A Phase I First-in-Human Study of ABBV-011, a Seizure-Related Homolog Protein 6–Targeting Antibody–Drug Conjugate, in Patients with Small Cell Lung Cancer

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor that accounts for approximately 15% of all lung cancers (1). It is characterized by rapid proliferation and a tendency to develop early widespread metastasis, with 75% to 80% of patients presenting with extensive-stage SCLC at diagnosis (2). The prognosis is poor, with a 5-year survival rate of 6.8% (3). The standard treatment for most patients with limited-stage disease is concurrent chemoradiotherapy, which is associated with a median progression-free survival (PFS) of 13.5 to 15.4 months (4, 5) and a 5-year PFS of 25% (5). For patients with extensive-stage disease, the standard first-line therapy is the combination of platinum with etoposide and an anti–PD-L1 antibody (6). In the second-line setting, topotecan and lurbinectedin are approved for patients whose disease progresses on or after platinum-based chemotherapy, and tarlatamab-dlle has recently been granted accelerated approval by the FDA in this patient population (7–9). Currently, there is no standard therapy for the third line and beyond. Despite the high response rates to first-line therapy, most patients experience relapse, with a median PFS of 5.1 months (10, 11). The benefit from treatment is even less pronounced in the second line, with a median PFS of 3.5 months following treatment with topotecan or lurbinectedin (7, 8). Hence, there remains a high unmet need for patients with SCLC.

Seizure-related homolog protein 6 (SEZ6) is a type I transmembrane protein involved in neuronal function and development (12–14). It is highly expressed in neuroendocrine tumors including SCLC, especially the ASCL1- and NEUROD1-positive subtypes (15). SEZ6 represents an attractive target in SCLC, as it is not expressed in most normal tissues, outside of neuronal tissues such as the brain, spinal cord, pituitary gland, and retina (15).

ABBV-011 is a novel antibody–drug conjugate (ADC) that targets SEZ6 (15). It comprises the SC17 anti–SEZ6 mAb, conjugated to the potent DNA-damaging N-acetyl-γ-calicheamicin payload via a novel noncleavable linker with a drug-to-antibody ratio of 2 (15). ABBV-011 is proposed to target SEZ6-expressing tumor cells with high affinity and release the calicheamicin payload intracellularly to induce cell death. Calicheamicin is also the payload in two approved ADC, gemtuzumab ozogamicin and inotuzumab ozogamicin (16, 17). The most relevant off-target toxicities with these ADC are cytopenia, hepatotoxicity [including veno-occlusive liver disease (VOD)], and infusion site reactions, which may limit their use (18, 19). Whereas the approved ADC contain an acid-labile linker, ABBV-011 uses a noncleavable linker; hence, off-target toxicity might be minimized. In preclinical studies, ABBV-011 had dose-dependent antitumor activity in patient-derived xenografts of SEZ6-expressing SCLC, and toxicities were consistent with those previously described for calicheamicin-based ADC (15).

Herein, we report the initial results from the monotherapy part of the currently ongoing first-in-human phase I trial to investigate the safety, determine the MTD, and/or establish the recommended phase II dose (RP2D) and assess the preliminary antitumor efficacy of ABBV-011 in patients with relapsed or refractory (R/R) SCLC.

This is a first-in-human, multicenter, open-label phase I study of ABBV-011 administered as monotherapy or in combination with budigalimab, a programmed cell death 1 inhibitor, in patients with R/R SCLC. The first part of the study assessed ABBV-011 as monotherapy and consisted of a dose-escalation phase followed by a dose-expansion phase; a cohort evaluating the recommended ABBV-011 dose in Japanese patients [Japanese dose-evaluation cohort (n = 3)] was included, as per the Japanese Pharmaceuticals and Medical Devices Agency requirements (20). The second part of the study planned to evaluate ABBV-011 and budigalimab combination in dose-escalation and dose-expansion phases. Here, we present the initial results of ABBV-011 monotherapy. The primary objectives were to assess the safety and tolerability and determine the MTD and/or RP2D. The secondary objectives included pharmacokinetics (PK) and antitumor activity per RECIST v1.1.

There was no randomization or blinding for this study, and patients were assigned a unique identification number at the screening visit. All patients provided written informed consent before study entry. The study was approved by the relevant institutional review boards and/or independent ethics committees and was conducted according to the International Conference on Harmonization Good Clinical Practice guidelines and the Declaration of Helsinki. The study is registered with ClinicalTrials.gov (NCT03639194).

