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
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
5.6% Treatment Discontinuation of Ivonescimab due to Adverse Events vs. 2.5% Treatment Discontinuation of Placebo
HARMONi-A was Featured in Oral Presentation at ASCO 2024 on
Conference Call to be Held at
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)
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 >1%), which was covered in a separate announcement. For clarity, the data in this release is with respect to the HARMONi-A trial.
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; 95% CI: 0.34 – 0.62; p<0.001), representing a 54% reduction in the risk of disease progression compared to chemotherapy. Median PFS for ivonescimab plus chemotherapy was 7.1 months (95% CI: 5.9 – 8.7), as compared to 4.8 months (95% CI: 4.2 – 5.6) for placebo plus chemotherapy. In addition, for the subgroup of patients receiving a 3rd generation TKI (e.g., osimertinib or other locally approved 3rd generation TKIs), patients experienced a reduced risk of disease progression of 52% (HR: 0.48; 95% CI: 0.35 – 0.66). The PFS benefit was demonstrated across all clinical subgroups.
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 (95% CI: 0.48 – 1.09). An additional analysis performed after approximately 17.6 months of median follow-up showed a hazard ratio of 0.80 (95% CI: 0.59 – 1.08). Both overall survival curves appear to demonstrate clear separation between the two arms of the trial and show a trend in improvement of survival towards ivonescimab plus chemotherapy.
Overall response rate (ORR) was 50.6% (95% CI: 42.6% – 58.6%) for those receiving ivonescimab plus chemotherapy vs. 35.4% (95% CI: 28.0% - 43.3%) for those receiving chemotherapy alone. Ivonescimab plus chemotherapy usage resulted in a disease control rate (DCR) – those
HARMONi-A (n=322) |
Ivonescimab + Chemo (n=161) |
Placebo + Chemo (n=161) |
Median PFS |
7.1 months (95% CI: 5.9 – 8.7) |
4.8 months (95% CI: 4.2 – 5.6) |
PFS HR |
0.46 (95% CI: 0.34 – 0.62) |
|
ORR |
50.6% (95% CI: 42.6% – 58.6%) |
35.4% (95% CI: 28.0% – 43.3%) |
DCR |
93.1% (95% CI: 88.0% – 96.5%) |
83.2% (95% CI: 76.5% – 88.6%) |
Median OS (at 10.2 months mFU) |
Not reached (95% CI: 14.3 – NE) |
14.3 months (95% CI: 11.2 – NE) |
OS HR (10.2 months mFU) |
0.72 (95% CI: 0.48 – 1.09) |
|
Median OS (at 17.6 months mFU) |
17.1 months (95% CI: 14.6 – NE) |
14.5 months (95% CI: 12.8 – 18.1) |
OS HR (17.6 months mFU) |
0.80 (95% CI: 0.59 – 1.08) |
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 (5.6%)
HARMONi-A (n=322) |
Ivonescimab + Chemo (n=161) |
Placebo + Chemo (n=161) |
TRAE Gr 3+ |
54.0% |
42.9% |
TRAE Gr 3+ Immune-related |
6.2% |
2.5% |
TRAE Gr 3+ VEGF-related |
3.1% |
2.5% |
Gr 3+ TRAEs with >10% Incidence: |
|
|
Gr 3+ WBC Count Decrease |
19.9% |
16.8% |
Gr 3+ Anemia |
13.7% |
12.4% |
Gr 3+ Neutrophil Count Decrease |
29.8% |
19.3% |
Gr 3+ Platelet Count Decrease |
16.1% |
11.8% |
“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
HARMONi-A data was presented by Dr.
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
Conference Call
Summit will host a live webcast of the conference call at
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
ASCO Abstract No.: 8508
Session Date & Time:
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:
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
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
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 is believed to impact approximately 600,000 people across
About
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
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
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1 Zhong, et al, SITC 2023
2
3 Schabath MB, Cote ML. Cancer Progress and Priorities:
4 About EGFR-Positive
5 Schabath MB, Cote ML. Cancer Progress and Priorities:
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
8 US
9 Han Y, et al. PD-1/PD-L1 Pathway: Current Researches in Cancer. Am J Cancer Res. 2020
10 Han Y, et al. PD-1/PD-L1 Pathway: Current Researches in Cancer. Am J Cancer Res. 2020
11
12
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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