Ifinatamab Deruxtecan Continues to Demonstrate Promising Objective Response Rates in Patients with Extensive-Stage Small Cell Lung Cancer in IDeate-Lung01 Phase 2 Trial
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Objective response rate of 54.8% seen with
Daiichi Sankyo and Merck’s ifinatamab deruxtecan at 12 mg/kg dose in pretreated patients - 12 mg/kg selected as optimal dose for extension part of IDeate-Lung01 phase 2 trial and recently initiated IDeate-Lung02 phase 3 study
Ifinatamab deruxtecan is a specifically engineered, potential first-in-class B7-H3 directed antibody drug conjugate (ADC) discovered by
Small cell lung cancer (SCLC) is the second most common type of lung cancer, accounting for about 15% of cases.1 SCLC is aggressive and progresses rapidly to the metastatic stage, which has a five-year survival rate of only 3%.2,3 Approximately 65% of all SCLC tumors have a moderate-to-high expression of the protein B7-H3, which is associated with disease progression and poor prognosis.4,5
“Most patients treated for small cell lung cancer experience rapid progression of disease and there is a high unmet need in the advanced setting,” said
A confirmed objective response rate (ORR) of 54.8% (95% CI: 38.7-70.2) and 26.1% (95% CI: 14.3-41.1) were observed in patients with ES-SCLC receiving ifinatamab deruxtecan in the 12 mg/kg (n=42) and 8 mg/kg (n=46) cohorts, respectively, as assessed by blinded independent central review (BICR). Twenty-three partial responses (PR) were seen in the 12 mg/kg cohort. One complete response (CR) and eleven PRs were seen in the 8 mg/kg cohort. A median duration of response (DoR) of 4.2 months (95% CI: 3.5-7.0) and 7.9 months (95% CI: 4.1-NE) and a disease control rate (DCR) of 90.5% (95% CI: 77.4-97.3) and 80.4% (95% CI: 66.1-90.6) were observed in the 12 mg/kg and 8 mg/kg cohorts, respectively. The median duration of treatment was 4.7 months for the 12 mg/kg dose (range, 0.03-15.2) and 3.5 months for the 8 mg/kg dose (range, 0.03–13.9). Median progression-free survival (PFS) of 5.5 months (95% CI: 4.2-6.7) and 4.2 months (95% CI: 2.8-5.6) and median overall survival (OS) of 11.8 months (95% CI: 8.9-15.3) and 9.4 months (95% CI: 7.8-15.9) were observed in the 12 mg/kg and 8 mg/kg cohorts, respectively. The 12 mg/kg dose has been selected for the dose expansion part of the trial. Median follow-up was 15.3 months (95% CI: 13.6-16.2) in the 12 mg/kg cohort and 14.6 months (95% CI: 13.4-16.5) in the 8 mg/kg cohort as of data cutoff of
In a subset of patients with brain target lesions at baseline, an intracranial ORR of 50.0% (95% CI: 18.7-81.3) and 66.7% (95% CI: 22.3-95.7) were observed as assessed by central nervous system (CNS) BICR in the 12 mg/kg (n=10) and 8 mg/kg (n=6) cohorts, respectively. In these patients, two intracranial CRs were seen in each cohort. Three and two intracranial PRs and five and two cases of stable disease (SD) were seen in the 12 mg/kg and 8 mg/kg cohorts, respectively.
“The objective response rate and median overall survival of nearly a year along with the preliminary intracranial responses observed reinforces the potential for ifinatamab deruxtecan to improve outcomes for patients living with this difficult-to-treat type of lung cancer,” said
“These results demonstrate promising objective response rates in patients with pre-treated extensive-stage small cell lung cancer, a patient population with a poor prognosis and limited treatment options,” said
The safety profile seen in IDeate-Lung01 is consistent with that observed for ifinatamab deruxtecan in previous trials with no new safety signals identified. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 50.0% and 43.5% of patients in the 12 mg/kg (n=42) and 8 mg/kg (n=46) cohorts, respectively. The most common treatment-related TEAEs (>20% of total population) across both doses include nausea (50.0% and 28.3%), decreased appetite (42.9% and 17.4%), anemia (35.7% and 13.0%), decreased neutrophil count/neutropenia (33.3% and 10.9%), white blood cell decreased (21.4% and 4.3%) and asthenia (1.4% and 13.0%). Five (11.9%) and four (8.7%) interstitial lung disease (ILD)/pneumonitis events were confirmed as treatment-related in the 12 mg/kg and 8 mg/kg doses, respectively, as determined by an independent adjudication committee. The majority of ILD events (four with 12 mg/kg, three with 8 mg/kg) were low grade (grade 1 or 2). There was one grade 3 (12 mg/kg) and one grade 5 (8 mg/kg) ILD. No ILD events were pending adjudication at the time of data cutoff of
Patients in IDeate-Lung01 receiving ifinatamab deruxtecan received a median of two lines of therapy in both dose groups including a majority (76.1%) previously treated with immunotherapy. The median treatment duration was 4.7 months (range: 0.03-15.2) in the 12 mg/kg cohort and 3.5 months (range: 0.03-13.9) in the 8mg/kg cohort.
