This is a global, multicenter, randomized, open-label, Phase 3 study designed to compare the efficacy and safety of I-DXd with the TPC in subjects with relapsed SCLC. Eligible subjects will have received one prior line of platinum-based therapy and at least 75% of whom will have received prior treatment with anti-programmed death-(ligand) 1 (PD-[L]1) antibody. Subjects must have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of ≤1.
This study is designed to randomize at least 468 subjects in a 1:1 ratio to receive I-DXd (n = 234) or TPC (n = 234; topotecan, amrubicin, or lurbinectedin). Comparator treatments will only be utilized in countries where they are approved in second line for SCLC subjects who progressed on or after platinum-based therapy.
At least 50% of subjects treated in the comparator group will receive topotecan.

This study is designed to randomize at least 468 subjects in a 1:1 ratio to receive I-DXd (n = 234) or TPC (n = 234; topotecan, amrubicin, or lurbinectedin). Comparator treatments will only be utilized in countries where they are approved in second line for SCLC subjects who progressed on or after platinum-based therapy. At least 50% of subjects treated in the comparator group will receive topotecan
I-DXd is an ADC that consists of an anti-B7-H3 antibody (MABX-9001a) conjugated to a cytotoxi exatecan-derived payload (MAAA-1181a).
Amrubicin is an anthracycline, which acts by inhibiting topoisomerase II. It is indicated for the treatment of relapsed SCLC in Japan.
Lurbinectedin is an alkylating drug indicated for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy.
Topotecan is a topoisomerase I inhibitor indicated for the treatment of SCLC in patients with chemotherapy-sensitive disease after failure of 1L chemotherapy.

Inclusion Criteria: voor volledige lijst zie protocol
Subjects must meet all the following criteria to be eligible for randomization into the study:

1. Sign and date the informed consent form prior to the start of any study-specific qualification procedures.
2. Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time the informed consent form is signed.
3. Has histologically or cytologically documented SCLC.
4. The subject must provide adequate baseline tumor samples with sufficient quantity and quality of tumor tissue content. Required tumor tissue can be provided as either of the following:
   a. If medically feasible, newly obtained pretreatment tumor biopsy from at least 1 lesion amenable to core biopsy.
   b. If the tumor is inaccessible or the subject is medically unfit for collection of the pretreatment tumor biopsy, archival tumor tissue collected from a biopsy performed within 6 months of consent and performed after treatment with their most recent anticancer therapy regimen. If, after all efforts have been made, the newly obtained pretreatment biopsy is not feasible or the procedure is unsuccessful and an appropriate archival sample is not available, the subject may be considered for study eligibility at the investigator’s discretion after discussion with the Sponsor medical monitor.
5. Has received prior therapy with only one prior platinum-based line as systemic therapy for SCLC with at least 2 cycles of therapy and a chemotherapy-free interval of ≥30 days. Subjects with or without prior immune-checkpoint inhibitor therapy are eligible. Subjects treated with a platinumbased line of therapy for prior limited-stage-small cell lung cancer may be eligible for the study. Subjects must not have received more than one prior line of systemic therapy. One line of therapy will be defined as 1 or more drugs received prior to newly documented disease progressions. Any switch between carboplatin and cisplatin for toxicity reasons will be regarded as one line overall.
6. Has at least 1 measurable lesion according to RECIST v1.1 as assessed by the investigator. Measurable lesions should not be from a previously irradiated site. If the lesion at a previously irradiated site is the only selectable target lesion, a radiological assessment showing significant progression of the irradiated lesion should be provided by the investigator.
7. Has documentation of radiological disease progression on or after the most recent systemic therapy.
8. Has ECOG PS of ≤1.
9. Subjects with untreated and asymptomatic brain metastases or subjects with treated brain metastases that are no longer symptomatic (ie, without neurologic signs or symptoms) and who require no treatment with steroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. Subjects must have a stable neurologic status for at least 2 weeks prior to the first dose of study drug. Note: A baseline magnetic resonance imaging scan or computed tomography of the brain is required for all subjects at baseline. Subjects with clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated or symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms, are not permitted.
10. Has adequate organ function within 7 days before the start of study treatment.
11. If the subject is a female of childbearing potential, she must have a negative serum pregnancy test during Screening (within 3 days prior to randomization
12. Male subjects randomized to I-DXd group must be surgically sterile or willing to use highly effective birth control upon randomization, during the Treatment Period, and for 4 months following the last dose of I-DXd. Males subjects randomized to the comparator group must be willing to use a highly effective birth control in compliance with the study drug locally approved label.
13. Male subjects randomized to the I-DXd group must not freeze or donate sperm starting at randomization, throughout the Treatment Period, and for at least 4 months following the last dose of the study drug. Preservation of sperm may be considered prior to enrollment in this study.
14. Female subjects randomized to the I-DXd group must not donate, or retrieve for their own use, ova from the time of randomization and throughout the Treatment Period, and for at least 7 months following the last dose of the study drug. Preservation of ova may be considered prior to enrollment in this study.
15. Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures (including patient-reported outcomes), and study restrictions