Eligible patients included adults (≥18 years of age) with histologically or cytologically confirmed R/R SCLC who received ≤3 lines of prior therapy, including ≥1 prior platinum-containing chemotherapy, Eastern Cooperative Oncology Group performance status score of 0 or 1, measurable disease according to RECIST v1.1, and adequate hematologic, liver, and renal function. Prior anticancer therapy had to be completed ≥4 weeks before the first ABBV-011 dose. Patients with previously treated central nervous system metastases with stable or improved lesions for ≥2 weeks after therapy completion were eligible. There were no preselection criteria for enrollment of patients in dose escalation based on tumor SEZ6 expression. For dose expansion, patients with SEZ6-positive tumors (≥25% tumor cells with ≥1+ staining intensity by IHC) were preselected.

In the dose-escalation phase, patients received ABBV-011 intravenously at dosages of 0.3, 0.6, 1.2, 1.6, and 2.0 mg/kg once every 3 weeks, on day 1 of each 21-day cycle, or at 0.5 mg/kg on days 1 and 8 of each 21-day cycle.

Dose escalation was guided by a Bayesian continual reassessment method, using a two-parameter Bayesian logistic regression model that incorporated the escalation with the overdose control principle for patient safety. The definitions of dose-limiting toxicities (DLT) are listed in the Supplementary Methods.

For dose evaluation in Japanese patients, ABBV-011 was administered at 1.0 mg/kg every 3 weeks. Three patients were enrolled for DLT evaluation, and the evaluation was considered completed if no DLT were identified.

DLT were assessed in dose-escalation and Japanese dose-evaluation parts during the first 6 weeks of treatment; patients were considered DLT evaluable if they completed the DLT evaluation period or experienced a DLT.

In the dose-expansion phase, ABBV-011 was further evaluated for safety, tolerability, PK, and antitumor efficacy in patients with SEZ6-positive tumors. Initially, the highest dosage from dose escalation, 2 mg/kg every 3 weeks, was selected for dose expansion based on safety in dose escalation. In consultation with the safety monitoring committee and approved by the institutional review boards and/or independent ethics committees, the expansion dose was reduced to 1.6 mg/kg in cycle 1, followed by 1.2 mg/kg in subsequent cycles, and further to 1.0 mg/kg every 3 weeks on the basis of review of long-term safety, tolerability, PK, and efficacy data, as well as the risk for delayed hepatotoxicity. A 0.8-mg/kg every 3 weeks cohort was included to further explore the optimal ABBV-011 monotherapy dose. Patients received ABBV-011 until disease progression (PD) or other treatment discontinuation criteria were met.

Safety parameters included physical examination, vital signs, laboratory tests, ECG, echocardiograms, and treatment-emergent adverse events (TEAE). TEAE were graded according to the NCI Common Terminology Criteria for Adverse Events, version 5.0. Serious adverse events (SAE) and non-SAE occurring from the time of consent until the first ABBV-011 dose were collected. Additionally, all TEAE and SAE from the time of ABBV-011 start until 60 days after the last dose were collected.

Blood samples for PK evaluation were collected on days 1 (preinfusion and 30 minutes and 2 hours postinfusion); on days 2, 4, 8, and 15 of cycles 1 and 3; and on day 1 (preinfusion and 30 minutes postinfusion) of cycles 2, 5, 7, and 9. Serum concentrations of ABBV-011 and plasma concentrations of the released catabolite of linker–drug (M8b) were determined using validated methods. PK parameters were estimated using noncompartmental analysis.

Tumor imaging response was evaluated every 6 weeks for the first 24 weeks of the study and then every 12 weeks for up to 4 years afterward until progression or treatment discontinuation. Clinical response was determined using RECIST v1.1 criteria by the investigator, including the objective response rate [ORR; included patients with confirmed complete response (CR) plus confirmed partial response] and clinical benefit rate (CBR; included patients with confirmed CR, confirmed partial response, and stable disease). Additionally, duration of response (DOR), duration of clinical benefit (DOCB), and PFS were determined.

Testing for SEZ6 expression was performed by IHC in a central Clinical Laboratory Improvement Amendments–certified laboratory using archived tumor tissue or fresh tumor biopsy at screening in dose-escalation and Japanese dose-evaluation parts and at prescreening in dose expansion to select patients with SEZ6-positive tumors for the expansion phase. The study sponsor, AbbVie, Inc., in collaboration with CellCarta, developed a novel IHC assay with a pathologist-based algorithm and scoring method (CD166) to evaluate SEZ6 expression in patient tumor biopsies. The CD166 scoring method comprises a semiquantitative evaluation of the percentage of tumor cells with overall (membranous and cytoplasmic) staining at different intensities (0, 1+, 2+, and 3+) in tumor samples. The cutoff for SEZ6 positivity was based on correlative analysis of ABBV-011 in vivo efficacy and SEZ6 expression in patient-derived xenograft models of SCLC with variable SEZ6 expression levels.

