m2 x 4 days) and fludarabine (30 mg/m2 x 4 days), subsequent infusion of 1-10 x109 IMA203 PRAME-directed TCR T cells, followed by low-dose IL-25 (subcutaneous). Patients in the control arm will receive either nivolumab/relatlimab, nivolumab, ipilimumab, pembrolizumab, lifileucel (in the US), or chemotherapy based on investigator’s choice. The primary endpoint is blinded independent central review ("BICR")-assessed (RECIST 1.1) PFS. Secondary endpoints include OS, ORR, safety and patient-reported outcomes about quality of life.

The expected median PFS in this post-checkpoint inhibitor patient population6 is 2-3 months, and the IMA203 Phase 1b data presented today at ASCO (Free ASCO Whitepaper) indicate a continued median PFS of ≥6 months.

SUPRAME is planned to be conducted in more than 50 sites in North America and Europe.

Patient enrollment and randomization for the trial was initiated in early 2025 and is expected to be completed in 2026. A pre-specified interim data analysis will be triggered upon the occurrence of a defined number of events for PFS (progressive disease or death)7, anticipated to occur after approximately 200 patients. Immatics aims to submit a Biologics License Application (BLA) to the FDA in 1Q 2027 for full approval.

About PRAME
PRAME is a target expressed in more than 50 cancers. Immatics is the global leader in precision targeting of PRAME and has the broadest PRAME franchise with the most PRAME indications and modalities. The Immatics PRAME franchise currently includes three product candidates, two therapeutic modalities and a combination therapy that target PRAME: IMA203 PRAME cell therapy, IMA203CD8 PRAME cell therapy (GEN2), IMA402 PRAME bispecific, IMA203 in combination with Moderna’s PRAME adaptive immune modulating therapy.

About IMA203 PRAME Cell Therapy
IMA203 is a PRAME-directed TCR T-cell therapy engineered to recognize an intracellular PRAME-derived peptide presented by HLA-A*02:01 on the cell surface and initiate a potent and specific anti-tumor response. IMA203 PRAME cell therapy is currently being evaluated in a registration-enabling randomized controlled Phase 3 trial, "SUPRAME," in patients with unresectable or metastatic cutaneous melanoma who have disease progression on or after treatment with at least one checkpoint inhibitor. In parallel, the Phase 1b clinical trial in patients with PRAME cancers is ongoing with a focus on uveal melanoma.

On May 31, 2025 Arvinas, Inc. (Nasdaq: ARVN) and Pfizer Inc. (NYSE: PFE) reported detailed results from the Phase 3 VERITAC-2 clinical trial (NCT05654623) evaluating vepdegestrant monotherapy versus fulvestrant in adults with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced or metastatic breast cancer (MBC) whose disease progressed following prior treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors and endocrine therapy (Press release, Arvinas, MAY 31, 2025, View Source [SID1234653542]). These data, which were highlighted in the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) press briefing and selected for Best of ASCO (Free ASCO Whitepaper), will be presented today in a late-breaking oral presentation (Abstract LBA1000) and have been simultaneously published in the New England Journal of Medicine.

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In the trial, vepdegestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) among patients with an estrogen receptor 1 (ESR1) mutation, reducing the risk of disease progression or death by 43% compared to fulvestrant [Hazard Ratio (HR)=0.57 (95% CI 0.42–0.77); 2-sided P<0.001]. The median PFS, as assessed by blinded independent central review (BICR), was 5.0 months with vepdegestrant versus 2.1 months with fulvestrant. Investigator-assessed PFS was consistent with the BICR-assessed PFS. In patients with ESR1 mutations, vepdegestrant demonstrated a consistent PFS benefit over fulvestrant across all pre-specified subgroups. The trial did not reach statistical significance in improvement in PFS in the intent-to-treat (ITT) population, with a median PFS of 3.7 months for vepdegestrant versus 3.6 for fulvestrant [HR=0.83 (95% CI 0.68–1.02); 2-sided P=0.07].

"Many patients with ER+/HER2- metastatic breast cancer who progress on endocrine therapy have tumors with ESR1 mutations, which drive resistance to standard treatments," said Erika P. Hamilton, M.D., Director, Breast Cancer Research, Sarah Cannon Research Institute, and a principal investigator of the VERITAC-2 trial. "The VERITAC-2 results are promising and suggest that vepdegestrant could offer a much-needed treatment option for these patients, with a low incidence of burdensome GI effects that can meaningfully affect daily life."

