Open-Label Pilot Study of Genetically Engineered NY-ESO-1 Specific T Cells (GSK3377794) Alone or in Combination with Pembrolizumab in Relapsed and Refractory Multiple Myeloma

Background: Emerging clinical data demonstrate that adoptive cellular therapy has potential to be practice-changing in the management of relapsed/refractory multiple myeloma (MM). NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR capable of recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A2. In prior studies, encouraging clinical activity has been observed with GSK3377794 treatment in patients with synovial sarcoma, melanoma, myxoid/round cell liposarcoma, and in MM patients receiving GSK3377794 after autologous stem cell transplant (ASCT). NY-ESO-1 and LAGE-1a are immunogenic cancer/testis antigens frequently overexpressed in MM and are linked to poor clinical outcome. While a number of phase 1 and 2 trials are evaluating GSK3377794 in solid tumors, this abstract presents a trial in progress aiming to evaluate safety and efficacy of GSK3377794 alone or in combination with the anti-PD1 inhibitor, pembrolizumab, in patients with MM. PD-1 expression on CD8 T cells has been observed in MM patients previously treated with GSK3377794 and can limit adaptive immune response. This has also been described as a mechanism of resistance and relapse in CD19 CAR T-cell trials (Fraietta et al, Nat Med 2018). Thus, we hypothesize that combining GSK3377794 and pembrolizumab may result in a synergistic antitumor effect. Study design and methods: This is an open-label, pilot study (NCT03168438) of GSK3377794 in patients who are HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive and have NY-ESO-1/LAGE-1a positive relapsed/refractory MM. Twenty patients who have received at least three prior therapies containing at least one of the following drug classes as separate or combined lines of therapy (including ASCT): an immunomodulatory imide, proteasome inhibitor, alkylator, CD38 monoclonal antibody, and glucocorticoid, will be assigned to one of two arms: GSK3377794 alone as a single infusion (Arm 1, n=10) or GSK3377794 as a single infusion in combination with pembrolizumab 200 mg IV every 3 weeks (Arm 2, n=10). Enrollment of Arm 1 will be completed before enrolling subjects to Arm 2. Administration of pembrolizumab will start from Week 3 (or Week 6 if toxicities preclude Week 3 treatment). Patients will undergo leukapheresis to obtain cells for the manufacture of autologous NY-ESO-1-specific T cells. Each patient will then undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by GSK3377794 infusion of 1−8x109 transduced T cells. Primary and secondary objectives are to assess safety and tolerability, and antitumor activity, respectively, of GSK3377794 treatment (with and without pembrolizumab). Patients will be monitored for adverse events and combination-related treatment-limiting toxicities; efficacy will be assessed using International Myeloma Working Group Response Criteria (Rajkumar et al, Blood 2011). In Arm 2, enrollment will be temporarily paused for a 3-week safety review period after the first 3 patients have received their first dose of pembrolizumab. Efficacy, safety, and biomarker assessments will be conducted at each visit. Patients will complete the treatment phase upon progression of disease or 108 weeks after GSK3377794 infusion. After completion of the treatment phase, patients will transfer to the long-term follow-up study (NCT03391778) to continue safety and survival monitoring for up to 15 years. As of January 27, 2019, 50 patients have undergone screening for HLA status and NY-ESO-1/LAGE-1a antigen expression. Among 50 patients screened for HLA, 25 (50%) tested positive for HLA-A*02:01, 05, and/or 06. Of these patients, bone marrow samples from 12/21 (57%) tested positive for NY-ESO-1, LAGE-1a, or both, illustrating high expression of this antigen in MM. To date, 3 patients have been treated with GSK3377794, demonstrating feasibility of identifying and treating HLA/antigen-positive patients with relapsed/refractory MM. Further work is underway towards introducing flexibility in screening procedures in order to permit wider screening of patients and to minimize time between screening and leukapheresis and for cell manufacturing, which will enhance patient eligibility. Acknowledgment: Medical writing support by O Conn PhD of Fishawack Indicia Ltd, funded by GSK. This study (NCT03168438) is funded by GSK. Disclosures Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Kaufman:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; TG Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Blouch:GSK: Employment, Equity Ownership. Pandit:GSK: Employment, Equity Ownership. Butler:GSK: Employment, Equity Ownership. Jain:GSK: Employment. Wu:GSK: Employment, Equity Ownership. DeYoung:GSK: Employment, Equity Ownership. Hasan:GSK: Employment, Equity Ownership; Atara Biotherapeutics: Patents & Royalties; Merck: Equity Ownership

Open-Label Pilot Study of Genetically Engineered NY-ESO-1 Specific T Cells (GSK3377794) Alone or in Combination with Pembrolizumab in Relapsed and Refractory Multiple Myeloma

NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A2. NY-ESO-1 and LAGE-1a are immunogenic cancer/testis antigens overexpressed in mutiple myeloma (MM) and linked to poor clinical outcome. Patients (pts) with MM who received GSK3377794 after autologous stem cell transplant (ASCT) showed encouraging clinical activity. PD-1 expression on CD8 T cells can occur in GSK3377794-treated MM pts and may limit adaptive immune response; this is a mechanism of resistance/relapse in CD19 CAR T-cell trials. Combining GSK3377794 with an anti-PD1 inhibitor (pembrolizumab) may have synergistic antitumor activity. Evaluate safety and efficacy of GSK3377794 alone or in combination with pembrolizumab in pts with relapsed MM. This is an open-label, pilot study (NCT03168438) of GSK3377794 in pts who are HLA-A*02:01, 05, ± 06 positive and have NY-ESO-1+/LAGE-1a+ relapsed/refractory MM. Twenty pts who have received ≥3 prior therapies containing ≥1 (separately or combined; including ASCT) of an IMiD, PI, alkylator, CD38 monoclonal antibody, and glucocorticoid, will be assigned to 1 of 2 arms: GSK3377794 as a single infusion (Arm 1, n=10) or GSK3377794 as a single infusion + pembrolizumab 200 mg IV every 3 wk (Arm 2, n=10). Arm 1 enrollment will complete before enrolling Arm 2. Pembrolizumab treatment will start from Wk 3 (Wk 6 if precluded by toxicity). Each patient will undergo leukapheresis to obtain cells for autologous NY-ESO-1-specific T-cell manufacturing, followed by lymphodepleting chemotherapy with fludarabine + cyclophosphamide, then GSK3377794 infusion of 1−8 × 109 transduced T cells. Study objectives are to assess safety and tolerability (primary) and antitumor activity (secondary) of GSK3377794 treatment (± pembrolizumab). At each visit, pts will be monitored for AEs and treatment-limiting toxicities, efficacy (using IMWG criteria), and biomarkers. Arm 2 enrollment will pause for a 3-wk safety review period after the first 3 pts receive their first pembrolizumab dose. Treatment will continue until disease progression or 108 wk after GSK3377794 infusion. After completing treatment, pts will transfer to long-term follow-up (NCT03391778) to continue safety/survival monitoring for up to 15 years. As of Jan 27, 2019, 50 pts have been screened. Half have tested positive for HLA-A*02:01, 05, ± 06; bone marrow samples from 12/21 (57%) tested positive for NY-ESO-1 ± LAGE-1a. To date, 3 pts have received GSK3377794. Further work is ongoing to enhance patient eligibility. These data are presented on behalf of the original authors with their permission. A similar presentation will be presented at the ASH Annual Meeting, Orlando, FL, USA, Dec 7-10, 2019. This study (NCT03168438) is funded by GSK

A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma.

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug

A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.status: publishe

Characterization of GSK2334470, a novel and highly specific inhibitor of PDK1

International audiencePhosphoinositide-dependent protein kinase-1 (PDK1) activates a group of protein kinases belonging to the AGC-kinase family that play important roles in mediating diverse biological processes. Many cancer-driving mutations induce activation of PDK1 targets including Akt, S6K and SGK. Here we describe the small molecule GSK2334470, which inhibits PDK1 with an IC50 of ~10 nM, but does not suppress the activity of 93 other protein kinases including 13 AGC-kinases most related to PDK1 at 500-fold higher concentrations. Addition of GSK2334470 to HEK293, U87 or fibroblast cells ablated T-loop residue phosphorylation and activation of SGK isoforms and S6K1 induced by serum or IGF1. GSK2334470 also inhibited T-loop phosphorylation and activation of Akt, but was more efficient at inhibiting Akt in response to stimuli such as serum that activated the PI 3-kinase pathway weakly. GSK2334470 inhibited activation of an Akt1 mutant lacking the PH domain more potently than full length Akt1, suggesting GSK2334470 is more effective at inhibiting PDK1 substrates that are activated in the cytosol rather than at the plasma membrane. Consistent with this, GSK2334470 inhibited Akt activation in knock-in embryonic stem cells, expressing a mutant of PDK1 that is unable to interact with phosphoinositides, more potently than in wild type cells. GSK2334470 also suppressed T-loop phosphorylation and activation of RSK2, another PDK1 target activated by the ERK pathway. However, prolonged treatment of cells with inhibitor was required to observe inhibition of RSK2, indicating that PDK1 substrates possess distinct T-loop dephosphorylation kinetics. Our data define how PDK1 inhibitors affect AGC signalling pathways and suggest that GSK2334470 will be a useful tool for delineating roles of PDK1 in biological processes