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Pfizer Lbrance and Gilead Trodelvy: Trial data are disappointing
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Pfizer Lbrance and Gilead Trodelvy: Trial data are disappointing.
Recently, at the ASCO annual meeting, Pfizer and Gilead announced the latest clinical data of their respective breast cancer drugs.
Pfizer announced final overall survival (OS) analysis data from the Phase 3 PALOMA-2 trial with disappointing results, with its CDK4/6 inhibitor Ibrance (palbociclib, palbociclib, palbociclib, palbociclib, palbociclib ) + letrozole first-line treatment failed to prolong the patient’s life.
Gilead announced the results of the Phase 3 TROPiCS-02 trial. The results were unsatisfactory. Although the data were statistically significant, they were lower than industry expectations. Compared with chemotherapy, the TROP-2-targeted antibody conjugated drug Trodelvy (sacituzumab govitecan, Goxatuzumab) extended progression-free survival (PFS) by only 1.5 months.
01Pfizer Phase 3 PALOMA-2 Trial
The trial evaluated Ibrance in combination with the hormone therapy letrozole in first-line treatment of postmenopausal women with ER+/HER2- metastatic breast cancer (mBC).
The data showed that with a median follow-up of 7.5 years (90 months), the Ibrance + letrozole regimen did not prolong the life of patients compared with placebo + letrozole.
Specifically, the median OS was 53.9 months in the Ibrance + letrozole group versus 51.2 months in the placebo + letrozole group, a non-significant difference (HR = 0.956 [95%CI: 0.777-1.177] ).
The trial was statistically designed to detect a 26% reduction in the risk of death, but Ibrance showed only a 4.4% advantage.
The setback makes Ibrance the only CDK4/6 inhibitor to not have successful OS results in a Phase 3 clinical trial.
In response to this result, the PALOMA-2 researchers noted that after so many years, a final overall survival analysis was not available for many patients, including 13% of patients initially enrolled in Ibrance and 21% of patients in the control group.
After excluding these patients, Ibrance fared slightly better, reducing the risk of death by 13.1 percent.
In addition, Ibrance reduced the risk of death by 27.2 percent in patients who had been disease-free for more than a year.
“Survival data were missing for a significant proportion of patients across treatment arms, limiting the interpretation of the overall survival benefit of the PALOMA-2 study,” said Dr. Chris Boshoff, chief development officer of Pfizer Oncology, in a statement. “We continue to believe in the Ibrance combination. Endocrine therapy can provide compelling benefit to this patient population, as demonstrated by the chemotherapy delay, maintenance of quality of life and consistent safety profile shown in the PALOMA-2 study data.”
It’s worth mentioning that this isn’t the first time Ibrance has disappointed with OS metrics.
Previously, Ibrance combined with AstraZeneca’s hormone therapy Faslodex (fulvestrant) also failed to achieve its goal of improving OS in the Phase 3 PALOMA-3 trial. Although in both trials, Ibrance met its primary goal of delaying tumor progression or death.
Separately, Ibrance also failed the PALLAS and PENELOPE-B Phase 3 trials, which used it as an adjuvant post-operative treatment in a slightly different population of patients with early-stage HR+/HER2 breast cancer.
Ibrance is in stark contrast to its 2 rivals, Novartis Kisqali and Eli Lilly Verzenio.
The latter two CDK4/6 inhibitors have significantly prolonged patient survival in various combinations and in various patient populations in multiple Phase 3 clinical trials.
Some analysts pointed out that although Ibrance still maintains a leading position in the market, due to the lack of survival advantage, the drug may be abandoned by more and more doctors and gradually lose market share.
02Gilead Phase 3 TROPiCS-02 Trial
The trial was conducted in patients with HR+/HER2- metastatic breast cancer (mBC) who had received extensive prior regimens of endocrine therapy, CDK4/6 inhibitors, and 2-4 lines of chemotherapy.
The data showed that Trodelvy reduced the risk of disease progression or death by 34 percent compared with physician-chosen chemotherapy (TPC).
After one year, the proportion of patients treated with Trodelvy were 3 times more disease-free than those treated with TPC (21% vs 7%), a benefit that was consistent across key patient subgroups, including those with visceral metastases, older patients, Patients who have received at least 3 prior chemotherapy regimens for metastatic disease.
Another key statistic was disappointing, however, as the median progression-free survival (PFS) was 5.5 months in the Trodelvy-treated group and 4.0 months in the TPC-treated group, a difference of only 1.5 months.
This small discrepancy has caused industry analysts to cast some doubts about Trodelvy’s value in this key potential market expansion opportunity.
Oncologists expected to see even bigger differences. Extending PFS by less than 2-3 months is “really not worth it,” said Debu Tripathy, MD, director of breast medical oncology at the University of Texas MD Anderson Cancer Center.
Ninety-two percent of oncologists surveyed by RBC Capital Markets (RBC) said they would like to see an advantage of at least 2 months.
Still, Gilead thinks Trodelvy is doing well. Bill Grossman, the company’s senior vice president of clinical development, oncology, said: “It is important to focus on the benefits of this population over time. PFS analysis of several time milestones has confirmed that Trodelvy continues to outperform chemotherapy, and multiple Subgroups of patients also showed consistent PFS benefit.”
At the time of the first interim analysis, in terms of overall survival (OS), Trodelvy showed a trend to prolong life compared with chemotherapy, reducing the risk of death by 16%.
The current OS data are immature, and follow-up OS analysis will continue with patient follow-up.
In response to this metric, Anderson Debu Tripathy, MD, said he would like to see a survival advantage of 2-3 months.
According to the RBC survey, 75% of doctors are willing to use Trodelvy if the survival advantage of Trodelvy reaches 2 months.
Dr. Hope Rugo, the lead investigator of the TROPiCS-02 trial and the University of California, San Francisco Comprehensive Cancer Center, believes that the data available are sufficient to support Trodelvy’s use in this previously heavily regimented patient population. Dr. Hope Rugo noted: “In these patients with very limited treatment options, a clinically significant reduction in the risk of disease progression or death was observed. Trodelvy will be an important potential future treatment option for these patients.”
Gilead also said it plans to hold a meeting with the U.S. FDA to discuss the data in the near future.
Still, industry analysts remain pessimistic about Trodelvy’s potential in HR+/HER2- disease, and not just because of weaker-than-expected TROPiCS-02 data.
Another reason is that AstraZeneca/Daisankyo demonstrated the breakthrough results of HER2-targeting antibody conjugated drug Enhertu in the treatment of HER2-low-expressing breast cancer at the ASCO annual meeting.
The HER2 low-expression group included HR+ patients, implying a patient overlap between Enhertu and Trodelvy.
Among physicians surveyed by RBC, an average of 39% of HR+/HER2- patients met Enhertu’s description of HER2 low expression.
1. ASCO: Pfizer’s Ibrance fails to extend lives in newly diagnosed breast cancer. Will doctors switch gears to Novartis, Lilly?
2. Gilead’s Trodelvy Data Leaves Some Questioning Clinical Advantage
3. ASCO: Gilead’s Trodelvy limps forward in new breast cancer lane as below-par showing casts doubt
(source:internet, reference only)