Shanghai Pulmonary Hospital

In the ITT population, ivonescimab demonstrated a clinically meaningful mPFS of 11.15 months vs. 5.82 months with pembrolizumab in 1L PD-L1 positive advanced NSCLC. ITT Stratified HR: Ivonescimab significantly reduced the risk of disease progression or death by 49% vs. pembrolizumab, with a PFS HR of 0.51 (P<0.0001). ITT ORR and DCR: Ivonescimab significantly improved the ORR to 50.0% vs. 38.5% with pembrolizumab, and the DCR was 89.9% vs.70.5%. PD-L1 high and low expression subgroups: In the PD-L1 TPS ≥50% population, ivonescimab achieved a PFS HR of 0.46 vs. pembrolizumab. In the PD-L1 TPS 1-49% population, the PFS HR was 0.54. Squamous and non-squamous histologies subgroups: In squamous NSCLC, ivonescimab showed a PFS HR of 0.48; in non-squamous NSCLC, the PFS HR was 0.54. Refractory subgroups: Ivonescimab showed significantly better clinical benefits compared to pembrolizumab in refractory patient populations, including those with liver metastases and brain metastases. Excellent safety profile: Ivonescimab demonstrated acceptable safety in IIT population including those with different levels of PD-L1 expression , sq-NSCLC and nsq-NSCLC, refractory conditions, and high bleeding risk. Akeso's partner, Summit will initiate HARMONi-7, a phase III trial in 1L PD-L1 high advanced NSCLC, in early 2025. HONGKONG and CALIFORNIA, Sept. 8, 2024 /PRNewswire/ -- Akeso (9926. HK) is thrilled to unveil groundbreaking data on its internally developed ivonescimab (a first-in-class PD-1/VEGF bispecific antibody) at the IASLC 2024 World Conference on Lung Cancer (WCLC24). The data, presented as a Late-Breaking Abstract (LBA) with an oral presentation, comes from a registration Phase III head-to-head clinical trial comparing ivonescimab monotherapy to pembrolizumab monotherapy as a first-line treatment for PD-L1 positive (PD-L1 TPS ≥1%) locally advanced or metastatic non-small cell lung cancer (NSCLC). The trial results were presented by Professor Caicun Zhou, MD, PhD, Chief Physician and Director of the Department of Medical Oncology at Shanghai Pulmonary Hospital, Tongji University School of Medicine, and President-Elect of IASLC. Furthermore, Professor Zhou participated in the official WCLC press conference, discussing the clinical significance of this study. In the HARMONi-2 study, baseline characteristics were well-balanced between the experimental and control groups. In the intention-to-treat (ITT) population, ivonescimab significantly improved progression-free survival (PFS) compared to pembrolizumab, markedly reducing the risk of disease progression or death. Subgroup analyses revealed that ivonescimab outperformed pembrolizumab across various factors, including age, sex, ECOG performance status, PD-L1 expression, histological type, and the presence of liver or brain metastases. This is the first randomized phase III study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in NSCLC. PFS Stratified HR 0.51, mPFS 11.14 Months Ivonescimab as first-line treatment for PD-L1 positive NSCLC significantly extends median progression-free survival (mPFS) compared to pembrolizumab, with both statistical and clinical significance. In the ITT population, ivonescimab demonstrated a median progression-free survival (mPFS) of 11.14 months compared to 5.82 months for pembrolizumab. The PFS hazard ratio (HR) was 0.51 (P<0.0001), indicating a significant 49% reduction in the risk of disease progression or death. Ivonescimab significantly improved the objective response rate (ORR) and disease control rate (DCR) compared to pembrolizumab in the first-line treatment of PD-L1 positive non-small cell lung cancer (NSCLC) patients. The ORR for ivonescimab was 50.0%, versus 38.5% for pembrolizumab, while the DCR was 89.9% for ivonescimab versus 70.5% for pembrolizumab. These results highlight ivonescimab's effective anti-tumor effect. Overall survival data was not yet mature at the time of the data cutoff and will be evaluated in the future. Significant Progression-Free Survival Benefits of Ivonescimab Across PD-L1 Expression Subgroups Ivonescimab demonstrated significant progression-free survival benefits in patients with both low and high PD-L1. The HARMONi-2 study enrolled participants with PD-L1 TPS ≥50%, accounting for 42.2%, aligning with the distribution in real-world populations. In the PD-L1 TPS ≥50% population, the PFS HR for ivonescimab versus pembrolizumab was 0.46, reducing the risk of disease progression/death by 54%. In the PD-L1 TPS 1-49% population, the PFS HR for ivonescimab versus pembrolizumab was 0.54, reducing the risk of disease progression/death by 46%. Ivonescimab showed meaningful progression-free survival benefits in both squamous and non-squamous subgroups In the HARMONi-2 study, 45.5% of the enrolled patients had sq-NSCLC, and 54.5% had nsq-NSCLC. In sq-NSCLC subgroup, the PFS HR for ivonescimab and pembrolizumab was 0.48. In nsq-NSCLC subgroup, the PFS HR for ivonescimab and pembrolizumab was 0.54. Ivonescimab monotherapy demonstrated significant efficacy regardless of liver metastasis, brain metastasis, or a history of hemoptysis. In this study, 12.6% of patients treated with ivonescimab had liver metastasis, and 16.7% had brain metastasis. The PFS HR for ivonescimab and pembrolizumab in patients with brain metastasis was 0.55; in those without brain metastasis, the PFS HR was 0.53. The PFS HR for ivonescimab and pembrolizumab in patients with liver metastasis was 0.47; in those without liver metastasis, the PFS HR was 0.53. Ivonescimab Demonstrated Acceptable and Manageable Safety Profile Across Subgroups In the HARMONi-2 study, 72.2% of patients with squamous