Many Gilead Sciences investors have lost faith in Trodelvy in HR-positive, HER2-negative breast cancer after disappointing data on tumor progression. But the antibody-drug conjugate has now made a surprise comeback with a life extension benefit that's greater than industry watchers’ expectations, reigniting blockbuster hopes.
Trodelvy extended patients’ lives by a median 3.2 months over physician’s choice of chemotherapy in heavily pretreated HR-positive, HER2-negative breast cancer. Takers of the TROP2-targed med lived a median of 14.4 months, versus 11.2 months for the chemo group, which translates to a 21% death risk reduction in the closely watched TROPiCS-02 trial.
“We’re hitting the upper end—if not exceeding—most of the expectations out there,” Bill Grossman, M.D., Ph.D., Gilead oncology’s therapeutic area head, noted in an interview with Fierce Pharma ahead of a presentation at the European Society for Medical Oncology (ESMO) congress 2022.
The 3.2-month survival difference came above RBC Capital Markets analysts’ previous estimates of around 2.5 months, which Gilead investors generally agreed on per an RBC survey. The actual showing also met the investors’ perception of an efficacy bar for Trodelvy to achieve at least $1 billion in peak sales in HR+/HER2- breast cancer. To reach that goal, RBC-polled investors suggested Trodelvy needs to show a survival advantage of above three months, a threshold that only 31% of them believed Trodelvy could meet.
In a separate RBC survey, doctors on average put the overall survival benefit at around 2.5 months for Trodelvy to be considered clinically meaningful. In an interview with Fierce Pharma in May, Debu Tripathy, M.D., chair of breast medical oncology at the University of Texas MD Anderson Cancer Center, also said he would like to see an improvement of at least two to three months.
Back in June, Trodelvy’s mere 1.5-month improvement on slowing tumor progression or death was widely viewed as lacking clinical meaningfulness. At the time, data on overall survival were immature, with Trodelvy slashing the risk of death by 16% and extending life expectancy by only 1.6 months at median.
At that first interim analysis, 293 patients in the 543-subject trial had died. Wall Street analysts and investors previously based their estimates on the TROPiCS-02 trial accruing altogether 350 deaths, which would trigger the second interim analysis. The reality is the current analysis counts 390 deaths, which likely worked in Trodelvy’s favor in terms of data maturity.
Still, doubling of survival benefit after only an additional 2.3 months of follow-up and an extra 100 events was no small feat, which makes one wonder whether there’s anything different in patient characteristics in the updated analysis.
During the original readout at 10.2 months of follow-up, more patients in the Trodelvy arm than in the control arm didn’t come back in time for that analysis, Grossman explained.
“There’s nothing different around the patient populations or anything like that; it’s really a matter of getting all the number of events and to have a more mature [survival] curve for us,” he said.
Gilead has filed the new results with the FDA, but Grossman didn’t say which line of therapy Gilead is seeking.
Trodelvy’s new survival showing may come as a pleasant surprise for Gilead investors, but the debate around its competitive profile against AstraZeneca and Daiichi Sankyo’s Enhertu is far from over.
Enhertu recently won an industry-first FDA nod for previously treated HER2-low breast cancer. The brand-new HER2-low category covers patients who were previously considered HER2-negative.
At ESMO 2022, Gilead also released a subgroup analysis of the HER2-low population in TROPiCS-02. There, Trodelvy cut the risk of tumor progression or death by 42% over chemo. In this group, Trodelvy takers lived a median 6.4 months without disease worsening, versus 4.2 months for chemo. The risk reduction was 28% for patients who were HER2-negative by the new standard as measured by an IHC 0 test.
In Enhertu’s DESTINY-Breast04 study, the HER2-targeted drug cut the risk of progression or death by 49% in HR-positive, HER2-low patients, as those who received Enhertu lived 10.1 months without disease worsening compared with 5.4 months for chemo.
Although all biopharma watchers are comparing the two studies side by side, Grossman pointed out these are not apple-to-apple comparisons. Trodelvy’s TROPiCS-02 enrolled a more advanced population that had received a median of three prior chemotherapies, versus one for Enhertu’s DESTINY-Breast04. And in TROPiCS-02, all enrolled patients had prior CDK4/6 inhibitor treatment, whereas in the Enhertu trial, 30% did not.
“I think our subpopulation analysis shows that we can go into that HER2-low population just as well as [Enhertu] can,” Grossman said. One of the potential benefits of Trodelvy, he added, is that it doesn’t necessarily require a HER2 diagnostic as an anti-TROP2 med.
Gilead has designated Trodelvy as the cornerstone of its emerging solid tumor franchise. The drug has shown it could work in triple-negative breast cancer patients who received two prior systemic therapies, including at least one for metastatic disease. Encouraged by the clinical data so far, Gilead is looking at earlier treatment for both TNBC and HR+/HER2- breast cancer, Grossman said.
“We’ve developed a robust, deep portfolio where we can look at orthogonal combinations that can really complement Trodelvy across many different tumor types,” Grossman said. “What you’ll see next is not only this movement into early lines of therapy with Trodelvy, but you’ll start seeing a lot of novel combinations for differentiation against our competitors emerge as well.”