The safety and efficacy populations included all patients who received ≥1 dose of ABBV-011. Patients without postbaseline tumor assessment were considered nonresponders; one patient at 0.8 mg/kg who received only one dose and had no postbaseline tumor assessment at the time of data cutoff was excluded from the response-evaluable analysis set. The PK population included patients with adequate blood sampling to estimate at least one PK parameter.

Safety analyses were performed using descriptive statistics. The two-sided 95% confidence intervals (CI) for ORR and CBR were calculated using the Clopper–Pearson (exact) method. Median PFS, DOR, and DOCB were estimated using the Kaplan–Meier method.

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Between November 2018 and August 2022, 99 patients were enrolled and received ≥1 dose of ABBV-011 [dose escalation, n = 36; Japanese dose evaluation, n = 3; dose expansion, n = 60 (1-mg/kg cohort: n = 40)]. Demographics and baseline disease characteristics are summarized in Table 1. Overall, the median age was 63 years (range, 41–79 years), 51% of patients were female, 88% were White, and 80% had an Eastern Cooperative Oncology Group performance status score of 1. The median number of prior lines of therapy was 2 (range, 1–4), which included a programmed cell death 1/PD-L1–targeted agent in 77% of patients. The median ABBV-011 treatment cycle received was 3 (range, 1–21). At data cutoff, 90 (91%) patients had discontinued treatment [PD (54%), AE (12%), consent withdrawal (4%), physician’s decision (4%), and other (17%; mostly clinical progression)]. Seventy-five percent of patients were off study due to death (69%), consent withdrawal (2%), physician’s decision (2%), loss to follow-up (1%), and other (1%). Patient disposition in the overall population and 1-mg/kg dose-expansion cohort is summarized in Supplementary Table S1. The representativeness of the study population to the real-world population is described in Supplementary Table S2.

A total of 445 SCLC tumor tissue samples were analyzed for SEZ6 expression by IHC from patients on this study (prescreened, screened, and/or enrolled). The majority (86%) had ≥1% tumor cells with ≥1+ staining intensity, and 55% met the dose-expansion enrollment cutoff of ≥25% tumor cells with ≥1+ staining intensity. This selection cutoff in the dose-expansion cohorts was determined based on a preclinical efficacy study in which xenograft models derived from patients with SCLC with various levels of SEZ6 expression, as measured by SEZ6 IHC, were treated with ABBV-011. As shown in Supplementary Fig. S1, correlative analysis of SEZ6 expression IHC with efficacy in the patient-derived xenograft study indicated that significant antitumor activity was observed in the patient-derived xenograft models with SEZ6 expression on ≥25% of tumor cells with ≥1+ staining intensity.

In dose escalation, one of nine patients in the 2-mg/kg dose cohort experienced a DLT of grade 3 fatigue. No MTD was identified, and the 2-mg/kg dosage every 3 weeks was initially selected for the expansion phase based on overall safety during the DLT evaluation period. However, the occurrence of delayed-onset hepatotoxicity [5/14 (36%; median time to onset: 65 days; range, 37–176) in patients with a γ-glutamyltransferase (GGT) increase and 4/14 (29%; median time to onset: 53.5 days; range, 37–65) in patients with a bilirubin increase in the 1.6- and 2-mg/kg dose cohorts combined] led to the reduction of the recommended dose for the expansion phase to 1.6 mg/kg in cycle 1 and 1.2 mg/kg in subsequent cycles. Continued findings of hepatotoxicity at that dose with 9/13 (69%; median time to onset: 50 days; range, 8–127) and 2/13 (15%; median time to onset: 64.5 days; range, 44–85) patients with GGT and bilirubin increase, respectively, led to another reduction of the recommended dose to 1 mg/kg, with 93% of patients receiving ≥80% relative dose intensity at this dose. The time to onset of the first hepatotoxicity events is listed in Supplementary Table S3. TEAE leading to treatment discontinuation, dose interruption, and dose reduction occurred, respectively, in 19%, 34%, and 8% of patients in the overall population and in 13%, 35%, and 15% in the 1-mg/kg dose-expansion cohort.

TEAE in the overall population (N = 99) and the 1-mg/kg dose-expansion cohort (n = 40) are summarized in Table 2. Overall, 96 (97%) of 99 patients experienced at least one TEAE. The most common TEAE (all grades) were fatigue (50%), nausea (42%), thrombocytopenia (41%), decreased appetite (40%), and vomiting (31%). Grade ≥3 TEAE occurred in 63 (64%) patients. Fatigue and thrombocytopenia (9% each) and increased GGT and pneumonia (7% each) were the most frequent. Treatment-related AE were reported in 76 (77%) patients and were grade ≥3 in 34 (34%; Table 2) patients; the most frequent treatment-related AE are summarized in Supplementary Table S4. Notably, no grade >2 neurologic events and no eye toxicities of any grade related to ABBV-011 treatment were reported.