Vepdegestrant was generally well tolerated in the trial, with a safety profile consistent with what has been observed in previous studies, and mostly low-grade treatment-emergent adverse events (TEAEs). Rates and severity of gastrointestinal adverse events were low with vepdegestrant (nausea, 13.5%; vomiting, 6.4%; diarrhea, 6.4%). Grade 4 TEAEs were reported in 5 patients (1.6%) in the vepdegestrant arm versus 9 patients (2.9%) in the fulvestrant arm. The three most common TEAEs observed with vepdegestrant were fatigue (26.6%), increased alanine transaminase (ALT) (14.4%) and increased aspartate aminotransferase (AST) (14.4%). TEAEs leading to treatment discontinuation occurred in 2.9% of patients taking vepdegestrant versus 0.7% of patients taking fulvestrant.

"Based on these strong data from VERITAC-2, we believe that vepdegestrant has the potential to be a best-in-class monotherapy treatment for patients in the second-line ESR1-mutant setting," said John Houston, Ph.D., Chairperson, Chief Executive Officer and President at Arvinas. "We are excited to engage with regulatory authorities on next steps to potentially bring vepdegestrant to healthcare providers and their patients as swiftly as possible."

Overall survival (OS), the key secondary endpoint in VERITAC-2, was immature at the time of the analysis, with less than a quarter of the required number of events having occurred. Additional secondary endpoints include clinical benefit rate (CBR) and objective response rate (ORR) and duration of response by BICR. In patients with an ESR1 mutation, CBR was 42.1% with vepdegestrant versus 20.2% with fulvestrant [odds ratio 2.88 (95% CI: 1.57–5.39); nominal P<0.001] and ORR was 18.6% with vepdegestrant versus 4.0% with fulvestrant [odds ratio 5.45 (95% CI: 1.69–22.73); nominal P=0.001]. The median duration of response was not reached.

"Patients whose tumors harbor ESR1 mutations can face a poor prognosis, often experiencing rapid disease progression on endocrine therapy," said Johanna Bendell, M.D., Chief Oncology Development Officer, Pfizer. "These results highlight the important role vepdegestrant may play in combating ESR1 mutation treatment resistance for these patients."

Approximately 2.3 million new breast cancer diagnoses were reported globally in 2022, and it is estimated there will be nearly 320,000 new diagnoses in the United States in 2025. ER+/HER2- breast cancer accounts for approximately 70% of all cases. Nearly 30% of women initially diagnosed with early-stage breast cancer will ultimately develop metastatic disease,1 with resistance to current standard-of-care treatments often emerging during first-line therapy, leading to disease progression. ESR1 mutations are a common cause of acquired resistance and are found in approximately 40% of patients in the second-line setting.2,3,4

Vepdegestrant, an investigational oral PROTAC ER degrader for ER+/HER2- breast cancer being jointly developed by Arvinas and Pfizer, is designed to harness the body’s natural protein disposal system to specifically target and degrade the ER. These detailed results follow the March 2025 announcement of the topline results from VERITAC-2. The companies plan to submit a New Drug Application (NDA) for vepdegestrant to the U.S. Food & Drug Administration (FDA) in the second half of 2025.

ASCO Presentation Details
"Vepdegestrant, a PROTAC Estrogen Receptor Degrader, vs Fulvestrant in ER-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results of the Global, Randomized, Phase 3 VERITAC-2 Study" will be presented by Dr. Erika Hamilton, MD, Sarah Cannon Research Institute, in the Oral Abstract Session, Breast Cancer—Metastatic on Saturday, May 31, 1:15 – 4:15 p.m. CDT in Hall B1. Abstract LBA1000.

Investor Call and Webcast Details
Arvinas will host a conference call and webcast on June 2, 2025, at 8:00 a.m. ET to review these data. Participants are invited to listen by going to the Events and Presentation section under the Investors page on the Arvinas website at www.arvinas.com. A replay of the webcast will be available on the Arvinas website following the completion of the event and will be archived for up to 30 days.

About the VERITAC-2 Clinical Trial
The Phase 3 VERITAC-2 clinical trial (NCT05654623) is a global randomized trial evaluating the efficacy and safety of vepdegestrant (ARV-471) as a monotherapy compared to fulvestrant in patients with ER+/HER2- advanced or metastatic breast cancer. The trial enrolled 624 patients at sites in 26 countries who had previously received treatment with a CDK4/6 inhibitor plus endocrine therapy.