cell carcinoma (sq-NSCLC) treated with ivonescimab had centrally located tumors, 10.0% had tumors with cavitation or necrosis, and 6.7% had tumors encasing large blood vessels. Despite these factors, which typically contraindicate traditional anti-VEGF therapies due to bleeding risks, ivonescimab did not significantly increase bleeding compared to the control group. The study confirms that ivonescimab has an acceptable and manageable overall safety profile, consistent with prior research. The incidence of grade 3 or higher treatment-related adverse events (TRAEs) in sq-NSCLC patients treated with ivonescimab was comparable to that in the pembrolizumab group (22.2% vs. 18.7%). HRQoL with ivonescimab was comparable to pembrolizumab. Based on the results of HARMONi-2, Akeso's partner, Summit, plans to initiate HARMONi-7 in early 2025. HARMONi-7 is currently planned as a multi-regional Phase III clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in metastatic NSCLC patients whose tumors have high PD-L1 expression (PD-L1 TPS≥50%) Dr. Michelle Xia, Founder, Chairwoman, President, and CEO of Akeso, said: "The research outcomes of HARMONi-2 are very encouraging. Pembrolizumab has been one of the most commercially successful innovative drugs globally in recent years. The clinically meaningful outcomes of ivonescimab versus pembrolizumab in a randomized, double-blind Phase III study, coupled with its demonstrated superior efficacy and manageable safety profile, affirm the immense potential of ivonescimab as a cornerstone treatment in cancer immunotherapy. This further substantiates the clinical benefit and market potential of ivonescimab on a global scale. The HARMONi-2 results presented today encourages Akeso and our partner SUMMIT to expand the clinical development of ivonescimab globally in more cancer indications for the benefit of patients with unmet medical needs. We are very impressed by Summit's ability to execute on clinical development since the start of our collaboration, and we are excited to work with them to pave the way for approvals in the US, Europe, and the rest of the license territories in the future." About ivonescimab Ivonescimab is a novel global first-in-class PD-1/VEGF bi-specific immunotherapy drug internally developed by Akeso. Ivonescimab has been approved in China for treating EGFR mutated locally advanced or metastatic non-squamous NSCLC patients who have progressed after EGFR TKI treatment. It is the world's first approved bispecific antibody with a "cancer immunotherapy + anti-angiogenesis" synergistic mechanism. Akeso out-licensed Summit Therapeutics exclusive rights to ivonescimab for the development and commercialization in certain territories including United States, Canada, Europe, Japan, Latin America, Africa and the Middle East. Ivonescimab is known as AK112 within Akeso and SMT112 in the territories licensed to Summit. Currently, a Phase III study of ivonescimab monotherapy versus pembrolizumab monotherapy as first-line treatment for PD-L1+ NSCLC has met its primary endpoint of progression-free survival (PFS) in an interim analysis, achieving a decisive positive outcome. Based on this study, a supplemental New Drug Application (sNDA) for ivonescimab monotherapy as first-line treatment for PD-L1+ NSCLC has been submitted and granted priority review. Additionally, a Phase III clinical study of ivonescimab combined with chemotherapy versus tislelizumab combined with chemotherapy as first-line treatment for squamous NSCLC is ongoing. The HARMONi study, an international multicenter Phase III clinical study led by Akeso's partner Summit, is investigating ivonescimab combined with chemotherapy for EGFR-mutated, locally advanced or metastatic nsq-NSCLC that has progressed after third-generation EGFR-TKI therapy. Another international multicenter Phase III study is comparing ivonescimab combined with chemotherapy to pembrolizumab combined with chemotherapy as first-line treatment for squamous NSCLC. Furthermore, 3 new Phase III clinical studies are either initiated or about to start, including ivonescimab combined with AK117 (CD47) as first-line treatment for PD-L1 positive squamous cell carcinoma of the head and neck (vs. pembrolizumab), ivonescimab combined regimen as first-line treatment for cholangiocarcinoma (vs. durvalumab combined regimen), and ivonescimab combined regimen as first-line treatment for pancreatic cancer. Overall, ivonescimab is engaged in over 25 clinical trials across 17 indications, including lung cancer, pancreatic cancer, breast cancer, hepatocellular carcinoma, and colorectal cancer, through both monotherapy and combination therapy approaches. About Akeso Akeso (HKEX: 9926.HK) is a leading biopharmaceutical company committed to the research, development, manufacturing and commercialization of the world's first or best-in-class innovative biological medicines. Founded in 2012, the company has created a unique integrated R&D innovation system with the comprehensive end-to-end drug development platform (ACE Platform) and bi-specific antibody drug development technology (Tetrabody) as the core, a GMP-compliant manufacturing system and a commercialization system with an advanced operation mode, and has gradually developed into a globally competitive biopharmaceutical company focused on innovative solutions. With fully integrated multi-functional platform, Akeso is internally working on a robust pipeline of over 50 innovative assets in the fields of cancer, autoimmune disease, inflammation, metabolic disease and other major diseases. Among them , 22 candidates have entered clinical trials (including 11 bispecific/multispecific antibodies and bispecific antibody-drug conjugates). Additionally, 4 new drugs are commercially available, and 5 new drugs across 7 indications are currently under regulatory review for approval. Through efficient and breakthrough R&D innovation, Akeso always integrates superior global resources, develops the first-in-class and best-in-class new drugs, provides affordable therapeutic antibodies for patients worldwide, and continuously creates more commercial and social values to become a global leading biopharmaceutical enterprise. SOURCE Akeso, Inc.

