Two FDA-approved antibody-drug conjugates (ADCs)—gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth) and belantamab mafodotin (Blenrep®; GSK)—were withdrawn from the U.S. market after confirmatory trials failed to verify clinical benefit, and both were later reapproved under revised clinical strategies. Their regulatory histories show that withdrawing an accelerated-approval indication does not necessarily indicate failure of the underlying ADC.
Key Takeaways
- Accelerated approval requires postmarketing confirmatory trials; failure to verify benefit can result in voluntary or US Food and Drug Administration (FDA) initiated withdrawal.
- Gemtuzumab ozogamicin was withdrawn in 2010 after SWOG S0106 showed no survival benefit and higher fatal induction toxicity, then reapproved in 2017 using a fractionated dosing regimen supported by ALFA-0701 data.
- Belantamab mafodotin was withdrawn in 2022 after DREAMM-3 failed to meet its progression-free survival endpoint as monotherapy, then reapproved in 2025 in combination regimens based on DREAMM-7 and DREAMM-8.
- In both cases, reapproval followed a change in dose, schedule, or combination strategy rather than a repeat of the original clinical approach.
- Regulatory outcomes are not uniform across jurisdictions: Japanese oncology guidelines retained gemtuzumab ozogamicin as a preferred option even after its original U.S. withdrawal.
Accelerated Approval Creates a Confirmatory Obligation
In oncology, overall response rate and duration of response have frequently served as the surrogate endpoints supporting accelerated approval, although other endpoints have also been used [1]. FDA’s Oncology Center of Excellence tracks the status of oncology accelerated approvals through Project Confirm, including indications under confirmatory evaluation, indications for which benefit has been verified, and indications that have been withdrawn [2]. Between December 1992 and July 2010, FDA granted accelerated approval to 35 oncology products across 47 indications; clinical benefit was subsequently confirmed for 26 of those indications, while three were withdrawn after confirmatory trials failed to verify benefit [3].
For an ADC specifically, an unsuccessful confirmatory study carries particular weight, since the outcome may implicate dose intensity, dosing schedule, patient selection, disease setting, combination partner, or the relationship between target engagement and systemic exposure. The regulatory history therefore warrants detailed examination rather than reduction to a sequence of approved, failed, withdrawn.
Gemtuzumab Ozogamicin: A Dosing Strategy Changed the Regulatory Outcome
Gemtuzumab ozogamicin received accelerated approval from the FDA in May 2000 for CD33-positive acute myeloid leukemia (AML) in patients 60 years of age or older in first relapse who were not candidates for other cytotoxic chemotherapy. The approval was based on an overall response rate of 30% across three phase 2 trials enrolling 142 patients, at a dose of 9 mg/m² administered intravenously over 4 hours and repeated on day 14 [5]. In the phase 2 population, 31% of patients exhibited abnormal liver enzymes, and one patient died of liver failure [5].
The confirmatory trial, SWOG S0106 (NCT00085709), evaluated gemtuzumab ozogamicin in combination with standard induction chemotherapy in 627 patients with newly diagnosed AML younger than 61 years. The trial was halted early after an interim analysis showed no improvement in survival and a significantly higher rate of fatal induction toxicity in the combination arm compared with chemotherapy alone (5.7% vs. 1.4%; P = .01) [6]. Following discussions with FDA, Pfizer (having acquired the product through its acquisition of Wyeth) voluntarily withdrew gemtuzumab ozogamicin from the U.S. market effective October 15, 2010 [6][7]. The FDA subsequently withdrew approval of the underlying new drug application in November 2011 [7].
Subsequent clinical investigation examined whether a fractionated dosing strategy—smaller doses administered over multiple treatment days rather than the original two-dose schedule—could preserve antileukemic activity while reducing toxicity. The phase 3 ALFA-0701 trial (NCT00927498) evaluated fractionated gemtuzumab ozogamicin (3 mg/m² on days 1, 4, and 7) added to standard induction chemotherapy in adults with de novo AML, demonstrating a 34% reduction in the risk of an event-free survival event compared with chemotherapy alone [8]. The single-arm MyloFrance-1 study evaluated the same fractionated regimen as monotherapy in relapsed CD33-positive AML, reporting a complete response rate of 26% and no cases of hepatic veno-occlusive disease. [9]*
Based on this evidence, the FDA reapproved gemtuzumab ozogamicin in September 2017, seven years after the original withdrawal, using a lower-dose, fractionated schedule and an expanded population that included adults with newly diagnosed CD33-positive AML and patients as young as 2 years of age with relapsed or refractory disease. [9][10] The indication was further extended in June 2020 to include newly diagnosed pediatric patients 1 month of age and older [11]. The 2017 reapproval represented a materially different clinical proposition from the original approval: the dosing regimen, treatment population, and combination strategy had each changed [9].
Belantamab Mafodotin: From Monotherapy to Combination Therapy
GSK received accelerated FDA approval for belantamab mafodotin in August 2020 for relapsed or refractory multiple myeloma in patients who had received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. The approval was based on overall response rate as a single agent in the phase 2 DREAMM-2 trial (NCT03525678). [12].