A summary of hepatic TEAE is shown in Table 2. Hepatic TEAE were observed in 42 (42%) patients in the overall population; the most common TEAE were increased aspartate aminotransferase (22%), increased GGT (21%), and hyperbilirubinemia (17%). In the 1-mg/kg dose-expansion cohort, 14 (35%) patients reported hepatic TEAE, including hyperbilirubinemia (18%), increased aspartate aminotransferase (15%), increased GGT (13%), ascites (10%), VOD (3%), and portal hypertension (3%). Hepatic TEAE grade ≥3 occurred in 12 (12%) patients in the overall population and five (13%) patients in the 1-mg/kg dose-expansion cohort. Two patients experienced grade 3 VOD that was resolved with appropriate management. The first patient developed VOD after one 1.6-mg/kg dose of ABBV-011 and was treated with ursodiol and diuretics. The second patient developed VOD after three 1-mg/kg doses of ABBV-011 and was treated with defibrotide and ursodiol.

TEAE leading to death occurred because of PD (n = 16) and stroke, cardiac failure, and respiratory distress (n = 1 each). No treatment-related deaths were reported.

Following ABBV-011 intravenous infusion in cycle 1, preliminary systemic exposures of the ADC were approximately dose proportional across 0.3- to 2.0-mg/kg doses. The harmonic mean elimination half-life of the ADC was 4.6 days (n = 87) across doses. ABBV-011 ADC serum concentration–time profiles and estimated PK parameters are shown in Supplementary Fig. S2 and Supplementary Table S5, respectively. Preliminary plasma concentrations of the catabolite of linker–drug M8b were generally low across doses. At 1.0 mg/kg every 3 weeks, M8b concentrations were quantifiable only at 24 hours postinfusion in some patients, with a geometric mean of approximately 0.2 ng/mL, slightly above the lower limit of quantitation of 0.15 ng/mL.

The best percentage changes from baseline in target lesions for the overall population and the 1-mg/kg dose-expansion cohort are shown in Fig. 1.

Confirmed responses were observed at doses ≥0.6 mg/kg. The ORR in the 98 evaluable patients was 19%, including CR in one (1%) patient. The CBR was 69%, and the CBR lasting >12 weeks was 37% (Table 3).

For the 1-mg/kg dose-expansion cohort, the ORR (n = 40) was 25%, CBR was 65%, and CBR lasting >12 weeks was 43% (Table 3). The median treatment duration was 12 weeks (range, 2–63), the median DOR was 4.2 months (95% CI, 2.6–6.7), and the median DOCB was 5.8 months (95% CI, 4.1–7.6). The evolution of response over time for each patient is shown in Fig. 2. In patients who had received 1 (n = 12) and ≥2 prior lines (n = 28) of therapy, the ORR was 25% and 25%, CBR was 75% and 61%, and CBR lasting >12 weeks was 58% and 36%, respectively (Supplementary Table S6). In patients who had a chemotherapy-free interval <90 (n = 12) and ≥90 days (n = 26) following a first-line platinum-based therapy, the ORR was 25% and 27%, CBR 58% and 69%, and CBR lasting >12 weeks 33% and 50%, respectively (Supplementary Table S6).

The median PFS was 3.5 months (95% CI, 1.5–4.2) in the 1-mg/kg dose-expansion cohort (n = 40), 5.4 months (95% CI, 1.4–8.3) for patients who had received one prior line of therapy, and 2.7 months (95% CI, 1.4–4.1) for patients who had received ≥2 prior lines (Fig. 3; Supplementary Table S6). The median PFS was 3.0 months (95% CI, 1.2–3.9) and 4.1 months (95% CI, 1.5–5.8) for patients with a chemotherapy-free interval <90 and ≥90 days, respectively (Supplementary Table S6).

In this first-in-human phase I study, ABBV-011 at 1 mg/kg every 3 weeks showed promising efficacy in SEZ6-positive R/R SCLC with an ORR of 25% and a median DOR of 4.2 months. The median PFS was 3.5 months (95% CI, 1.5–4.2) for all patients and 5.4 months (95% CI, 1.4–8.3) for patients receiving ABBV-011 as second-line therapy, which compares favorably with that observed in previous studies with second-line topotecan (3.5 months; 95% CI, 2.9–4.2) and lurbinectedin (3.5 months; 95% CI, 2.6–4.3; refs. 7, 8).

