Immunomedics, Inc.

Following a disappointing confirmatory clinical trial, Gilead Sciences has officially decided to withdraw its product Trodelvy from the bladder cancer treatment market in the United States. The decision was announced Friday by the California-based biotechnology company after extensive discussions with the U.S. Food and Drug Administration (FDA). This directly affected the accelerated approval status of Trodelvy in a specific patient population - those with advanced urothelium carcinoma who had previously received PD-1/L1 inhibitors and chemotherapy. Gilead emphasized that despite the setbacks in bladder cancer, Trodelvy remains effective in other indications for breast cancer in the United States. The divestment did not come without warning. Back in May, Gilead had already heralded the substandard results of the troics-04 study, which was intended as a confirmative trial for Trodelvy in bladder cancer. Specifically, the TROP2-directed antibo-drug conjugate failed to demonstrate efficacy over conventional chemotherapy in extending survival in certain bladder cancer patients. So far, details about the failed test have not been made public. Looking back at history, Trodelvy received approval for a bladder cancer treatment in 2021 based on positive data from a single-arm Phase 2 clinical trial. At that time, the drug triggered a tumor response in 27.7 percent of patients, with 5.4 percent achieving a complete response and a median response duration of 7.2 months. Gilead's chief financial officer, Andrew Dickinson, noted during the company's second-quarter earnings call in August that bladder cancer treatment is a relatively small part of Trodelvy's many indications, contributing less than 10% of sales. The first-of-its-kind TROP2 ADC drug generated $320 million in sales for Gilead in the three months ended June. It is important to note that Trodelvy's failure in the bladder cancer field was not an isolated incident, it came on the heels of the failure of another key trial, the IUX-01 study. Trodelvy also failed to achieve significant results in a trial comparing chemotherapy with second-line non-small cell lung cancer (NSCLC). As a result of the setback, Gilead took a $2.4 billion impairment charge. Trodelvy's performance has been highly anticipated as a core asset in Gilead's $21 billion acquisition of Immunomedics in 2020. The successive failures of two important trials have certainly clouded Trodelvy's prospects. Once upon a time, Trodelvy was expected to be the cornerstone of Gilead's solid tumor franchise. However, as competitors such as Astrazeneca and Daiichi Sankyo, Merck and Kelun Biotech advance their respective TROP2 ADCs and pursue extensive Phase III programs, Trodelvy's first-mover advantage is gradually being eroded. Looking ahead, Trodelvy's next major milestone will be the results of the IUX-03 trial. The trial is evaluating Gilead's drug in combination with Merck's PD-1 inhibitor Keytruda in patients with NSCLC with high PD-L1 expression. The trial started in February 2023 and is expected to be primarily completed in January 2027. At the same time, with the shift in first-line bladder cancer treatment options - particularly Keytruda in combination with Pfizer and Astellas Nectin-4 ADC drug Padcev in favor - Trodelvy's exit from the bladder cancer space is particularly notable. This shift has sparked a new round of discussion about Trodelvy's status as a PD-1/L1 inhibitor and post-chemotherapy treatment. Faced with an increasingly stringent regulatory review environment by the FDA, biopharmaceutical companies often tend to act quickly after the failure of confirmatory trials to withdraw expedited approval of related products. There have been several examples of this trend in recent years: GlaxoSmithKline withdrew its multiple myeloma ADC from Blenrep just days after its Phase 3 trial failed; Takeda voluntarily withdrew its lung cancer drug Exkivity about two months after receiving negative confirmation; And last month Pfizer abruptly pulled its sickle cell drug Oxbryta from global shelves over safety data.

Gilead is withdrawing the accelerated approval for its blockbuster antibody-drug conjugate Trodelvy for bladder cancer after it failed to improve survival odds for patients in a Phase 3 study earlier this year. The company decided to voluntarily pull the drug’s accelerated label after consulting with the FDA, according to Friday’s announcement . Trodelvy’s bladder cancer indication makes up a small percentage of its overall sales since the drug is primarily used to treat breast cancer, but the withdrawal occurs amid mounting criticism of Gilead’s business decisions. Much of Wall Street’s concern centers around the company’s $21 billion buyout of Immunomedics in 2020 that brought it Trodelvy, a drug that generated $1.1 billion in sales last year and that Gilead has described as a “cornerstone” of its cancer portfolio. The FDA in 2021 granted accelerated approval to Trodelvy for patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-based chemotherapy and a checkpoint inhibitor. However, in May, Gilead disclosed that Trodelvy did not improve survival in bladder cancer patients compared to chemotherapy, and there were more deaths in the Trodelvy arm than the chemo control arm primarily due to infections from low white blood cell counts, a known serious side effect of the drug. Gilead said it plans to share detailed bladder cancer data at an upcoming medical meeting. Back in January, the company said Trodelvy also failed a pivotal study in non-small cell lung cancer, dealing a blow to its expansion plans for the antibody-drug conjugate. And earlier this year, Gilead recorded a $2.4 billion loss related to assets from the Immunomedics deal. The company has stumbled as it has tried to build out its cancer pipeline. It spent $4.9 billion in 2020 to buy Forty Seven for its experimental CD47-targeted cancer drug, but the company this year stopped work on the drug, called magrolimab, after it failed to improve survival odds in pivotal blood cancer studies and came with worrying safety risks. Gilead announced in July that its chief medical officer Merdad Parsey would be leaving in early 2025.

