3904 - SELPAC - a 3 arm randomised Phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel (PT) in metastatic uveal melanoma (UM)

Background

The MAPK pathway is constitutively activated in uveal melanoma (UM), a disease for which there remains no standard of care for metastatic disease. In a randomised phase II clinical trial, selumetinib (AZD6244, ARRY-142886), a MEKi, showed superiority vs dacarbazine (DTIC). A phase III study of the combination of selumetinib (SEL) + DTIC however failed to show superiority over DTIC alone. Pre-clinical data support synergistic cytotoxic activity for MEKi + taxane combinations in a number of cancer cell line models and suggest that interrupting selumetinib before taxane exposure may be beneficial.

Methods

Following ethical approval, 77 patients with metastatic UM who had not received previous chemotherapy were randomised to either A: SEL 75mg bd po B: SEL 75mg bd po + PT 80mg/m² weeks 1, 2 and 3 (q28) or C: SEL 75mg bd po interrupted for 2 days before exposure to PT 80mg/m² weeks 1, 2, 3 (q28) at 13 UK and 1 German sites. Primary endpoint was PFS; OS, ORR and toxicity were secondary endpoints. After an amendment, arms B & C were combined and compared to arm A for PFS, OS and ORR using intention to treat analyses. Reflecting the pooled comparison, the sample size was re-adjusted to detect hazard ratio: 0.55, 80% power at 1-sided 5% significance level. Sensitivity analysis was performed to explore whether there were detectable differences in outcome between patients receiving continuous or interrupted SEL in combination with PT (arms B & C).

Results

Primary analysis was triggered after 68 events. The median PFS in the combination arms B & C was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (95% CI: 2.0 - 3.9) in the SEL alone arm A (hazard ratio 0.61 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in arms B & C and A respectively. Median OS in arms B & C was 9 months and was not significantly different from arm A at 10 months (hazard ratio 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469). SAEs and grade 3+ toxicities were similar between treatment arms.

Conclusions

SelPac met its primary endpoint, demonstrating a statistically significant improvement in PFS for SEL + PT without a significant increase in toxicity. No trend for a prolongation of OS was observed.

Clinical trial identification

ISRCTN 29621851.

Editorial acknowledgement

Legal entity responsible for the study

University of Liverpool & Liverpool Cancer Trials Unit.

Funding

Cancer Research UK and AstraZeneca.

