Highlights
- •Demonstration of the feasibility of precision oncology for advanced uveal melanoma.
- •Complete whole-genome and RNA sequencing data were generated for 87% of patients.
- •Following treatment recommendations, 60% of patients received ≥1 matched therapy.
- •First-line therapies included inhibitors of MEK, MET, sorafenib, and nivolumab.
- •Clinical benefit rate in 56% of patients with one partial response under nivolumab.
Abstract
Background
Targeted therapies for metastatic uveal melanoma have shown limited benefit in biomarker-unselected
populations. The Treat20 Plus study prospectively evaluated the feasibility of a precision
oncology strategy in routine clinical practice.
Patients and methods
Fresh biopsies were analyzed by high-throughput genomics (whole-genome, whole-exome,
and RNA sequencing). A multidisciplinary molecular and immunologic tumor board (MiTB)
made individualized treatment recommendations based on identified molecular aberrations,
patient situation, drug, and clinical trial availability. Therapy selection was at
the discretion of the treating physician. The primary endpoint was the feasibility
of the precision oncology clinical program.
Results
Molecular analyses were available for 39/45 patients (87%). The MiTB provided treatment
recommendations for 40/45 patients (89%), of whom 27/45 (60%) received ≥1 matched
therapy. First-line matched therapies included MEK inhibitors (n = 15), MET inhibitors (n = 10), sorafenib (n = 1), and nivolumab (n = 1). The best response to first-line matched therapy was partial response in one
patient (nivolumab based on tumor mutational burden), mixed response in two patients,
and stable disease in 12 patients for a clinical benefit of 56%. The matched therapy
population had a median progression-free survival and overall survival of 3.3 and
13.9 months, respectively. The growth modulation index with matched therapy was >1.33
in 6/17 patients (35%) with prior systemic therapy, suggesting clinical benefit.
Conclusions
A precision oncology approach was feasible for patients with metastatic uveal melanoma,
with 60% receiving a therapy matched to identify molecular aberrations. The clinical
benefit after checkpoint inhibitors highlights the value of tumor mutational burden
testing.
Keywords
Abbreviations:
UM (Uveal melanom), NGS (Next Generation Sequencing), TKI (Tyrosine Kinase Inhibitor), CPI (Checkpoint Inhibitor), TML (Tumor Mutational Load)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The Zimmerman-McLean-Foster hypothesis: 25 years later.Br J Ophthalmol. 2004; 88: 962-967
- Molecular pathology of uveal melanoma.Eye. 2013; 27: 230-242
- Collaborative ocular oncology group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma.Ophthalmology. 2012; 119: 1596-1603
- Dual immunological checkpoint blockade for uveal melanoma.J Clin Oncol. 2021; 39: 554-556
- Overall survival benefit with tebentafusp in metastatic uveal melanoma.N Engl J Med. 2021; 385: 1196-1206
- Integrative analysis identifies four molecular and clinical subsets in uveal melanoma.Cancer Cell. 2018; 33: 151
- Comprehensive genetic landscape of uveal melanoma by whole-genome sequencing.Am J Hum Genet. 2016; 99: 1190-1198
- Uveal melanoma: towards a molecular understanding.Prog Retin Eye Res. 2020; 75: 100800
- Emerging therapeutic opportunities based on current knowledge of uveal melanoma biology.Cancers. 2019; 11
- Targeted therapy of uveal melanoma: recent failures and new perspectives.Cancers. 2019; 11
- High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial.Cancer Discov. 2017; 7: 586-595
- First results of the EORTC-SPECTA/Arcagen study exploring the genomics of rare cancers in collaboration with the European reference network EURACAN.ESMO Open. 2020; 5e001075
- Molecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors.Nat Commun. 2017; 8: 14262