MIAMI--( BUSINESS WIRE )--Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit," "we," or the "Company") today announced data from the primary analysis of the Phase III HARMONi-2 trial featuring the novel, potential first-in-class investigational bispecific antibody, ivonescimab. The data was presented this morning as part of the Presidential Symposium at the International Association for the Study of Lung Cancer’s (IASLC) 2024 World Conference on Lung Cancer (WCLC 2024) in San Diego, California. The HARMONi-2 presentation, Phase 3 Study of Ivonescimab (AK112) vs. Pembrolizumab as First-line Treatment for PD-L1-positive Advanced NSCLC: Primary Analysis of HARMONi-2 , evaluated monotherapy ivonescimab against monotherapy pembrolizumab in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose tumors have positive PD-L1 expression (PD-L1 TPS > 1%). HARMONi-2 is a single region, multi-center, double-blinded Phase III study conducted in China sponsored by our collaboration partner, Akeso, Inc. (Akeso, HKEX Code: 9926.HK), with data generated and analyzed by Akeso. The trial results were presented by Professor Caicun Zhou, MD, PhD, Chief Physician and Director of the Department of Medical Oncology at Shanghai Pulmonary Hospital, Tongji University School of Medicine, and President-Elect of IASLC. Clinically Meaningful Efficacy In the HARMONi-2 primary analysis, ivonescimab monotherapy demonstrated a statistically significant improvement in the trial’s primary endpoint, progression-free survival (PFS) by Independent Radiologic Review Committee (IRRC), when compared to monotherapy pembrolizumab, achieving a hazard ratio (HR) of 0.51 (95% CI: 0.38, 0.69; p<0.0001). A clinically meaningful benefit was demonstrated across clinical subgroups, including those with PD-L1 low expression (PD-L1 TPS 1-49%), PD-L1 high expression (PD-L1 TPS ≥ 50%), squamous and non-squamous histologies, as well as other high-risk patients. Both the overall response rate (ORR) measured according to RECIST v1.1 criteria as well as the disease control rate (DCR) were higher in patients treated with ivonescimab compared to those treated with pembrolizumab. HARMONi-2 ITT (n=398); Median Follow-up: 8.67 mos Ivonescimab (n=198) Pembrolizumab (n=200) Median PFS 11.14 mos (95% CI: 7.33, NE) 5.82 mos (95% CI: 5.03, 8.21) PFS Stratified HR 0.51 (95% CI: 0.38, 0.69; p<0.0001) ORR 50.0% (95% CI: 42.8%, 57.2%) 38.5% (95% CI: 31.7%, 45.6%) DCR 89.9% (95% CI: 84.8%, 93.7%) 70.5% (95% CI: 63.7%, 76.7%) HARMONi-2 Subgroup Analyses Ivonescimab vs. Pembrolizumab PD-L1 High (PD-L1 TPS ≥50%) PFS stratified HR Ivonescimab n=83; Pembrolizumab n=85 0.46 (95% CI: 0.28, 0.75) PD-L1 Low (PD-L1 TPS 1-49%) PFS stratified HR Ivonescimab n=115; Pembrolizumab n=115 0.54 (95% CI: 0.37, 0.79) Squamous histology PFS stratified HR Ivonescimab n=90; Pembrolizumab n=91 0.48 (95% CI: 0.31, 0.74) Non-Squamous histology PFS stratified HR Ivonescimab n=108; Pembrolizumab n=109 0.54 (95% CI: 0.36, 0.82) Overall survival data was not yet mature at the time of the data cutoff and will be evaluated in the future. Manageable Safety Profile Ivonescimab demonstrated an acceptable and manageable safety profile, which was consistent with previous studies. There were three patients (1.5%) who discontinued ivonescimab due to TRAEs compared to six patients (3.0%) who discontinued pembrolizumab due to TRAEs. There was one patient in the ivonescimab arm and two patients in the pembrolizumab arm who died as a result of TRAEs in this Phase III study. The most frequent treatment-related adverse events (TRAEs) for ivonescimab treatment were proteinuria (Grade 3+: ivonescimab, 3.0%; pembrolizumab 0.0%), hypertension (Grade 3+: ivonescimab, 5.1%; pembrolizumab 0.5%), and various laboratory abnormalities, including AST increases, hypercholesterolemia, anemia, and bilirubin increases. Grade 3 or higher immune-related adverse events occurred in 7.1% of patients receiving ivonescimab and 8.0% of patients receiving pembrolizumab. Grade 3 or higher adverse events that were possibly VEGF-related in the ivonescimab monotherapy arm were 10.2% vs. 1.0% for pembrolizumab, all of which were classified as Grade 3. Of note, Grade 3 hemorrhage events were observed in two patients in the ivonescimab arm (both were of non-squamous histology) compared to one patient in the pembrolizumab arm in this study. HARMONi-2 (n=396) Ivonescimab (n=197) Pembrolizumab (n=199) TRAEs Grade 3+ 29.4% 15.6% Serious TRAEs (TRSAEs) 20.8% 16.1% TRAEs Leading to Drug Discontinuation 1.5% 3.0% TRAEs Leading to Death 0.5% 1.0% Grade 3+ Immune-related 7.1% 8.0% Grade 3+ Possibly VEGF-related* 10.2% 1.0% *All Grade 3+ adverse events that were possibly VEGF-related were classified as Grade 3 events in both arms; there were no Grade 4 or 5 adverse events that were possibly VEGF-related observed in either arm. “This is a historic moment for ivonescimab, Team Summit, our partners at Akeso, and most importantly, we believe this is the beginning of a landscape shift for treatment options for patients living with cancer,” stated Robert W. Duggan, Chairman and Chief Executive Officer of Summit. “We