Summary of IDeate-Lung01 Results
Efficacy Measure |
Ifinatamab deruxtecan (12 mg/kg) n=42 |
Ifinatamab deruxtecan (8 mg/kg) n=46 |
Confirmed ORR, % (95% CI) |
54.8% (38.7-70.2) |
26.1% (14.3-41.1) |
CR, n (%) |
0 |
1 (2.2%) |
PR, n (%) |
23 (54.8%) |
11 (23.9%) |
Stable disease (SD)/non-CR/non-PD, n (%) |
15 (35.7%) |
25 (54.3%) |
Progressive disease (PD), n (%) |
2 (4.8%) |
5 (10.9%) |
DCR, % (95% CI) |
90.5% (77.4-97.3) |
80.4% (66.1-90.6) |
DoR, median (95% CI), months |
4.2 months (3.5-7.0) |
7.9 months (4.1-NE) |
TTR, median (95% CI), months |
1.4 months (1.0-8.1) |
1.4 months (1.2-1.5) |
PFS, median (95% CI), months |
5.5 months (4.2-6.7) |
4.2 months (2.8-5.6) |
OS, median (95% CI), months |
11.8 months (8.9-15.3) |
9.4 months (7.8-15.9) |
CR, complete response; DCR, disease control rate; DoR, duration of response; ORR, objective response rate; OS, overall survival, PR, partial response; PD, progressive disease; PFS, progression-free survival; TTR, time to response; SD, stable disease
About the IDeate-Lung01 Trial
IDeate-Lung01 is a global, multicenter, randomized, open-label two-part phase 2 trial evaluating the safety and efficacy of ifinatamab deruxtecan in patients with ES-SCLC. In the first part of the trial (dose optimization), patients were previously treated with at least one prior line of platinum-based chemotherapy and a maximum of three prior lines of therapy. In the second part (extension), patients were previously treated with a minimum of two previous lines of systemic therapy.
In the first part of the trial, patients were randomized 1:1 to receive either 8 mg/kg or 12 mg/kg of ifinatamab deruxtecan. In the second part of the trial, patients will receive the recommended dose for expansion (12 mg/kg) of ifinatamab deruxtecan.
The primary endpoint is ORR as assessed by BICR. Secondary endpoints include DoR, PFS, OS, DCR, time to response and overall safety profile. Intracranial ORR was assessed by BICR as an exploratory analysis.
IDeate-Lung01 is enrolling patients in
About Small Cell Lung Cancer
More than 2.48 million lung cancer cases were diagnosed globally in 2022.6 SCLC is the second most common type of lung cancer, accounting for approximately 15% of cases.1 SCLC is aggressive and progresses rapidly to the metastatic stage, which has a five-year survival rate of only 3%.2,3 While conventional first-line therapy for patients with advanced SCLC may help some patients live longer, the current second-line standard of care offers limited clinical benefit and new treatment approaches are needed.7,8,9,10
About B7-H3
B7-H3 is a transmembrane protein that belongs to the B7 family of proteins which bind to the CD28 family of receptors that includes PD-1.11,12 B7-H3 is overexpressed in a wide range of cancer types, including SCLC, and its overexpression has been shown to correlate with poor prognosis, making B7-H3 a promising therapeutic target.4,12,13,14,15 There are currently no B7-H3 directed medicines approved for the treatment of any cancer.
About Ifinatamab Deruxtecan
Ifinatamab deruxtecan (I-DXd) is an investigational potential first-in-class B7-H3 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ifinatamab deruxtecan is comprised of a humanized anti-B7-H3 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
Ifinatamab deruxtecan is being evaluated in a global development program, which includes IDeate-Lung01, a phase 2 monotherapy trial in patients with previously treated ES-SCLC; IDeate-Lung02, a phase 3 trial in patients with relapsed SCLC versus investigator’s choice of chemotherapy; IDeate-Lung03, a phase 1b/2 trial in patients with ES-SCLC in combination with atezolizumab with or without carboplatin as first-line induction or maintenance therapy; IDeate-PanTumor01, a phase 1/2 first-in-human trial in patients with advanced solid malignant tumors in collaboration with
Ifinatamab deruxtecan was granted orphan drug designation by the
About the
About the ADC Portfolio of
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by
The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with
The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.
Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.
About
Merck’s Focus on Cancer
Every day, we follow the science as we work to discover innovations that can help patients, no matter what stage of cancer they have. As a leading oncology company, we are pursuing research where scientific opportunity and medical need converge, underpinned by our diverse pipeline of more than 25 novel mechanisms. With one of the largest clinical development programs across more than 30 tumor types, we strive to advance breakthrough science that will shape the future of oncology. By addressing barriers to clinical trial participation, screening and treatment, we work with urgency to reduce disparities and help ensure patients have access to high-quality cancer care. Our unwavering commitment is what will bring us closer to our goal of bringing life to more patients with cancer. For more information, visit https://www.merck.com/research/oncology/.
About
At
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References:
1 Schabath MB, et al. Cancer Epidemiol Biomarkers Prev. 2019 Oct;28(10):1563-1579.
2 Rudin CM, et al. Nat Rev Dis Primers. 2021;7(1):3.
3 Cancer.net. Lung Cancer - Small Cell: Statistics. Accessed
4 Qiu M-j, et al. Front. Oncol. 2021;11:600238.
5 Dong P, et al. Front Oncol. 2018;8:264
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8 Liu SV, et al. J Clin Oncol. 2021;39(6):619-30.
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11 Zhao B, et al.J Hematol Oncol. 2022;15(1):153.
12 Janakiram M, et al. Immunol Rev. 2017;276(1):26-39.
13 Picarda E, et al.
14 Bendell JC, et al. J Clin Oncol. 2020;39(15 suppl 1). Abstract TPS3646.
15 Kontos F, et al.
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