Brightline-1: phase II/III trial of the MDM2–p53 antagonist BI 907828 versus doxorubicin in patients with advanced DDLPS
Abstract
Dedifferentiated liposarcoma (DDLPS) is a rare, aggressive liposarcoma associated with poor prognosis. First-line treatment for advanced/metastatic DDLPS is systemic chemotherapy, but efficacy is poor and toxicities substantial. Most DDLPS tumors have amplification of the MDM2 gene, which encodes a negative regulator of the p53 suppressor protein. BI 907828 is a highly potent, oral MDM2–p53 antagonist that inhibits the interaction between p53 and MDM2, thereby restoring p53 activity. BI 907828 has shown promising activity in preclinical studies and in a phase Ia/Ib study in patients with solid tumors, particularly those with DDLPS. This manuscript describes the rationale and design of an ongoing multicenter, randomized, phase II/III trial (Brightline-1; NCT05218499) evaluating BI 907828 versus doxorubicin as first-line treatment for advanced DDLPS.
Plain language summary
Dedifferentiated liposarcoma (DDLPS) is a rare, fast-growing cancer that begins in fat cells. Patients with DDLPS that cannot be removed surgically or has spread to other areas of the body are usually treated with chemotherapy at first, but this typically stops working only 2–4 months after the start of treatment and has a lot of side effects. The drug BI 907828 works differently to chemotherapy by specifically targeting a gene called MDM2. This gene is abnormally increased in most DDLPS tumors and causes cancer by shutting down one of the pathways that the body uses to kill cancerous cells. BI 907828 restores this pathway, leading to the targeted destruction of tumor cells. Results from initial studies show that BI 907828 is able to slow the growth of DDLPS, and is now being investigated further, in a study called Brightline-1. Brightline-1, which is currently underway, is comparing BI 907828 with the chemotherapy drug doxorubicin for the initial treatment of DDLPS that is inoperable or has spread to other areas of the body.
Clinical Trial Registration:NCT05218499 (ClinicalTrials.gov)
Soft tissue sarcomas (STSs) are rare malignancies, comprising only about 1% of adult malignancies [1]. Using data from between 1995 and 2002, the RARECARE project estimated there were 23,400 new cases of STS per year in the EU [2]. Liposarcomas comprise about 15–20% of STS, with an age-adjusted incidence of 0.6–1.0 per 100,000 person–years [3–5]. The major subtypes of liposarcoma are dedifferentiated liposarcoma (DDLPS), well-differentiated liposarcoma (WDLPS), myxoid/round cell liposarcoma (MLPS), pleomorphic liposarcoma (PLPS), and myxoid pleomorphic liposarcoma (MPLPS) [6]. WDLPS is considered the least aggressive form with little-to-no metastatic potential and the others are considered more aggressive [7]. The average age at diagnosis is 50 years, with the age of peak incidence varying slightly by subtype [7].
DDLPSs comprise about 15–20% of liposarcomas and arise from cases of WDLPS, with 90% of DDLPS found within a primary WDLPS lesion and 10% within areas of locally recurrent WDLPS [7]. When areas of WDLPS and DDLPS are found within the same tumor, patients are classified as having DDLPS. WDLPS appears as a proliferation of mature and variably pleomorphic adipocytes with fibrous septa containing single, enlarged hyperchromatic nuclei. DDLPS has more highly cellular areas of high-grade undifferentiated sarcoma, which typically transition abruptly within a background of WDLPS [7]. In 90% of cases, DDLPS presents as a high-grade tumor (equivalent to grade 3), with a local recurrence rate of at least 40%, and metastasizes in at least 20% of cases to the lungs, liver, bone, skin or brain [8–12]. Metastatic disease is observed in slightly more male than female patients [10,11]. The other 10% of DDLPS cases are low-grade tumors (equivalent to grade 2), which often have morphological differences to their high-grade counterparts, and can present as histologically similar to other tumor types, such as fibromatosis and inflammatory myofibroblastic tumors. Low-grade DDLPS can have a better prognosis and overall survival rate compared with high-grade DDLPS tumors [12–14]. Anatomical location of the DDLPS is also an important prognostic factor, with patients with grade 3 retroperitoneal tumors having a particularly poor prognosis [9,15]. 5-year disease-specific survival for advanced DDLPS is 20–44%, compared with 83–93% for WDLPS [8,16,17].
