Evidence map›Paper›PMID 35635631›Full record

ArticleInvestigational new drugs2022

Targeting wild-type TP53 using AMG 232 in combination with MAPK inhibition in Metastatic Melanoma; a phase 1 study.

Stergios J Moschos, Shahneen Sandhu, Karl D Lewis, Ryan J Sullivan, Igor Puzanov, Douglas B Johnson, Haby A Henary, Hansen Wong, Vijay V Upreti, Georgina V Long and 1 more

Open access · hybridAbstract readClinical Trial, Phase I
PubMed Full text at PMC Publisher
In one paragraph

Article in Investigational new drugs, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.

0numbers the graph read from it
0cells of the map it votes in
12citing papers in PubMed
0.9field-weighted citation impact, top 29% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

12 citing papers in PubMed, 14 citations in OpenAlex.

  1. Milademetan in Advanced Solid Tumors with MDM2 Amplification and Wild-type TP53: Preclinical and Phase II Clinical Trial Results.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025
    Trial
  2. Review
  3. Article
  4. Review
  5. Review
  6. Role of Ubiquitin-regulated EMT in Cancer Metastasis and Chemoresistance.International journal of biological sciences · 2025
    Review
  7. Article
  8. Review
  9. Review
  10. Advancements in MDM2 inhibition: Clinical and pre-clinical investigations of combination therapeutic regimens.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023
    Review
  11. Article
  12. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 7 institutions in 2 countries.

Stergios J MoschosDepartment of Medicine, Division of Medical Oncology, The University of North Carolina at Chapel Hill and the Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA. moschos@med.unc.edu.ORCID http://orcid.org/0000-0002-8943-0845
Shahneen SandhuDepartment of Medical Oncology, Peter MaCallum Cancer Center and the University of Melbourne, Melbourne, VIC, Australia.
Karl D LewisDivision of Medical Oncology, Anschultz Medical Campus, University of Colorado, Denver, CO, USA.
Ryan J SullivanDevelopmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Igor PuzanovDepartment of Medicine, Vanderbilt University Medical Center and Ingram Cancer Center, Nashville TN, USA.
Douglas B JohnsonDepartment of Medicine, Vanderbilt University Medical Center and Ingram Cancer Center, Nashville TN, USA.
Haby A HenaryMedical Affairs, Amgen Inc, Thousand Oaks, CA, USA.
Hansen WongClinical Pharmacology, Modeling & Simulation, Amgen Inc, South San Francisco, CA, USA.
Vijay V UpretiClinical Pharmacology, Modeling & Simulation, Amgen Inc, South San Francisco, CA, USA.
Georgina V LongMelanoma Institute Australia, The University of Sydney and Royal North Shore, and Mater Hospitals, Sydney NSW, Australia.
Keith T FlahertyDevelopmental Therapeutics and Melanoma Programs, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
Amgen (United States) · USMassachusetts General Hospital · USVanderbilt University Medical Center · USThe University of Melbourne · AUThe University of Sydney · AUUniversity of Colorado Denver · USUniversity of North Carolina at Chapel Hill · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundTargeting the MDM2-p53 interaction using AMG 232 is synergistic with MAPK inhibitors (MAPKi) in preclinical melanoma models. We postulated that AMG 232 plus MAPKi is safe and more effective than MAPKi alone in TP53-wild type, MAPKi-naïve metastatic melanoma.

methodsPatients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of AMG 232 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type). Patients were treated for seven days with AMG 232 alone before adding T±D. Safety and efficacy were assessed using CTCAE v4.0 and RECIST v1.1 criteria, respectively. Pharmacokinetic (PK) analysis was performed at baseline and steady-state levels for AMG 232.

results31 patients were enrolled. Ten and 21 patients were enrolled in Arm 1 and Arm 2, respectively. The most common AMG 232-related adverse events (AEs) were nausea (87%), diarrhea (77%), and fatigue (74%). Seven patients (23%) were withdrawn from the study due to AMG 232-related AEs. Three dose-limiting AEs occurred (Arm 1, 180 mg, nausea; Arm 2, 240 mg, grade 3 pulmonary embolism; Arm 2, 180 mg, grade 4 thrombocytopenia). AMG 232 PK exposures were not altered when AMG 232 was combined with T±D. Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively.

conclusionThe maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit.

Indexed as

MelanomaTumor Suppressor Protein p53AcetatesAntineoplastic Combined Chemotherapy ProtocolsHumansNauseaPiperidonesProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesPyrimidinones2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acidAcetatesPiperidonesProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesPyrimidinonesTP53 protein, humanTumor Suppressor Protein p53BRAFV600EDabrafenibMDM2 inhibitorsMetastatic melanomaTrametinib

Identifiers

PMID35635631
PMCPMC9395504
OpenAlexW4282009902

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.