After Gilead Sciences dropped an ambiguous line for Trodelvy’s performance in HR-positive, HER2-negative breast cancer in March, all eyes are on this weekend's data presentation. And those detailed results don’t exactly meet doctors’ expectations.
In heavily pretreated patients with HR+/HER2-breast cancer, Trodelvy slashed the risk of disease progression or death by 34% over physicians’ choice of chemotherapy. While the magnitude of that risk reduction represents a decent, statistically significant showing, Trodelvy disappoints on another key metric: extending the time patients lived without their disease worsening.
Patients who received Trodelvy went a median 5.5 months without tumor progression, a mere 1.5-month improvement over the median four months registered in the chemotherapy arm of the trial. And that small difference throws some doubt on the drug’s value in this key potential market expansion opportunity.
The data, from the phase 3 TROPiCS-02 trial, were presented Saturday at the 2022 American Society of Clinical Oncology (ASCO) annual meeting.
Is Trodelvy's benefit clinically meaningful?
When Gilead said in March that the study had hit its primary endpoint of improving progression-free survival (PFS), the company itself gave investors the impression that the benefit wasn’t necessarily clinically meaningful, with this sentence: “There is a broad range of views on what is ‘clinically meaningful’ in this population.”
Oncologists were expecting more. Debu Tripathy, M.D., chair of breast medical oncology at the University of Texas MD Anderson Cancer Center, told Fierce Pharma that a progression-free survival extension of less than two to three months “would not really be worth it.” Ninety-two percent of oncologists surveyed by RBC Capital Markets also said they wanted to see an advantage of at least two months.
Still, Gilead argues Trodelvy did well.
“I think it’s important to look at the benefit of this population over time,” Bill Grossman, M.D., Ph.D., Gilead’s senior vice president of oncology clinical development, said in an interview with Fierce Pharma.
He was referring to analyses of PFS rates at several time milestones, which showed a continued edge by Trodelvy over chemo. Most notably, at the one-year mark, 21% of Trodelvy patients were still alive without disease progression, versus just 7% for the chemo group.
Grossman also pointed to multiple subgroup analyses in which Trodelvy showed a PFS benefit in all but three groups.
The TROPiCS-02 trial enrolled HR+/HER2- breast cancer patients who had previously tried endocrine therapy, CDK4/6 inhibitors and two to four lines of chemotherapy. In those who had received at least three prior chemo regimens for metastatic disease, Trodelvy slashed the risk of disease progression or death by 30%. In patients who had received a CDK4/6 inhibitor less than a year before getting on treatment in TROPiCS-02, Trodelvy did improve that PFS by two months, Grossman said.
Life extension data awaits maturation
On the marker of overall survival, Trodelvy showed a trend toward helping patients live longer at this first interim analysis. The Gilead drug cut the risk of death by 16% and extended patients' lives by 1.6 months to 13.9 months at the median.
The 543-subject trial reached those numbers after 293 patients had died. Investigators will run another analysis after about 350 deaths, and then perform their final calculations at 438, Grossman said.
MD Anderson’s Tripathy said he would like to see a survival edge of two to three months, and RBC’s survey showed 75% doctors would be willing to use Trodelvy if the number reaches two months.
Hope Rugo, M.D., at the University of California San Francisco Comprehensive Cancer Center and lead investigator of the TROPiCS-02 trial, argued existing data already support Trodelvy in this heavily pretreated patient population.
“To observe a clinically meaningful reduction in the risk of disease progression or death in these patients with limited treatment options is remarkable,” Rugo said in a statement. “[Trodelvy] will be an important potential future treatment option for these patients.”
Gilead has scheduled a meeting with the FDA “in the near future” to discuss the data, Grossman said, adding that the current data set was previously agreed upon with the agency. But in a March note, RBC analyst Brian Abrahams said Gilead appeared reluctant to file Trodelvy right now. Given physician feedback, “there would likely be limited use of the agent in HR+/HER2- patients if it were approved near-term,” Abrahams said then.
Gilead forges ahead despite uncertain future
Gilead has tagged Trodelvy as a cornerstone of its ambition to have a third of its revenue from oncology by 2030. The TROP2-targeted antibody-drug conjugate was the centerpiece of Gilead’s $21 billion acquisition of Immunomedics in 2020.
The drug is currently approved in triple-negative breast cancer and bladder cancer. But analysts have assigned a large proportion of Trodelvy’s peak sales estimate to the HR+/HER2- breast cancer field. And the current late-line setting is the first test of that theory.
Now, Trodelvy’s potential in HR+/HER2- disease looks less certain, and not just because of weaker-than-expected TROPiCS-02 data. At ASCO 2022, AstraZeneca and Daiichi Sankyo are presenting positive data for their HER2-targeted antibody-drug conjugate Enhertu in a population with low HER2 expression levels that have traditionally been characterized as HER2-negative.
The HER2-low group also includes patients who are HR-positive, meaning there could be patient overlap between Enhertu and Trodelvy. Among the doctors RBC surveyed, an average 39% of HR+/HER2- patients actually fit Enhertu’s HER2-low description.
Grossman suggested that Trodelvy’s TROPiCS-02 and Enhertu’s DESTINY-Breast04 trial can’t be compared side by side because their participants are different. For example, the Trodelvy study required at least one prior CDK4/6 treatment, while pretreatment with a CDK4/6 drug was optional for the Enhertu study. Patients had received at least two prior chemotherapies in the Trodelvy trial, versus a minimum of one chemo for Enhertu.
Despite debate around Trodelvy’s evidence in heavily pretreated patients, Gilead remains committed to moving Trodelvy to earlier breast cancer, Grossman said.
Once a drug shows a benefit as a monotherapy in later-line treatment, it’s typical to see better results in earlier lines of therapy, especially in combinations, Grossman said. “That’s where we have strong belief that we’ll be able to continue to bring even better or enhanced benefit to earlier lines of patients.”