Safety, pharmacokinetics, and antitumor response of depatuxizumab mafodotin as monotherapy or in combination with temozolomide in patients with glioblastoma

Abstract

Background

We recently reported an acceptable safety and pharmacokinetic profile of depatuxizumab mafodotin (depatux-m), formerly called ABT-414, plus radiation and temozolomide in newly diagnosed glioblastoma (arm A). The purpose of this study was to evaluate the safety and pharmacokinetics of depatux-m, either in combination with temozolomide in newly diagnosed or recurrent glioblastoma (arm B) or as monotherapy in recurrent glioblastoma (arm C).

Methods

In this multicenter phase I dose escalation study, patients received depatux-m (0.5–1.5 mg/kg in arm B, 1.25 mg/kg in arm C) every 2 weeks by intravenous infusion. Maximum tolerated dose (MTD), recommended phase II dose (RP2D), and preliminary efficacy were also determined.

Results

Thirty-eight patients were enrolled as of March 1, 2016. The most frequent toxicities were ocular, occurring in 35/38 (92%) patients. Keratitis was the most common grade 3 adverse event observed in 6/38 (16%) patients; thrombocytopenia was the most common grade 4 event seen in 5/38 (13%) patients. The MTD was set at 1.5 mg/kg in arm B and was not reached in arm C. RP2D was declared as 1.25 mg/kg for both arms. Depatux-m demonstrated a linear pharmacokinetic profile. In recurrent glioblastoma patients, the progression-free survival (PFS) rate at 6 months was 30.8% and the median overall survival was 10.7 months. Best Response Assessment in Neuro-Oncology responses were 1 complete and 2 partial responses.

Conclusion

Depatux-m alone or in combination with temozolomide demonstrated an acceptable safety and pharmacokinetic profile in glioblastoma. Further studies are currently under way to evaluate its efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Survival from glioblastoma remains poor. Epidermal growth factor receptor (EGFR) alterations (amplification, overexpression, and mutation) have a high prevalence in glioblastoma and therefore remain a very attractive target for novel drug development.¹ However, EGFR-directed therapies have thus far displayed limited or no therapeutic efficacy in glioblastoma clinical trials.^2–5 The hypothesized reasons for the lack of efficacy of these agents are varied and include poor penetrance into the central nervous system, multiple redundant signaling resistance pathways, and downregulation of EGFR.⁶

An alternative approach to targeting EGFR in glioblastoma is through antibody–drug conjugates (ADCs) that do not rely on abrogation of signaling to achieve their therapeutic effect. Depatuxizumab mafodotin (depatux-m), formerly called ABT-414, is an ADC comprised of an antibody (ABT-806), which selectively targets EGFR amplification, linked to a potent microtubule cytotoxin called monomethyl auristatin F (MMAF) by a noncleavable maleimido-caproyl (mc) linker (Fig. 1).^7,8 EGFR amplification and EGFR variant III mutation (formed by the deletion of exons 2–7) expose a unique conformational epitope that acts as a binding site for depatux-m. Upon binding, the complex is internalized and MMAF is released by the intracellular proteolytic enzymes. MMAF inhibits microtubule function within the cell and leads to cell death. Several preclinical and clinical studies have shown that ABT-806 binds to EGFR-expressing tumors, specifically in human gliomas.^8,9 In contrast, there is limited or no binding to non-activated, wild-type EGFR expressed on normal tissues such as skin and other epithelial tissue.^10–13 Thus, depatux-m can potentially avoid common EGFR inhibitor–associated toxicities.

In this phase I study we determined the safety, pharmacokinetics (PK), and preliminary antitumor activity of depatux-m either alone in recurrent glioblastoma or in combination with 5-day temozolomide (TMZ) in newly diagnosed (following radiotherapy [RT]) or recurrent glioblastoma (Supplementary Figure S1A). Primary objectives were to determine the recommended phase II dose (RP2D) and maximum tolerated dose (MTD) of depatux-m. Secondary objectives included determination of the preliminary antitumor activity of depatux-m and correlating of EGFR status in patient tumors with efficacy.

Methods

This study was part of a larger multicenter, phase I, open-label, 3-arm clinical trial to assess the safety and PK of depatux-m in patients with glioblastoma. Each arm consisted of a dose escalation cohort and a safety expansion cohort (Supplementary Figure S1A). We recently reported the results of arm A escalation and expansion cohorts (depatux-m plus RT and TMZ in newly diagnosed glioblastoma) in which depatux-m displayed an acceptable safety and PK profile in patients with newly diagnosed glioblastoma.¹⁴ Herein we report the results of dose escalation cohorts of arm B (depatux-m plus TMZ after RT in either newly diagnosed glioblastoma or recurrent glioblastoma) and arm C (depatux-m monotherapy in recurrent glioblastoma).