Disclosure

P. Nathan: Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: AstraZeneca; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: BMS; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Merck; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: MSD; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Immunocore; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Pfizer; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Ipsen; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: 4SC; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Roche; Research grant / Funding (self), Audit: Pfizer; Leadership role, Non-remunerated activity/ies, Chair: NCRI Bladder and Renal CSG; Leadership role, Non-remunerated activity/ies, Steering Committee and Uveal Melanoma Lead: EORTC Melanoma Group; Leadership role, Non-remunerated activity/ies, IRCI UK Uveal Melanoma Lead: IRCI UK . P.G. Corrie: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker fees and Advisory Boards: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker fees and Advisory Boards: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker fees and Advisory Boards: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker fees and Advisory Boards: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Advisory Board: Incyte; Honoraria (self), Advisory / Consultancy, Consultancy : LifeArc; Honoraria (self), Advisory / Consultancy, ISDMC membership: Celgene; Shareholder / Stockholder / Stock options, Stock ownership: Genesiscare; Research grant / Funding (institution), Commercial-sponsored clinical trials: BMS; Research grant / Funding (institution), Commercial-sponsored clinical trials: MSD; Research grant / Funding (institution), Commercial-sponsored clinical trials: Celgene; Research grant / Funding (institution), Commercial-sponsored clinical trials: Array Pharmaceuticals; Research grant / Funding (institution), Commercial-sponsored clinical trials: Immunocore; Research grant / Funding (institution), Commercial-sponsored clinical trials: Novartis; Research grant / Funding (institution), Grant for investigator led trials: Celgene; Non-remunerated activity/ies, UK Chief Investigator for clinical trials sponsored by Halozyme: Halozyme; Non-remunerated activity/ies, UK Chief Investigator for clinical trials sponsored by Novartis: Novartis; Non-remunerated activity/ies, UK Chief Investigator for clinical trials sponsored by BMS: BMS; Leadership role, Non-remunerated activity/ies, Chair : NCRI pancreatic cancer workstream. S. Danson: Honoraria (self), Speaker Bureau / Expert testimony, Speaker bureau, lecturer: Amgen; Honoraria (self), Travel / Accommodation / Expenses, Conference attendance and travel: MSD; Honoraria (self), Travel / Accommodation / Expenses, Conference attendance and travel: BMS; Honoraria (self), Advisory / Consultancy, Consultancy: GSK; Honoraria (self), Advisory / Consultancy, Consultancy: Incanthera; Honoraria (self), Travel / Accommodation / Expenses, Conference attendance and travel: AbbVie; Honoraria (self), Advisory / Consultancy, Advisory board: MSD; Honoraria (self), Advisory / Consultancy, Advisory board: BMS; Honoraria (self), Honararium: Aquarius; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: BMS; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: MSD; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Boehringer; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Virttu; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Amgen; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Novartis; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Sierra; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Bayer; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Lilly; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: AstraZeneca; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Astex; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Immunocore; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: NeRRe therapeutics; Leadership role, NIHR National specialty head for cancer; early phase trials (renumerated for 4 hours per week) : NIHR ; Leadership role, Sheffield ECMC Lead - funding from CRUK and Department of Health: Sheffield Experimental Cancer Medicine Centre (ECMC); Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: GSK. J. Evans: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker, Advisory Board: BMS; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker, Advisory Board: Eisai; Honoraria (institution), Speaker Bureau / Expert testimony, Speaker: Bayer; Honoraria (institution), Speaker Bureau / Expert testimony, Speaker: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker, Advisory Board: Celgene; Honoraria (institution), Speaker Bureau / Expert testimony, Speaker: MSD; Honoraria (institution), Advisory / Consultancy, Advisory Board: Nucana; Honoraria (institution), Advisory / Consultancy, Advisory Board: Modulate Therapeutics; Honoraria (institution), Advisory / Consultancy, Chair ISDMC: Genmab; Honoraria (institution), Advisory / Consultancy, Member TSC: BMS; Honoraria (institution), Advisory / Consultancy, Leadership role, Membership of advisory board (honorarium payments to employing institution): Karus Therapeutics; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: AstraZeneca; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Basilea; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: BMS; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Bayer; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Celgene; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: MSD; Honoraria (institution), Leadership role, Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Mina