The confirmatory trial, DREAMM-3 (NCT04162210), compared single-agent belantamab mafodotin with pomalidomide plus low-dose dexamethasone. The trial did not meet its primary progression-free survival endpoint required under the accelerated-approval regulations [13]. Following this outcome, GSK announced in November 2022 that it had initiated withdrawal of the U.S. marketing authorization for belantamab mafodotin at FDA’s request. [13][14]
Subsequent development shifted from single-agent use toward combination regimens evaluated against active comparators. DREAMM-7 (NCT04246047) compared belantamab mafodotin with bortezomib and dexamethasone against daratumumab, bortezomib, and dexamethasone, reporting a 51% reduction in the risk of death and a substantial improvement in median progression-free survival for the belantamab mafodotin combination [15][16]. DREAMM-8 (NCT04484623) evaluated belantamab mafodotin with pomalidomide and dexamethasone against a bortezomib-based comparator. [16][17]
In October 2025, FDA approved belantamab mafodotin in combination with bortezomib and dexamethasone for relapsed or refractory (R/R) multiple myeloma in patients who had received at least two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent [15][18]. The approval is administered through the BLENREP Risk Evaluation and Mitigation Strategy (REMS) program; prescribing information carries a boxed warning for ocular toxicity, which occurred in 92% of DREAMM-7 patients receiving belantamab mafodotin (grade 3/4 in 77%), with dosage modification required in 83% [18,19]. The interval between withdrawal and reapproval was approximately three years, shorter than the seven-year interval observed for gemtuzumab ozogamicin. [13][15]
FDA’s Oncologic Drugs Advisory Committee reviewed the belantamab mafodotin combination applications in July 2025 with divided opinions on the benefit-risk profile, and agency reviewers noted high rates of ocular toxicity and dose modification in their briefing materials [20]. DREAMM-7 and DREAMM-8 also showed high rates of dose interruption and reduction, with fewer than half of patients in each trial receiving the intended dose by cycle 3 [20].
What These Two ADCs Have in Common
Neither development program ended with the initial regulatory withdrawal, and neither subsequent program simply reproduced the original clinical strategy. For gemtuzumab ozogamicin, the modification centered on dose fractionation and schedule. For belantamab mafodotin, the modification centered on combination therapy and treatment-line positioning. Both cases illustrate the distinction between the failure of a specific clinical strategy and the failure of an ADC’s underlying target, antibody, or payload.
That distinction should not be generalized to suggest that every withdrawn ADC indication can or should return to development. Some ADC programs fail because the target is poorly validated, the therapeutic window is inadequate, systemic pharmacology cannot support effective tumor exposure, or toxicity cannot be adequately controlled through dose or schedule modification.
Four Questions for an ADC Confirmatory-Trial Failure
- Was the dose appropriate? ADC development requires balancing exposure sufficient for target-mediated activity against systemic and target-independent toxicity. A retrospective analysis of gemtuzumab ozogamicin dosing found that doses above 6 mg/m² per administration were associated with increased toxicity without added survival benefit, while repeated 3 mg/m² doses reaching a 9 mg/m² cumulative dose were better tolerated [21].
- Was the schedule appropriate? Fractionated administration—altering the timing and distribution of a given total dose—was central to the gemtuzumab ozogamicin regimen that supported reapproval [8,9].
- Was the ADC used in the appropriate clinical setting? Standards of care evolve over the years required for ADC development. An agent studied as monotherapy may later face more effective competitors or combination regimens, or may show greater utility in combination. The belantamab mafodotin development program illustrates this consideration directly [16,17].
- Did the safety profile remain manageable in the new context? An ADC’s clinical utility depends on benefit-risk balance rather than efficacy alone. Ocular toxicity, including keratopathy associated with off-target uptake of the monomethyl auristatin F (MMAF) payload in the corneal epithelium, remains a defining safety consideration for belantamab mafodotin in its combination indications and requires ongoing ophthalmologic monitoring [16]. For gemtuzumab ozogamicin, hepatotoxicity and veno-occlusive disease/sinusoidal obstruction syndrome remain relevant considerations, particularly around hematopoietic stem cell transplantation, and expert management guidance published after the 2017 reapproval addresses them [22].
Regulatory Divergence Across Jurisdictions
Regulatory outcomes for accelerated-approval oncology drugs have not been uniform across jurisdictions. A cross-sectional analysis of Japanese professional society guidelines examined seven accelerated-approval oncology drugs withdrawn from the U.S. market but remaining approved in Japan, including gemtuzumab ozogamicin [23].
Four of the seven drugs, including gemtuzumab ozogamicin, were recommended as highly or moderately preferred treatment options in Japanese guidelines despite the U.S. withdrawal [23]. The analysis noted that gemtuzumab ozogamicin’s original U.S. withdrawal reflected both a failure to demonstrate benefit and specific safety concerns, and identified this regulatory divergence as warranting greater transparency regarding the evidentiary basis for guideline recommendations in Japan [23].