The study was conducted in accordance with applicable principles governing ethical and clinical trial conduct, as provided in the Declaration of Helsinki and its later amendments. The trial was registered with Clinical Trials Registry (clinicaltrials.gov; NCT01800695) before study initiation and was approved by the Independent Ethics Committee/Institutional Review Board of all participating institutions. Before enrollment, written informed consent was obtained from all patients or their legally authorized representatives.

Patients

Patient eligibility criteria for this study have been reported previously.¹⁴ Importantly, eligible patients were adults who had newly diagnosed or recurrent supratentorial glioblastoma or subvariants, Karnofsky Performance Status (KPS) ≥70, and no significant postoperative hemorrhage. They also had adequate bone marrow, renal, and hepatic functions. For arm B, the eligible patients with newly diagnosed glioblastoma had completed postoperative RT and concurrent TMZ but had not progressed; depatux-m was added to standard adjuvant TMZ. Recurrent glioblastoma patients in arms B and C had disease progression and a gap of at least 12 weeks after RT. Prior treatments with head and neck RT (arm B newly diagnosed), Gliadel wafers or other intratumoral therapies, bevacizumab, and/or nitrosoureas (arm B recurrent disease) were exclusionary. In the dose escalation arms described herein, patients were accrued independently of their EGFR amplification or mutation status in archival tumor tissue.

Study Design

A modified continual reassessment methodology (modified-CRM, mCRM) was followed for dose escalation with the objective of describing a relationship between dose and rate of dose-limiting toxicities (DLTs). The model was then used to estimate MTD for subsequent cohorts utilizing all available data. Any of the following adverse events (AEs) not due to disease progression or any underlying disease was considered a DLT, if occurring during the DLT assessment period: grade 4 anemia or neutropenia (>7 days), grade ≥3 febrile neutropenia, grade ≥3 thrombocytopenia (>7 days), grade ≥3 nonhematologic AEs (except grade 3 nausea, vomiting, or diarrhea if adequately managed within 48 hours), and >14 days dose delays due to attributable toxicity. Other toxicities occurring within or after the DLT assessment period were also evaluated by the investigator and sponsor. The DLT assessment period for arms B and C was first 4 weeks of treatment with either depatux-m plus TMZ or depatux-m monotherapy. The MTD was defined as the highest dose level at which ≤33.3% of patients experienced a DLT with a minimum of 6 patients enrolled. The RP2D was a dose not higher than the MTD and was selected based on the type of DLTs observed.

The mCRM followed the traditional 3 + 3 design at stage 1 and CRM at stage 2. In contrast to a more traditional rule-based design (eg, 3 + 3 design), CRM incorporates information from all prior events (such as the previous doses and tolerability) into a statistical dose-response model in real time and selects subsequent doses as the clinical trial progresses.^15–17 The sample dose escalation scheme is shown in Supplementary Figure S1B. In stage 1, depatux-m dosing began at 0.5 mg/kg in a cohort of 3 patients in arm B. After these patients completed the DLT assessment period, dose escalation decisions were made. Each dose level increased by no more than 100% until the first grade ≥2 drug-related AE was observed. Subsequent dose levels were increased by no more than 50%. Once the first DLT was observed, the study proceeded to stage 2. In stage 2, the relationship between depatux-m dose and rate of DLT was determined by fitting the 2-parameter logistic regression model, and MTD was estimated. Three patients were dosed at this estimated MTD. After following these patients for the DLT assessment period, the logistic regression model was updated and a new MTD was obtained. At each step of stage 2, the new dose was no more than 50% higher than the prior dose. Once a patient experienced a DLT, the cohort at that dose level was expanded and 3 more patients were dosed at that dose level. The design continued until either the target dose changed by less than 15% and never exceeded 25% or the estimated MTD was less than zero. Information gained from arm B was used to inform the model for arm C. Since a DLT was observed in arm B, the dose escalation for arm C was started using the mCRM approach in stage 2.

