What to Expect at ASCO 2020: GSK’s Transformational Medicines

As part of its ongoing work to advance potentially transformational medicines, GlaxoSmithKline (GSK) will present new data at the virtual annual meeting of the American Society of Clinical Oncology (ASCO) being held May 29 – June 2, 2020.

The depth and breadth of the presentations represent GSK’s progress in helping people affected by cancer achieve better outcomes and build on the recent U.S. Food and Drug Administration (FDA) approval of a new indication for niraparib (Zejula^®).

Researchers at GSK have has advanced the company’s innovative pipeline by focusing on science related to the immune system, the use of human genetics, and cutting-edge technologies that will advance the next wave of cancer therapies with the potential to transform outcomes for patients.

What to expect
Dring this virtual ASCO 2020 annual meeting, expect presentations on investigational therapies, including belantamab mafodotin (GSK2857916), an antibody-drug conjugate for multiple myeloma, and GSK3359609, an inducible T-cell co-stimulator (ICOS) agonist for patients with recurrent or metastatic head and neck squamous cell carcinoma.

“These are challenging times and while we are working to combat the COVID19 pandemic, we are also continuing to progress our goal of supporting patients with cancer by developing and delivering transformational medicines that may help to improve survival and bring us closer to potentially achieving cures. We’re pleased to share this progress with our peers at ASCO, with the knowledge that there is more to come as we work to outpace the cancers we fight,” noted Axel Hoos, M.D., Ph.D., Senior Vice President and Head of Oncology R&D.

Targeting of BCMA in Relapsed/Refractory Multiple Myeloma
B-cell maturation antigen (BCMA) is universally expressed in patients with multiple myeloma, and targeting this cell-surface protein has become an actively researched investigational approach in this cancer. [2]

Data from GSK’s extensive DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program of belantamab mafodotin designed to evaluate its potential in different relapsed/refractory and newly diagnosed multiple myeloma treatment settings are presented during the virtual ASCO meeting. The data includes:

• Updated nine-month results from the pivotal DREAMM-2 study of single-agent belantamab mafodotin (2.5 or 3.4 mg/kg) in patients with relapsed/refractory multiple myeloma refractory (RRMM) to proteasome inhibitors, immunomodulatory agents and refractory and/or intolerant to anti-CD38 monoclonal antibodies. [3] The investigators are studing the drug in patients with RRMM after ≥3 prior therapy lines and refractory to an immunomodulatory agent, a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 mAb. The study’s primary endpoint was overall response rate (ORR; ≥partial response per independent review committee). The median follow-up after 9 months showed an ORR of 31% in the 2.5 mg/kg (19% with ≥very good partial responses [VGPR]) and 35% (24% with ≥VGPR) in the 3.4 mg/kg groups. The duration of response (DoR) was not reached in the 2.5 mg/kg and 6.2 months in the 3.4 mg/kg groups. The 1-year overall survival (OS) estimate was 53%. Common Grade 3/4 adverse events ( > 10% in either group) were keratopathy (2.5: 29%; 3.5: 24%), thrombocytopenia (2.5: 21%; 3.4: 32%), anemia (2.5: 20%; 3.4: 27%), pneumonia (2.5: 6%; 3.4: 13%), and neutropenia (2.5: 11%; 3.4: 16%). These side effects were managed with dose delays (2.5: 54%; 3.4: 62%) and reductions (2.5: 34%; 3.4: 43%). However, discontinuations as a result of these adverse events were uncommon (2.5: 9%; 3.4: 12%). Based on these results, the investigators concluded that single-agent belantamab mafodotin was well-tolerated, and clinically meaningful responses were sustained despite dose modifications with longer follow-up.
• Preliminary data from the DREAMM-6 study, an ongoing, two-part, two-arm, study evaluating the safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone (BorDex) in relapsed/refractory multiple myeloma. [4] During the ASCO meeting, researchers present data for belantamab mafodotin in combination with BorDex from the dose-escalation part and the dose-expansion part of the study in which belantamab mafodotin was either administered as a single dose at 2.5 and 3.4 mg/kg administered or as a SPLIT dose, divided equally on Days 1 and 8) in combination with BorDex. The investigators noted that from the 52 patients enrolled, 6 patients were enrolled at 2.5 mg/kg single dose and 7 at 3.4 mg/kg single dosing in the dose-escalation part of the trial while 45 patients were enrolled in the dose-expansion part. The investigators did not observe dose-limiting toxicities (DLTs) and corneal events, including keratopathy, blurred vision, and dry eye, and thrombocytopenia were the most frequently reported but clinically manageable adverse events. Based on these preliminary results, the combination of belantamab mafodotin and BorDex is considered to have an acceptable safety profile, with no new safety signals identified.

