On January 8, 2024 Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit," "we," or the "Company") reported substantial updates to the promising development of ivonescimab, as well as near-term corporate catalysts that it will present at the 42nd Annual J.P. Morgan Healthcare Conference on Tuesday, January 09, 2024, at 1:30 PM PT in San Francisco, CA (Press release, Summit, JAN 8, 2024, View Source [SID1234639132]).
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AK112-201 (NCT04736823) is an open-label Phase II study evaluating ivonescimab plus chemotherapy across three cohorts of patients. In part, data generated from this trial has supported Summit’s decision to advance ivonescimab into two global Phase III clinical trials. Updated data includes patients from Cohorts 1 & 2 of this study:
Cohort 1: Patients with first line advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (i.e., patients’ tumors do not have actionable mutations in endothelial growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK)).
The updated data centers on the 63 patients whose tumors are of squamous histology.
Cohort 2: Patients with second or third line advanced or metastatic NSCLC whose tumors are positive for EGFR mutations (EGFRm) and have progressed following an EGFR tyrosine kinase inhibitor (TKI) (n=19).
Notably, the estimated 1-year overall survival rate was 85.6%, and the 2-year overall survival rate was 64.8% for patients in Cohort 1 with squamous histology NSCLC. After a median follow-up time of 21.0 months, the median overall survival (OS) was not reached.1 The frequency of treatment-related adverse events (TRAEs) leading to discontinuation of ivonescimab was 11%; there were no TRAEs leading to the death of a patient. The most frequent treatment-emergent adverse events were anemia, decreased neutrophil counts, and decreased white-blood cell counts.
The 19 patients in Cohort 2, primarily second or third line patients with EGFRm NSCLC, demonstrated a median overall survival of 22.5 months. After a median follow-up time of 25.8 months, the estimated 1-year overall survival rate was 74%.1 Ivonescimab had an acceptable safety profile in combination with platinum-doublet chemotherapy for patients with advanced or metastatic NSCLC who had progressed following an EGFR-TKI. There were no TRAEs leading to permanent discontinuation of therapy or patient death.
AK112-201 Phase II Trial1
Cohort 1: 1L SQ-NSCLC only
(n=63)
Cohort 2: 2L / 3L+ EGFR-TKI
Progressors NSCLC (n=19)
Overall Response Rate (ORR)*
67%
68%
Disease Control Rate (DCR)*
95%
95%
Median Duration of Response (DOR)*
12.8 months
8.7 months
Median PFS
(95% CI)
11.1 months
(9.5 – 16.3 months)
8.5 months
(5.5 – 13.3 months)
Median OS
(95% CI)
Not Reached
(22.5 months – NE**)
22.5 months
(10.4 months – NE**)
12-month OS Rate
85.6%
73.7%
24-month OS Rate
64.8%
40.9%
* Confirmed responses for patients with at least one post-baseline scan; SQ-NSCLC n=60; EGFR-TKI n=19
** NE – Not Established
AK112-201 is a clinical trial that is sponsored and conducted in China by our collaboration and licensing partner, Akeso, Inc. (HKEX Code: 9926.HK). The aforementioned data related to AK112-201 was generated and analyzed by Akeso.
Summit is enrolling patients in two global Phase III clinical trials involving ivonescimab:
HARMONi intends to evaluate ivonescimab combined with chemotherapy compared to a placebo plus chemotherapy in patients with EGFR-mutated, locally advanced or metastatic non-squamous NSCLC who have progressed after treatment with a third-generation EGFR TKI (NCT05184712), and
HARMONi-3 is designed to evaluate ivonescimab combined with chemotherapy compared to pembrolizumab combined with chemotherapy in patients with 1L metastatic squamous NSCLC (NCT05899608).
Near-Term Catalyst Events for Summit & the Development of Ivonescimab
In addition to the ongoing Phase III clinical trials sponsored by Summit, Akeso is sponsoring four Phase III clinical trials investigating ivonescimab in China in NSCLC. Near-term catalyst events for both Summit and Akeso include expected key milestones for two of Akeso’s Phase III randomized clinical trials evaluating ivonescimab in China:
AK112-301, which reflects the patient population of Summit’s HARMONi trial, was submitted for marketing approval to the Chinese health authority in 2023, and a decision from the Chinese Center for Drug Evaluation (CDE) is expected in Q2 2024, along with a read-out of topline data from the study by Akeso, and
AK112-303, which is evaluating monotherapy ivonescimab vs. pembrolizumab in 1L NSCLC patients whose tumors have a PD-L1 TPS >1%, has a planned interim analysis by Akeso, which is expected to be completed in Q2 2024.
Both studies represent ivonescimab in randomized, pivotal clinical trials against the standard of care in their respective settings.
"As the data continues to mature in Phase II studies evaluating ivonescimab, including data related to the survival of patients impacted by these terrible diseases, our belief and conviction in ivonescimab is reinforced," stated Summit’s Chief Executive Officers, Robert W. Duggan and Dr. Maky Zanganeh. "The speed and purpose with which Team Summit acts reflect the opportunity to accomplish our mission of making a significant difference in the lives of patients facing difficult odds from a cancer diagnosis. We believe that the potential created by the differentiated mechanism of action and supporting trial data for ivonescimab deserves a swift development plan to bring ivonescimab to those patients who can benefit most. We are honored to work with our partners at Akeso to continue to strive to achieve this common goal."
In addition to live attendance at the JPM 2024 conference, the audio presentation will be available live from our website: www.smmttx.com.
Update Regarding Current Financial Position
As of December 31, 2023, the company’s preliminary unaudited balance of cash, cash equivalents, and short-term investments was no less than $186 million. This amount is preliminary and is subject to completion of financial closing procedures. As a result, this amount may differ materially from the amount that will be reflected in the Company’s consolidated financial statements for the year ended December 31, 2023.
About Ivonescimab
Ivonescimab, known as SMT112 in Summit’s license territories, the United States, Canada, Europe, 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 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 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.2 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 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. Summit has begun its clinical development of ivonescimab in NSCLC, commencing enrollment in 2023 in its two Phase III clinical trials. Over 1,600 patients have been treated with ivonescimab in clinical studies in China and Australia, with enrollment beginning in 2023 in Summit’s license territories.
About Lung Cancer
Lung cancer is believed to impact approximately 600,000 people across the United States, United Kingdom, Spain, France, Italy, Germany, and Japan.3 NSCLC is the most prevalent type of lung cancer and represents approximately 80% to 85% of all incidences.4 Among patients with non-squamous NSCLC, approximately 15% have EGFR-sensitizing mutations in the United States and Europe.5 Patients with squamous histology represent approximately 25% to 30% of NSCLC patients.