Treatment Regimen

Patients in arm B received TMZ (150 mg/m²) for cycle 1 (which could be escalated up to 200 mg/m², if tolerated) on days 1 through 5 of each 28-day cycle. Depatux-m (0.5, 1.0, 1.25, and 1.5 mg/kg) was administered via intravenous (i.v.) infusion on days 2 and 15 of cycle 1 and then on days 1 and 15 of every subsequent 28-day cycle. At the time of enrollment in arm C, the RP2D of depatux-m had been established in arm B at 1.25 mg/kg in combination with TMZ, thus patients in arm C began dosing of depatux-m at 1.25 mg/kg via an i.v. infusion on days 1 and 15 of every 28-day cycle. Treatment continued until either disease progression per Response Assessment in Neuro-Oncology (RANO) criteria¹⁸ or the patient experienced a DLT, needed a dose modification for depatux-m below 0.5 mg/kg, or required other anticancer treatment, such as surgery or alternate anticancer agents, during the study period.

A baseline ophthalmology exam was performed for all patients during screening. Dexamethasone (0.1%) eye drops were administered prophylactically to all patients who received 1.0 mg/kg or higher dose of depatux-m. Two drops were administered in each eye 3 times a day (TID) either starting 2 days prior to depatux-m dosing and continuing for a total of 7 days or at the recommendation of the ophthalmologist.

PK Assessments

In arm B dose escalation cohorts, serum samples were collected to determine the concentrations of depatux-m and total ABT-806 (including both depatux-m and unconjugated antibody). Plasma samples were collected to determine the concentrations of cysteine-mcMMAF (cys-mcMMAF). Samples were taken immediately before and at 0.5, 4, 24, 48, 96, 168, and 336 hours after depatux-m dose administration on day 2 of cycle 1 (first day of depatux-m dosing) and day 1 of cycle 2. Plasma samples were also collected to assess TMZ concentrations prior to TMZ dosing and at 0.5, 1, 2, 4, and 6 hours after dosing on day 1 of cycles 1 and 2. In the arm C dose escalation cohort, samples were taken after depatux-m dose administration on day 1 of cycles 1 and 2 using a similar sampling schedule as in arm B.

Depatux-m and total ABT-806 serum concentrations were determined using validated electrochemiluminescence immunoassays. Plasma concentrations of cys-mcMMAF and TMZ were determined using validated liquid chromatography methods with tandem mass spectrometric detection. PK parameters such as maximum concentration (C_max), area under the curve (AUC), half-life (t_1/2), and systemic clearance (CL) of depatux-m, total ABT-806, cys-mcMMAF, and TMZ were determined using noncompartmental methods.

Determination of EGFR Amplification and Mutation

Exploratory post-hoc analysis was done centrally to determine EGFR amplification and EGFRvIII mutation on formalin-fixed, paraffin-embedded (FFPE) tumor tissues collected prior to treatment as previously described.¹⁴ Briefly, fluorescence in situ hybridization (FISH) was used to detect locus-specific EGFR amplification. Two probes were employed: (i) Vysis Locus Specific Identifier EGFR SpectrumOrange Probe and (ii) Vysis Chromosome Enumeration Probe (CEP) 7 SpectrumGreen Probe (Abbott Molecular). EGFR was considered amplified if ≥15% of cells with EGFR/CEP7 had a copy number ratio ≥2 as described previously.¹⁴ Quantitative real-time reverse-transcription PCR (qRT-PCR) was performed to detect the levels of total EGFR and EGFRvIII mutation (Qiagen FFPE RNA kit, modified manufactured protocol by Abbott Molecular).

Statistical Analyses

Patient baseline characteristics were summarized using descriptive statistics. Toxicity was studied in patients who received at least one dose of depatux-m and was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.1 and listed by MedDRA v19.0 system organ class and preferred term. Responses were assessed using RANO criteria.¹⁸ Response rate was calculated among patients with measurable disease at baseline. Progression-free survival (PFS) duration was defined as the time period from first dose of depatux-m to RANO defined disease progression or date of death, if disease progression did not occur. Duration of overall survival (OS) was determined from the time of first dose of depatux-m to death from any cause. PFS and OS were analyzed using the Kaplan–Meier method with 95% confidence interval.

Results

Patient Characteristics

Between April 2013 and March 2016, a total of 38 patients (18 men, 20 women; median age 56 y, range: 20–78) were enrolled in the escalation cohorts of arms B and C. Of those, 29 patients were in arm B (14 newly diagnosed and 15 recurrent glioblastoma patients) and 9 were in arm C (all recurrent glioblastoma patients). The demographics and baseline characteristics are shown in Table 1. Data for the last TMZ dose prior to study enrollment as well as the percentage of patients who received intervening therapy (after 1L chemoradiation) prior to study enrollment are summarized in Supplementary Table S1.