ABBV-011 was well tolerated at the dosage of 1 mg/kg every 3 weeks; the most common TEAE were fatigue, nausea, thrombocytopenia, and decreased appetite. Notably, no on-target neurologic or ocular toxicities were reported. Hepatotoxicity, including VOD, is a class effect of calicheamicin-based ADC, such as gemtuzumab ozogamicin (14, 18, 21) and inotuzumab ozogamicin (15, 19), and the cumulative dosing of ABBV-011 led to GGT and bilirubin increases along with cases of VOD. Two patients experienced ABBV-011–related grade 3 VOD that was resolved with medical management. Efforts to further refine the optimal dosing of ABBV-011 are ongoing, and the RP2D will be confirmed once the results from the 0.8-mg/kg dose cohort become available.

Study limitations include the modest number of patients enrolled at the preliminary RP2D of 1 mg/kg every 3 weeks and the lack of a control treatment arm. Additionally, patients enrolled in the dose-expansion group were preselected for SEZ6, although it is currently unknown if SEZ6 expression in tumor cells is associated with a favorable prognosis. These limitations preclude drawing definitive conclusions on efficacy outcomes, such as DOR and PFS, indicating the need for larger, confirmatory randomized studies.

Insights on the predictive value of SEZ6 will come from the ongoing correlative analysis of SEZ6 expression levels and response to ABBV-011. Preliminary data did not show a correlation between objective response and SEZ6 expression levels in the dose-expansion cohort. However, this observation remains inconclusive because of the small number of patients and the heterogeneity in prior treatments among the patient population (data not shown). It is also important to note that in addition to SEZ6 expression, other molecular features including, but not limited to, innate sensitivity to the payload and disease molecular subtypes may confer differential therapeutic vulnerabilities to ABBV-011. One potential limitation that may confound the analysis of the predictive value of SEZ6 expression is that SEZ6 expression was mainly analyzed in archival tissue collected before any anticancer treatment, as the majority of samples received were from the original diagnosis, and it is unclear whether SEZ6 expression levels changed after exposure to chemotherapy and/or immunotherapy. This topic and the aforementioned molecular features are being investigated in the ongoing correlative analysis of ABBV-011’s efficacy.

Current outcomes for patients with R/R SCLC are poor, and there is a clear need for more effective treatment options beyond chemotherapy. Although SCLC is characterized by a high mutational burden, immune checkpoint inhibitors failed to show a survival benefit compared with chemotherapy in patients with R/R disease (22). Previous attempts with agents against potential targets have failed consistently, and there are still no approved targeted therapies for SCLC (23–25). Recent studies have identified novel potential targets including PARP, WEE1, EZH2, and delta-like ligand 3 (DLL3; refs. 26–30). Of these, two DLL3-targeting agents, rovalpituzumab tesirine and tarlatamab-dlle have reached phase III trials. Rovalpituzumab tesirine development has been discontinued due to a lack of efficacy and the presence of significant toxicity (29, 30). Tarlatamab-dlle, a DLL3–CD3 bispecific T-cell engager, was recently granted accelerated approval by the FDA on the basis of promising efficacy in a phase II study in patients with R/R extensive-stage SCLC (9) and is currently under investigation in a phase III study in relapsed SCLC (NCT05740566; ref. 31). Thus, identifying novel targeted therapies remains a key focus of SCLC research. Our study results suggest that SEZ6 is broadly expressed in SCLC, and ABBV-011 had encouraging efficacy in patients with R/R disease, establishing SEZ6 as a valid therapeutic target. As a follow-up to this study, a different SEZ6-targeted ADC, using a topoisomerase 1 inhibitor payload (ABBV-706), is currently being evaluated in a first-in-human phase I study (NCT05599984). Preliminary results show that ABBV-706 has a manageable safety profile in patients with SCLC, neuroendocrine neoplasms, and central nervous system tumors, as well as promising preliminary efficacy in R/R SCLC and neuroendocrine neoplasms (32).