Patients were randomized 1:1 to receive either vepdegestrant once daily, orally on a 28-day continuous dosing schedule, or fulvestrant, administered intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each 28-day cycle starting from Day 1 of Cycle 2. In the trial, 43% of patients (n=270) had ESR1 mutations detected. The primary endpoint was progression-free survival (PFS) in the ESR1-mutation and intent-to-treat populations as determined by blinded independent central review. Overall survival is the key secondary endpoint.

About Vepdegestrant
Vepdegestrant is an investigational, orally bioavailable PROteolysis TArgeting Chimera (PROTAC) protein degrader designed to specifically target and degrade the estrogen receptor (ER) for the treatment of patients with ER-positive (ER+)/human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) breast cancer. Vepdegestrant is being developed as a potential monotherapy for ER+/HER2- advanced or metastatic breast cancer with estrogen receptor 1 (ESR1) mutations in the second line-plus setting.

In July 2021, Arvinas announced a global collaboration with Pfizer for the co-development and co-commercialization of vepdegestrant; Arvinas and Pfizer will share worldwide development costs, commercialization expenses, and profits.

The U.S. Food and Drug Administration (FDA) has granted vepdegestrant Fast Track designation as a monotherapy in the treatment of adults with ER+/HER2- advanced or metastatic breast cancer previously treated with endocrine-based therapy.

On May 30, 2025 Iksuda Therapeutics (Iksuda), the developer of class-leading antibody drug conjugates (ADCs) with clinically validated tumour-selective payload release formats, reported the completion of dosing of its first patient with IKS03, a CD19-directed ADC, in a phase 1, first-in-human, clinical trial in patients with advanced B cell non-Hodgkin lymphoma (Press release, Iksuda Therapeutics, MAY 30, 2025, View Source [SID1234653540]).

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This first-in-human study (View Source) will evaluate the safety, tolerability, preliminary antineoplastic activity, pharmacokinetics and pharmacodynamics of increasing dose levels of IKS03, and determine the recommended dose for dose-expansion. Efficacy will be further evaluated in disease-specific expansion cohorts. The study is currently enrolling patients across clinical sites in Italy, Spain, Australia, United States and Canada.

Dr Dave Simpson, Chief Executive Officer, Iksuda Therapeutics, said:

"With the first patient successfully completing the safety evaluation period with IKS03, Iksuda demonstrates its continued commitment to drive its differentiated ADCs through clinical proof of concept, further solidifying our position as a clinical-stage ADC-focused company. Although there have been advances in the treatment of non-Hodgkin lymphoma in recent years, there remains a significant unmet patient need, and we hope that IKS03 will be able to build on the potential benefit-risk profile suggested by the data generated in preclinical studies."

About IKS03

IKS03 is a best-in-class CD19-targeting ADC delivering a tumour-activated prodrug pyrrolobenzodiazepine (PBD) which was licensed from LigaChem Biosciences (formerly LegoChem Biosciences) (View Source). Preclinical testing demonstrates best-in-class efficacy (vs in-clinic and marketed CD19-targeted therapies) in in vivo xenograft models and significantly raised maximum tolerated dose (MTD) in non-human primate disease models, demonstrating its potential to be the leading anti-CD19 therapy in B-cell cancers.

On May 30, 2025 Parabilis Medicines, a clinical-stage biopharmaceutical company committed to creating extraordinary medicines for people living with cancer, reported the presentations of trial-in-progress posters on the Company’s first-in-human clinical trial evaluating FOG-001, the first and only direct inhibitor of β-cateninTCF4, at the ASCO (Free ASCO Whitepaper) Annual Meeting, which begins on May 30 in Chicago, Illinois, and the ESMO (Free ESMO Whitepaper) Gastrointestinal Cancers Congress 2025, which begins on July 2 in Barcelona, Spain (Press release, Parabilis Medicines, MAY 30, 2025, View Source;cateninTCF4-Inhibitor-at-Upcoming-Medical-Meetings [SID1234653539]).

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FOG-001 is being evaluated in a Phase 1/2 trial (NCT05919264). The multicenter, open-label, non-randomized trial aims to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of FOG-001 in patients with solid tumors with Wnt pathway activating mutations (WPAM+), including colorectal cancer (CRC) and desmoid tumors.

More than 65 patients with locally advanced or metastatic tumors have been dosed with FOG-001 to date, and early clinical data demonstrate monotherapy antitumor activity and in-tumor target engagement. Phase 1/2 data are expected to be shared publicly in 2025.