are incredibly proud of our partnership with Akeso and their accomplishment with HARMONi-2.” Based on the results of HARMONi-2, Summit announced its intention to initiate HARMONi-7 in early 2025. HARMONi-7 is currently planned as a multi-regional Phase III clinical trial that will compare ivonescimab monotherapy to pembrolizumab monotherapy in patients with metastatic NSCLC whose tumors have high PD-L1 expression (PD-L1 TPS > 50%). “HARMONi-2 clearly demonstrates that ivonescimab has the potential to be the next generation in PD-1 directed immunotherapy, and potentially make a significant difference in the lives of patients with lung cancer and prospectively other tumors,” added Dr. Maky Zanganeh, Chief Executive Officer and President of Summit. “We want to again congratulate Akeso for this incredible result and their work to advance the patient-friendly standards of care today and well into the future. We look forward to initiating HARMONi-7 and sharing additional details about our expanded clinical development plan in early 2025.” Phase II Perioperative NSCLC In addition to the HARMONi-2 data presentation, a second oral presentation featuring ivonescimab was presented by Xiaoliang Zhao, MD, Deputy Chief Physician, Department of Lung Cancer at Tianjin Medical University Cancer Institute & Hospital, and Visiting Scholar at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, D.C. The presentation was entitled, A Phase II Study of Perioperative Ivonescimab Alone or Combined with Chemotherapy in Resectable Non-Small Cell Lung Cancer , presenting the results from AK112-205, a single-region (China), multi-center, open-label Phase II study of patients with Stage II or III resectable NSCLC. The study is designed to assess patients receiving either ivonescimab monotherapy or ivonescimab plus chemotherapy prior to surgical resection and then ivonescimab monotherapy after surgery. Due to the maturity of the data and the timing of the data cutoff, the results were limited to the neo-adjuvant, or pre-surgery, portion of the clinical trial. At the time of data cutoff, 49 patients had been enrolled into the ivonescimab plus chemotherapy arm in the neo-adjuvant setting; of these 49 patients, 39 went on to complete surgery. Of the 39 patients who received ivonescimab plus chemotherapy in the neo-adjuvant stage and completed surgery, 71.8% of patients experienced a major pathological response (MPR) and 43.6% of patients experienced a pathological complete response (pCR). In the 49 patients enrolled in this cohort, median event-free survival (EFS) was not yet reached after 8.9 months of median follow-up time; the 12-month EFS rate was 80.3% (95% CI: 59.6, 91.1). These results are encouraging compared to the historical data that has been observed in global pivotal studies in a similar setting. The safety profile was manageable: of the 49 patients who received ivonescimab plus chemotherapy in the neo-adjuvant setting, Grade 3 or higher adverse events were observed in 32.7% of patients; there was one patient who experienced a treatment-related serious adverse event. There were no TRAEs leading to delayed or cancelled surgery or that led to the death of a patient. Additional Phase II Data to be Presented at ESMO 2024 Beyond the data recently featured at WCLC 2024, Phase II data featuring ivonescimab will be presented at the European Society of Medical Oncology (ESMO) Congress 2024. ESMO 2024 will take place in Barcelona, Spain, from September 13 – 17, 2024. These presentations, which will feature data from studies sponsored by Akeso including first-line treatment for triple-negative advanced breast cancer (TNBC), first-line treatment for advanced head and neck squamous cell carcinoma (HNSCC), and first-line treatment of advanced colorectal cancer (CRC). About the ESMO 2024 Presentations Presentation Title: The efficacy and safety of ivonescimab with or without ligufalimab in combination with FOLFOXIRI (chemotherapy) as first-line treatment for metastatic colorectal cancer (mCRC) ESMO Presentation No.: 514MO Session Date & Time: Saturday, September 14, 3:50 to 3:55pm CET Presentation Title : The safety and efficacy of ivonescimab in combination with chemotherapy as first-line treatment for triple-negative breast cancer (TNBC) ESMO Presentation No.: 347MO Session Date & Time: Monday, September 16, 8:30 to 8:35pm CET Poster Title: Evaluation of the safety and efficacy of ivonescimab in combination with ligufalimab as first-line treatment for PD-L1 positive recurrent/metastasis head and neck squamous cell carcinoma (R/M HNSCC) ESMO Poster No.: 876P Poster Display Date & Time: Saturday, September 14, 12:00 to 1:00pm CET Conference Call Summit Therapeutics Inc. will host a conference call to discuss recent updates related to ivonescimab, including data released at WCLC, on Monday September 9, 2024, before the market opens. Summit will host a live webcast of the conference call at 8:30am ET, which will be accessible through our website www.smmttx.com , and can also be accessed via the following link: https://events.q4inc.com/attendee/904766612 . The dial-in information for US attendees is toll-free at (800) 715-9871. Additionally, all attendees may access through the toll number, (646) 307-1963. The Conference ID is 9820029. 