Therapeutics; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Roche; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Medovia; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Pfizer; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Sierra; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Verastem; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Lilly; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Eisai; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Nucana; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: GSK; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Novartis; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Immunocore; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Bicycle therapeutics; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Halozyme; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Berg; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Johnson and Johnson; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Cytomx; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Beigene; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Vertex; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Plexxikon; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Biolinerx; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Boehringer; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Athenex; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Lion / Iovance; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Adaptimmune; Leadership role, Non-remunerated activity/ies, Clinical expert review panel, Clinical research committee, ECMC - industry alliance joint SC: Cancer Research UK; Leadership role, Non-remunerated activity/ies, NCRI Upper GI Clinical Group, member of occular and pancreas subgroup: NCRI; Leadership role, Non-remunerated activity/ies, Chair - catalyst committee: Breast Cancer Now; Leadership role, Non-remunerated activity/ies, Member of the grants panel : Pancreatic Cancer Research Fund; Leadership role, Non-remunerated activity/ies, EORTC GI group member: EORTC; Honoraria (institution), Leadership role, Clinical subjects editor, honorarium payable to institution : British Journal of Cancer; Leadership role, Non-remunerated activity/ies, Chair, ISDMC: Wales Clinical Trials Unit; Leadership role, Non-remunerated activity/ies, Abstract reviewer committee: ILCA; Non-remunerated activity/ies, Member: British Association for Cancer Research; Non-remunerated activity/ies, Member : European Association for Cancer Research; Non-remunerated activity/ies, Member: Association of Cancer Physicians ; Non-remunerated activity/ies, Member: ESMO; Non-remunerated activity/ies, Member: ASCO; Non-remunerated activity/ies, Member: AACR; Travel / Accommodation / Expenses, Support to attend conferences : BMS; Travel / Accommodation / Expenses, Support to attend conferences: MSD; Travel / Accommodation / Expenses, Support to attend conferences : Eisai; Travel / Accommodation / Expenses, Support to attend conferences: Bayer; Travel / Accommodation / Expenses, Support to attend conferences : Roche; Travel / Accommodation / Expenses, Support to attend conferences : Celgene; Advisory / Consultancy, Chair - review panel of clinical trial centres programme: Institut National Du Cancer . S. Ochsenreither: Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): Merck; Honoraria (self): Ipsen; Honoraria (self): Janssen; Honoraria (self): CureVac; Honoraria (self): Glenmark; Honoraria (self): Incyte. J.M.G. Larkin: Honoraria (self), Advisory / Consultancy, Consultancy: Achilles; Honoraria (self), Advisory / Consultancy, Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Consultancy: Boston Biomedical; Honoraria (self), Advisory / Consultancy, Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Consultancy : Eisai; Honoraria (self), Advisory / Consultancy, Consultancy: EUSA Pharma; Honoraria (self), Advisory / Consultancy, Consultancy: GSK; Honoraria (self), Advisory / Consultancy, Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy, Consultancy: Imugene; Honoraria (self), Advisory / Consultancy, Consultancy: Incyte; Honoraria (self), Advisory / Consultancy, Consultancy: iOnctura; Honoraria (self), Advisory / Consultancy, Consultancy: Kymab; Honoraria (self), Advisory / Consultancy, Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Consultancy: Nektar; Honoraria (self), Advisory / Consultancy, Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Consultancy: Roche/Genentech; Advisory / Consultancy, Consultancy: Secarna; Research grant / Funding (institution), Currently 3 studies estimated total for these studies: £290K: Novartis; Research grant / Funding (institution), Currently 13 studies estimated total for these studies up to £1.7M: BMS; Research grant / Funding (institution), Currently 4 studies estimated total for these studies up to present: £178: Roche; Research grant / Funding (institution), Currently 4 studies estimated total for these studies up to present: £470K: Pfizer; Research grant / Funding (institution), Currently 1 study estimated total for these studies up to present: £275K: Covance; Advisory / Consultancy, Currently 1 study estimated total for these study up to present: £30K: Immunocore; Advisory / Consultancy, Currently 1 study estimated total for these study up to present: £20K: Pharmacyclics; Research grant / Funding (institution), Currently 1 study estimated total for these study up to present: £40K: Aveo; Research grant / Funding (institution), Currently 1 study estimated total for these study up to present: £20K: Nektar Therapeutics; Research grant / Funding (institution), Currently 4 studies estimated total for these studies up to present: £200K: Merck, Sharp & Dohme