Surgery is the main treatment for localized liposarcomas, and complete tumor resection with wide surgical margins can be curative [5]. Local recurrences are frequent in DDLPS [8] and radiotherapy may improve local disease control; however, DDLPS is considered poorly sensitive to radiotherapy [7]. In patients with unresectable, advanced or metastatic DDLPS, systemic treatment is usually the only treatment option, but outcomes are currently unsatisfactory, responses are sporadic, and such tumors are generally considered incurable [7]. First-line therapy for STS is usually systemic chemotherapy, namely doxorubicin, doxorubicin plus ifosfamide, or doxorubicin plus dacarbazine [5]. Most studies investigating systemic treatments have included all forms of STS, and do not provide specific data for liposarcoma, or its subtypes, resulting in weak evidence for these treatments in DDLPS.
Among a small group of studies that have provided information on outcomes of treatment with first-line chemotherapy in patients with DDLPS, the overall response rate (ORR) was less than 15%, median progression-free survival (PFS) was 2–4 months, and median overall survival (OS) was 8–14 months [18–21]. In addition, doxorubicin is associated with multiple side effects, including the risk of irreversible cardiotoxicity [22–24].
Nearly all cases of DDLPS have amplification of the MDM2 gene [25–29]. MDM2 encodes a negative regulator of the tumor suppressor protein p53. Central to its activities, the MDM2 protein binds to and blocks the transcription activation domain of p53, and also targets p53 for proteasomal degradation [27]; hence, MDM2 amplification inhibits p53 tumor suppressor activity and promotes p53 degradation. Inhibition of the MDM2–p53 interaction would thus allow restoration of p53 activity, allowing it to induce apoptosis, cell-cycle arrest and DNA repair [27]. A number of MDM2 antagonists are currently in clinical development [30,31].
In this article, we will discuss the ongoing Brightline-1 phase II/III trial (NCT05218499; 1403-0008) comparing the MDM2–p53 antagonist BI 907828 with doxorubicin as first-line treatment for patients with advanced DDLPS.
Brightline-1 trial
Background & rationale
BI 907828 is a MDM2–p53 antagonist that inhibits the interaction between the p53 and MDM2 proteins (Figure 1). In tumors with wild-type p53, this leads to p53 stabilization and restoration of p53 function, including target gene induction, which in turn leads to cell-cycle arrest and apoptosis. Early preclinical studies provided evidence to support the clinical development of BI 907828. In two patient-derived xenograft mouse models of DDLPS tissue harboring MDM2 amplifications, 15 days of treatment with BI 907828 at 2.5 mg/kg or 10 mg/kg significantly inhibited tumor growth compared with vehicle and doxorubicin controls. Indeed, in one of the models, complete responses were observed with no tumor regrowth during the follow-up period. These experiments provided a strong rationale for clinical testing of BI 907828, including in patients with DDLPS [32].
wt: Wild-type.
In the clinic, BI 907828 is currently being investigated as monotherapy in a phase Ia/Ib study in patients with advanced solid tumors, including patients with advanced/metastatic STS (NCT03449381) [33–35]. Pharmacokinetic analysis indicated that BI 907828 has a long half-life (28–59 h), allowing for an intermittent schedule with oral administration every 3 weeks (Q3W) [36]. As of July 2022, 107 patients had been treated with BI 907828 in this monotherapy study including 39 with DDLPS. Based on results from the phase Ia dose-escalation part of this trial, the recommended dose for expansion was identified as BI 907828 45 mg Q3W. Among the 59 patients who received BI 907828 45 mg Q3W, 88.1% had a treatment-related adverse event (AE), of which nausea was the most common (66.1%); 40.7% of patients had treatment-related grade ≥3 AEs, the most common being neutropenia (20.3%), thrombocytopenia (18.6%) and anemia (10.2%) [35]. Of note, no signs or symptoms of bleeding were associated with the cases of thrombocytopenia and, in general, patients recovered within 1–3 weeks. Among 36 evaluable patients with DDLPS, 6 (16.7%) achieved a partial response (PR) and 26 (72.2%) had stable disease (SD) as their best overall response, giving a disease control rate (DCR) of 88.9%. Preliminary median PFS for the patients with DDLPS was 8.1 months (range 0.8–21.0 months), but study treatment is ongoing for 13 patients.