This history predates the fractionated-dose regimen that later supported U.S. reapproval and underscores that regulatory status in one jurisdiction, at a given point in time, does not necessarily reflect the full evidentiary record available elsewhere.
Regulatory History as Part of the Scientific Record
An approval, withdrawal, or reapproval reflects the evidence available to regulators at a given point in development and the benefit-risk assessment associated with a specific clinical strategy. For ADCs, that history can carry information about dose and exposure, dosing schedule, target biology, patient selection, treatment line, combination strategy, safety management, and the evolving standard of care.
Separately, an analysis of industry payments associated with oncology drugs granted accelerated approval found that promotional activity did not uniformly decline after confirmatory trials failed. Among six accelerated-approval oncology drugs with negative confirmatory results and available payment data, average monthly industry payments to physicians for belantamab mafodotin fell from $152,417 before the DREAMM-3 result to $119,066 between the negative result and market withdrawal, a smaller proportional decline than observed for some other agents in the same analysis [24]. This observation does not bear on the subsequent DREAMM-7 and DREAMM-8 combination data but is relevant to the broader regulatory and commercial context surrounding confirmatory-trial outcomes in oncology.
Linker and Payload Considerations
Dose and clinical positioning are not the only variables influencing an ADC’s regulatory trajectory. Linker stability and payload chemistry can independently determine whether an ADC achieves an acceptable therapeutic window; premature payload release increases systemic exposure to cytotoxic payload and can produce off-target toxicity independent of dosing schedule or clinical setting. A program affected by premature payload release presents a different developmental problem than one affected by inadequate target expression, an unfavorable treatment population, excessive peak exposure, or an increasingly competitive standard of care—reinforcing the need to examine the specific cause of an unsuccessful confirmatory trial rather than treating ADC failures as interchangeable.
Conclusion
The regulatory histories of gemtuzumab ozogamicin and belantamab mafodotin are not evidence that withdrawal is inconsequential; both withdrawals followed clinically meaningful confirmatory-trial failures with defined safety findings. They do, however, demonstrate that a withdrawal’s implications depend on its underlying cause.
For gemtuzumab ozogamicin, a modified dosing strategy supported reapproval seven years later. For belantamab mafodotin, combination-regimen data supported a new approval approximately three years after withdrawal. In both cases, the development program identified a specific, addressable limitation in how the ADC was used, rather than establishing that the underlying molecule lacked a therapeutic role.
Note
- Gemtuzumab ozogamicin Resources for clinicians
- MYLOTARG® (Gemtuzumab Ozogamicin) in Acute Myeloid Leukemia: Clinical Applications, Toxicity Management, Biomarker-Driven Patient Selection, and Multidisciplinary Care Part 1
- MYLOTARG® (Gemtuzumab Ozogamicin) in Acute Myeloid Leukemia: Clinical Applications, Toxicity Management, Biomarker-Driven Patient Selection, and Multidisciplinary Care Part 2
Clinical Trials
- S0106 Cytarabine and Daunorubicin w/ or w/o Gemtuzumab Followed By HD Cytarabine and Either Gemtuzumab or Nothing in de Novo AML – ClinicalTrials.gov ID NCT00085709
- A Randomized Study of Gemtuzumab Ozogamicin (GO) With Daunorubicine and Cytarabine in Untreated Acute Myeloid Leukemia (AML) Aged of 50-70 Years Old – ClinicalTrials.gov ID NCT00927498
- Gemtuzumab Ozogamicin+Cytarabine vs Idarubicin+Cytarabine in Elderly Patients With AML. Mylofrance 4 (ALFA1401) – ClinicalTrials.gov ID NCT02473146
- Study of Gemtuzumab Ozogamicin Therapy in DNA Samples From Patients With Acute Myeloid Leukemia Treated on COG-AAML0531
ClinicalTrials.gov ID NCT01407757 - A Study to Investigate the Efficacy and Safety of Two Doses of GSK2857916 in Participants With Multiple Myeloma Who Have Failed Prior Treatment With an Anti-CD38 Antibody – ClinicalTrials.gov ID NCT03525678
- Study of Single Agent Belantamab Mafodotin Versus Pomalidomide Plus Low-dose Dexamethasone (Pom/Dex) in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM-3) – ClinicalTrials.gov ID NCT04162210
- Evaluation of Efficacy and Safety of Belantamab Mafodotin, Bortezomib and Dexamethasone Versus Daratumumab, Bortezomib and Dexamethasone in Participants With Relapsed/Refractory Multiple Myeloma (DREAMM 7) – ClinicalTrials.gov ID NCT04246047
- Belantamab Mafodotin Plus Pomalidomide and Dexamethasone (Pd) Versus Bortezomib Plus Pd in Relapsed/Refractory Multiple Myeloma (DREAMM 8) – ClinicalTrials.gov ID NCT04484623
Highlights of Prescribing Information
Gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth)[Prescribing information]
Belantamab mafodotin (Blenrep®; GSK)[Prescribing Information]
References
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Disclamer
This article is intended for informational purposes for healthcare and life-sciences professionals.
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