- Support of a molecular tumour board by an evidence-based decision management system for precision oncology.Eur J Cancer. 2020; 127: 41-51
- Evaluation of treatment effect with paired failure times in a single-arm phase II trial in oncology.Comput Math Methods Med. 2018; 2018: 1672176
- Drug development in tissue-agnostic indications.Cancers. 2021; 13
- Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study.Ann Oncol. 2019; 30: 1370-1380
- Molecular landscape and actionable alterations in a genomically guided cancer clinical trial: national cancer institute molecular analysis for therapy choice (NCI-MATCH).J Clin Oncol. 2020; 38: 3883-3894
- Real-world data from a molecular tumor board demonstrates improved outcomes with a precision N-of-One strategy.Nat Commun. 2020; 11: 4965
- The MEK1/2 inhibitor, selumetinib (AZD6244; ARRY-142886), enhances anti-tumour efficacy when combined with conventional chemotherapeutic agents in human tumour xenograft models.Br J Cancer. 2012; 106: 858-866
- Selumetinib-based therapy in uveal melanoma patient-derived xenografts.Oncotarget. 2018; 9: 21674-21686
- Chloroquine sensitizes GNAQ/11-mutated melanoma to MEK1/2 inhibition.Clin Cancer Res. 2020; 26: 6374-6386
- Selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma: a phase III, multicenter, randomized trial (SUMIT).J Clin Oncol. 2018; 36: 1232-1239
- How to MEK the best of uveal melanoma: a systematic review on the efficacy and safety of MEK inhibitors in metastatic or unresectable uveal melanoma.Eur J Cancer. 2018; 103: 41-51
Network. NCC. Melanoma: uveal (version 2.2021).
- Randomized phase II trial and tumor mutational spectrum analysis from cabozantinib versus chemotherapy in metastatic uveal melanoma (alliance A091201).Clin Cancer Res. 2020; 26: 804-811
- Alternative transcription initiation leads to expression of a novel ALK isoform in cancer.Nature. 2015; 526: 453-457
- Trametinib (GSK1120212).Recent Results Cancer Res. 2018; 211: 91-100
- Correlation of novel ALK(ATI) with ALK immunohistochemistry and clinical outcomes in metastatic melanoma.Histopathology. 2020; 77: 601-610
- Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.Lancet Oncol. 2020; 21: 1353-1365
- Prolonged stable disease in a uveal melanoma patient with germline MBD4 nonsense mutation treated with pembrolizumab and ipilimumab.Immunogenetics. 2019; 71: 433-436
- Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors.Nat Commun. 2018; 9: 1866
- Mutations associated with acquired resistance to PD-1 blockade in melanoma.N Engl J Med. 2016; 375: 819-829
- Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes.Cancer Discov, 2021
- Guideline on the evaluation of anticancer medicinal products in man.2019 ([(accessed on 9 September 2019)])
- Prospective high-throughput genome profiling of advanced cancers: results of the PERMED-01 clinical trial.Genome Med. 2021; 13: 87
- Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study.Nat Med. 2019; 25: 744-750
- Dysregulated GPCR signaling and therapeutic options in uveal melanoma.Mol Cancer Res. 2017; 15: 501-506
- Functional characterization of uveal melanoma oncogenes.Oncogene. 2021; 40: 806-820
- Combined inhibition of galphaq and MEK enhances therapeutic efficacy in uveal melanoma.Clin Cancer Res. 2021; 27: 1476-1490
- Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer.Nat Med. 2019; 25: 628-640
- BRD4-targeted therapy induces Myc-independent cytotoxicity in Gnaq/11-mutatant uveal melanoma cells.Oncotarget. 2015; 6: 33397-33409
- First-in-Human study of mivebresib (ABBV-075), an oral pan-inhibitor of bromodomain and extra terminal proteins, in patients with relapsed/refractory solid tumors.Clin Cancer Res. 2019; 25: 6309-6319
Article info
Publication history
Published online: May 12, 2022
Accepted:
April 1,
2022
Received in revised form:
March 30,
2022
Received:
January 19,
2022
Identification
Copyright
© 2022 Elsevier Ltd. All rights reserved.
