Daiichi Sankyo and Merck & Co/MSD have voluntarily withdrawn the Biologics License Application (BLA) for ifinatamab deruxtecan (I-DXd; DS-7300a), a B7-H3-directed antibody-drug conjugate (ADC), for adults with previously treated extensive-stage small cell lung cancer (ES-SCLC). The withdrawal follows discussions with the U.S. Food and Drug Administration (FDA), which concluded that the data submitted with the application, including results from the Phase 2 IDeate-Lung01 trial, did not satisfy the requirements for accelerated approval in the proposed indication.[1]
Key Takeaways
- Daiichi Sankyo and Merck & Co/MSD voluntarily withdrew the BLA for ifinatamab deruxtecan after discussions with FDA determined that the available data did not support accelerated approval for previously treated ES-SCLC.[1]
- In the primary analysis of IDeate-Lung01, the 137-patient 12 mg/kg population had a confirmed objective response rate (ORR) of 48.2% by blinded independent central review (BICR), a median duration of response (DOR) of 5.3 months, and median progression-free survival (PFS) of 4.9 months.[3]
- Tarlatamab-dlle (Imdelltra) received traditional FDA approval in November 2025 for ES-SCLC following progression on or after platinum-based chemotherapy, based on randomized Phase 3 DeLLphi-304 data demonstrating an overall survival benefit compared with chemotherapy.[8,9]
- I-DXd remains investigational in the United States and is available only through clinical trials.
- Enrollment in the randomized Phase 3 IDeate-Lung02 study is continuing, and the companies reported it is near completion. Two additional Phase 3 studies are evaluating
- ifinatamab deruxtecan in castration-resistant prostate cancer and esophageal squamous cell carcinoma.[1]
A Voluntary Withdrawal
The BLA sought accelerated approval for ifinatamab deruxtecan in adults with ES-SCLC whose disease had progressed on or after platinum-based chemotherapy. Daiichi Sankyo and Merck voluntarily withdrew the application following discussions with FDA concerning the supporting data.[1] The companies stated that FDA determined the available data, including results from IDeate-Lung01, did not meet the requirements to support accelerated approval for the proposed indication.[1] The companies and FDA have not publicly identified the specific data requirement or requirements that were not met.
The withdrawal occurred 15 days before the previously scheduled October 10, 2026, Prescription Drug User Fee Act (PDUFA) action date.
The BLA had received Priority Review in April 2026. The submission was based primarily on the Phase 2 IDeate-Lung01 trial (NCT05280470), with supporting information from the Phase 1/2 IDeate-PanTumor01 study (NCT04145622). The program had also received Real-Time Oncology Review and Project Orbis designations, and ifinatamab deruxtecan received Breakthrough Therapy Designation from FDA in August 2025.[2][14]
Under 21 CFR §601.41, accelerated approval of a biological product may be based on an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on certain clinical endpoints other than survival or irreversible morbidity. The accelerated-approval framework is intended for serious conditions where available evidence can support an earlier regulatory decision while additional studies verify clinical benefit.[12]
The regulatory record for ifinatamab deruxtecan shows that the submitted dataset did not support accelerated approval in the proposed indication. It does not establish which individual component of the dataset FDA considered insufficient.