The trial is currently enrolling patients with desmoid tumors in its monotherapy arm. It is also enrolling multiple cohorts of microsatellite-stable CRC (MSS-CRC) patients to evaluate combination regimens of FOG-001, supported by strong scientific rationale:

Combinations with FOLFOX+bevacizumab and trifluridine/tipiracil+bevacizumab: Paired biopsy data from the ongoing FOG-001 trial indicate that FOG-001 drives reduction in markers of stemness and upregulation of the angiogenesis pathway, pointing to potentially greater susceptibility to both chemotherapy and bevacizumab. Preclinical studies employing patient-derived xenograft (PDX) mouse models indicate FOG-001 can significantly deepen and extend the benefit of both chemotherapy backbone agent 5-FU and bevacizumab.
A second combination regimen, pairing FOG-001 with PD-1 checkpoint inhibitors, is supported by paired biopsy data from the ongoing trial indicating that FOG-001 induces the Merck tumor inflammation signature in otherwise immunologically "cold" tumors. Preclinical studies in MC38 mouse models suggest this potential, demonstrating synergistic combination efficacy between FOG-001 and PD-1 checkpoint inhibitors. These observations indicate that FOG-001 could improve CRC responses to immunotherapy, which currently has minimal to no monotherapy efficacy in MSS-CRC.
ASCO poster information:

Title: "A Phase 1/2 study of FOG-001, a first-in-class direct β-catenin:TCF inhibitor, in patients with colorectal cancer (CRC) and other locally advanced or metastatic solid tumors"
Abstract Number: TPS3169
Date and Time: June 2, 2025, 1:30-4:30 p.m. CDT
Session: Developmental Therapeutics – Molecularly Targeted Agents and Tumor Biology
Location: Hall A – Posters and Exhibits

ESMO GI poster information:

Title: "FOG-001 – a first-in-class direct β-catenin:TCF inhibitor, in patients with colorectal cancer (CRC) and other locally advanced or metastatic solid tumors: Phase 1/2 study design"
Presentation Number: 145TiP
Date and Time: July 3, 2025, 3:30-4:30 p.m. CET
Session: Poster display session
Location: Foyer

About FOG-001
FOG-001 is an investigational first-in-class competitive inhibitor of β-catenin interactions with the T-cell factor (TCF) family of transcription factors, and is currently in clinical development. By directly targeting the β-cateninTCF4 protein-protein interaction, FOG-001 is intended to block the Wnt signaling pathway irrespective of the various APC and beta-catenin mutations that typically drive disease.

FOG-001 combines key features that distinguish it from previously reported Wnt/β-catenin pathway modulators: FOG-001 acts inside the cell where it binds directly to the key oncogenic driver β-catenin; and FOG-001 blocks the Wnt pathway at the most downstream node, disrupting the interaction between β-catenin and the transcription factor TCF, thereby abrogating the signal transmission by which Wnt pathway mutations are believed to drive oncogenesis. FOG-001 is currently being evaluated in a first-in-human Phase 1/2 clinical trial in patients with locally advanced or metastatic solid tumors.

On May 30, 2025 Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit," "we," or the "Company") reported topline results from the Phase III clinical trial, HARMONi, the first global Phase III study evaluating ivonescimab, successfully met the progression-free survival (PFS) primary endpoint and showed a positive trend in the other primary endpoint, overall survival (OS) (Press release, Summit Therapeutics, MAY 30, 2025, View Source [SID1234653538]).

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HARMONi is a multiregional, double-blinded, placebo-controlled, Phase III study sponsored by Summit evaluating ivonescimab plus platinum-doublet chemotherapy compared to placebo plus platinum-doublet chemotherapy in patients with epidermal growth factor receptor (EGFR)-mutated, locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have progressed after treatment with a 3rd generation EGFR tyrosine kinase inhibitor (TKI). This is a clinical setting with a patient population where PD-1 monoclonal antibodies have previously been unsuccessful in Phase III global clinical trials in showing either a PFS or OS benefit.

Approximately 38% of patients were randomized from western countries (ex-Asia), consistent with other recent multiregional Phase III studies in patients with EGFR-mutated NSCLC.