Limited (MSD); Research grant / Funding (institution), Currently 1 study estimated total for these study up to present: £100K: Achilles Therapeutics. I. Karydis: Honoraria (self), Advisory / Consultancy, Consultancy, public speaking : Delcath Inc; Honoraria (self), Advisory / Consultancy, Advisory board: Merck Serono ; Honoraria (self), Advisory / Consultancy, Public speaking : Pierre Fabre Ltd. N.M. Steven: Honoraria (institution), Speaker Bureau / Expert testimony, Fee for speaking paid to employees: Merck Serono; Leadership role, Non-remunerated activity/ies, Chair melanoma subgroup NCRI skin cancer CSG. member of same CSG: NCRI. R. Plummer: Honoraria (self), Advisory / Consultancy: Pierre Faber; Honoraria (self), Advisory / Consultancy: Genmab; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Octimet; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Karus Therapeutics; Honoraria (self), Advisory / Consultancy: Biosceptre; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Honoraria for attending advisory boards: Sanofi Aventis; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: Tesaro ; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: BMS; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: Expert Medical Events ; Licensing / Royalties, Discretionary payment from Newcastle University (royalty payments received Clovis Oncology): Newcastle University; Research grant / Funding (self), Part funding of CASE PhD studentship: AstraZeneca; Research grant / Funding (institution), Clinical trial costs from multiple trial sponsors to cover costs of clinical investigators: Sponsor’s; Non-remunerated activity/ies, Principal Investigator on multiple trials with multiple sponsors (>30 over last 2 years): Sponsor’s. P. Patel: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker & Ad hoc Advisory Board: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Ad hoc Advisory Board: Novartis; Honoraria (self), Advisory / Consultancy, Ad hoc Advisory Board: Eisai; Honoraria (self), Advisory / Consultancy, Ad hoc Advisory Board: Merck; Honoraria (self), Speaker Bureau / Expert testimony, Speaker: Pfizer; Honoraria (self), Advisory / Consultancy, Ad hoc Advisory Board: Ipsen; Research grant / Funding (institution), Research funding: Scancell; Non-remunerated activity/ies, PI for clinical trial sponsored by Scancell: Scancell; Leadership role, Non-remunerated activity/ies, Head of Division of Cancer & Stem Cells, University of Nottingham: Cancer & Stem Cells, University of Nottingham; Leadership role, Non-remunerated activity/ies, Chairman of NCRI, Skin Cancer Study Group: NCRI, Skin Cancer Study Group. H.M. Shaw: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory/consulting/speakers bureau: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory/consulting/speakers bureau: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory/consulting/speakers bureau: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory/consulting/speakers bureau: Sanofi-Genzyme; Research grant / Funding (institution), Clinical trial funding: Novartis; Research grant / Funding (institution), Clinical trial funding: Sanofi-Genzyme; Research grant / Funding (institution), Clinical trial funding: Genmab; Research grant / Funding (institution), Clinical trial funding: Roche; Research grant / Funding (institution), Joint working project - project manager funding: BMS; Research grant / Funding (institution), Joint working project - NMP funding: Novartis; Research grant / Funding (institution), Data manager funding: Immunocore; Non-remunerated activity/ies, Principal Investigator: Novartis; Non-remunerated activity/ies, Principal Investigator: Merck; Non-remunerated activity/ies, Principal Investigator: Genmab; Non-remunerated activity/ies, Principal Investigator: Roche; Non-remunerated activity/ies, National Coordinating Investigator: Idera; Non-remunerated activity/ies, National Coordinating Investigator: Iovance; Non-remunerated activity/ies, National Coordinating Investigator : MacroGenics; Non-remunerated activity/ies, Project board - BMS/Mount Vernon - Immuno Pt Pathway: Bristol-Myers Squibb; Non-remunerated activity/ies, Project lead - Novartis/Mount Vernon - Non-Medical Prescriber Clinic: Novartis. S. Leyvraz: Honoraria (self), Advisory / Consultancy, Consultancy: Bayer. C. Rawcliffe: Research grant / Funding (institution), Externally sponsored scientific research grant: AstraZeneca . J.J. Sacco: Honoraria (self), Advisory / Consultancy, Speaker/ presenter/ interview for video: BMS; Honoraria (self), Advisory / Consultancy, Advisory board: MSD; Honoraria (self), Advisory / Consultancy, Advisory board: Delcath; Honoraria (self), Advisory / Consultancy, Advisory board: Amgen; Honoraria (self), Advisory / Consultancy, Speaker : Pierre Fabre; Honoraria (self), Advisory / Consultancy, Advisory board/ consultancy: Immunocore; Research grant / Funding (institution), Trial funding (as co-CI): AstraZeneca; Research grant / Funding (institution), Trial funding (as CI): BMS; Research grant / Funding (institution), Trial funding (local PI): Immunocore; Research grant / Funding (institution), Trial funding (local PI): Replimune; Research grant / Funding (institution), Trial funding (local PI): Amgen ; Research grant / Funding (institution), Trial funding (local PI): MSD; Research grant / Funding (institution), Trial funding (local PI): Delcath; Leadership role, Non-remunerated activity/ies, Member of the H&N clinical studies group: H&N clinical studies group; Travel / Accommodation / Expenses, travel and conference attendance-: BMS; Travel / Accommodation / Expenses, Travel and conference attendance-: MSD. All other authors have declared no conflicts of interest.