Molecular Design
Ifinatamab deruxtecan is a B7-H3-directed ADC comprising a humanized anti-B7-H3 IgG1 monoclonal antibody conjugated to DXd, an exatecan-derived topoisomerase I inhibitor, through tetrapeptide-based cleavable linkers (a stable, enzyme-cleavable linker, such as GGFG, that remains intact in circulation but breaks down inside the cancer cell via lysosomal enzymes to release the drug). The ADC uses Daiichi Sankyo’s DXd ADC technology.[1]
B7-H3, also known as CD276, is a transmembrane protein of the B7 family and is expressed across a range of solid tumors, including SCLC. Researchers have investigated B7-H3 expression as a therapeutic target in multiple tumor types. No B7-H3-directed medicine has received FDA approval for cancer treatment.[1]
The Evidence Submitted: IDeate-Lung01
IDeate-Lung01 was a global, multicenter, randomized, open-label, two-part Phase 2 study evaluating ifinatamab deruxtecan in patients with previously treated ES-SCLC.[3] The study enrolled patients who had received at least one prior line of platinum-based chemotherapy and no more than three prior lines of therapy. Patients with asymptomatic brain metastases were eligible. Patients with a history of interstitial lung disease (ILD) or pneumonitis requiring steroid treatment were excluded.[1][3]
The dose-optimization portion randomized patients 1:1 to Ifinatamab deruxtecan at 8 mg/kg or 12 mg/kg every three weeks. Patients in the dose-expansion portion received 12 mg/kg.[3] The primary endpoint was ORR assessed by BICR according to RECIST version 1.1. The study enrolled 187 patients; 183 received treatment and were included in the published analysis: 88 in the dose-optimization portion and 95 in the dose-expansion portion.[1][3]
In the dose-optimization population, ORR was 26.1% among patients receiving 8 mg/kg (n=46) and 54.8% among those receiving 12 mg/kg (n=42). In the pooled 12 mg/kg population from both study parts (n=137), the confirmed ORR was 48.2% (95% CI, 39.6%-56.9%). Median DOR was 5.3 months, median PFS was 4.9 months, and the estimated 9-month OS rate was 59.1%.[3]
An earlier analysis of the 12 mg/kg cohort reported a median OS of 11.8 months.[4]
Intracranial Activity
Intracranial activity was evaluated as an exploratory endpoint. Among patients with baseline brain metastases, the confirmed intracranial ORR was 46.2%.[7] These data are relevant to the clinical development of an ADC in SCLC because patients with brain metastases represent an important population within the disease. However, the intracranial analysis was exploratory and should be distinguished from the primary efficacy analysis of IDeate-Lung01.
Safety Profile
The safety findings reported from IDeate-Lung01 are consistent with the known adverse-event profile of ifinatamab deruxtecan and the DXd ADC platform. In the 12 mg/kg population, the primary JCO analysis reported treatment-related adverse events (TRAEs) of any grade in 89.8% of patients and grade ≥3 TRAEs in 36.5%.[3] The most common TRAEs were nausea (43.1%), anemia (34.3%), and neutropenia (34.3%). TRAEs led to treatment discontinuation in 9.5% of patients and were associated with death in 4.4%.[3]
Treatment-related ILD, as determined by an ILD adjudication committee, occurred in 12.4% of patients, including grade ≥3 ILD in 4.4%.[3] ILD was also observed during the dose-escalation portion of IDeate-PanTumor01. Among 97 treated patients receiving doses from 0.8 to 16.0 mg/kg, the maximum tolerated dose was not reached. One death from ILD was considered related to study treatment by the investigator.[6]
The PanTumor01 investigators emphasized the need for prompt evaluation and appropriate management of ILD. Pulmonary toxicity is a recognized safety consideration across DXd-based ADCs.[6]
The Treatment Landscape at the Time of Review
The regulatory context for second-line ES-SCLC changed substantially between the initiation of IDeate-Lung01 and the FDA’s review of the Ifinatamab deruxtecan BLA.
Tarlatamab-dlle (Imdelltra®, Amgen), a DLL3-directed bispecific T-cell engager or BiTE immunotherapy that acts as a bridge, binding to CD3 proteins on healthy T-cells and delta-like ligand 3 (DLL3) proteins on small cell lung cancer cells, received accelerated approval from the FDA in 2024 and traditional approval on November 19, 2025, for adults with ES-SCLC with disease progression on or after platinum-based chemotherapy.[8]
The randomized Phase 3 DeLLphi-304 trial (NCT05740566) supported the traditional approval; it enrolled 509 patients and compared tarlatamab with investigator’s choice of topotecan (Hycamtin®; GSK and available in multiple generic brands), amrubicin (Calsed®; Sumito Pharma), or lurbinectedin (Zepzelca®; PharmaMar/Jaxx Pharmaceuticals). The trial’s primary endpoint was OS.[8][9] At the prespecified interim analysis, median OS was 13.6 months with tarlatamab compared with 8.3 months with chemotherapy (HR, 0.60; 95% CI, 0.47-0.77).[9] Thus, by the time FDA reviewed the ifinatamab deruxtecan BLA, the U.S. second-line ES-SCLC treatment landscape included a traditionally approved therapy supported by randomized OS data.