At the prespecified primary data analysis, ivonescimab in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival, with a hazard ratio of 0.52 (95% CI: 0.41 – 0.66; p<0.00001). PFS was measured by blinded independent central radiology review committee (BICR) compared to placebo in combination with chemotherapy. A clinically meaningful hazard ratio was observed in both Asia and ex-Asia sub-populations. The primary analysis demonstrated the consistency of the magnitude of the PFS benefit between patients randomized in Asia and ex-Asia, as well as the consistency in a single-region study (HARMONi-A) with this multiregional study.

Ivonescimab in combination with chemotherapy showed a positive trend in OS in the primary analysis without achieving a statistically significant benefit with a hazard ratio of 0.79 (95% CI: 0.62 – 1.01; p=0.057). This trend provides further support for its 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. There are no current FDA-approved regimens that have demonstrated a statistically significant overall survival benefit in this patient setting. The median follow-up time for western patients was less than the median overall survival at the time of the analysis, and these patients may continue to be followed for long-term outcomes. Both Asian and North American patients demonstrated a positive trend in overall survival. The results of the primary analysis in this multiregional study were consistent with that of the single-region HARMONi-A study, which demonstrated an overall survival hazard ratio of 0.80 at 52% data maturity in a similar patient population.

There were no new safety signals noted in this Phase III study. Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported for 56.9% of patients in the ivonescimab + chemotherapy arm vs 50.0% with chemotherapy alone. Fatal TEAEs (excluding disease progression) were reported for 1.8% of patients in the ivonescimab + chemotherapy arm vs. 2.8% in those patients receiving chemotherapy alone. The safety profile of ivonescimab + chemotherapy was acceptable and manageable in the context of the observed clinical benefit.

"The evidence of a consistent benefit in PFS for both Asian and western patients, as well as the consistent overall survival results between the single-region HARMONi-A study and our global HARMONi study demonstrates the potential benefit ivonescimab has to bring to patients around the world, including the United States," stated Robert W. Duggan, Chairman and Co-Chief Executive Officer of Summit Therapeutics.

Based on the results of the HARMONi clinical trial, Summit, at present time, intends to file a Biologics License Application (BLA) in order to seek approval for ivonescimab plus chemotherapy in this setting. Based on discussions with the United States Food & Drug Administration (FDA), under our determination and subject to our review, Summit will consider the timing of the filing of this BLA. The FDA noted that a statistically significant overall survival benefit is necessary to support marketing authorization, which will weigh into Summit’s considerations regarding the timing of a potential BLA filing.

A more complete data presentation from the clinical study is intended to be shared at a future major medical conference.

"Our conviction in the promise that this therapy holds for patients continues to be validated: we believe that ivonescimab has the potential to make a meaningful difference for the betterment of patients’ lives," added Dr. Maky Zanganeh, President and Co-CEO of Summit.

The positive Phase III HARMONi study results, along with the approval of ivonescimab in China in combination with chemotherapy based on the results of the HARMONi-A trial and the subsequent supplemental approval of ivonescimab monotherapy in China for first-line treatment of patients with advanced NSCLC whose tumors have positive PD-L1 expression based on the results of the HARMONi-2 trial, further substantiates the purposefully-engineered, differentiated mechanism of action of ivonescimab, a PD-1 / VEGF bispecific antibody evidencing cooperative binding characteristics, and its opportunity to improve upon the existing standards of care for solid tumors, including in settings where existing immune checkpoint inhibitors are indicated.

We would like to offer our heartfelt gratitude to each of the patients, physicians, nurses, and caregivers who participated in and supported this clinical study. We are grateful to the dedication of our investigators and patients who are essential in advancing innovative therapies and bringing to patients the most advanced therapies for those facing unfortunate diagnoses.

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 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), 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 2,300 patients have been treated with ivonescimab in clinical studies globally.

Summit has begun 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, and the Company has begun to enroll patients in the United States for HARMONi-7.

HARMONi is a Phase III clinical trial which is evaluating 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 a 3rd generation EGFR TKI (e.g., osimertinib). Top-line results were announced in May 2025, which included a statistically significant and clinically meaningful benefit in progression-free survival and a positive trend in overall survival, the trial’s two primary endpoints. Consistent results were noted between the single region HARMONi-A study and the multiregional HARMONi study.

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 and non-squamous NSCLC.

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.

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. Approximately 85% of patients received a 3rd generation EGFR-TKI prior to randomization in the study.

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.

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, and its label was expanded in China in April 2025. Ivonescimab was granted Fast Track designation by the US Food & Drug Administration ("FDA") for the HARMONi clinical trial setting.