In this phase Ia/Ib monotherapy study, a particularly striking response was seen after only two oral administrations of BI 907828 in a 37-year-old female diagnosed with DDLPS in the pelvic region with synchronous pulmonary metastases. The tumor had MDM2, cyclin dependent kinase 4 (CDK4), and FGF amplification according to fluorescence in situ hybridization and next-generation sequencing, but TP53 wild-type status. The patient had early progressive disease (PD) during initial treatment with doxorubicin and ifosfamide, achieved stable disease with second-line treatment with eribulin (8 months disease control) and early progression on treatment with trabectedin. In the phase Ia/Ib monotherapy trial she received two oral administrations of BI 907828 and experienced a clinical benefit (improvement of tumor pain) and achieved PR (according to the Response Evaluation Criteria In Solid Tumors [RECIST]), with 43% shrinkage of target lesions [31].
BI 907828 is also being investigated in combination with the anti-programmed cell death protein-1 (PD-1) antibody ezabenlimab in a phase Ia/Ib study in patients with advanced solid tumors (NCT03964233) due to its immunomodulatory effects. In addition to the effects outlined above, activation of p53 also promotes an antitumor immune response by increased CD8+ T-cell infiltration in the tumor and induces antitumor immune memory. Consequently, the combination of BI 907828 and immune checkpoint inhibitors targeting PD-1 may show synergistic activity. As of August 2022, 27 patients had received the combination of BI 907828 30/45 mg and ezabenlimab 240 mg Q3W, including five patients with DDLPS. Among the five patients with DDLPS, two achieved a PR and three had SD [37].
Thus, there is strong preclinical and clinical evidence supporting the continued development of BI 907828 in patients with MDM2-amplified DDLPS in the phase II/III Brightline-1 trial. To try to bring this novel medicine faster to a patient population with a high unmet need, a seamless phase II/III trial design will be used: following regulatory authority guidance [38], dose optimization of BI 907828 will be undertaken in the phase II part and the selected dose will be taken forward for comparison with the control arm in the phase III part of the trial.
Trial objectives
The primary trial objective is to evaluate whether BI 907828 is superior to doxorubicin as first-line systemic treatment for advanced or metastatic DDLPS. The primary end point is PFS, defined as the time interval from randomization until tumor progression according to RECIST version (v)1.1. Secondary objectives are to select an optimal dose of BI 907828 and evaluate whether BI 907828 improves the ORR, duration of response (DOR), OS, DCR, and tolerability, and delays worsening of health-related quality of life (HRQoL) compared with doxorubicin.
Design
Trial design
This multinational phase II/III trial has an active-controlled, randomized, open-label, seamless, parallel design (Figure 2). The trial will start with three arms in the phase II part that will investigate two doses of BI 907828 and doxorubicin. An interim analysis will be performed during phase II in which one of the BI 907828 doses will be selected for phase III. This interim analysis is expected to take place when pharmacokinetic/pharmacodynamic (PK/PD) and safety data from at least 20 evaluable patients treated with BI 907828 30 mg and 20 evaluable patients treated with BI 907828 45 mg are available. Enrollment to all three arms will continue while the interim analysis is conducted. A separate interim futility analysis of PFS will be performed after ∼56 PFS events, which is expected to align with the end of phase II. Enrollment of patients will continue while this analysis is performed. If the selected investigational arm passes the futility boundary, the phase III part of the trial will start in which patients will be randomized to BI 907828 at the dose selected in phase II, or doxorubicin.
Patients may continue treatment with doxorubicin for up to six cycles (maximum cumulative dose of 450 mg/m2); patients randomized to the doxorubicin arm will be eligible to cross-over to receive BI 907828 following confirmed progressive disease and if eligibility criteria are met.
IV: Intravenous; PD: Pharmacodynamic; PFS: Progression-free survival; PK: Pharmacokinetic; Q3W: Every 3 weeks.
Patients will be randomized using an Interactive Response Technology system in a 1:1:1 ratio in phase II and a 1:1 ratio in phase III. In phase II, patients will receive oral BI 907828 at a starting dose of 30 mg or 45 mg Q3W, or doxorubicin 75 mg/m2 as an intravenous infusion on Day 1 of each 21-day cycle (i.e., Q3W). The BI 907828 doses were selected based on the phase I monotherapy study which determined that 60 mg Q3W was the maximum tolerated dose and 45 mg Q3W was the recommended dose for expansion [34]. BI 907828 45 mg Q3W was determined to be the highest dose fulfilling the escalation with overdose control criterion from a Bayesian Logistic Regression Model analysis. The 30 mg dose was selected as the next lower potentially efficacious dose.