Exclusion Criteria; voor volledige lijst zie protocol
Subjects who meet any of the following criteria will be disqualified from entering the study:

1. Has received prior treatment with orlotamab, enoblituzumab, or other humanized anti-B7 homologue 3 (B7-H3) targeted agents, including I-DXd.
2. Prior discontinuation of an antibody drug conjugate (ADC) that consists of an exatecan derivative (eg, trastuzumab deruxtecan) due to treatment-related toxicities.
3. Has received any of the comparators used in this study or any topoisomerase I inhibitor
4. Has inadequate washout period before randomization, defined as follows:
   a. Major surgery (placement of vascular access will not be regarded as a major surgery) <4 weeks; surgery for low-invasive cases (eg, colostomy) <2 weeks.
   b. Radiation therapy <4 weeks; palliative stereotactic radiation therapy without abdominal radiation ≤2 weeks; radiation therapy to the lung >30 Gy <6 months; palliative radiotherapy affecting lung areas at lower dose <3 weeks; cranial irradiation, including whole brain radiation therapy and stereotactic radiosurgery ≤2 weeks.
   c. Any systemic anticancer therapy (including immunotherapy [other than antibodies] and investigational drugs) <3 weeks or 5 half-lives, whichever is longer; hormonal therapy (except for luteinizing hormone-releasing hormone agonists/antagonists) <2 weeks.
   d. Antibody-based anticancer therapy <3 weeks.
   e. Chloroquine or hydroxychloroquine ≤14 days.
5. Has any of the following conditions within the past 6 months: cerebrovascular accident, transient ischemic attack, or another arterial thromboembolic event.
6. Has uncontrolled or significant cardiovascular disease, including the following:
   a. Has a corrected QT interval (by Fridericia’s formula) >470 ms (females) or >450 ms (males) based on average of the Screening triplicate 12-lead electrocardiogram.
   b. Diagnosed or suspected long QT syndrome or known family history of long QT syndrome.
   c. History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes.
   d. Subject has bradycardia of less than 50 bpm unless the subject has a pacemaker.
   e. History of second- or third-degree heart block. Subjects with a history of heart block may be eligible if they currently have pacemakers and have no history of fainting or clinically relevant arrhythmia with pacemakers.
   f. Acute myocardial infarction within 6 months prior to Screening.
   g. Uncontrolled angina pectoris within 6 months prior to Screening.
   h. Symptomatic congestive heart failure defined as New York Heart Association Class II to
   i. Coronary/peripheral artery bypass graft or any coronary/peripheral angioplasty within 6 months prior to Screening.
   j. Grade ≥3 hypertension, graded according to the NCI-CTCAE V5.0.
   k. Complete left or right bundle branch block.
   l. Left ventricular ejection fraction (LVEF) <50% by either an echocardiogram (ECHO) or a multigated acquisition (MUGA) scan.
7. Has clinically significant corneal disease.
8. Has history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at Screening.
9. Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, etc) and potential pulmonary involvement caused by any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis, etc), prior pneumonectomy, or requirement for supplemental oxygen.
10. On chronic steroid treatment (dose of 10 mg daily or more prednisone equivalent), except for lowdose inhaled steroids (for asthma/chronic obstructive pulmonary disease), topical steroids (for mild skin conditions), or intra-articular steroid injections.
11. Has history of malignancy other than SCLC within the 3 years prior to randomization, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, superficial gastrointestinal tract tumors, and non-muscle invasive bladder cancer curatively resected by endoscopic surgery.
12. Has history of allogeneic bone marrow, stem cell, or solid organ transplant.
13. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Event V5.0, Grade ≤1 or baseline.
    Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade >2 for at least 3 months prior to randomization and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, following discussion with the Sponsor, such as the following:
    a. Chemotherapy-induced neuropathy
    b. Fatigue
    c. Endocrinopathies, which may include hypothyroidism, hyperthyroidism, type I diabetes, hyperglycemia, adrenal insufficiency, adrenalitis
    d. Skin hypopigmentation (vitiligo)
14. Has history of hypersensitivity to any study drug substances, inactive ingredients in the drug product, or severe hypersensitivity reactions to other monoclonal antibodies.
15. Has evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection. Note: Subjects with localized fungal infections of the skin or nails are eligible.
16. Has known human immunodeficiency virus (HIV) infection that is not well controlled. Subjects should be tested for HIV prior to randomization if required by local regulations or institutional review board (IRB)/ethics committee (EC).
17. Has active or uncontrolled hepatitis B or C infection; zie protocol
18. Has active, known, or suspected autoimmune disease. The following examples may be enrolled as an exception:
    a. Type I diabetes mellitus/hypothyroidism only requiring hormone replacement
    b. Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment
    c. Conditions not expected to recur in the absence of an external trigger
19. Has any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, psychiatric illness/social situations, substance abuse) or other factors that, in the investigator’s opinion, make it undesirable for the subject to participate in the study or would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
20. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live-attenuated vaccines and are not allowed.
21. Female who is pregnant or breastfeeding or planning to become pregnant
22. Has prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator’s opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results.
23. Has psychological, social, familial, or logistical factors that would prevent regular follow-up