On September 8, 2024 Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit," "we," or the "Company") reported data from the primary analysis of the Phase III HARMONi-2 trial featuring the novel, potential first-in-class investigational bispecific antibody, ivonescimab (Press release, Summit Therapeutics, SEP 8, 2024, View Source [SID1234646416]). 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.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
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 (Free ESMO Whitepaper) 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) (Free ESMO Whitepaper) Congress 2024. ESMO (Free ESMO Whitepaper) 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 (Free ESMO Whitepaper) 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: View Source
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 (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 (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 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 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.
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.