On May 31, 2024 Summit Therapeutics Inc. (NASDAQ: SMMT) ("Summit," "we," or the "Company") reported that, on May 24, 2024, our partner, Akeso Inc. (Akeso, HKEX Code: 9926.HK), received marketing authorization in China from the National Medical Products Administration (NMPA) (Press release, Summit Therapeutics, MAY 31, 2024, View Source [SID1234643915]). The approval is based on the positive dataset associated with HARMONi-A, a single region, multi-center, Phase III study conducted in China sponsored by Akeso with data generated and analyzed by Akeso.
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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 >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 who either responded or were considered to have stable disease under RECIST 1.1 criteria – of 93.1% (95% CI: 88.0% – 96.5%) vs. 83.2% (95% CI: 76.5% – 88.6%) for those receiving placebo plus chemotherapy.
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%) who discontinued ivonescimab due to TRAEs compared to four patients (2.5%) who discontinued placebo due to TRAEs. Grade 3 or higher immune-related adverse events occurred in 6.2% of patients receiving ivonescimab plus chemotherapy and 2.5% of patients receiving placebo plus chemotherapy. Grade 3 or higher VEGF-related adverse events between the two arms were similar (3.1% vs. 2.5%, respectively); there were no Grade 3 bleeding or arterial thrombotic events in the ivonescimab plus chemotherapy arm. No TRAEs resulted in the death of a patient in either arm in this Phase III study.
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 China further validates the benefits that ivonescimab has the potential to bring to patients around the globe," stated Robert W. Duggan, Chairman and Chief Executive Officer of Summit.
"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 North America, China, and Europe. HARMONi intends to include all patients from the HARMONi-A trial who previously received a 3rd generation TKI – representing approximately 276 patients (85%) of the HARMONi-A trial. The planned total enrollment for the Phase III multi-regional HARMONi trial is approximately 420 patients, which Summit intends to complete enrolling during the second half of 2024.
HARMONi-A data was presented by Dr. Li Zhang, Sun Yat-Sen University Cancer Center, at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL.
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 (Free ASCO Whitepaper), 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: 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 4259251.
An archived edition of the webcast will be available on our website later in the day on Monday.
About the ASCO (Free ASCO Whitepaper) 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, 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.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 the United States and Europe. Ivonescimab was approved for marketing authorization in China in May 2024.
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.2 NSCLC is the most prevalent type of lung cancer and represents approximately 80% to 85% of all incidences.3 Among patients with non-squamous NSCLC, approximately 15% have EGFR-sensitizing mutations in the United States and Europe.4 Patients with squamous histology represent approximately 25% to 30% of NSCLC patients.