Patients will continue treatment until documented disease progression, unacceptable AEs, withdrawal of consent, or other reasons requiring treatment discontinuation for all arms. Additionally, in the doxorubicin arm, treatment will be discontinued after a maximum cumulative dose of 450 mg/m2. Dosing of BI 907828 may be delayed or reduced if neutrophil or platelet counts are reduced and do not recover within specified timeframes; dose reductions are permanent. BI 907828 45 mg may be reduced to 30 mg and then 20 mg, if necessary; BI 907828 30 mg may be reduced to 20 mg and then 10 mg, if necessary. Importantly for patients, those randomized to the doxorubicin arm will be able to cross over to receive BI 907828 following confirmed PD by central independent review and if eligibility criteria are met.
Eligibility criteria, planned sample size & planned trial period
Key inclusion and exclusion criteria are shown in Table 1. In brief, the trial will include adult patients with histologically proven locally advanced or metastatic MDM2-amplified DDLPS with at least one target lesion, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1, and no prior systemic therapy for liposarcoma. It is planned to randomize up to 270 patients in the phase II part of the trial and at least an additional 120 patients in the phase III part of the trial (60 per arm).
| Inclusion criteria | Exclusion criteria |
|---|---|
| Confirmed, advanced/metastatic, unresectable, progressive/recurrent DDLPS† | Known mutation in the TP53 gene (screening for TP53 status is not required) |
| Adult patients (≥18 years old) | Major surgery performed within 4 weeks prior to randomization or planned within 6 months after screening |
| Positive MDM2 immunohistochemistry as demonstrated by fluorescence in situ hybridization or MDM2 amplification demonstrated by next generation sequencing | Prior systemic therapy for LPS or prior treatment with anthracyclines in any setting |
| At least one measurable target lesion according to RECIST v1.1 | Previous or concomitant malignancies other than DDLPS or WDLPS, treated within 5 years |
| ECOG PS 0 or 1 | History/presence of human immunodeficiency virus infection, hepatitis B or C virus infection, gastrointestinal disorders, cardiovascular abnormalities or brain metastases |
| Adequate liver, bone marrow and renal function |
Trial end points
The primary end point is PFS based on central independent review, defined as the time from randomization until tumor progression according to RECIST v1.1 (based solely on blinded central independent review) or death from any cause. PFS will be assessed at the end of phase II of the trial (interim futility analysis) and during phase III (primary PFS analysis). Secondary end points include: (i) objective response (OR), defined as a best overall response of confirmed complete response (CR) or confirmed PR according to RECIST v1.1; (ii) DOR, defined as the time interval from first documented confirmed OR until disease progression or death among patients with confirmed OR; (iii) disease control (DC), defined as a best overall response of CR, PR or SD according to RECIST v1.1; (iv) OS, defined as the time interval from randomization until death from any cause, assessed at the end of the phase III part of the trial; (v) occurrence of treatment-related AEs; (vi) occurrence of treatment-related AEs leading to study drug discontinuation; and (vii) HRQoL, based on data collected through the Quality of Life Questionnaire for cancer patients (QLQ-C30), 5-level EuroQol 5 Dimension (EQ-5D5L), fatigue, pain and Patient Global Impression questionnaires. For the QLQ-C30, EQ-5D5L, and Patient Global Impression questionnaires, a minimal clinically important difference (MCID) will be identified. The MCID for the Patient Reported Outcome Measures (PROMs) for fatigue and pain will be defined in the phase II part of the trial and confirmed in the phase III part of the trial.
Trial procedures
Tumor response will be evaluated according to RECIST v1.1. Imaging of all known or suspected sites of disease using an appropriate method will be conducted at baseline and every 6 weeks starting 6 weeks after cycle 1 Day 1. Safety will be assessed using physical examination, measurement of vital signs, laboratory parameters, electrocardiograms, measurement of left ventricular ejection function, and monitoring of AEs. AEs, together with serious AEs and AEs of special interest (including hepatic injury, hematologic AEs, gastrointestinal AEs, and fatigue) will be assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0; the causal relationship of AEs to the study treatments will also be assessed.