Safety

Patients in arm B received escalating doses of depatux-m (0.5–1.5 mg/kg). The MTD in arm B was 1.5 mg/kg and was used to guide the starting dose for arm C (1.25 mg/kg). The MTD was not reached for arm C, but the RP2D was declared at 1.25 mg/kg because 4/9 (44%) patients displayed grade 2 or higher ocular toxicity at this dose level. Median duration of treatment in arm B was 5.1 months (range: 0.5–30) and for arm C 1.5 months (range: 1–15). Overall treatment emergent adverse events (TEAEs; ≥25% of patients in at least one group), grade 3/4 TEAEs (≥10% patients in at least one group), and DLTs (>1 patient) are summarized in Table 2.

The most important toxicities observed in arms B and C dose escalation cohorts were ocular, occurring in 35/38 (92%) patients. These toxicities improved once depatux-m was dose reduced (in 7/38 [18%] patients) or interrupted (in 14/38 [37%] patients), leading to only a 5% study discontinuation rate due to toxicity (2/38 patients). Since some patients overlapped between these groups (dose reduction/interruption/discontinuation) and some patients were lost to follow-up, these numbers do not add up to a total of 35 patients who experienced any grade ocular toxicities. The most common ocular TEAEs were blurred vision (63%), photophobia (39%), dry eye (29%), foreign body sensation in eyes (26%), and keratitis (26%). Other common TEAEs (≥25% of patients) were fatigue (53%), nausea (47%), thrombocytopenia (34%), headache (26%), and seizure (26%). Eleven of thirty-eight (29%) patients experienced grade 3 ocular toxicity, with keratitis being the most common, occurring in 6/38 (16%) patients. Other common grade 3 toxicities were thrombocytopenia (13%), blurred vision, fatigue, and increased gamma-glutamyltransferase (GGT) (8% each). Thrombocytopenia was the most common grade 4 toxicity and occurred in 5/38 (13%) patients. Keratitis was the only grade 4 ocular toxicity, seen in 2/38 (5%) patients. Ocular side effects related to treatment with depatux-m demonstrated a trend toward reversibility after treatment was discontinued, with a median time to resolution of approximately 13 weeks (Supplementary Figure S2). However, it should be noted that the aggressive nature of recurrent GBM results in a number of competing risks (clinical decline, loss to follow-up, death, etc.), leading to a high censoring rate. Therefore, caution is warranted in the interpretation of this estimate. A total of 5/9 (56%) patients experienced grade 3/4 toxicities when treated with depatux-m alone (arm C): keratitis (33%), cerebrovascular accident, hyperglycemia, hyponatremia, and optic nerve disorder (11% each). There were no hematological grade 3/4 toxicities in arm C. Four of twenty-nine (14%) patients in arm B experienced DLTs, including corneal deposits, keratitis, increased GGT, and vomiting (n = 1 each). No DLTs were seen in arm C. Four deaths occurred within 60 days of the last dose of depatux-m, all due to disease progression (n = 3 in arm B, n = 1 in arm C).

Pharmacokinetics

C_max and AUC of depatux-m, total ABT-806, and cys-mcMMAF were approximately dose proportional over the dose range studied (0.5–1.5 mg/kg; Table 3). A very low C_max of free circulating cys-MMAF was seen in the plasma samples. The CL of depatux-m was about 0.15 mL/h/kg. The observed mean terminal t_1/2 of depatux-m, total ABT-806, and cys-mcMMAF across all doses studied were 9.5, 13.6, and 4.5 days, respectively. The PK parameters of TMZ were comparable in the presence and absence of depatux-m coadministration, suggesting that depatux-m had no effect on PK parameters of TMZ (Supplementary Figure S3). Likewise, the PK parameters of depatux-m and cys-mcMMAF were comparable between arms B and C, suggesting that TMZ had no effect on the PK profile of depatux-m (Table 4).

Biomarker Analysis

Archival tumor tissue from all 38 patients was tested centrally for EGFR status; 20 (53%) displayed EGFR amplification. Ten of these 20 (50%) tumors also harbored EGFRvIII mutation. Among 24 patients with recurrent glioblastoma, 16 (67%) had EGFR amplified tumors. Seven of these 16 (44%) patients also harbored EGFRvIII mutation (Table 1).

Exploratory Antitumor Activity

All efficacy assessments were performed on recurrent glioblastoma patients, except where noted otherwise.