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, 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, 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 when in the presence of both PD-1 and 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 with over 18-fold increased binding affinity to PD-1 in the presence of VEGF in vitro , and over 4-times increased binding affinity to VEGF in the presence of PD-1 in vitro (Zhong, et al , SITC, 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 (Zhong, et al , SITC, 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 1,800 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 multi-regional Phase III clinical trials, HARMONi and HARMONi-3, with a plan to initiate HARMONi-7 in early 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 have progressed after treatment with a 3 rd generation EGFR TKI (e.g., osimertinib). HARMONi-3 is a Phase III clinical trial which is designed to evaluate ivonescimab combined with chemotherapy compared to pembrolizumab combined with chemotherapy in patients with first-line metastatic squamous NSCLC. HARMONi-7 is a planned 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 (PD-L1 TPS > 50%). In addition, Akeso has recently had positive read-outs in two single-region (China), randomized Phase III clinical trials for ivonescimab in NSCLC, HARMONi-A and HARMONi-2. 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 (PD-L1 TPS > 1%). 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 approved for marketing authorization in China in May 2024. About Summit Therapeutics 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 our shares are listed on the Nasdaq Global Market (symbol "SMMT"). We are headquartered in Miami, Florida, and we have additional offices in Menlo Park, California, and Oxford, UK. For more information, please visit https://www.smmttx.com and follow us on X @SMMT_TX . Summit Forward-looking Statements Any statements in this press release about the Company’s future expectations, plans and prospects, including but not limited to, statements about the clinical and preclinical development of the Company’s product candidates, entry into and actions related to the Company’s partnership with Akeso Inc., including the expected benefits of the amendment to the collaboration and license agreement, the intended use of the net proceeds from the private placement, the Company's anticipated spending and cash runway, the therapeutic potential of the Company’s product candidates, the potential commercialization of the Company’s product candidates, the timing of initiation, completion and availability of data from clinical trials, the potential submission of applications for marketing approvals, potential acquisitions, statements about the previously disclosed At-The-Market equity offering program (“ATM Program”), the expected proceeds and uses thereof, and other statements containing the words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "would," and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including the Company’s ability to sell shares of our common stock under the ATM Program, the conditions affecting the capital markets, general economic, industry, or political conditions, including the results of our evaluation of the underlying data in connection with the development and commercialization activities for ivonescimab, the outcome of discussions with regulatory authorities, including the Food and Drug Administration, the uncertainties inherent in the initiation of future clinical trials, availability and timing of data from ongoing and future clinical trials, the results of such trials, and their success, and global public health crises, that may affect timing and status of our clinical trials and operations, whether preliminary results from a clinical trial will be predictive of the final results of that trial or whether results of early clinical trials or preclinical studies will be indicative of the results of later clinical trials, whether business development opportunities to expand the Company’s pipeline of drug candidates, including without limitation, through potential acquisitions of, and/or collaborations with, other entities occur, expectations for regulatory approvals, laws and regulations affecting government contracts and funding awards, availability of funding sufficient for the Company’s foreseeable and unforeseeable operating expenses and capital expenditure requirements and other factors discussed in the "Risk Factors" section of filings that the Company makes with the Securities and Exchange Commission. Any change to our ongoing trials could cause delays, affect our future expenses, and add uncertainty to our commercialization efforts, as well as to affect the likelihood of the successful completion of clinical development of ivonescimab. Accordingly, readers should not place undue reliance on forward-looking statements or information. In addition, any forward-looking statements included in this press release represent the Company’s views only as of the date of this release and should not be relied upon as representing the Company’s views as of any subsequent date. The Company specifically disclaims any obligation to update any forward-looking statements included in this press release. Appendix: Glossary of Critical Terms Contained Herein Affinity – Affinity is the strength of binding of a molecule, such as a protein or antibody, to another molecule, such as a ligand. Avidity – Avidity is the accumulated strength of multiple binding interactions. Angiogenesis – Angiogenesis is the development, formation, and maintenance of blood vessel structures. Without sufficient blood flow, tissue may experience hypoxia (insufficient oxygen) or lack of nutrition, which may cause cell death. 1 Cooperative binding – Cooperative binding occurs when the number of binding sites on the molecule that can be occupied by a specific ligand (e.g., protein) is impacted by the ligand’s concentration. For example, this can be due to an affinity for the ligand that depends on the amount of ligand bound or the binding strength of the molecule to one ligand based on the concentration of another ligand, increasing the chance of another ligand binding to the compound. 