Gilead Sciences encountered a major setback in late May when its antibody-drug conjugate Trodelvy failed to reach the primary endpoint in a confirmatory Phase III trial in patients with metastatic urothelial cancer. In addition to missing the mark in overall survival, Gilead reported a higher number of deaths in the Trodelvy arm of the study. However, Wall Street analysts are still optimistic when it comes to the drug’s blockbuster potential as a future cornerstone of Gilead’s oncology franchise.
TROPiCS-04 was the late-stage confirmatory trial meant to upgrade Trodelvy’s accelerated approval in previously-treated urothelial carcinoma (UC), which was granted by the FDA in 2021. The study compared Trodelvy to chemotherapy as a second-line treatment for patients with locally advanced or metastatic UC (mUC). The bottom line: the TROP2-directed antibody-drug conjugate (ADC) did not extend patients’ lives any better than chemotherapy.
Hartaj Singh, managing director and senior analyst at Oppenheimer, told BioSpace that while the TROPiCS-04 results were a “bummer” and “deflating” for Gilead, there are extenuating circumstances that must be taken into consideration. Singh said the mUC trial was designed by Immunomedics, which was acquired by Gilead in 2020 for $21 billion, and that issues with the design involve some patients’ “one-off events” that may have “tilted the odds against the trial.”
“I think that [Gilead] feel[s] that really nothing is altered about Trodelvy and that they’ll go to the regulators and . . . I would speculate that there’s a better than 50-50 chance the drug stays on the market for that [mUC] indication,” Singh said.
Trodelvy, which is also FDA-approved for the treatment of breast cancer, earlier this year also failed a Phase III trial in non-small cell lung cancer (NSCLC), missing its overall survival endpoint. While the back-to-back losing streak for the ADC is not encouraging, there are still paths forward for Trodelvy’s expansion in oncology.
From The Jaws of Defeat
At the recent American Society of Clinical Oncology (ASCO) annual meeting, Gilead presented further details of the data from the EVOKE-01 NSCLC trial. The results showed that Trodelvy, when put up against the chemotherapy docetaxel, demonstrated a median overall survival of 11.1 months versus 9.8 months for docetaxel.
Still, Gilead observed a more than three-month difference in median overall survival in a subgroup of patients, providing the company with the motivation to continue trialing efficacy in these patients.
A Jefferies analyst note to investors acknowledged there “continues to be a debate on the next steps with Trodelvy” and that a critical factor in the future will be whether Gilead can file for NSCLC in the second line.
“We think they will likely need to run another Phase III study, but we expect an update likely later this year after FDA discussions,” Jefferies analysts wrote. “If they are able to file for [second line plus] NSCLC in PD-1 refractory, we think this is all upside. Another option is they could focus their strategy on [first-line] given recent data looked good [with] 13 months [progression-free survival] for Trodelvy in PD-1 positive patients.”
The Jefferies analysts also commented that the EVOKE-01 data “remains debated” among doctors as the ADC appears efficacious in PD-1 refractory NSCLC. Still, it remains unclear how the FDA will perceive Gilead’s data and whether the regulator will require a new Phase III trial to confirm efficacy.
“If they are able to file on the subgroup analysis, this would certainly drive upside,” the analysts opined.
Despite Trodelvy’s recent NSCLC stumble, some data did go Gilead’s way at ASCO. The Phase II EVOKE-02 trial, which investigated the ADC in combination with Merck’s blockbuster cancer drug Keytruda in NSCLC, showed a median PFS of 13.1 months. Gilead also touted the results as supporting “promising activity” in squamous and non-squamous populations. Jefferies analysts noted that the EVOKE-02 results had an overall response rate better than PD-1 monotherapies and better than a PD-1-chemotherapy combination.
Even though Trodelvy this year has reported less-than-stellar results, Singh remains optimistic about the ADC’s future.
He said he has models for the drug reaching around $1 billion annually “soon” and $2 billion within a year or two. By comparison, Trodelvy pulled in $309 million in sales in the first quarter of 2024, a 39% increase versus the same period in 2023.
While there might be a “momentary downtick” in mUC sales, Singh pointed to the fact that the ADC is still a significant treatment in triple-negative and hormone receptor-positive HER2-negative breast cancer, an approval Gilead secured in early 2023.
“I’m happy people are bummed out about Trodelvy because expectations have come down so low,” Singh said. “Trodelvy is growing like 20%-plus every quarter. And if that continues, which we believe it will, then people are just going to be surprised to the upside.”
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