The distinction is important. IDeate-Lung01 was a Phase 2 study in which ORR was the primary endpoint, whereas DeLLphi-304 was a randomized Phase 3 study with OS as its primary endpoint.[3][9]
Emerging Randomized Data in B7-H3-Directed ADCs
Randomized survival data have also emerged within the B7-H3 ADC field. At the 2026 World Conference on Lung Cancer, held September 12 to 15, 2026, in Seoul, South Korea, researchers presented interim results from the Phase 3 ARTEMIS-008 study (NCT06498479) of risvutatug rezetecan (HS-20093; GSK5764227). The study compared risvutatug rezetecan with topotecan in patients with SCLC in China and reported an OS hazard ratio of 0.46 (95% CI, 0.35-0.62), with median OS of 18.5 versus 10.3 months.[10]
ARTEMIS-008 was conducted in China and has not been the subject of a U.S. regulatory submission. A separate global Phase 3 study, EMBOLD SCLC-301 (NCT07099898), is evaluating risvutatug rezetecan in relapsed ES-SCLC outside China.[10] These results provide additional randomized evidence for the B7-H3 ADC class, but cross-trial comparisons should not be used to directly compare efficacy among agents. The studies differ in patient populations, geographic regions, prior treatment, comparator therapies, and trial design.
Precedent Within the DXd Collaboration
The ifinatamab deruxtecan withdrawal follows the May 2025 withdrawal of the BLA for patritumab deruxtecan (HER3-DXd) in previously treated EGFR-mutated locally advanced or metastatic non-small cell lung cancer.[11]
That application was based on the Phase 2 HERTHENA-Lung01 study (NCT04619004). Its withdrawal followed the failure of the confirmatory Phase 3 HERTHENA-Lung02 trial (NCT05338970) to demonstrate a statistically significant OS benefit and subsequent discussions with FDA.[11] The regulatory circumstances differ between the two programs. For patritumab deruxtecan, the withdrawal followed the availability of confirmatory randomized survival data. For I-DXd, the BLA was withdrawn before the confirmatory Phase 3 IDeate-Lung02 study (NCT06203210) reported its pivotal results.
Future Development
Small Cell Lung Cancer
IDeate-Lung02 is a global, randomized, open-label Phase 3 trial evaluating I-DXd at 12 mg/kg every three weeks against treatment of physician’s choice with topotecan, amrubicin, or lurbinectedin.[5] The study is designed to enroll approximately 540 patients with relapsed SCLC following one prior line of systemic therapy that included platinum-based chemotherapy.[5]
The published study design specifies dual primary endpoints of ORR by BICR and OS. Secondary endpoints include PFS, DOR, disease control rate, time to response, patient-reported outcomes, safety, pharmacokinetics, immunogenicity, and the relationship between B7-H3 expression and clinical outcomes.[5]
Patients with asymptomatic untreated or previously treated brain metastases may participate.[5] The companies have said enrollment is nearly complete and that they will assess a potential future regulatory filing based on the IDeate-Lung02 results.[1] An important feature of the trial is its chemotherapy comparator. IDeate-Lung02 was designed around topotecan, amrubicin, or lurbinectedin, and does not include tarlatamab as a comparator.[5]
Consequently, the eventual interpretation of IDeate-Lung02 will occur against a treatment landscape that has evolved since the study was designed.
Other Indications
The Ifinatamab deruxtecan development program extends beyond SCLC.
IDeate-Prostate01 (NCT06925737) is evaluating Ifinatamab deruxtecan in castration-resistant prostate cancer, while IDeate-Esophageal01 (NCT06644781) is evaluating the ADC in esophageal squamous cell carcinoma.[1][13] Ifinatamab deruxtecan has received orphan drug designation from the FDA, the European Commission, Japan’s Ministry of Health, Labor and Welfare, and Taiwan’s FDA for SCLC. FDA has also granted orphan drug designation for esophageal cancer.[1]
The B7-H3 ADC Class
Ifinatamab deruxtecan is one of several B7-H3-directed ADCs in clinical development. The class includes programs using different antibody constructs, linkers, and cytotoxic payloads, including exatecan-derived topoisomerase I inhibitors.[10] The class has also included approaches that were later discontinued. These include vobramitamab duocarmazine (MGC018)*, which uses a duocarmycin payload, as well as non-ADC approaches such as enoblituzumab and the CD3×B7-H3 DART molecule MGD009.[10]
The continued development of B7-H3-directed therapies will provide additional clinical data on target expression, payload selection, therapeutic window, and the role of B7-H3 as a therapeutic target across tumor types.
What’s Next
The withdrawal of the ifinatamab deruxtecan BLA removes the immediate U.S. regulatory pathway for the drug in previously treated ES-SCLC, but it does not end development of the investigational agent. The central dataset now to watch is IDeate-Lung02. Unlike the Phase 2 IDeate-Lung01 study, the Phase 3 trial was designed to evaluate ifinatamab deruxtecan against established chemotherapy using randomized comparisons that include OS as a primary endpoint.[5]
The future regulatory position of ifinatamab deruxtecan in SCLC will therefore depend on the results of that randomized study and on how those results are interpreted within the evolving treatment landscape. For the broader ADC field, the ifinatamab deruxtecan experience also illustrates the growing importance of randomized evidence as ADC development moves from single-arm, response-based studies to trials designed to establish comparative clinical benefit.