2 Immunotherapy – Immunotherapy is a type of treatment, including cancer treatments, that help a person’s immune system fight cancer. Examples include anti-PD-1 therapies. 3 Intracranial - Within the cranium or skull. Monotherapy – a medical treatment that consists of a single drug or therapy. PD-1 – Programmed cell Death protein 1 is a protein on the surface of T cells and other cells. PD-1 plays a key role in reducing the regulation of ineffective or harmful immune responses and maintaining immune tolerance. However, with respect to cancer tumor cells, PD-1 can act as a stopping mechanism (a brake or checkpoint) by binding to PD-L1 ligands that exist on tumor cells and preventing the T cells from targeting cancerous tumor cells. 4 PD-L1 – Programmed cell Death Ligand 1 is expressed by cancerous tumor cells as an adaptive immune mechanism to escape anti-tumor responses, thus believed to suppress the immune system’s response to the presence of cancer cells. 5 PD-L1 TPS – PD-L1 Tumor Proportion Score represents the percentage of tumor cells that express PD-L1 proteins. Perioperative – around the time of surgery, typically considered to mean both before and after a surgery. PFS – Progression-Free Survival. RANO – R esponse A ssessment in N euro- O ncology, the standard for assessing the response of a brain or spinal cord tumor to therapy. RECIST v1.1 – A generally-accepted way to measuring and evaluating the response of a tumor in clinical trials. The criteria is designated by an international group of experienced physicians in drug development from academic research backgrounds, government backgrounds and industry backgrounds, as well as imaging specialists and statisticians, referred to as the RECIST Working Group. 6 SQ-NSCLC – Non-small cell lung cancer tumors of squamous histology. T Cells – T cells are a type of white blood cell that is a component of the immune system that, in general, fights against infection and harmful cells like tumor cells. 7 Tetravalent – A tetravalent molecule has four binding sites or regions. Tumor Microenvironment – The tumor microenvironment is the ecosystem that surrounds a tumor inside the body. It includes immune cells, the extracellular matrix, blood vessels and other cells, like fibroblasts. A tumor and its microenvironment constantly interact and influence each other, either positively or negatively. 8 VEGF – Vascular Endothelial Growth Factor is a signaling protein that promotes angiogenesis. 9 Summit Therapeutics and the Summit Therapeutics logo are trademarks of Summit Therapeutics Inc. Copyright 2024, Summit Therapeutics Inc. All Rights Reserved. ____________________ 1 Shibuya M. Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer. 2011 Dec;2(12):1097-105 2 Stefan MI, Le Novère N. Cooperative binding. PLoS Comput Biol. 2013;9(6) 3 US National Cancer Institute, a part of the National Institute of Health (NIH). https://www.cancer.gov/about-cancer/treatment/types/immunotherapy . Accessed April 2024. 4 Han Y, et al. PD-1/PD-L1 Pathway: Current Researches in Cancer. Am J Cancer Res. 2020 Mar 1;10(3):727-742. 5 Han Y, et al. PD-1/PD-L1 Pathway: Current Researches in Cancer. Am J Cancer Res. 2020 Mar 1;10(3):727-742. 6 Eisenhauer, et. al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1), Eur J Cancer. 2009 Jan;45(2):228-47. 7 Cleveland Clinic. https://my.clevelandclinic.org/health/body/24630-t-cells . Accessed April 2024. 8 MD Anderson Cancer Center. https://www.mdanderson.org/cancerwise/what-is-the-tumor-microenvironment-3-things-to-know.h00-159460056.html . Accessed April 2024. 9 Shibuya M. Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes Cancer. 2011 Dec;2(12):1097-105.

Akeso and Summit Therapeutics' ivonescimab, a PD-1/VEGF bispecific drug, handily beat Merck's Keytruda at delaying tumor progression or death in first-line lung cancer. The Keytruda-beating data from Akeso and Summit’s ivonescimab that oncology industry watchers had been awaiting are here. The China-only data are impressive, signaling the PD-1/VEGF bispecific antibody’s potential as a new standard of care in non-small cell lung cancer (NSCLC).Ivonescimab slashed the risk of disease progression or death by a whopping 49% compared with Merck’s Keytruda in the phase 3 HARMONi-2 study that Akeso is conducting in Chinese patients with previously untreated, PD-L1-positive NSCLC. The number, presented at the 2024 World Conference on Lung Cancer, was highly statistically significant.Compared with Keytruda, ivonescimab extended the median time that patients lived without tumor progression by 5.32 months, reaching 11.14 months.The magnitude of ivonescimab’s progression-free survival (PFS) improvement over Keytruda was consistent across key subgroups in HARMONi-2, including those whose tumors were squamous (50%), nonsquamous (45%), PD-L1-high as defined by a TPS score of at least 50% (52%), PD-L1-low (46%), plus patients with brain metastases (45%), nonsmokers (61%), as well as current (49%) and former (43%) smokers.