Gilead Sciences has been looking for a win for Trodelvy after two surprise trial failures earlier this year. But it looks like that win won’t come from a triplet regimen that combines the antibody-drug conjugate with Merck’s Keytruda and chemotherapy in newly diagnosed non-small cell lung cancer (NSCLC)
A combination of Trodelvy, Keytruda and carboplatin triggered 43.1% and 39% tumor response rates in treatment-naïve NSCLC patients with nonsquamous and squamous histologies, respectively, according to results from cohort C and D of the phase 2 EVOKE-02 trial presented at the 2024 World Conference on Lung Cancer.
Nonsquamous patients who took the triplet lived a median 8.1 months without disease progression, compared with 11.1 months for squamous patients. The patients had various levels of PD-L1 expression and no actionable genomic alterations.
The results are disappointing because in cohort B of the EVOKE-02 trial, Trodelvy and Keytruda—without chemo—showed a 44% response rate in front-line patients with PD-L1 tumor proportion scores (TPS) below 50% regardless of histology, according to results published last fall. In cohort A, the doublet pulled off a 67% response rate across histologies in PD-L1-high patients, according to an update in May.
More than 80% of patients in cohort C and D had PD-L1 TPS scores below 50%.
Bilal Piperdi, M.D., who leads oncology clinical development at Gilead, argued that the new findings from cohort C and D support the company’s phase 3 strategy. The EVOKE-03 trial, launched last year, is testing Trodelvy-Keytruda doublet in PD-L1-high first-line NSCLC.
“We’re really not finding a lot of differentiation from additional chemotherapy in combination with [Trodelvy],” Piperdi said in an interview with Fierce Pharma. “So, it is giving more confidence in our current ongoing strategy with [Trodelvy plus Keytruda] with full doses of [Trodelvy].”
It’s worth noting that investigators had to lower Trodelvy’s dose from the original 10 mg/kg to 7.5 mg/kg in the triplet tests after a planned safety evaluation flagged an increased risk of neutropenia. About two-thirds of patients in the efficacy analysis received the lower dose.
The latest Trodelvy data also mirrored findings from a study of AstraZeneca and Daiichi Sankyo’s rival TROP2 ADC, datopotamab deruxtecan (Dato-DXd). In the early-phase TROPION-Lung02 trial, a doublet combination of Dato-DXd and Keytruda induced a 52% response rate in first-line NSCLC patients without actionable genomic alterations. The number was 56% for a triplet that also includes chemo, according to an update in May.
The median PFS was 11.1 months for the AZ doublet and 6.8 months for the triplet. Researchers have attributed the lower PFS for the triplet to more patients receiving a lower dose of Dato-DXd and a higher proportion of patients with brain metastases.
At the time, Leerink Partners analysts wrote in a note that the data “suggest that the addition of chemo is unwarranted.”
Still, AZ’s phase 3 TROPION-Lung07 study for Dato-DXd in first-line, PD-L1-low nonsquamous NSCLC patients includes a triplet arm, and the phase 3 AVANZAR study is combining AZ’s Imfinzi with Dato-DXd and chemo also in first-line NSCLC.
After Trodelvy recently failed as a monotherapy in second-line NSCLC, EVOKE-03 is the sole phase 3 study for the Gilead drug in the cancer type. In terms of the number of trials, the first-to-market TROP2 ADC is falling behind its would-be rivals. AZ/Daiichi and Merck together have a dozen global phase 3 trials running for their TROP2 candidates in various combinations and treatment settings, including in the postsurgical adjuvant setting for early-stage tumors.
Piperdi suggested that Gilead is “reasonably invested” in NSCLC across the three EVOKE studies. He also pointed to Gilead’s partnership with Arcus Biosciences on the PD-1 inhibitor zimberelimab and TIGIT inhibitor domvanalimab. Gilead is pairing those two immune checkpoint inhibitors with Trodelvy in a mid-stage platform study.
“We had a really nicely built program for lung cancer, and I think there’s going to be a lot of data that’s going to read out that will really help us out to where else we can push the envelope,” Piperdi said.
Gilead has many options but wants to think carefully about where to place its Trodelvy investments in first-line NSCLC, he said.
“I think earlier lines of treatment are even more interesting,” he said. “But we’re waiting to see how the landscape changes.”