The best overall response and study duration of each enrolled patient are summarized in Supplementary Figure S4. Investigator-reported best responses per RANO criteria in the 24 recurrent disease patients were 1 complete response (CR, arm C), 2 partial responses (PR, arm B), 10 stable disease (SD), and 11 progressive disease (PD); both the 1 CR and 2 PRs were seen in patients with EGFR amplified tumors, among whom best responses were 1 CR, 2 PR, 5 SD, and 8 PD.

Best percent change in tumor size from baseline (regardless of duration) for each patient and their individual responses over time are shown in Fig. 2A and B, respectively. Two patients displayed 100% reduction in tumor size (n = 1 each in arm B and arm C) and 3 patients displayed >50% (but not 100%) reduction in tumor size (all in arm B). Of note, these numbers do not match the number of CR and PR mentioned above, since RANO criteria also take into account other clinical conditions such as confirmatory scans, measurable disease, etc, for assessment. We also noted that 4/5 (80%) patients with >50% reduction in tumor size harbored EGFR amplification in their tumors.

The median duration of PFS in all recurrent glioblastoma patients (n = 24) was 2.3 months (95% CI = 1.6, 6.7); for arm B patients (n = 15) it was 3.7 months (95% CI = 1.5, 6.7), and for arm C patients (n = 9) it was 2.3 months (95% CI = 1.1, 15.5). The PFS estimate at 6 months (PFS6) in all recurrent glioblastoma patients (n = 24) was 30.8% (95% CI = 12.4, 51.6), that in arm B patients (n = 15) was 26.7% (95% CI = 6.9, 52.0), and in arm C patients 40% (95% CI = 9.8, 69.7). The PFS6 in EGFR amplified recurrent glioblastoma patients (n = 16) was 29.2% (95% CI = 9.6, 52.3) and in EGFR mutated (EGFRvIII) recurrent glioblastoma patients (n = 8) was 37.5% (95% CI = 8.7, 67.4).

The median survival for patients with recurrent glioblastoma (n = 24) was 10.7 months (95% CI = 5.4, 18.0); for arm B patients (n = 15), it was 17.9 months (95% CI = 6.7, 18.7), and for arm C patients (n = 9), it was 7.2 months (95% CI = 3.1, 18.0). The median survival in EGFR amplified recurrent glioblastoma patients (n = 16) and EGFR mutated (EGFRvIII) recurrent glioblastoma patients (n = 8) was also 10.7 months but with a wider 95% CI (95% CI = 5.5, 18.7 for EGFR amplified recurrent glioblastoma, and 95% CI = 1.7, 18.7 for EGFRvIII recurrent glioblastoma).

Discussion

The RP2D for depatux-m, both as monotherapy and in combination with TMZ, was determined as 1.25 mg/kg in patients with recurrent glioblastoma. This dose level caused frequent ocular AEs despite prophylactic use of steroid ophthalmologic solution. However, careful monitoring and supportive care allowed patients to remain on therapy. Dose reductions and interruptions were effective at managing ocular toxicities, resulting in only a 5% discontinuation rate. While detailed follow-up regarding ocular side effects was not available, as these patients withdrew from the study, all patients whose follow-up data were available have reported improvement of ocular symptoms. Given this, the current depatux-m global randomized recurrent glioblastoma study uses a starting dose of 1.0 mg/kg. This dose level is lower than that determined in combination with RT and TMZ in the upfront setting,¹⁴ with a tolerable dose of 2.0 mg/kg as part of chemoradiotherapy. It is unclear why a higher dose can be administered in combination with RT and TMZ. Hypotheses include different schedules of TMZ, lack of prior chemotherapy exposure, use of systemic steroids in the radiation phase of therapy, as well as any effects that RT may have in protecting the transient amplifying cells (TACs) of the cornea. TACs of cornea, if damaged, may form small deposits, or microcysts (microcystic keratopathy), causing blurry vision and irritation or pain in the eyes. However, since the cornea regenerates over a period of 21–28 days, these microcysts are “sloughed off” and the toxicity resolves. Similar ophthalmologic toxicities have been reported previously with other MMAF compounds, such as SGN-75,¹⁹ SGN-CD19A,²⁰ AGS-16C3F, and AGS-16M8F,²¹ and also with high-dose cytarabine.²²

We found that depatux-m drug exposure was dose related, as depicted by a linear PK profile at the dose range studied. Depatux-m did not affect the exposures of TMZ and vice versa. As expected, given that MMAF is covalently bound to the antibody, the levels of free circulating cys-MMAF in patient samples were extremely low, near the lower range of assay detection. This explains the low incidence of bone-marrow suppression and peripheral neuropathy seen in our patients.