The pharmacokinetics of BI 907828 will be determined after administration of a single dose in cycle 1; maximum plasma concentration and, if feasible, area under curve (AUC) from 0 to 168 days (AUC0–168) and from 0 to the time of the last quantifiable data point (AUC0-tz) will be evaluated. In addition, samples will be taken for biomarker analysis, including a fresh biopsy at cycle 2 Day 2–4, and blood samples for the isolation of circulating tumor DNA, circulating micro-RNA, and circulating proteins. Patients will also complete HRQoL questionnaires at regular intervals until week 48 or progressive disease, and annually thereafter.
Statistical analysis
The trial is designed to evaluate whether BI 907828 is superior to doxorubicin as first-line systemic treatment for advanced or metastatic DDLPS based on PFS. Randomization will be stratified by extent of disease (locally advanced vs metastatic disease). As noted above, the interim futility analysis will be performed once the required number of approximately 56 PFS events have occurred across the selected investigational arm (BI 907828 at the 30 mg dose or at the 45 mg dose) and the control arm. Sample size re-estimation will be considered around the end of phase II to support sufficient conditional power. The primary PFS analysis during phase III will be performed once approximately 92 PFS events have occurred in patients enrolled before the interim futility analysis and approximately 65 PFS events have occurred in patients enrolled after the interim futility analysis according to option A (patient separation approach) as reported in Jenkins et al. [39]. The weighted inverse normal method described by Lehmacher and Wassmer [40] combining one-sided p-values from a stratified log-rank test (locally advanced vs metastatic) will be the primary analysis method for PFS. If statistical significance is obtained for PFS at the primary PFS analysis during phase III, then selected secondary end points (i.e., ORR and OS) will be tested following a hierarchical testing framework. Kaplan–Meier estimates (and corresponding 95% confidence intervals) of median PFS and OS will be calculated. Additionally, the p-values for PFS and OS from the stratified log-rank test will be calculated. The median unbiased estimator [41] will be used as the primary estimator to estimate the hazard ratios for PFS and OS. The Cochrane-Mantel-Haenszel method will be used to test for a difference in ORR between the treatment arms, generating a one-sided p-value. Safety data will be analyzed descriptively.
Ethical considerations
The trial is being carried out in compliance with the protocol, the ethical principles laid down in the Declaration of Helsinki, and in accordance with the International Conference on Harmonization Guideline for Good Clinical Practice, relevant standard operating procedures of the sponsor, plus all other local regulatory requirements.
Conclusion
This paper details the design of what is anticipated to be the largest prospective trial in patients with advanced/metastatic DDLPS to date. The active-controlled, phase II/III randomized trial (Brightline-1; NCT05218499) will evaluate the optimal dose of BI 907828 in the phase II part before seamlessly evaluating the selected dose in comparison with doxorubicin in the phase III part, and has recently been granted Fast Track Designation by the US FDA.
While rare, DDLPS is an aggressive cancer, with low 5-year disease-specific survival rates [7,8,16,17]. Systemic chemotherapy, the current standard-of-care, is supported by a low level of evidence in this form of liposarcoma and associated with low response and PFS rates [18–21]. As more than 90% of DDLPS tumors have amplification of MDM2, a negative regulator of the p53 tumor suppressor protein [27], restoration of p53 activity by antagonism of MDM2 is an attractive therapeutic strategy and is being investigated in a number of clinical trials [30,31]. BI 907828 is a highly potent, oral MDM2–p53 antagonist that is in clinical development. Preclinical and early clinical data demonstrated that BI 907828 had antitumor activity in MDM2-amplified DDLPS, leading to the initiation of this trial [32,35].
The Brightline-1 trial is actively recruiting patients and aims to demonstrate the superiority of BI 907828 to doxorubicin as first-line systemic treatment for advanced or metastatic DDLPS in terms of PFS, thereby providing a targeted treatment option in this area of high unmet clinical need.
Background
Dedifferentiated liposarcoma (DDLPS) is a rare, aggressive liposarcoma with 5-year disease-specific survival of 20–44%.
At present, systemic chemotherapy is the first-line treatment of choice in patients with unresectable, advanced, or metastatic disease, but is associated with both poor efficacy and significant toxicities.
Nearly all DDLPS have amplification of the MDM2 gene, which encodes a negative regulator of the p53 tumor suppressor protein. Antagonism of MDM2, restoring p53 activity, is an attractive treatment approach for MDM2-driven tumors.