“These results highlight ivonescimab’s potential as a new standard of care” in first-line PD-L1-positive NSCLC, Caicun Zhou, Ph.D., from Shanghai Pulmonary Hospital, who presented the HARMONi-2 data at the WCLC conference, said in a statement. Zhou is the president-elect of the International Association for the Study of Lung Cancer, the organizer of WCLC. The idea of dual targeting PD-1/L1 and tumor vasculature is not new. Roche’s PD-L1 inhibitor Tecentriq boasts an approval alongside the company’s VEGF inhibitor Avastin and chemotherapy for the first-line treatment of nonsquamous NSCLC. But Avastin is contraindicated in squamous patients because of an increased risk of bleeding in the lungs known as hemoptysis. Ivonescimab, a bispecific, didn’t seem to have the same problem in the study. Hemorrhages were recorded in 14.7% of patients in HARMONi-2’s ivonescimab arm, including in 1% at grade 3 with no more serious cases. The rates were 11.1% and 0.5% for the Keytruda arm. The grade 3 hemorrhage cases reported for ivonescimab were actually in nonsquamous patients.Akeso’s newly minted CFO, Bing Wang, Ph.D., credited ivonescimab’s ability to leverage an anti-VEGF mechanism without Avastin’s bleeding problem to two factors. First, the PD-1 component of the bispecific helps anchor the whole antibody to the surface of the tumor, whereas a separate VEGF drug would float around in the blood. Second, Akeso’s proprietary Tetrabody technology, which produces antibodies with four antigen-binding sites, can create a very stable structure that enables a “collaborative binding” to further improve the binding specificity of both the PD-1 and VEGF, Wang explained in an interview with Fierce Pharma.In general, the ivonescimab group in HARMONi-2 experienced higher rates of possible VEGF-related adverse events, most notably proteinuria at 31.5% and hypertension at 15.7%, versus 10.5% and 2.5% for Keytruda, respectively. But no VEGF-related events were above grade 3, and no treatment discontinuations happened because of them. In squamous patients, the rate of all serious treatment-related adverse events was 18.9% for ivonescimab, versus 18.7% for Keytruda.But before ivonescimab can be crowned the new cancer immunotherapy king, there are few important considerations to note with the current trial. “If these benefits are confirmed, it is possible that the therapeutic harmony we’ve had in this first-line space may finally come to an end, and I think that’s a disharmony that we all should be rooting for,” John Heymach, M.D., Ph.D., chair of thoracic/head and neck medical oncology at MD Anderson Cancer Center, said during a discussant presentation of the HARMONi-2 results at WCLC. The new standard of care?First of all, HARMONi-2 was conducted solely in China, and therefore it likely won’t be able to support a filing with the FDA, which requires global studies. But Wang said Akeso didn’t spot any factors in HARMONi-2 that could have given ivonescimab’s Chinese results an edge that may be hard to replicate in a global phase 3 study.Keytruda’s PFS performance in HARMONi-2, at a median of 5.82 months, was roughly in line with past experience with that drug. In the China extension component of the phase 3 KEYNOTE-042 trial in first-line, PD-L1-positive NSCLC, Keytruda monotherapy demonstrated a median PFS of 6.3 months, which matched the global trial population’s 6.4 months. Compared with HARMONi-2, that Merck study and its Chinese portion enrolled a slightly higher percentage of PD-L1-high patients, who generally respond better to PD-1 inhibitors.  Wang acknowledged that Asian NSCLC patients tend to have better prognoses than non-Asians. So, the median PFS number may not be the best way to interpret ivonescimab’s efficacy. However, PD-1/L1 inhibitors’ treatment effects—at least against chemo—tend to be similar for Asian and non-Asian patients, he noted, pointing to an FDA analysis published in 2019. That’s why the 49% reduction in the risk of progression or death versus Keytruda gives Akeso confidence: it’s a relative comparison between ivonescimab and Keytruda in the same patient population. On the safety side, Leerink Partners analysts in a Sunday note flagged that Asia has a higher adoption of anti-VEGF drugs than Western countries, especially in lung cancer. The team therefore wondered whether doctors’ familiarity with the mechanism positively impacted treatment discontinuation.Based on HARMONi-2’s findings, Akeso’s partner Summit plans to start a global phase 3 trial pitting ivonescimab against Keytruda in first-line PD-L1-high NSCLC, Summit’s CEO Maky Zanganeh told Fierce Pharma in a separate interview.“The key was willingness to go head to head with [Keytruda] and and to be superior, too; that takes courage, but what’s the alternative?” Bob Duggan, Summit’s executive chairman, said during an interview. “We’ll kind of sneak up on them over a four- or five-year period of time.”Still, with better efficacy, Keytruda’s various combinations with chemotherapy have become the true standard of care in patients who can tolerate them, especially among those with PD-L1-low or -negative disease, as opposed to Keytruda monotherapy.Summit has an ongoing phase 3 trial, HARMONi-3, that is combining ivonescimab with chemotherapy in first-line squamous NSCLC, with Keytruda and chemo serving as the comparator. The reason why Summit started in squamous “had nothing to do with lack of confidence in nonsquamous as much as exceedingly high confidence in the squamous population,” Dave Gancarz, Summit’s chief business & strategy officer, said during an interview, pointing to how Roche wasn’t able to reach squamous patients with Avastin.Ivonescimab’s current data bode well for a potential showdown with Keytruda and chemo, even though ivonescimab doesn’t have to face Keytruda-chemo as a monotherapy. In fact, ivonescimab single agent’s 11.14-month median progression-free survival (PFS) length in an inclusive patient group is in the same ballpark of the 11.1 months that Keytruda and chemotherapy showed in PD-L1-high nonsquamous NSCLC patients in the landmark KEYNOTE-189 trial in an updated analysis. That’s a high