D. Morgensztern reports other support from AbbVie, G1 Therapeutics, Mirati, Arcus, Merck, Celgene, AstraZeneca, Incyte, Bristol Myers Squibb, Eli Lilly and Company, Array, Pfizer, Surface, Boehringer Ingelheim, and Genprex outside the submitted work. N. Ready reports personal fees from AbbVie outside the submitted work. M.L. Johnson reports grants, nonfinancial support, and other support from AbbVie during the conduct of the study; grants and other support from AbbVie, Amgen, Arcus Biosciences, ArriVent Biopharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly and Company, Fate Therapeutics, Genentech/Roche, Genmab, GlaxoSmithKline, Gritstone Oncology, Immunocore, Janssen, Merck, Mirati Therapeutics, Novartis, Pfizer, Revolution Medicines, Sanofi, and Takeda Pharmaceuticals; grants from Adaptimmune, Array BioPharma, Artios Pharma, Bayer, BeiGene, BerGenBio, BioAtla, Black Diamond, Calithera Biosciences, Carisma Therapeutics, City of Hope National Medical Center, Conjupro Biotherapeutics, Corvus Pharmaceuticals, Curis, CytomX, Dracen Pharmaceutical, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Genocea Biosciences, Harpoon, Helsinn Healthcare, Hengrui Therapeutics, Hutchison MediPharma, IDEAYA Biosciences, IGM Biosciences, Immuneering Corporation, Immunitas Therapeutics, IMPACT Therapeutics, Incyte, Kartos Therapeutics, LockBody Therapeutics, Loxo Oncology, Memorial Sloan Kettering, Merus, Mythic Therapeutics, NeoImmune Tech, Neovia Oncology, NextPoint Therapeutics, Numab Therapeutics, Nuvalent, OncoC4, Palleon Pharmaceuticals, PMV Pharma, Rain Therapeutics, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Ribon Therapeutics, Rubius Therapeutics, Seven and Eight Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Summit Therapeutics, Syndax Pharmaceuticals, SystImmune, Taiho Oncology, TCR2 Therapeutics, Tempest Therapeutics, Theras, Tizona Therapeutics, Tmunity Therapeutics, Turning Point Therapeutics, Vividion, Vyriad, and Y-mAbs Therapeutics; and other support from Alentis Therapeutics, Biohaven Pharmaceuticals, D3 Bio Limited, Gilead Sciences, Hookipa Biotech, Jazz Pharmaceuticals, ModeX Therapeutics, Molecular Axiom, Normunity, Novocure, Pyramid Biosciences, Seagen, Synthekine, and Zai Lab outside the submitted work. A. Dowlati reports other support from AstraZeneca, Amgen, and AbbVie during the conduct of the study. N. Choudhury reports other support from AbbVie during the conduct of the study, as well as other support from Harpoon Therapeutics, AbbVie, Amgen, Monte Rosa Therapeutics, Roche/Genentech, Sanofi, G1 Therapeutics, and Merck outside the submitted work. D.P. Carbone reports other support from GSK, inThought, Pfizer, Iovance Biotherapeutics, Mirati, Arcus Biosciences, Roche, Bristol Myers Squibb (Israel), AstraZeneca, AbbVie, Novartis, Regeneron, Merck Sharp & Dohme, Pfizer (Egypt), Genentech, Novocure, OncoHost, Merck US, Amgen, Daiichi Sankyo, Bristol Myers Squibb (Brazil), Eli Lilly and Company, Janssen, J&J, Merck, Lumanity, DAVA, and Pfizer during the conduct of the study. S.M. Arnold reports other support from AbbVie during the conduct of the study. S. Puri reports personal fees from Pfizer, Bristol Myers Squibb, Novocure, Takeda, and OncoHost and nonfinancial support from Henlius outside the submitted work. Z. Piotrowska reports grants, personal fees, and nonfinancial support from AstraZeneca and Janssen; personal fees from Black Diamond Therapeutics, Taiho, Sanofi, C4 Therapeutics, Merck, Bayer, Boehringer Ingelheim, and Eli Lilly and Company; personal fees and other support from Genentech; grants and personal fees from Daiichi Sankyo, Blueprint Medicines, Takeda, and Cullinan; and grants from Novartis, Spectrum, and TESARO/GSK outside the submitted work. A. Hegde reports other support from Revolution Medicines outside the submitted work. A.C. Chiang reports personal fees and other support from AstraZeneca Amgen, and Genentech (any division); other support from AbbVie; personal fees from Janssen, Zai Lab, and Daiichi; and other support from Bristol Myers Squibb during the conduct of the study. W. Iams reports personal fees from Novocure, Genzyme Corporation, EMD Serono, Bristol Myers Squibb, Daiichi Sankyo, Gilead Sciences, AbbVie, Amgen, Genentech, and Janssen outside the submitted work. A. Tolcher reports personal fees and other support from AbbVie, Inc., Aclaris Therapeutics, Affinia Therapeutics, Inc., Agenus, Inc., Asana BioSciences, Ascentage, Astex Pharmaceuticals, AxImmune, Bayer, BluPrint Oncology, Coretag Therapeutics, Cytel, Daiichi Sankyo, Inc., Exelixis, Inc., FibroGen, Gilde Healthcare Partners, HBM Partners, IDEA Pharma, Ikena Oncology, Immuneering, ImmunoMet Therapeutics, Inc., IMPACT Therapeutics US, Inc., Karma Oncology B.V., Kirilys Therapeutics, Inc., Lengo Therapeutics, Inc., Link Immunotherapeutics, Medicxi, Merck KGaA, MEKanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, Nerviano Medical Sciences S.r.I., Novo Nordisk Inc., Novo Venture, Nurix Therapeutics, Ocellaris Pharma, Inc. & Eli Lilly, Partner Therapeutics, Pfizer Inc., Pierre Fabre, Praxis Precision Medicines, Pyramid Biosciences, Qualigen Therapeutics, Mythic Therapeutics, Roche, Ryvu Therapeutics, Seattle Genetics, Singzyme Pte Ltd., SK Life Science, SOTIO Biotechnology Co., Senti Biosciences, Sun Pharma Advanced Research