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.
Dave Fredrickson“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 uncorks Phase 2 Trodelvy data in lung cancer
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%).
Bilal Piperdi“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.