Series Note
This article follows ADC Review’s April 13, 2026 report on FDA’s acceptance of the I-DXd BLA with Priority Review[14] and the September 13, 2026 report on ARTEMIS-008.[10]
Note
The synthetic duocarmycin-based linker-drug payload platform used in MacroGenics’s B7-H3-targeting ADC (vobramitamab duocarmazine; MGC018) was predominantly developed by Patrick Beusker, Ph.D., and Ronald Elgersma, Ph.D., at Byondis, who engineered fully synthetic duocarmycin analogs and site-specific cleavable linkers. The proprietary payload design—vc-seco-DUBA (valine-citrulline-seco-duocarmycin-hydroxybenzamide-azaindole)—has been licensed and utilized in several clinical-stage ADCs, including vobramitamab duocarmazine. The parent duocarmycin compounds are a family of ultrapotent antitumor antibiotics originally isolated from Streptomyces soil bacteria in the 1970s and 1980s.
Clinical Trials
- Ifinatamab Deruxtecan (I-DXd) in Subjects With Pretreated Extensive-Stage Small Cell Lung Cancer (ES-SCLC) (IDeate-Lung01) – ClinicalTrials.gov ID NCT05280470
- A Study of Ifinatamab Deruxtecan Versus Treatment of Physician’s Choice in Subjects With Relapsed Small Cell Lung Cancer (IDeate-Lung02) – ClinicalTrials.gov ID NCT06203210
- Study of Ifinatamab Deruxtecan (DS-7300a, I-DXd) in Participants With Advanced Solid Malignant Tumors – ClinicalTrials.gov ID NCT04145622
- A Clinical Study of Ifinatamab Deruxtecan (I-DXd) in People With Metastatic Prostate Cancer (MK-2400-001) – ClinicalTrials.gov ID NCT06925737
- A Study of Ifinatamab Deruxtecan in Subjects With Pretreated Advanced or Metastatic Esophageal Squamous Cell Carcinoma (ESCC) (IDeate-Esophageal01) – ClinicalTrials.gov ID NCT06644781
- Study Comparing Tarlatamab With Standard of Care Chemotherapy in Relapsed Small Cell Lung Cancer (DeLLphi-304) – ClinicalTrials.gov ID NCT05740566
- ARTEMIS-008: HS-20093 Compared With Topotecan in Subjects With Relapsed Small Cell Lung Cancer – ClinicalTrials.gov ID NCT06498479
- HERTHENA-Lung01: Patritumab Deruxtecan in Subjects With Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer – ClinicalTrials.gov ID NCT04619004
- HERTHENA-Lung02: A Study of Patritumab Deruxtecan Versus Platinum-based Chemotherapy in Metastatic or Locally Advanced EGFRm NSCLC After Failure of EGFR TKI Therapy – ClinicalTrials.gov ID NCT05338970
- A Study of GSK5764227 in Participants With Relapsed Small Cell Lung Cancer (SCLC) [EMBOLD SCLC-301] – ClinicalTrials.gov ID NCT07099898
Highlights of Prescribing Information
Tarlatamab-dlle (Imdelltra®, Amgen)[Prescribing Information]
References
[1] Merck & Co., Inc.; Daiichi Sankyo. Ifinatamab deruxtecan biologics license application for certain patients with previously treated extensive-stage small cell lung cancer voluntarily withdrawn. September 25, 2026. Last accessed on September 25, 2026
[2] Daiichi Sankyo. Ifinatamab deruxtecan granted priority review in the U.S. for adult patients with previously treated extensive-stage small cell lung cancer who experienced disease progression on or after platinum-based chemotherapy. April 13, 2026. Online. Last accessed on September 25, 2026.
[3] Rudin CM, Johnson ML, Paz-Ares L, Nishio M, Hann CL, Girard N, Rocha P, Hayashi H, Sakai T, Kim YJ, Hu H, Qian M, Singh J, Godard J, Tang M, Ahn MJ. Ifinatamab Deruxtecan in Patients With Extensive-Stage Small Cell Lung Cancer: Primary Analysis of the Phase II IDeate-Lung01 Trial. J Clin Oncol. 2026 Feb;44(4):261-273. doi: 10.1200/JCO-25-02142. Epub 2025 Oct 14. PMID: 41086386; PMCID: PMC12834294..
