Trodelvy Triplet Falls Short, but Gilead Exec Supports Phase 3 Lung Cancer Plan

Gilead Sciences has been striving for a breakthrough for its drug Trodelvy following two unexpected trial failures earlier this year. Hopes were high for a triplet regimen that combines Trodelvy with Merck’s Keytruda and chemotherapy to treat newly diagnosed non-small cell lung cancer (NSCLC). However, recent trial results indicate that the addition of chemotherapy to this combination does not provide significant benefits.

The phase 2 EVOKE-02 trial, presented at the 2024 World Conference on Lung Cancer, tested the efficacy of a triplet regimen comprising Trodelvy, Keytruda, and carboplatin in treatment-naïve NSCLC patients. Specifically, the cohorts C and D exhibited tumor response rates of 43.1% in nonsquamous patients and 39% in squamous patients. These patients exhibited varying levels of PD-L1 expression and had no actionable genomic alterations.

The median progression-free survival (PFS) for nonsquamous patients was 8.1 months, while squamous patients experienced a median PFS of 11.1 months. The outcomes were somewhat disappointing, especially when contrasted with previous results from cohort B of the same trial. In cohort B, a combination of Trodelvy and Keytruda without chemotherapy achieved a 44% response rate in patients with PD-L1 tumor proportion scores (TPS) below 50%, irrespective of histology. Moreover, cohort A reported a 67% response rate in PD-L1-high patients using just the doublet combination, as per an update in May.

Importantly, more than 80% of patients in cohorts C and D had PD-L1 TPS scores below 50%. Dr. Bilal Piperdi, who leads oncology clinical development at Gilead, suggested that these findings bolster the company's phase 3 strategy. The ongoing EVOKE-03 trial, initiated last year, is evaluating the effectiveness of the Trodelvy-Keytruda doublet in PD-L1-high first-line NSCLC patients. Dr. Piperdi mentioned that the new findings provide more confidence in their current strategy involving full doses of Trodelvy without the addition of chemotherapy.

Interestingly, the dose of Trodelvy had to be reduced from the initial 10 mg/kg to 7.5 mg/kg in the triplet regimen after a safety evaluation revealed an increased risk of neutropenia. Approximately two-thirds of the patients in the efficacy analysis received this lower dosage.

These latest findings are in line with earlier research on AstraZeneca and Daiichi Sankyo’s competing TROP2 antibody-drug conjugate, datopotamab deruxtecan (Dato-DXd). In the early-phase TROPION-Lung02 trial, a combination of Dato-DXd and Keytruda achieved a 52% response rate in first-line NSCLC patients without actionable genomic alterations. When chemotherapy was added to the mix, the response rate increased slightly to 56%. However, the median PFS was 11.1 months for the doublet combination and 6.8 months for the triplet, with researchers attributing the lower PFS for the triplet to a higher proportion of patients receiving a reduced dose of Dato-DXd and more patients with brain metastases.

Despite the data suggesting that the addition of chemotherapy may not be necessary, AstraZeneca is still exploring triplet regimens in its phase 3 TROPION-Lung07 and AVANZAR studies. These trials involve Dato-DXd and Imfinzi in combination with chemotherapy for first-line NSCLC patients.

After Trodelvy’s recent failure as a monotherapy for second-line NSCLC, the EVOKE-03 trial remains Gilead’s only phase 3 study for this drug in lung cancer. While Gilead appears to be lagging behind its competitors in terms of the number of trials, the company remains committed through its collaboration with Arcus Biosciences. This partnership involves pairing Trodelvy with zimberelimab, a PD-1 inhibitor, and domvanalimab, a TIGIT inhibitor, in a mid-stage platform study.

Dr. Piperdi emphasized that Gilead’s broader program for lung cancer is robust and that forthcoming data will likely guide future strategies. He indicated that there are multiple avenues for Trodelvy in first-line NSCLC, but stressed the importance of careful consideration in deciding where to invest. He concluded that earlier lines of treatment hold significant potential, but the company is waiting to see how the treatment landscape evolves.