We observed 1 CR and 2 PRs as RANO responses in our study. All of these responses were in EGFR amplified, recurrent glioblastoma patients. Similarly, 4/5 recurrent glioblastoma patients with >50% reduction in their tumor size from baseline had EGFR amplified tumors. The remaining 1 patient with non-amplified EGFR was a previous responder to TMZ, and it is hypothesized that his response to depatux-m +TMZ (arm B) was TMZ driven. Although in a small sample size, our results suggest that patients with EGFR amplified tumors (with or without EGFRvIII mutation) are most likely to benefit from depatux-m.

In our study, we observed an encouraging PFS6 of 30.8% in recurrent glioblastoma patients treated with depatux-m alone or with TMZ. In general, a PFS6 of 20% or higher is seen as a support for further studies. PFS6 data in the present study should be interpreted with caution due to the small sample size and heterogeneous patient population (eg, the CI for PFS6 includes a 20% cutoff limit). Irrespective of PFS6, several responders were observed (1 CR, 2 PRs, and 2 patients with 100% reduction in tumor size) despite the small sample size in this study. These encouraging preliminary signs of efficacy warrant further investigation. Bevacizumab trials among recurrent glioblastoma patients, alone or in combination with TMZ or other chemotherapy, have shown a PFS6 in the range of 6.7%–50.3%.²³ TMZ or lomustine alone have demonstrated a PFS6 rate of almost 20%.^24–26 Thus, further evaluation of depatux-m alone or with TMZ is warranted in recurrent glioblastoma. To this end, a randomized, global study of depatux-m versus depatux-m + TMZ versus TMZ or lomustine has been initiated through the European Organisation for Research and Treatment of Cancer (EORTC 1410-BTG, Intellance 2, M14-483 study).

Supplementary Material

Supplementary material is available at Neuro-Oncology online.

Funding

AbbVie provided financial support for this study (NCT01800695) and participated in the design, study conduct, analysis, and interpretation of data as well as the writing, review, and approval of the manuscript. All authors were involved in the data gathering, analysis, review, and interpretation.

Acknowledgments

We thank patients and their families and investigators and their research teams. Additional scientific support was provided by David Maag, PhD, and medical writing support was provided by Namrata Bhatnagar, PhD. Both are employees of AbbVie.

Conflict of interest statement. Hui K. Gan has an investigator-initiated study with AbbVie; received travel support and research funding from AbbVie; received honoraria from AbbVie, Pfizer, BMS, and Merck Serono; and is affiliated with the Ludwig Institute for Cancer Research.

David A. Reardon received honoraria from and has a consulting or advisory role with AbbVie, Bristol-Myers Squibb, Cavion, Celldex, Inovio, Juno Pharmaceuticals, Merck, Novartis, Roche/Genentech, Amgen, Novocure, Oxigene, Regeneron, and Stemline Therapeutics; is involved in speakers’ bureaus with Roche and Merck; and received research funding from Incyte, Midatech, and Celldex.

Andrew B. Lassman received personal compensation within the last 12 months from AstraZeneca, Novocure, Sapience Therapeutics, Abbvie, Kadmon, and Cortice Biosciences.

Ryan Merrell serves on an advisory board for AbbVie.

Martin van den Bent received honoraria from Roche, AbbVie, Celldex, Novocure, Merck Ag, Cavion, Actelion, BMS, and Blue Earth Diagnostics; and received research funding from AbbVie.

Nicholas Butowski received honoraria from and has a consulting or advisory role with Roche/Genentech, Medicenna, VBL Therapeutics, Omniox, and Celldex; is involved in speakers’ bureaus with Roche and Merck; and received research funding from Insys.

Andrew M. Scott owns stock in and has a consulting or advisory role with Life Science Pharmaceuticals; received research funding from AbbVie, Daiichi Sankyo, and Avipep; and has patents, royalties, or other intellectual property with Life Science Pharmaceuticals, AbbVie, Kalobios, and Ludwig Institute for Cancer Research.

Erica Gomez, JuDee Fischer, Helen Mandich, Hao Xiong, Ho-Jin Lee, Wijith Munasinghe, Lisa Roberts-Rapp, Peter Ansell, and Kyle Holen are employed by AbbVie and may own AbbVie stock.

Priya Kumthekar received honoraria for an advisory role with AbbVie within the last 12 months.

Zarnie Lwin, Helen Wheeler, and Lisa Fichtel have no conflicts of interest to disclose.

References