[4] Wespiser M, Gille R, Pérol M. Clinical progress of B7-H3 targeted antibody drug conjugate ifinatamab deruxtecan for small-cell lung cancer. Expert Opin Investig Drugs. 2025 Jun;34(6):463-471. doi: 10.1080/13543784.2025.2512566. Epub 2025 May 29. PMID: 40418751.
[5] Owonikoko TK, Byers L, Cheng Y, Hayashi H, Paz-Ares L, Pérol M, Hu H, Qian M, Garcia CR, Godard J, Tang M, Rudin CM. IDeate-Lung02: a Phase 3 study of second-line ifinatamab deruxtecan in patients with relapsed small cell lung cancer. Future Oncol. 2025 Oct;21(25):3275-3282. doi: 10.1080/14796694.2025.2565995. Epub 2025 Oct 7. PMID: 41055143; PMCID: PMC12536792.
[6] Johnson ML, Patel MR, Falchook GS, Koyama T, Gutierrez M, Awad MM, Piha-Paul SA, Friedman CF, Satoh T, Okamoto N, Singh J, Yoshizuka N, Windish HP, Qian M, Tran BP, Doi T. Ifinatamab deruxtecan, a B7-H3-directed antibody-drug conjugate, in patients with advanced solid tumours (IDeate-PanTumor01): dose-escalation results from a phase 1/2 trial. Lancet Oncol. 2026 Apr;27(4):491-501. doi: 10.1016/S1470-2045(25)00733-8. PMID: 41926962.
[7] Simoes da Rocha PF, Kim YJ, Han JY, et al. Intracranial activity of ifinatamab deruxtecan (I-DXd) in patients with extensive-stage small cell lung cancer and baseline brain metastases: primary analysis of IDeate-Lung01. Presented at: ESMO Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract 2760MO.
[8] U.S. Food and Drug Administration. FDA grants traditional approval to tarlatamab-dlle for extensive-stage small-cell lung cancer. November 19, 2025. Online. Last accessed on September 25, 2026.
[9] Mountzios G, Sun L, Cho BC, Demirci U, Baka S, Gümüş M, Lugini A, Zhu B, Yu Y, Korantzis I, Han JY, Ciuleanu TE, Ahn MJ, Rocha P, Mazières J, Lau SCM, Schuler M, Blackhall F, Yoshida T, Owonikoko TK, Paz-Ares L, Jiang T, Hamidi A, Gauto D, Recondo G, Rudin CM; DeLLphi-304 Investigators. Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy. N Engl J Med. 2025 Jul 24;393(4):349-361. doi: 10.1056/NEJMoa2502099. Epub 2025 Jun 2. PMID: 40454646.
[10] Hofland P. Risvutatug Rezetecan Demonstrates Overall Survival Benefit Over Topotecan in Relapsed Small Cell Lung Cancer. ADC Review | J Antibody-drug Conjugates. September 13, 2026. Online. Last accessed on September 25, 2026.
[11] Merck & Co., Inc.; Daiichi Sankyo. Patritumab deruxtecan biologics license application for patients with previously treated locally advanced or metastatic EGFR-mutated non-small cell lung cancer voluntarily withdrawn. May 29, 2025. Online. Last accessed on September 26, 2026
[12] 21 CFR §601.41. Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.
[13] ClinicalTrials.gov. NCT06203210; NCT06925737; NCT06644781. Accessed September 25, 2026.
[14] Hofland P. Ifinatamab Deruxtecan Receives FDA Priority Review for Previously Treated Extensive-Stage Small Cell Lung Cancer. ADC Review | J Antibody-drug Conjugates. April 13, 2026. doi:10.14229/jadc.2026.13.04.009.
[15] Yamato M, Hasegawa J, Maejima T, Hattori C, Kumagai K, Watanabe A, Nishiya Y, Shibutani T, Aida T, Hayakawa I, Nakada T, Abe Y, Agatsuma T. DS-7300a, a DNA Topoisomerase I Inhibitor, DXd-Based Antibody-Drug Conjugate Targeting B7-H3, Exerts Potent Antitumor Activities in Preclinical Models. Mol Cancer Ther. 2022 Apr 1;21(4):635-646. doi: 10.1158/1535-7163.MCT-21-0554. PMID: 35149548; PMCID: PMC9377751.
Featured image: © 2026 CHA ONC ADCR. Used with permission
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