Company, Theratechnologies, Transcenta Therapeutics Inc., Transgene, Trillium Therapeutics Inc., Tubulis, Venus Oncology, Verastem Oncology, Vida Ventures Advisors, LLC, Adagene, Inc., BioInvent, Boehringer Ingelheim International GmbH, Bright Peak Therapeutics, Cullinan Oncology, Elucida Oncology, EMD Serono/Merck KGaA, Hexagon Bio, Inc., Immunome, Jazz, Leerink, Mirati, NBE Therapeutics, Nested Therapeutics, Inc., Pheon Therapeutics, Pyxis Oncology, Roche, Sun Pharma Advanced Research Company, Spirea Limited Inc., Tagworks Pharmaceuticals, Vincerx, VRise Therapeutics, Inc., Zentalis Pharmaceuticals, and ZielBio, Inc. during the conduct of the study; personal fees and other support from AbbVie, Inc., Aclaris Therapeutics, Affinia Therapeutics, Inc., Agenus, Inc., Asana BioSciences, Ascentage, Astex Pharmaceuticals, AxImmune, Bayer, BluPrint Oncology, Coretag Therapeutics, Daiichi Sankyo, Inc., Exelixis, Inc., FibroGen, Gilde Healthcare Partners, HBM Partners, IDEA Pharma, Ikena Oncology, Immuneering, ImmunoMet Therapeutics, Inc., IMPACT Therapeutics US, Inc., Karma Oncology B.V., Kirilys Therapeutics, Inc., Lengo Therapeutics, Inc., Link Immunotherapeutics, Medicxi, Merck KGaA, MEKanistic Therapeutics, Menarini Ricerche, Mersana, Nanobiotix, Nerviano Medical Sciences S.r.I., Novo Nordisk Inc., Novo Venture, Nurix Therapeutics, Ocellaris Pharma, Inc. & Eli Lilly, Partner Therapeutics, Pfizer Inc., Pierre Fabre, Praxia Precision Medicines, Pyramid Biosciences, Qualigen Therapeutics, Roche, Ryvu Therapeutics, Seattle Genetics, Singzyme Pte Ltd., SK Life Science, SOTIO Biotechnology Co., Senti Biosciences, Sun Pharma Advanced Research Company, Theratechnologies, Transcenta Therapeutics Inc., Transgene, Trillium Therapeutics Inc., Tubulis, Venus Oncology, Verastem Oncology, Vida Ventures Advisors, LLC, Adagene, Inc., BioInvent, Boehringer Ingelheim International GmbH, Bright Peak Therapeutics, Cullinan Oncology, Elucida Oncology, EMD Serono/Merck KGaA, Hexagon Bio, Inc., Immunome, Jazz, Leerink, Mirati, NBE Therapeutics, Nested Therapeutics, Inc., Pheon Therapeutics, Pyxis Oncology, Spirea Limited Inc., Tagworks Pharmaceuticals, Vincerx, VRise Therapeutics, Inc., Zentalis Pharmaceuticals, and ZielBio, Inc. outside the submitted work; and a patent for Zentalis issued and a patent for Acentage Pharma issued. K. Nosaki reports grants and personal fees from Takeda, AstraZeneca, MSD, and Chugai Pharma; grants from AbbVie, Daiichi Sankyo, and AnHeart Therapeutics; and personal fees from Eli Lilly and Company, Pfizer, Taiho Pharmaceutical, Janssen, Ono Pharmaceutical, Novartis, and Merck outside the submitted work. T. Kozuki reports grants and personal fees from MSD, Daiichi Sankyo, Eisai, AbbVie, Kyowa Hakko Kirin, Bayer, Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical Co., Bristol Myers Squibb, and Ono Pharmaceutical Co.; personal fees from Sawai; and grants from Gilead Sciences, Labcorp Development Japan, IQVIA Services Japan, and Sanofi outside the submitted work. T. Li reports grants from AbbVie during the conduct of the study; grants from Amgen, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Duality Biologics, Genentech/La Roche, Jounce Therapeutics, LabyRx Immuno-Oncology, Merck, OncoC4/BioNTech, Novartis, Rascal Therapeutics, Tempus, and Xilio Therapeutics; and other support from Janssen, Bristol Myers Squibb, and InxMed outside the submitted work. R. Santana-Davila reports grants from AbbVie during the conduct of the study. H. Akamatsu reports grants and personal fees from Amgen Inc., Chugai Pharmaceutical Co. Ltd., and MSD K.K.; and personal fees from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly Japan K.K., Nippon Kayaku Co. Ltd., Novartis Pharma K.K., Ono Pharmaceutical Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd, Janssen Pharmaceutical K.K., GSK, and Sandoz outside the submitted work. H. Murakami reports grants from AbbVie during the conduct of the study; as well as grants and personal fees from Chugai Pharma, AstraZeneca, Daiichi Sankyo, and Taiho Pharmaceutical; grants from IQVIA and Bayer; and personal fees from Takeda, Amgen, Ono Pharmaceutical, Bristol Myers Squibb Japan, MSD, Pfizer, Novartis, Lilly Japan, Eisai, Nippon Kayaku, Kyowa Kirin, and GAIA BioMedicine outside the submitted work. H. Yokouchi reports grants from AbbVie during the conduct of the study; grants and personal fees from AstraZeneca and Chugai Pharmaceutical; and grants from Bristol Myers Squibb, Sanofi, Takeda Pharmaceutical, MSD, and Daiichi Sankyo outside the submitted work. J. Zha reports personal fees from AbbVie, Inc. outside the submitted work. R. Li reports other support from AbbVie during the conduct of the study, as well as other support from AbbVie outside the submitted work. R.R. Robinson reports other support from AbbVie during the conduct of the study. M. Furqan reports grants and personal fees from AbbVie during the conduct of the study, as well as grants and personal fees from AstraZeneca, BeiGene, and Mirati; grants from GSK, Bristol Myers Squibb, Celgene, Checkmate, Elicio, Fate Therapeutics, Amgen, APREA, Genmab, Gilead, Genentech, Immunocore, Incyte, Jacobio, Eli Lilly and Company, Merck, and Novartis; and personal fees from Omega Therapeutics and Jazz Pharma outside the submitted work. No disclosures were reported by the other authors.

