Ivonescimab in Combination with Chemotherapy Approved in China by NMPA for 2L+ EGFRm NSCLC based on HARMONi-A Clinical Trial: Positive Trend Observed in Overall Survival towards Ivonescimab Plus Chemotherapy
Summit Therapeutics (NASDAQ: SMMT) has announced that its partner, Akeso, has received marketing authorization from China's National Medical Products Administration (NMPA) for ivonescimab in combination with chemotherapy for treating patients with EGFR-mutated non-squamous non-small cell lung cancer (NSCLC). This approval is based on the Phase III HARMONi-A clinical trial, which showed a significant improvement in progression-free survival (PFS) and a positive trend in overall survival (OS). Ivonescimab plus chemotherapy achieved a 54% reduction in disease progression risk compared to chemotherapy alone, with a median PFS of 7.1 months versus 4.8 months for the placebo group. The trial also reported a disease control rate of 93.1% for the combination therapy. Safety profile was manageable, with 5.6% of patients discontinuing ivonescimab due to adverse events. The positive results were presented at the 2024 ASCO Annual Meeting. Summit will host a conference call on June 3, 2024, to discuss these updates.
- Marketing authorization in China for ivonescimab plus chemotherapy.
- 54% reduction in the risk of disease progression with ivonescimab plus chemotherapy.
- Median progression-free survival of 7.1 months versus 4.8 months for the placebo.
- Overall response rate of 50.6% for ivonescimab plus chemotherapy.
- Disease control rate of 93.1% for ivonescimab plus chemotherapy.
- Positive trend in overall survival for ivonescimab plus chemotherapy.
- Manageable safety profile with 5.6% treatment discontinuation due to adverse events.
- 5.6% of patients discontinued ivonescimab due to treatment-related adverse events.
- Higher incidence of Grade 3 or higher immune-related adverse events (6.2%) in the ivonescimab group.
- Grade 3 or higher white blood cell count decrease in 19.9% of ivonescimab patients.
Insights
The approval of ivonescimab in combination with chemotherapy for second-line or later treatment of EGFR-mutated non-small cell lung cancer (NSCLC) marks a significant milestone. Ivonescimab, a bispecific antibody targeting both PD-1 and VEGF, showcased a 54% reduction in the risk of disease progression compared to chemotherapy alone, indicating a substantial improvement in progression-free survival (PFS). This is particularly noteworthy given that PD-1 monoclonal antibodies have previously failed in similar clinical settings. The manageable safety profile, with discontinuations due to adverse events being relatively low (5.6% for ivonescimab vs. 2.5% for placebo), further supports its potential as a valuable treatment option. While the overall survival (OS) data is still immature, the trends show promise and this could eventually lead to broader adoption if the positive trajectory continues.
Given these findings, ivonescimab could fill a important gap in the current treatment landscape for EGFR-mutated NSCLC patients who have progressed after TKI therapy. The success of this trial may also encourage further research and investment into bispecific antibodies as a therapeutic strategy.
Summit Therapeutics, along with its partner Akeso Inc., stands to benefit significantly from this recent approval in China. The market authorization for ivonescimab could drive substantial revenue growth given the high prevalence and treatment demand for EGFR-mutated NSCLC. The positive data from the HARMONi-A trial, particularly the strong efficacy signals and manageable safety profile, positions ivonescimab as a competitive player in the oncology market. Investors should note the potential for increased market share in China and, potentially, future approvals in other regions.
It is also pertinent to consider the broader implications for Summit's stock. Positive trial results and subsequent regulatory approvals generally serve as catalysts for stock price appreciation. However, investors should remain cautious due to the ongoing need for additional supportive data, particularly regarding overall survival. The company’s strategy to continue enrolling patients in the HARMONi trial across multiple regions, including North America and Europe, underscores its commitment to establishing ivonescimab as a global standard for this patient population.
The clinical benefit observed in the HARMONi-A trial for ivonescimab plus chemotherapy is quite promising. As an oncologist, the most compelling aspect is the clinically meaningful improvement in PFS and the trend towards better overall survival. These results indicate ivonescimab’s potential to become a pivotal treatment option for a challenging patient population. The efficacy observed across all clinical subgroups further suggests its broad applicability. Additionally, the safety profile is manageable, with adverse events being mostly hematological, which are relatively well-understood and manageable in clinical practice.
