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Merck’s Keytruda is bound for new bladder cancer territory. But can it hold up against gene therapy?

Currently, five PD-1/L1 inhibitors boast FDA approvals to treat certain bladder cancer patients. But only one of them is about to enter a different segment of the disease—though possibly with some company from a novel gene therapy.

Monday, Merck & Co. nabbed an FDA priority review for Keytruda’s potential use in patients with high-risk non-muscle invasive bladder cancer (NMIBC) that’s unresponsive to standard-of-care Bacillus Calmette-Guérin (BCG) therapy.

Blessed by the designation, Merck is expecting an FDA decision by January 2020. But before that, it will need to make a case before an independent FDA oncology expert panel on Dec. 17, a procedure not common for a label expansion application for an approved therapy.

NMIBC is a new territory for checkpoint inhibitors. Keytruda, as well as rivals Bristol-Myers Squibb’s Opdivo, Roche’s Tecentriq, AstraZeneca’s Imfinzi and Pfizer and Merck KGaA’s Bavencio bear green lights for locally advanced or metastatic bladder cancer, in which the tumor has already spread into the muscle layer of the bladder wall.

Of the estimated 80,000 new cases of bladder cancer to be diagnosed in 2019 in the U.S., about 75% are NMIBC, according to Merck. The common treatment options for these superficial cancer cases include surgical tumor removal and BCG. But about 60% to 70% of patients may not respond to BCG or see their tumors return afterward, eventually progressing to metastatic cancer, SVB Leerink analyst Daina Graybosch noted in a Tuesday report to clients.For BCG-unresponsive NMIBC, the gold standard of treatment is removal of the entire bladder, known as radical cystectomy. However, that procedure is associated with disability, death and a negative impact on quality of life. All things considered, Graybosch is pegging Keytruda’s peak annual U.S. sales in NMIBC at $250 million.

At this year’s European Society for Medical Oncology annual meeting, Ronald de Wit of the Erasmus MC Cancer Institute provided an update to the Keynote-057 study, a single-arm phase 2 trial that forms the basis of the new application for Keytruda.

In cohort A, which enrolled NMIBC patients with carcinoma in situ, the Merck drug eliminated signs of cancer in 41.2% of patients, or 42 of 102 patients. Of them, the median time patients spent with no signs of tumors was 13.5 months and 57.2% responded completely for at least a year. What’s more, at a median follow-up of 21.1 months, no patients in that cohort had developed muscle-invasive cancer or metastatic urothelial carcinoma (mUC).

Even though Keytruda could become the first PD-1/L1 to enter NMIBC, it will likely face competition from outside the class.

The FDA recently also granted priority review to a gene therapy in the same setting. The drug, dubbed nadofaragene firadenovec, uses an adenovirus vector to deliver the gene interferon alfa-2b. Once administered into the bladder, it starts expressing the cancer-fighting protein.

In fact, Merck has a stake in that therapy. The New Jersey pharma licensed it, along with other programs in its gene therapy portfolio, to FKD Therapies in 2011 in exchange for an equity stake in the Finnish company. Last year, FKD offloaded the global rights to Ferring Pharmaceuticals, which with help from Blackstone Life Sciences, has just spun out that drug into a subsidiary called FerGene to take care of its potential commercialization.

Complete response results on nadofaragene firadenovec from a phase 3 study will be presented Thursday during the Society of Urologic Oncology annual meeting. In its phase 2 trial involving 40 patients, it triggered a complete response rate of 30% and a disease-free survival rate of 35% at the one-year mark, Graybosch noted.

Besides the possible imminent threat from the gene therapy, Keytruda’s PD-1/L1 rivals are also running studies in NMIBC. BMS is testing Opdivo on its own, or with BCG and/or its investigational IDO1 inhibitor BMS-986205 in the phase 2 CheckMate 9UT trial. Roche and AstraZeneca are also pairing Tecentriq and Imfinzi, respectively, in NMIBC patients who haven’t yet received BCG.

Keytruda currently has two FDA bladder cancer nods, both in mUC: one for second-line use after platinum-containing chemotherapy, and the other for PD-L1-positive patients who are not eligible for cisplatin-containing chemo or regardless of PD-L1 status in those who are ineligible for any platinum chemo.

The restriction on Keytruda’s use cisplatin-ineligible patients—limiting use to those with a PD-L1 combined positive score of at least 10—came last year after the FDA noticed the Merck star drug might even lag chemo at extending the lives of some previously untreated bladder cancer patients. A similar limitation was also slapped on Tecentriq, stating that the Roche drug can only be used for those whose PD-L1 immune cells cover at least 5% of their tumor area.

Tecentriq’s bladder cancer nod was previously in jeopardy after it failed to show a significant survival benefit among previously treated patients in the IMvigor 211 study. But the drug recently came back with a win, showing it, when paired with chemo, could cut the risk of disease progression or death by 18% in previously untreated patients regardless of PD-L1 status, compared with chemo alone.