Gilead's Trodelvy Surpasses Investors' Low Bar At ASCO, But Faces A Commercial Climb
Executive Summary
The Phase III TROPICS-02 study in HR-positive/HER2-negative breast cancer was successful, but data for rival drug Enhertu overshadowed the results.
Gilead Sciences, Inc. prepared investors to be underwhelmed by the Phase III data results from TROPICS-02, testing Trodelvy (sacituzumab govitecan-hziy) versus chemotherapy in heavily pre-treated HR-positive/HER2-negative metastatic breast cancer. So the data – presented at the American Society of Clinical Oncology (ASCO) annual meeting on 4 June – were about what investors were expecting or slightly better.
Nonetheless, impressive Phase III data at ASCO for a different antibody drug conjugate (ADC), AstraZeneca PLC/Daiichi Sankyo Co., Ltd.'s Enhertu (trastuzumab deruxtecan), undercut the positive results from Gilead and raised questions about the commercial potential of Trodelvy in that setting.
"TROPICS-02 detailed data at ASCO were better than the worst-case scenario following the company's disclosure in March, but Trodelvy's potential role in HR-positive/HER2-negative metastatic breast cancer remains TBD," SVB Securities analyst David Risinger said in a 6 June research note.
In March, Gilead gave investors mixed messages about the data. The company, disclosing the top-line results, said the trial met the primary endpoint of progression-free survival (PFS), but it also said in an 8-K filing with the Securities and Exchange Commission that there are a range of views on what is considered "clinically meaningful" in the setting, which led investors to anticipate a modest benefit. (Also see "Trodelvy’s Phase III Breast Cancer Results Raise More Questions Than Answers" - Scrip, 7 Mar, 2022.)
As it turns out, in TROPICS-02, patients treated with Trodelvy had a statistically significant and clinically meaningful 34% reduction in the risk of disease progression or death compared to those treated with chemotherapy. The median PFS in the Trodelvy arm was 5.5 months versus four months for those on chemotherapy, at a hazard ratio of 0.66. On a key secondary endpoint of overall survival, a trend towards an improvement was seen, but the data are not yet mature. Patients will be followed for a subsequent OS analysis which will be important for informing the drug's efficacy profile.
"Sacituzumab govitecan demonstrated a significant and clinically meaningful benefit in patients with heavily pretreated, endocrine-resistant, hormone receptor-positive advanced breast cancer and should be considered a potential treatment option in this patient population," principal investigator Hope Rugo, from the University of California, San Francisco, said while presenting the data at ASCO.
However, Rugo was pressed about the clinical meaningfulness of the PFS improvement of 1.5 months in a panel session. She pointed out that it can be challenging to interpret data in patients who are so heavily pretreated with metastatic disease. Patients in TROPICS-02, which enrolled 543 patients, were previously treated with endocrine therapy, a CD4/6 inhibitor and two to four lines of chemotherapy.
"We suffer a little bit from our statistics in patients who are heavily pretreated for metastatic disease," she said. "When you are looking at median progression free survival differences you can actually see a fairly modest absolute difference, but a very robust hazard ratio, as we saw in this trial, a hazard ratio of 0.66, which exceeded the goal, which was 0.7.
"Then, the landmark analyses help us to some degree because we could see that there were three times as many patients who were progression-free at 12 months with sacituzumab compared to those on chemotherapy," she added. "I think that is what we have to take out of trials in this late-line setting."
Mizuho Securities analyst Salim Syed questioned the clinical meaningfulness of the benefit in a 6 June research note, however. "That's good," he said of the PFS benefit, "but in terms of clinical meaningfulness, the 1.5-month delta falls short of the 2.5 months plus for which investors had initially hoped."
Gilead said it is continuing to discuss the data with regulatory authorities to determine how Trodelvy can impact patients in this setting. The TROP2-targeting ADC is already approved for triple negative breast cancer (TNBC) and urothelial carcinoma (UC), but HR-positive/HER2-negative breast cancer is the most common form of breast cancer and expansion into the indication would represent an important commercial opportunity. Gilead paid $21bn to buy Trodelvy developer Immunomedics in 2020. (Also see "Gilead Buys Pipeline-In-A-Product With $21bn Immunomedics Deal" - Scrip, 13 Sep, 2020.)
A Competitor In The Way
Even if Trodelvy is approved for the indication, a commercial roadblock is developing in the form of the HER2-targeting ADC Enhertu from AstraZeneca and Daichi Sankyo. Enhertu was one of the stars of ASCO this year with data presented during a plenary session on 5 June that is viewed by experts in the field as paradigm-changing.
The notable development is that Enhertu showed for the first time the benefit of a HER2-targeted treatment for patients with tumors categorized as HER2-low, currently classified as HER2-negative under existing treatment guidelines. Experts said the results of the study will change the way doctors classify metastatic breast cancer patients going forward.
In the Phase III DESTINY-Breast04 study, Enhertu showed a 49% reduction in the risk of disease progression or death versus chemotherapy in patients with HER2-low metastatic breast cancer with HR-positive disease. Treatment with Enhertu yielded a median PFS of 10.1 months compared to 5.4 months for patients treated with chemotherapy; overall survival was 23.9 months versus 17.5 months.
Cross trial comparisons are challenging and there were several differences between the two studies, including the patients recruited for the trial, of which TROPICS-02 recruited more heavily treated patients.
Nonetheless, Enhertu appears poised to capture a large potential treatment market in the HR-positive category among those with tumors recognized as HER2 low.
"We believe Enhertu's efficacy profile in HR-positive metastatic breast cancer and the potential for reclassification to make more patients eligible for AstraZeneca's drug over time will make a Trodelvy launch in the HR-positive population an uphill battle," Risinger said.