Abstract 2689
Background
Activation of the mTOR pathway is associated with shorter overall survival (OS) in patients (p) with metastatic renal cell carcinoma (mRCC). This outcome could be reversed with mTOR inhibitors (mTORi).
Methods
We retrospectively analized by amplicon-seq mutations in mTOR, VEGF, and cell cycle pathways in 90 mRCC p who had received mTORi. A multivariate Cox model including sex, age, non-clear or sarcomatoide component, metastatic sites, IMDC subgroup, and line of mTORi was adjusted to isolate the effect of having mTORi mutations on progression-free survival (PFS), death form diagnosis (OS1) and death from mTORi treatment (OS2).
Results
We identified 33% of p having mutations in the mTOR pathway: mTOR (17.8%), PIK3CA (5.6%), PTEN (3.3%), TSC1 (5.6%) and TSC2 (4%). No mutations were found in AKT (AKT1, AKT2, AKT3). OS for favorable, intermediate and poor prognosis of the IMDC were 43.7, 22.2 and 8.7 months respectively. As summarized in the table, in the best adjusted model there were no statistically differences in the hazard ratios (HR) of PFS, OS1 or OS2, between patient with and without mutations (M/NotM). Four long-term responders to mTORi (> 7 years) harboured mutations in one or more genes of this pathway (p53, PTEN and mTOR). Upon progression one patient adquired an LRPB1 mutation.Table:
975P
Adjusted HR (Cox) | PFS | OS1 | OS 2 |
---|---|---|---|
M/NoM | 1.12 | 1.02 | 1.18 |
95% CI | 0.67 – 1.89 | 0.61 – 1.69 | 0.63 – 2.21 |
p | 0.660 | 0.946 | 0.607 |
Conclusions
In a multivariate adjusted model in patients with mRCC treated with mTORi, we did not find the expected worse prognosis associated with mTOR mutations. This finding can be considered as an indirect signal of the effect of mTORi on PFS and OS in patients with mTOR mutations. Although, not the most effective treatment in the overall population, some patients with specific alterations in the mTOR pathway should be considered for an mTORi.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Vall d´Hebron Institute of Oncology.
Funding
Has not received any funding.
Disclosure
C. Suarez Rodriguez: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Advisory / Consultancy: Eusa; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Sanofi-Aventis; Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Roche; Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): AstraZeneca AB; Research grant / Funding (institution): Aveo Pharmaceuticals INC; Research grant / Funding (institution): Bayer AG; Research grant / Funding (institution): Blueprint Medicines Corporation; Research grant / Funding (institution): BN Immunotherapeutics INC; Research grant / Funding (institution): Boehringer Ingelheim España, S.A; Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Cougar Biotechnology INC; Research grant / Funding (institution): Deciphera Pharmaceuticals LLC; Research grant / Funding (institution): Exelixis INC; Research grant / Funding (institution):, F. Hoffmann-La Roche LTD; Research grant / Funding (institution): Genentech INC; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Janssen-Cilag International NV; Research grant / Funding (institution): Karyopharm Therapeutics INC; Research grant / Funding (institution): Laboratoires Leurquin Mediolanum SAS; Research grant / Funding (institution): Lilly, S.A; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Millennium Pharmaceuticals; Research grant / Funding (institution): Nanobiotix SA. J.A. Arranz Arija: Advisory / Consultancy, Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pierre-Fabre; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Pfizer; Travel / Accommodation / Expenses: Janssen-Cilag. R. Morales Barrera: Research grant / Funding (institution): AB Science; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Arog Pharmaceuticals, INC; Research grant / Funding (institution), Travel / Accommodation / Expenses: Astellas Pharma.; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca AB; Research grant / Funding (institution): Aveo Pharmaceuticals INC; Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer AG; Research grant / Funding (institution): Blueprint Medicines Corporation; Research grant / Funding (institution): BN Immunotherapeutics INC; Research grant / Funding (institution): Boehringer Ingelheim España, S.A.; Research grant / Funding (institution): Bristol-Myers Squibb International Corporation (BMS); Research grant / Funding (institution), Travel / Accommodation / Expenses: Clovis Oncology, INC,; Research grant / Funding (institution): Cougar Biotechnology INC; Research grant / Funding (institution): Deciphera Pharmaceuticals LLC; Research grant / Funding (institution): Exelixis INC; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: F. Hoffmann-La Roche LTD/Genentech,; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Janssen-Cilag International NV; Advisory / Consultancy: Johnson and Johnson; Research grant / Funding (institution): Karyopharm Therapeutics INC.,; Research grant / Funding (institution): Laboratoires Leurquin Mediolanum SAS; Research grant / Funding (institution), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Medimmune, Millennium Pharmaceuticals, INC.; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: MSD; Research grant / Funding (institution): Nanobiotix SA,; Research grant / Funding (institution): Novartis Farmacéutica, S.A; Research grant / Funding (institution): Puma Biotechnology; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi-Aventis; Research grant / Funding (institution): Pharma LTD; Research grant / Funding (institution): Teva Pharma S.L.U.; Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma. J. Puente: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Astellas; Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen-Cilag; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer; Advisory / Consultancy: Clovis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eusa; Advisory / Consultancy: Sanofi-Aventis; Speaker Bureau / Expert testimony: Pierre-Fabre; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Kiowa; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Lilly. O. Reig: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Pfizer. L. Faez: Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Pfizer. A. González del Alba: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Novartis; Advisory / Consultancy: Eusa; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: MSD. B. P. Valderrama: Honoraria (self), Advisory / Consultancy: Pierre-Fabre; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self): Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Bayer; Advisory / Consultancy: Sanofi-Aventis; Advisory / Consultancy: Ipsen; Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: Janssen-Cilag; Travel / Accommodation / Expenses: Pfizer. E. Gallardo: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses, Non-remunerated activity/ies: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: Rovi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Daiichi Sankyo; Advisory / Consultancy: Techdow; Travel / Accommodation / Expenses: Pierre Fabre. B. Mellado: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Janssen-Cilag; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Astellas; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Sanofi-Aventis; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer. E. Esteban: Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer. A. Vivancos: Advisory / Consultancy, Research grant / Funding (institution): Sysmex; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Guardan Health; Licensing / Royalties: Ferrer; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Cellestia Biotech; Honoraria (institution): Chittern. J. Carles: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Johnson & Johnson; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Astellas; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Sanofi-Aventis; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Ipsen; Research grant / Funding (institution): AB Science,; Research grant / Funding (institution): Aragon Pharmaceuticals; Research grant / Funding (institution): Arog Pharmaceuticals; Research grant / Funding (institution): Aveo Pharmaceuticals INC; Research grant / Funding (institution): Blueprint Medicines Corporation; Research grant / Funding (institution): BN Immunotherapeutics INC; Research grant / Funding (institution): Boehringer Ingelheim España, S.A; Research grant / Funding (institution): Clovis Oncology; Speaker Bureau / Expert testimony: Asofarma; Research grant / Funding (institution): Cougar Biotechnology INC; Research grant / Funding (institution): Deciphera Pharmaceuticals LLC; Research grant / Funding (institution): Exelixis INC; Research grant / Funding (institution): Genentech INC; Research grant / Funding (institution): GlaxoSmithKline, SA; Research grant / Funding (institution): Incyte Corporation; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Laboratoires Leurquin Mediolanum SAS; Research grant / Funding (institution): Lilly, S.A; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Millennium Pharmaceuticals; Research grant / Funding (institution): Nanobiotix SA; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): SFJ Pharma; Research grant / Funding (institution): Teva Pharma. All other authors have declared no conflicts of interest.
Resources from the same session
3252 - Genes involved in DNA replication, chromatin remodeling and cell cycle as potential biomarkers for therapy outcome to immune therapy in patients with metastatic cutaneous malignant melanoma
Presenter: Fernanda Costa Svedman
Session: Poster Display session 3
Resources:
Abstract
5545 - Phase Ib/II Study (SENSITIZE) assessing safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical outcome of domatinostat in combination with pembrolizumab in patients with advanced melanoma refractory/non-responding to prior checkpoint inhibitor therapy
Presenter: Jessica Hassel
Session: Poster Display session 3
Resources:
Abstract
5213 - Genomic landscape of primary malignant melanoma of esophagus
Presenter: Jie Dai
Session: Poster Display session 3
Resources:
Abstract
2716 - A phase III, randomised, double-blind study of adjuvant cemiplimab versus placebo post-surgery and radiation in patients with high-risk cutaneous squamous cell carcinoma (CSCC)
Presenter: Danny Rischin
Session: Poster Display session 3
Resources:
Abstract
3550 - ILLUMINATE 301: A randomized phase 3 study of tilsotolimod in combination with ipilimumab compared with ipilimumab alone in patients with advanced melanoma following progression on or after anti-PD-1 therapy
Presenter: Marcus Butler
Session: Poster Display session 3
Resources:
Abstract
1645 - PRIME002 - Early phase II study of Azacitidine and Carboplatin priming for Avelumab in patients with advanced melanoma who are resistant to immunotherapy
Presenter: Andre Van Der Westhuizen
Session: Poster Display session 3
Resources:
Abstract
4440 - Pembrolizumab (pembro) Plus Lenvatinib (len) for First-Line Treatment of patients (pts) With Advanced Melanoma: Phase 3 LEAP-003 Study
Presenter: Alexander Eggermont
Session: Poster Display session 3
Resources:
Abstract
3454 - Proof of concept study with the histone deacetylase inhibitor vorinostat in patients with resistant BRAFV600 mutated advanced melanoma
Presenter: Sanne Huijberts
Session: Poster Display session 3
Resources:
Abstract
1832 - A phase Ia/Ib clinical study to evaluate the safety, pharmacokinetics (PK) and preliminary anti-tumor activity of FCN-159 in patients with advanced melanoma harboring NRAS-aberrant (Ia) and NRAS-mutation (Ib).
Presenter: Lu Si
Session: Poster Display session 3
Resources:
Abstract
3996 - A Phase I Clinical Trial Investigating the Therapeutic Cancer Vaccine UV1 in Combination with Pembrolizumab as First-Line Treatment of Patients with Malignant Melanoma
Presenter: Sanjiv Agarwala
Session: Poster Display session 3
Resources:
Abstract