This approval not only offers a new therapeutic option but also validates the concept of bispecific antibodies in lung cancer treatment. For clinicians, this offers an exciting new tool to combat resistance in EGFR-mutated NSCLC patients who have limited options after TKI therapy. The continued development and future data will be critical in determining its long-term role in clinical practice.
Separate & Distinct from HARMONi-2 Announcement, HARMONi-A Showed Clinically Meaningful and Statistically Significant Benefit: PFS Hazard Ratio of 0.46
For Subset of Patients Previously Receiving 3rd Generation EGFR-TKI: PFS Hazard Ratio of 0.48
HARMONi-A was Featured in Oral Presentation at ASCO 2024 on May 31, 2024
Conference Call to be Held at 8:00am ET on Monday, June 3, 2024
HARMONi-A evaluated ivonescimab combined with 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 an EGFR tyrosine kinase inhibitor (TKI) against placebo plus platinum-doublet chemotherapy. This is a clinical setting with a patient population where PD-1 monoclonal antibodies have previously been unsuccessful in Phase III global clinical trials. The Phase III HARMONi-A study provides further evidence supporting the differentiated mechanism of action of ivonescimab, a PD-1 / VEGF bispecific antibody evidencing cooperative binding characteristics.
This data and trial are separate and distinct from the Phase III HARMONi-2 trial in locally advanced or metastatic NSCLC whose tumors have positive PD-L1 expression (PD-L1 TPS >
Clinically Meaningful Efficacy
Progression free survival (PFS), the primary endpoint of the study, was significantly improved in the ivonescimab plus chemotherapy arm (HR 0.46;
While not yet mature, overall survival (OS) analyses performed on request of the NMPA trended positively for ivonescimab plus chemotherapy vs. chemotherapy alone: after 10.2 months of median follow-up, the hazard ratio (HR) was 0.72 (
Overall response rate (ORR) was
HARMONi-A (n=322) |
Ivonescimab + Chemo (n=161) |
Placebo + Chemo (n=161) |
Median PFS |
7.1 months
( |
4.8 months
( |
PFS HR |
0.46
( |
|
ORR |
( |
( |
DCR |
( |
( |
Median OS (at 10.2 months mFU) |
Not reached
( |
14.3 months
( |
OS HR (10.2 months mFU) |
0.72
( |
|
Median OS (at 17.6 months mFU) |
17.1 months
( |
14.5 months
( |
OS HR (17.6 months mFU) |
0.80
( |
|
mFU = median follow-up; NE = not estimable; mFU is 7.89 months unless otherwise noted above
Manageable Safety Profile
Ivonescimab demonstrated an acceptable and manageable safety profile. The most common treatment related adverse events (TRAEs), both all grades and Grade 3 or higher, were hematological, laboratory count-based events: white blood cell count decreases, anemia, neutrophil count decreases, and platelet count decreases. There were nine patients (
HARMONi-A (n=322) |
Ivonescimab + Chemo (n=161) |
Placebo + Chemo (n=161) |
TRAE Gr 3+ |
|
|
TRAE Gr 3+ Immune-related |
|
|
TRAE Gr 3+ VEGF-related |
|
|
Gr 3+ TRAEs with > |
|
|
Gr 3+ WBC Count Decrease |
|
|
Gr 3+ Anemia |
|
|
Gr 3+ Neutrophil Count Decrease |
|
|
Gr 3+ Platelet Count Decrease |
|
|
“After yesterday’s announcement regarding the HARMONi-2 trial, these results from HARMONi-A – including its strong efficacy, across subgroups, and its differentiated, manageable safety profile – and the associated approval of ivonescimab in
“We are excited to continue to develop ivonescimab with appropriate, accelerated pace and with the intent to make a significant difference for those patients who may benefit most from new, innovative therapies in lung cancer and other solid tumors,” added Dr. Maky Zanganeh, Chief Executive Officer and President of Summit.