BI 907828
BI 907828 is an oral, MDM2–p53 antagonist that inhibits the interaction between p53 and MDM2. It demonstrated strong antitumor activity against DDLPS xenograft models in preclinical studies.
In a phase Ia/Ib study, among 36 evaluable patients with DDLPS, a disease control rate (DCR) of 88.9% was observed, and preliminary median progression-free survival (PFS) was 8.1 months (range 0.8–21.0 months; 13 patients were ongoing on treatment). BI 907828 had a manageable toxicity profile with hematologic adverse events (AEs) being the most common grade ≥3 AEs.
Brightline-1 trial
Brightline-1 is an ongoing phase II/III, multicenter, active-controlled, randomized, open-label, parallel-design trial comparing BI 907828 with doxorubicin in patients with DDLPS.
Eligible patients are adults with histologically confirmed locally advanced or metastatic MDM2-amplified DDLPS with at least one measurable target lesion and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
In the phase II part, patients will be randomized to BI 907828 30 or 45 mg orally every 3 weeks (Q3W), or doxorubicin 75 mg/m2 intravenously Q3W (up to a maximum cumulative dose of 450 mg/m2). An interim analysis for dose selection will be performed during phase II in which one of the BI 907828 doses will be selected for phase III. A separate interim futility analysis of PFS will be performed after ∼56 PFS events, which is expected to align with the end of phase II. Enrolment of patients will continue while these analyses are performed.
The primary end point is PFS based on central independent review. Secondary end points include overall response rate, duration of response, DCR, overall survival and health-related quality of life. Safety will be assessed by monitoring AEs, their severity, and relatedness to study treatment throughout the study.
The trial is actively recruiting; approximately 270 patients are expected to be enrolled in the phase II part and at least 120 in the phase III part.
Supplementary data
An infographic accompanies this paper. To view or download this infographic in your browser please click here: https://www.futuremedicine.com/doi/suppl/10.2217/fon-2022-1291
Author contributions
All authors were involved in the conception and design of the Brightline-1 trial. All authors were involved in the drafting of the manuscript and/or critically revised the manuscript for important intellectual content. All authors gave final approval of the manuscript and agree to be accountable for all aspects of the work, which includes ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.
Acknowledgments
The authors would like to thank the patients and their families, the investigators as well as the sites staff. The authors would like to acknowledge V Chen and J Geng for their work on the statistical design of the Brightline-1 trial, M Teufel for his work on the translational and biomarker-related aspects of the trial, and H Jones and T Liu for their support in clinical operations associated with the trial.
Financial & competing interests disclosure
The Brightline-1 trial is funded by Boehringer Ingelheim. The authors did not receive payment related to the development of this manuscript. P Schöffski reports research funding (institutional) from CoBioRes NV, Eisai, G1 Therapeutics, PharmaMar, Genmab, Merck, Sartar Therapeutics, ONA Therapeutics; consulting or advisory role (personal) for Blueprint Medicines, Deciphera, Ellipses Pharma, Blueprint Medicines, Transgene, Exelixis, Boehringer Ingelheim, Studiecentrum voor Kernenergie, SQZ Biotechnology, CRT Pioneer Fund LP, Acendo, PharmaMar, Merck Healthcare KGaA, Ysios Capital. M Lamar and A Lucarelli report employment with Boehringer Ingelheim. RG Maki reports consulting or advisory role (personal) for Bayer, Karyopharm Therapeutics, TRACON Pharma, Deciphera, Ipsen, Daiichi Sankyo/Lilly, PEEL Therapeutics, UpToDate; speakers' bureau fees (personal) from PER; travel, accommodations, expenses (personal) from TRACON Pharma, SpringWorks Therapeutics; patents, royalties, other intellectual property (personal) from Uptodate; research funding (institutional) from Regeneron, Daiichi Sankyo, Bayer, SpringWorks Therapeutics, Amgen, Astex Pharmaceuticals, Boehringer Ingelheim, Rain Therapeutics, BioAtla, C4 Therapeutics, Exelixis, InhibRx, PEEL Therapeutics, Regeneron, Presage Biosciences, SARC: Sarcoma Alliance for Research though Collaboration, SynOx, TRACON Pharma.
Medical writing support for the development of this manuscript, under the direction of the authors, was provided by J Saunders of Ashfield MedComms, an Inizio Company, and was funded by Boehringer Ingelheim.
Open access
This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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