D. Morgensztern: Conceptualization, investigation, visualization, writing–original draft, writing–review and editing. N. Ready: Conceptualization, investigation, writing–original draft, writing–review and editing. M.L. Johnson: Conceptualization, investigation, writing–original draft, writing–review and editing. A. Dowlati: Conceptualization, investigation, writing–original draft, writing–review and editing. N. Choudhury: Conceptualization, investigation, writing–original draft, writing–review and editing. D.P. Carbone: Conceptualization, investigation, writing–original draft, writing–review and editing. E. Schaefer: Conceptualization, investigation, writing–original draft, writing–review and editing. S.M. Arnold: Conceptualization, investigation, writing–original draft, writing–review and editing. S. Puri: Conceptualization, investigation, writing–original draft, writing–review and editing. Z. Piotrowska: Conceptualization, investigation, writing–original draft, writing–review and editing. A. Hegde: Conceptualization, investigation, writing–original draft, writing–review and editing. A.C. Chiang: Conceptualization, investigation, writing–original draft, writing–review and editing. W. Iams: Conceptualization, investigation, writing–original draft, writing–review and editing. A. Tolcher: Conceptualization, investigation, writing–original draft, writing–review and editing. K. Nosaki: Conceptualization, investigation, writing–original draft, writing–review and editing. T. Kozuki: Conceptualization, investigation, writing–original draft, writing–review and editing. T. Li: Conceptualization, investigation, writing–original draft, writing–review and editing. R. Santana-Davila: Conceptualization, investigation, writing–original draft, writing–review and editing. H. Akamatsu: Conceptualization, investigation, writing–original draft, writing–review and editing. H. Murakami: Conceptualization, investigation, writing–original draft, writing–review and editing. H. Yokouchi: Conceptualization, investigation, writing–original draft, writing–review and editing. S. Wang: Formal analysis, writing–original draft, writing–review and editing. J. Zha: Formal analysis, writing–original draft, writing–review and editing. R. Li: Formal analysis, writing–original draft, writing–review and editing. R.R. Robinson: Conceptualization, writing–original draft, writing–review and editing. P. Hingorani: Conceptualization, writing–original draft, writing–review and editing. E.E. Jeng: Conceptualization, writing–original draft, writing–review and editing. M. Furqan: Conceptualization, investigation, writing–original draft, writing–review and editing.

AbbVie, Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Medical writing support was provided by Iratxe Abarrategui, PhD, CMPP, of Aptitude Health, The Hague, the Netherlands, and funded by AbbVie. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.