AstraZeneca is focusing on a subgroup of lung cancer patients as it seeks a path to approval for its TROP2-directed antibody-drug conjugate, which earlier this year failed to hit the goal of improving overall survival in a key study. In detailed results shared Monday at the World Conference on Lung Cancer, AstraZeneca and its partner Daiichi Sankyo said that the drug, datopotamab deruxtecan (Dato-DXd), extended life by a median of about one month compared to standard chemotherapy in second-line lung cancer patients. The data come ahead of an anticipated December FDA decision on AstraZeneca and Daiichi Sankyo’s TROP2-targeted ADC which, if approved, would make Dato-DXd the second TROP2 ADC on the market after Gilead’s Trodelvy, albeit in different indications. AstraZeneca previously announced in May that the TROPION-Lung01 study , which looked at approximately 600 patients with non-small cell lung cancer, failed to hit its overall survival goal (though it did reach its progression-free survival primary endpoint). Median overall survival was 12.9 months in the Dato-DXd group and 11.8 months in the chemotherapy group, but the difference was not statistically significant. The researchers detailed a divergence in survival outcomes between two key subgroups. In squamous non-small cell lung cancer, median overall survival was 7.6 months for Dato-DXd and 9.4 months on chemotherapy — meaning the Dato-DXd group appeared to do worse. But in patients with non-squamous lung cancer, which typically develops in peripheral lung tissue, the median overall survival was 14.6 months for Dato-DXd compared to 12.3 months on chemotherapy. “The discussion with the agencies across the globe has really focused in on non-squamous,” said Dave Fredrickson, EVP of AstraZeneca’s oncology business unit. AstraZeneca also shared a biomarker analysis suggesting that it can select patients for whom the treatment may be more effective. It used a method called Quantitative Continuous Scoring to measure TROP2 expression. In patients considered biomarker-positive, those who received Dato-DXd had a 32.7% response rate and 6.9-month median progression-free survival, compared with a 16.9% response rate and 2.9-month median PFS in those who were biomarker-negative. Fredrickson said AstraZeneca has included the biomarker measure as an endpoint in a Phase 3 open-label study called AVANZAR that is looking at a Dato-DXd combination for certain advanced lung cancer patients. Leerink Partners analyst Daina Graybosch wrote that the “presentation of Trop2 biomarker data from TL-01 supports the company’s continued advancement of their antigen selection strategy, but may not retrospectively aid in securing Dato-DXd’s accelerated approval by 4Q24.” Gilead also presented new data from a Phase 2 lung cancer trial, looking to move past a failure in a separate lung cancer study earlier this year. In two cohorts of its EVOKE-02 trial, researchers enrolled 95 patients with first-line metastatic non-small cell lung cancer, 54 of whom had non-squamous cancers and 41 of whom had squamous cancers. Patients were given Trodelvy in combination with Merck’s Keytruda and chemotherapy. The company tested two different dose levels: the recommended Phase 2 dose of 7.5 mg/kg, and a slightly higher dose of 10 mg/kg. Gilead saw 23 of 51 (45.1%) evaluable non-squamous patients achieve a partial response, as well as 16 of 41 (39%) squamous patients. (Three patients enrolled in the non-squamous group had no measurable disease at baseline, Gilead said.) The respective progression-free survival rates were 8.1 months and 8.3 months. Broken down by dose level, 16 of 30 non-squamous patients who took the 7.5 mg/kg dose achieved a partial response, while seven of 14 had a partial response at the 10 mg/kg dose. (Seven patients weren’t evaluable.) Additionally, 13 of 27 squamous patients at the 7.5 mg/kg dose level had a partial response at 7.5 mg/kg, while four of nine did so at 10 mg/kg. (Six patients weren’t evaluable.) Gilead also broke down the data by patients’ PD-L1 levels. Nineteen of 44 patients with low PD-L1 (tumor proportion score of less than 1%) saw a partial response (43.2%); 12 of 36 patients with medium PD-L1 (tumor proportion score between 1% and 49%) achieved a partial response (33.3%); and eight of 12 patients with high PD-L1 (at least 50%) hit a partial response (66.7%). “What you’re clearly seeing here from this, and also from the EVOKE-01 study, probably is an active drug in metastatic non-small cell lung cancer, and it works across histology and across different spectrum of PD-L1 positive tumors,” said Bilal Piperdi, Gilead’s VP of oncology clinical development. The company is attempting to move Trodelvy into different kinds of cancers, having already received approval for breast and bladder cancer. But EVOKE-01, the drug’s first Phase 3 trial in lung cancer, failed earlier this year in the second-line setting. Trodelvy’s confirmatory study in bladder cancer also failed, with results showing more deaths from adverse events in the active arm than placebo. Gilead bought the drug in its $21 billion buyout of Immunomedics in 2020. Earlier this year, it took a $2.4 billion impairment charge related to the deal. The company is also conducting a Phase 3 in the first-line setting called EVOKE-03. Piperdi said the trial is “on track,” but declined to say when a data readout could be expected.