[Corrected 6/17/20, 1:48 pm PT. See below.] GlaxoSmithKline’s years-long oncology resurgence is on track to have two new drugs approved in the US in mid-2020, after the company won a key first-line ovarian cancer indication for Zejula (niraparib) in April. The belantamab mafodotin and dostarlimab approvals also anticipated this year will give GSK its first commercial footholds in the immuno-oncology market – one of four cancer drug categories where the company is developing new therapies.
“We have been a little bit in the shadows and are just getting into the spotlight with some of the more recent work that we’ve made public,” GSK (NYSE: GSK) senior vice president and oncology research and development head Axel Hoos told Scrip.
The company reported data for several clinical-stage cancer drug candidates during the American Society of Clinical Oncology (ASCO) meeting held online 29-31 May, including updated results for belantamab mafodotin that showed durable responses and relatively lengthy overall survival for heavily pretreated multiple myeloma patients.
Approval of the B-cell maturation antigen (BCMA)-targeting antibody-drug conjugate (ADC) belantamab mafodotin in fourth-line or later treatment of multiple myeloma would give GSK a first-in-class therapy. (Also see “GSK Files Its BCMA Drug In Multiple Myeloma”—Scrip, 17 Dec, 2019.) It also would be the company’s first approval for a novel oncology drug since GSK completed the sale of its targeted cancer drugs to Novartis AG for $16bn in 2015. (Also see “It’s a wrap: GSK and Novartis megadeal completes”—Scrip, 3 Mar, 2015.)
“Our objective is to be one of the lead players in oncology by offering truly transformational benefit for patients,” Hoos said. “We have shifted our portfolio from oncology 1.0 before the Novartis transaction and it’s now called oncology 2.0 after the Novartis transaction where we basically shifted from largely me-too products or follow-on products to now leading-edge innovation that is able to compete with any other oncology company in the industry.”
While dostarlimab will be the seventh PD-1/L1 inhibitor approved in the US, it will be the second approved for endometrial cancer and it will expand PD-1 inhibition for this disease beyond the front-line treatment of microsatellite stability-high (MSI-high) tumors, where market leader Merck & Co. Inc.’s Keytruda (pembrolizumab) is approved.
Dostarlimab was acquired along with Zejula in the $5bn purchase of Tesaro Inc. (Also see “GSK Embraces PARP Promise With Tesaro Buy”—Scrip, 3 Dec, 2018.) GSK is seeking approval for the drug to treat MSI-high and microsatellite-stable (MSS) recurrent endometrial cancer based on the pivotal Phase 1/2 GARNET clinical trial. (Also see “Tesaro’s On The Right Path With Anti-PD-1 Dostarlimab In Endometrial Cancer”—Scrip, 22 Mar, 2019.)
Similar to dostarlimab, Zejula was not the first PARP inhibitor approved in the first-line ovarian cancer maintenance setting, but it is the first one indicated to treat tumors regardless of BRCA mutation status. The top-selling PARP inhibitor – AstraZeneca PLC/Merck’s Lynparza (olaparib)—is approved as a first-line maintenance therapy, but only for women with BRCA-positiveand homologous recombination deficient (HRD)-positive ovarian cancer. (Also see “GSK’s Zejula Wins First-Line Ovarian Cancer Use“—Scrip, 30 Apr, 2020.) [Corrected to reflect the types of cancer for which olaparib is approved.]
“Our portfolio is still smaller than that of many lead players, but we’re coming,” Hoos said. “I think you see that in terms of some of the success stories that we recently had.”
ADVANCES ACROSS FOUR KEYS CATEGORIES
The oncology R&D head explained that GSK’s cancer drug development strategy falls into four major categories, the first and largest of which is immuno-oncology – including belantamab mafodotin, dostarlimab, the inducible T-cell co-stimulator (ICOS) agonist GSK3359609 and several earlier clinical-stage candidates against TIM-3, LAG-3, OX40, STING and TLR4.
The ICOS agonist GSK3359609 already has shown promising activity in combination with Keytruda in recurrent or metastatic PD-1/L1 naive head and neck squamous cell carcinoma (HNSCC) patients, and more data from that open-label study were presented during ASCO. The overall response rate among 34 evaluable patients was 24 percent with eight patients responding, including four complete responses and four partial responses that were durable, lasting six months or more.
In terms of the other cancer drug categories important to GSK, Zejula is included in the synthetic lethality category because of PARP’s role in DNA repair.
In the company’s cell and gene therapy category, the T-cell receptor (TCR) therapy GSK3377794 targeting NY-ESO-1—developed in partnership with Adaptimmune Therapeutics PLC under a deal signed in 2014—has shown efficacy in synovial sarcoma and multiple myeloma. (Also see “$350m Adaptimmune deal shows GSK still does cancer R&D“—Scrip, 2 Jun, 2014.) GSK partnered with Lyell Immunopharma in October on its technology to improve T-cell function and fitness, which it planned to use initially to upgrade GSK3377794. (Also see “Deal Watch: GSK Furthers Cancer Gene Therapy Plans Via Lyell Collaboration“—Scrip, 10 Oct, 2019.)
“We have seen very good data in certain types of soft tissue sarcoma, in multiple myeloma and we’re now testing it in lung cancer,” Hoos said. “There will also be more data coming out this year, actually more substantive data. What I think is the most important to know about this program is it’s the very first cell therapy program across the entire industry that works in solid tumors.”
Being able to treat solid tumors effectively with a cell therapy is important to GSK, because solid tumors are a bigger market than hematological malignancies, making the NY-ESO-1-targeting TCR therapy more attractive commercially and in terms of being able to serve more patients. “That’s our aim—to access solid tumors through the cell therapy story that we’re building at GSK,” Hoos said. “So far, we’re industry-leading in that area, so we are quite excited about that.”
In cancer epigenetics, GSK’s fourth cancer drug development category, the company is 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.”