bar because Keytruda and chemo have historically shown notably shorter median PFS time in PD-L1-low or in squamous patients.However, such cross-trial comparisons should be viewed with a grain of salt because of different patient characteristics. For example, in a small subgroup of Japanese patients enrolled in the global KEYNOTE-189 trial, the Keytruda-chemo regimen’s median PFS reached 16.5 months. Overall survival dataBesides being a single-country study, HARMONi-2 has yet to report data on whether ivonescimab can extend patients’ lives. That datapoint remained immature, as the current PFS analysis came after a median follow-up of just 8.67 months. In KEYNOTE-042, Keytruda showed a median overall survival of 16.7 months, or 20.2 months in the China extension portion.Both Akeso and Summit were tight-lipped about how the overall survival (OS) number looks right now or its maturity level before a final analysis. But Wang did note that a PFS improvement above 40% will give some physicians confidence in ivonescimab’s strength. As Keytruda secured its various NSCLC indications based on OS improvements, ivonescimab likely needs OS results to win over the FDA and doctors.An analysis of past studies done in July by Citi analyst Yigal Nochomovitz, Ph.D., found that a PFS improvement above 30% for an immuno-oncology trial in NSCLC is “very likely” to translate into a statistically significant OS benefit. A separate calculation by Citi analyst Wangbin Zhou, who highlighted the challenge of mounting an OS showing when subsequent therapies may blur the front-line treatment effect, argued that a PFS advantage of around 40% would likely bring ivonescimab a “clinically meaningful” OS benefit that’s stronger than 20%.In a Monday note to clients, Nochomovitz said ivonescimab exceeded “just about all clinical expectations” against Keytruda. He highlighted that HARMONi-2 doesn’t allow crossover, “which should protect an expected OS benefit given the highly clinically meaningful PFS.”“[W]ith necessary validating data (OS in HARMONi-2, then HARMONi-3, HARMONi-7 readouts) ivonescimab is poised to potentially deliver a practice-changing novel therapy for lung cancer,” Nochomovitz wrote. Merck has previously tried to improve upon Keytruda with Eisai-partnered VEGFR inhibitor Lenvima in first-line PD-L1-positive NSCLC. In the phase 3 LEAP-007, the doublet led to a statistically significant 22% improvement in PFS but was linked to a 10% potential detriment to OS compared with Keytruda alone.Nasty side effects played a role in the negative OS finding for the Keytruda-Lenvima pairing, Akeso CEO Michelle Xia, Ph.D., pointed out during an interview. A drug may be efficacious at shrinking tumors, but toxicity—and hence how long patients can stay on that drug—is very important in helping translate the antitumor effect into good OS, she said.In HARMONi-2, treatment-related adverse events led to 1.5% rate of discontinuation and a 0.5% rate of death in the ivonescimab arm, versus 3% and 1%, respectively, for Keytruda. In LEAP-007, the treatment-related discontinuation rate was 29.1% for Keytruda-Lenvima and 11.2% for Keytruda. Accelerating a 'cornerstone drug'Akeso’s goal is to turn ivonescimab into a “next-generation I-O cornerstone drug,” Xia said. The Chinese biotech has performed several combination studies of ivonescimab with other in-house molecules, including its PD-1/CTLA-4 bispecific cadonilimab and its CD47 antibody ligufaliumab, and has seen acceptable safety profiles, Xia said. Thanks to positive data from the HARMONi-A trial in China, ivonescimab in May got its initial approval in its home country as part of a combination with chemotherapy for previously treated EGFR-mutant NSCLC.Meanwhile, Summit is conducting the international phase 3 HARMONi trial evaluating ivonescimab plus chemo in NSCLC patients who progressed after treatment with a third-generation EGFR inhibitor such as AstraZeneca’s Tagrisso. The trial will include those patients in HARMONi-A who fit the description.  Summit obtained rights to ivonescimab in the U.S., Canada, Europe and Japan in late 2022. At that time, the hefty $500 million upfront payment and the potential deal value of up to $5 billion was a shock to many.Now, as ivonescimab is the first to beat Keytruda in a head-to-head phase 3 trial, it could come into question whether Summit, which counts ivonescimab its lone asset, is the best company to manage the drug against a standard-of-care that generated $25 billion sales last year. Looking at Merck, the Keytruda maker in-licensed a TROP2-directed antibody-drug conjugate from China’s Kelun Biotech in late 2022 and has already launched 10 global phase 3 trials—including five in NSCLC—for the drug, which has not been approved anywhere.Xia and Wang said Akeso partnered with Summit because of its leadership team’s experience. Duggan was the CEO of Pharmacyclics until the Imbruvica developer was bought out by AbbVie in 2015. Zanganeh was then Pharmacyclics’ chief operating officer.In a “100-meter-race, we’re at the 10-meter mark now,” Duggan said in an interview. “We will accelerate, not decelerate. We have access to the funds [and] access to people that are as good as or better than any Big Pharma, and we’re all-in on this.”As to whether Summit would seek out help from a larger company, Duggan said, “we’re going to optimize patient benefit, and we don’t need money. We don’t need partners per se. We need to focus on our business.”Editor's Note: The story has been updated with a comment from John Heymach, M.D., Ph.D., during a WCLC presentation, plus additional input from investor notes by Leerink Partners and Citi analysts Sunday and Monday.