PARP inhibitor
Earlier this year, the FDA approved niraparib, an oral, once-daily poly (ADP-ribose) polymerase (PARP) inhibitor, as a monotherapy maintenance treatment for women with an advanced form of epithelial ovarian, fallopian tube or primary peritoneal cancer who responded to first-line platinum-based chemotherapy, regardless of biomarker status. This year, during the 2020 ASCO meeting, five presentations are expected to further explore the potential use of niraparib in ovarian cancer.

Head and Neck Squamous Cell Carcinoma
GSK3359609 is an investigational ICOS agonist antibody that is designed to selectively enhance T-cell function and enable anti-tumor responses in patients. Presentations at ASCO report findings on our ongoing studies into the anti-tumor potential of targeting the ICOS receptor through this agonist antibody alone and in combination with immune checkpoint therapies for the treatment of head and neck squamous cell carcinoma.

• Updated Analysis will be presented of the Inducible T-cell co-stimulatory Receptor Agonist (ICOS), GSK3359609 (GSK609), Combination with Pembrolizumab in Patients with Anti-PD-1/L1 Treatment-naïve Head and Neck Squamous Cell Carcinoma (HNSCC) study. [5] Results from the study, supported by GSK in collaboration with Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co.), identified a range of dose levels (≥0.1–1 mg/kg) in which for GSK609 has biological and clinical activity. A dose level of 0.3 mg/kg was selected to be evaluated in the expansion phase of the investigational drug. The expansion cohorts showed GSK609 has single-agent activity in patients with relapsed/refractory disease, and early clinical activity in combination with Pembrolizumab in patients with anti-PD-1/L1 treatment-naïve disease.
• INDUCE-1: Report on Safety Run-in Cohorts Combining the Inducible T-Cell Co-Stimulatory Receptor (ICOS) Agonist GSK3359609 (GSK609) with Platinum+5-FU Chemotherapy (5-FU/plat), with or without Pembrolizumab, for the Treatment of Advanced Solid Tumors. [6] Based on the study results, the investigators concluded that GSK609 in combination with 5-FU/plat±PE has a manageable safety profile with mostly Grades 1 or 2 adverse events which was consistent with Pembrolizumab and chemotherapy toxicities. Hence, continued follow-up to investigate long-term safety and efficacy of this combination seems to be warranted.

Endometrial Cancer
Dostarlimab (TSR-042), is an investigational anti-programmed death-1 (PD-1) humanized monoclonal antibody, that has demonstrated clinically meaningful results in women with recurrent or advanced mismatch repair-deficient (dMMR) endometrial cancer who progressed on or after a platinum-based regimen. Dostarlimab continues to be evaluated as a monotherapy and in combination with other assets across solid tumors. The drug is being developed by Tesaro, an oncology-focused drug development company acquired by GSK. Data from the phase I/II GARNET study evaluating dostarlimab in women with recurrent or advanced endometrial cancer who progressed on or after a platinum-based regimen presented at the annual meeting of the 2019 Society for Gynecologic Oncology (SGO) demonstrated demonstrate clinically meaningful and durable response rates of dostarlimab in this patient population, regardless of microsatellite instability status, while showing safety findings. Based on these results investigators concluded that dostarlimab is well tolerated with a safety profile consistent with what is expected of anti-PD-1 therapy. During te 2020 ASCO meeting one presentation of interest includes:

• ENGOT-EN6/NSGO-RUBY: A Phase III, Randomized, Double-blind, Multicentre Study of Dostarlimab + Carboplatin-paclitaxel Versus Placebo + Carboplatin-paclitaxel in Recurrent or Primary Advanced Endometrial Cancer (EC) [7]

Other presentations

Clinical trial
A Study to Investigate the Efficacy and Safety of Two Doses of GSK2857916 in Participants With Multiple Myeloma Who Have Failed Prior Treatment With an Anti-CD38 Antibody – NCT03525678
To Evaluate Safety, Tolerability, and Clinical Activity of the Antibody-drug Conjugate, GSK2857916 Administered in Combination With Lenalidomide Plus Dexamethasone (Arm A), or in Combination With Bortezomib Plus Dexamethasone (Arm B) in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) – NCT03544281
Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1) – NCT02723955
A Study of Dostarlimab (TSR-042) Plus Carboplatin-paclitaxel Versus Placebo Plus Carboplatin-paclitaxel in Patients With Recurrent or Primary Advanced Endometrial Cancer (RUBY) – NCT03981796

References
[1] NCI Drug Dictionary – Anti-BCMA Antibody-Drug Conjugate GSK2857916. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/anti-bcma-antibody-drug-conjugate-gsk2857916. Accessed March 2019.
[2] Trudel S, Lendvai N, Popat R, et al. Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose-escalation and expansion phase 1 trial. The Lancet Oncology. 2018;19(12):1641-1653. doi:10.1016/s1470-2045(18)30576-x.
[3] Lonial S, Chulhee Lee H, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AA, et al. Pivotal DREAMM-2 study: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs). J Clin Oncol 38: 2020 (suppl; Abstract 8536). 10.1200/JCO.2020.38.15_suppl.8536
[4] Nooka AK, Stockerl-Goldstein K, Quach H, Forbes A, Mateos MV, Khot A, Tan A, et al. DREAMM-6: Safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 38: 2020 (suppl; Abstract 8502), 10.1200/JCO.2020.38.15_suppl.8502
[5] Angevin E, Groenland SL, Ling Lim AM, Martin-Liberal J, Moreno V, Trigo JM, Le Tourneau C, et al. Updated analysis of the inducible T-cell co-stimulatory receptor (ICOS) agonist, GSK3359609 (GSK609), combination with pembrolizumab (PE) in patients (pts) with anti-PD-1/L1 treatment-naïve head and neck squamous cell carcinoma (HNSCC). J Clin Oncol 38: 2020 (suppl; Abstract 6517) 10.1200/JCO.2020.38.15_suppl.6517
[6] Massarelli E, Balmanoukian AS, Vieito M, Le Tourneau C, Hernandez-Guerrero T, Trigo JM, Aljumaily R, et al. INDUCE-1: Report on safety run-in cohorts combining Inducible T-cell co-stimulatory receptor (ICOS) agonist GSK3359609 (GSK609) with platinum+5-FU chemotherapy (5-FU/plat), with or without pembrolizumab (PE), for the treatment of advanced solid tumors. J Clin Oncol 38: 2020 (suppl; Abstract 6544); 10.1200/JCO.2020.38.15_suppl.6544.
[7] Mirza MR, Coleman RL, Hanker LC, Slomovitz BM, Valabrega G, Im E, Walker M, Guo W, et al. ENGOT-EN6/NSGO-RUBY: A phase III, randomized, double-blind, multicenter study of dostarlimab + carboplatin-paclitaxel versus placebo + carboplatin-paclitaxel in recurrent or primary advanced endometrial cancer (EC). J Clin Oncol 38: 2020 (suppl; Abstract TPS6107), 10.1200/JCO.2020.38.15_suppl.TPS6107

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