testing the protein arginine methyltransferase 5 (PRMT5) inhibitor GSK3326595 in a Phase 1/2 solid tumor and hematological malignancy study as well as GSK3368715, a type 1 PRMT inhibitor, in a Phase 1 study.
ZEJULA STRATEGY: COMBINATIONS, NEW INDICATIONS AND TUMORS
Expanding the reach of its only commercially available cancer drug, Zejula, is a priority for GSK. The PARP inhibitor generated £229m ($288.3m) in 2019 sales, including £66m ($83.1m) in the fourth quarter, increasing sequentially to £81m ($101.9m) in the first quarter of 2020.
“Our strategy is based on two major components. The first is adding combination agents to Zejula to maximize the benefits in the categories in which Zejula already works,” Hoos said. “And the second is to take Zejula into new territory where we believe we have an advantage over other companies or other PARP inhibitors, because ours seems to work in a broader spectrum of patients.”
The drug’s indication for all women with ovarian cancer regardless of BRCA status in the first-line maintenance setting gives Zejula a big advantage over AstraZeneca’s Lynparza, which is limited to ovarian cancer patients with BRCA mutations and those who are HRD-positive. [Corrected to reflect the types of cancer for which olaparib is approved.] GSK is now testing its drug in lung cancer and other indications where it may work in patients beyond those with BRCA patients.
In terms of combination regiments, Zejula is being tested in combination with dostarlimab in a registrational trial enrolling more than 1,000 patients in the first-line ovarian cancer setting. Similar combinations may also show improved activity for the PARP inhibitor in lung, breast and other cancers, Hoos noted.
IMMUNO-ONCOLOGY STRATEGY: PD-1, BCMA AND BEYOND
Dostarlimab and belantamab mafodotin represent the first step of GSK’s immuno-oncology strategy as the most advanced IO agents in its portfolio.
Coming up behind those near-term approvals is the bifunctional fusion protein bintrafusp alfa (GSK4045154/M7824), which combines a transforming growth factor beta (TGFbeta) trap with a PD-1 inhibitor and is being developed in partnership with Merck KGaA. (Also see “GSK Makes I-O Move With Merck KGaA Deal Worth Up To €3.7bn“—Scrip, 5 Feb, 2019.)
“We believe that this has a chance with a double mechanism to be more effective than a PD-1-blocking antibody alone,” Hoos said. “We have several studies running—a registrational [Phase 2] study in biliary tract cancer and a randomized Phase 2 trial in non-small cell lung cancer and several other studies.”
Two-year results presented at ASCO from a Phase 1 data set showed an overall response rate of 27.5 percent and median duration of response of 18 months for the Phase 2 dose of 1,200mg given every two weeks in 40 NSCLC patients whose cancer progressed after first-line treatment with standard-of-care therapies, excluding immunotherapy. Median overall survival in PD-L1-positive (1 percent or higher) NSCLC was 21.7 months and six of seven patients with high PD-L1 expression (80 percent or higher) were alive at two years.
The third layer of GSK’s IO strategy is the company’s other novel agents, including the ICOS agonist, which is the most advanced immuno-oncology agent developed internally at GSK, Hoos noted.
ICOS “is an agonist receptor on T-cells, but if you bind that with an antibody that signals to that receptor you can make those T-cells grow and you can basically grow an army of cells that can kill tumor cells. ICOS has moved into Phase III now [in head and neck cancer] in December last year and that study is open and accruing patients. And we’re building the story of ICOS further by looking at other diseases, like non-small cell lung cancer, bladder cancer, cervical cancer and others,” Hoos continued.
The ICOS agonist is being tested in an ongoing 500-patient first-in-human study across tumor types and GSK will present results in tumors beyond head and neck cancer at medical meetings as the data mature. “And maybe, if we have more proof-of-concept in other diseases, I would expect we should be able to start other larger trials on the basis of that,” Hoos said. “I think for ICOS the story is really just unfolding, there’s a lot more to be expected.”