Summit Therapeutics continues to enroll in the HARMONi clinical trial, a multi-regional Phase III study evaluating ivonescimab plus platinum-doublet chemotherapy vs. placebo plus platinum-doublet chemotherapy with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a 3rd generation EGFR TKI. HARMONi will analyze patients enrolled in
HARMONi-A data was presented by Dr. Li Zhang, Sun Yat-Sen University Cancer Center, at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting in
In addition to the HARMONi-A oral presentation, there will be a poster featuring Phase II clinical trial data for ivonescimab in combination with chemotherapy in front-line biliary tract cancer presented on Saturday, June 1, 2024.
Conference Call
Summit Therapeutics Inc. will host a conference call to discuss recent updates related to ivonescimab, including data released at ASCO, on Monday June 3, 2024, before the market opens.
Summit will host a live webcast of the conference call at 8:00am 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/130822402.
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 4259251.
An archived edition of the webcast will be available on our website later in the day on Monday.
About the ASCO 2024 Data
Presentation Title: Ivonescimab combined with chemotherapy in patients with EGFR-mutant non-squamous NSCLC who progressed on EGFR TKI treatment (HARMONi-A): A randomized, double-blind, multi-center, phase 3 trial
ASCO Abstract No.: 8508
Session Date & Time: Friday, May 31 at 4:57pm CT
Poster Title: The safety and efficacy of ivonescimab in combination with chemotherapy as first-line treatment for advanced biliary tract cancer
ASCO Abstract No.: 4095
Session Date & Time: Saturday, June 1 at 1:30pm CT
About Ivonescimab
Ivonescimab, known as SMT112 in Summit’s license territories,
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 tumor microenvironment 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.1 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,1 is to improve upon previously established efficacy thresholds, in addition to side effects and safety profiles associated with these targets.
Ivonescimab was discovered by Akeso Inc. (HKEX Code: 9926.HK) and is currently engaged in multiple Phase III clinical trials. Over 1,600 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 Phase III clinical trials, HARMONi and HARMONi-3.
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 3rd 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.
Ivonescimab is an investigational therapy that is not approved by any regulatory authority in Summit’s license territories, including
About Lung Cancer
Lung cancer is believed to impact approximately 600,000 people across
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
For more information, please visit https://www.smmttx.com and follow us on X @summitplc.
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., 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 use 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.6
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.7
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.8
Intracranial - Within the cranium or skull.
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.9
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.10
PD-L1 TPS – PD-L1 Tumor Proportion Score represents the percentage of tumor cells that express PD-L1 proteins.
PFS – Progression-Free Survival.
RANO – Response Assessment in Neuro-Oncology, the standard for assessing the response of a brain or spinal cord tumor to therapy.
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.11
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.12
VEGF – Vascular Endothelial Growth Factor is a signaling protein that promotes angiogenesis.13
___________
1 Zhong, et al, SITC 2023
2 American Cancer Society: www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html. Accessed April 2024; World Health Organization: International Agency for Research on Cancer, Globocan data by country (
3 Schabath MB, Cote ML. Cancer Progress and Priorities: Lung Cancer. Cancer Epidemiology, Biomarkers & Prevention. (2019).
4 About EGFR-Positive Lung Cancer | Navigating EGFR (lungevity.org).
5 Schabath MB, Cote ML. Cancer Progress and Priorities: Lung Cancer. Cancer Epidemiology, Biomarkers & Prevention. (2019).
6 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
7 Stefan MI, Le Novère N. Cooperative binding. PLoS Comput Biol. 2013;9(6)
8 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.
9 Han Y, et al. PD-1/PD-L1 Pathway: Current Researches in Cancer. Am J Cancer Res. 2020 Mar 1;10(3):727-742.
10 Han Y, et al. PD-1/PD-L1 Pathway: Current Researches in Cancer. Am J Cancer Res. 2020 Mar 1;10(3):727-742.
11 Cleveland Clinic. https://my.clevelandclinic.org/health/body/24630-t-cells. Accessed April 2024.
12 MD Anderson Cancer Center. https://www.mdanderson.org/cancerwise/what-is-the-tumor-microenvironment-3-things-to-know.h00-159460056.html. Accessed April 2024.
13 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.
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Senior Director, Investor Relations
Source: Summit Therapeutics Inc.
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