2022 ASCO Breast Cancer Updates: Pfizer’s Ibrance Fails to Show OS Benefit, Gilead’s Trodelvy Delivers Modest PFS Gain

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Recently, at the ASCO Annual Meeting, Pfizer and Gilead respectively announced the latest clinical data for their breast cancer drugs.

Pfizer announced the final overall survival (OS) analysis data from the Phase 3 PALOMA-2 trial, but the results were disappointing. Compared with placebo plus letrozole, its CDK4/6 inhibitor Ibrance (palbociclib) plus letrozole as first-line treatment failed to prolong patients' lives.

Gilead announced the results of the Phase 3 TROPiCS-02 trial, which were disappointing. Although the data was statistically significant, it fell below industry expectations. Compared with chemotherapy, the TROP-2 targeted antibody-drug conjugate Trodelvy (sacituzumab govitecan) extended progression-free survival (PFS) by only 1.5 months.

01Pfizer Phase 3 PALOMA-2 Trial

This trial evaluated Ibrance in combination with hormone therapy letrozole as a first-line treatment for postmenopausal women with ER+/HER2- metastatic breast cancer (mBC). Data showed that, with a median follow-up time of 7.5 years (90 months), the Ibrance + letrozole regimen did not extend patient survival compared to placebo + letrozole.

Specifically, the median OS was 53.9 months in the Ibrance + letrozole treatment group and 51.2 months in the placebo + letrozole treatment group, with no statistically significant difference (HR=0.956 [95% CI: 0.777-1.177]). The statistical design of the trial aimed to detect a 26% reduction in the risk of death, but Ibrance demonstrated only a 4.4% advantage.

This setback made Ibrance the only CDK4/6 inhibitor that did not achieve a successful OS result in a phase 3 clinical trial. Regarding this outcome, researchers from the PALOMA-2 trial noted that after so many years, a significant number of patients could not be included in the final overall survival analysis, including 13% of the patients initially enrolled to receive Ibrance and 21% of those in the control group.

After excluding these patients, Ibrance performed slightly better, reducing the risk of death by 13.1%. Additionally, in patients who had been disease-free for more than a year, Ibrance reduced the risk of death by 27.2%.

Chris Boshoff, MD, PhD, Chief Development Officer, Oncology, Pfizer, said in a statement: “A considerable proportion of patients in each treatment arm are missing survival data, which limits the interpretation of the overall survival benefit in the PALOMA-2 study. We continue to believe that Ibrance in combination with endocrine therapy offers a compelling benefit for this patient population, as evidenced by the chemotherapy delay, maintenance of quality of life, and consistent safety profile demonstrated in the PALOMA-2 study data.”

It is worth mentioning that this is not the first time Ibrance has disappointed in terms of OS metrics. Previously, Ibrance in combination with AstraZeneca's hormone therapy Faslodex (fulvestrant) also failed to achieve the goal of improving OS in the Phase 3 PALOMA-3 trial. Despite this, in both trials, Ibrance achieved its primary goal of delaying tumor progression or death. Additionally, Ibrance also failed in the PALLAS and PENELOPE-B Phase 3 trials, which evaluated it as a post-surgical adjuvant treatment for slightly different populations of early-stage HR+/HER2- breast cancer patients.

Ibrance contrasts sharply with its two competitors, Novartis' Kisqali and Eli Lilly's Verzenio. These two CDK4/6 inhibitors have significantly extended patient survival across various combinations and different patient populations in multiple Phase 3 clinical trials. Some analysts have pointed out that although Ibrance still maintains market leadership, it may gradually lose market share as more doctors could stop using it due to the consistent lack of survival benefit.

02Gilead Phase 3 TROPiCS-02 Trial

The trial was conducted in HR+/HER2- metastatic breast cancer (mBC) patients who had previously received multiple treatment regimens, including endocrine therapy, CDK4/6 inhibitors, and 2-4 lines of chemotherapy.

Data show that, compared with chemotherapy (TPC) chosen by doctors, Trodelvy reduced the risk of disease progression or death by 34%. One year later, the proportion of patients without disease progression in the Trodelvy treatment group was three times that of the TPC treatment group (21% vs 7%). This benefit remained consistent across key patient subgroups, including those with visceral metastases, elderly patients, and those who had previously received at least three chemotherapy regimens for metastatic disease.

However, another key statistic was disappointing, as the median progression-free survival (PFS) was 5.5 months for the Trodelvy treatment group and 4.0 months for the TPC treatment group, with a difference of only 1.5 months. This slight difference has led industry analysts to question the value of Trodelvy in this crucial potential market expansion opportunity.

Oncologists expect to see a larger difference. Dr. Debu Tripathy, Professor and Chairman of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, pointed out that extending PFS by less than 2-3 months "is really not worth it." Ninety-two percent of oncologists surveyed by RBC Capital Markets said they hoped to see at least a 2-month advantage.

Nevertheless, Gilead believes Trodelvy is performing well. Bill Grossman, the company's Senior Vice President of Oncology Clinical Development, stated, "It is important to focus on the benefits for this population over time. PFS analysis at several time milestones has confirmed that Trodelvy consistently outperforms chemotherapy, and multiple patient subgroups have also shown consistent PFS benefits."

At the first interim analysis, in terms of overall survival (OS), Trodelvy showed a trend of life extension compared to chemotherapy, reducing the risk of death by 16%. The OS data is currently immature, and continued follow-up of patients will be conducted for subsequent OS analysis.

For this indicator, Dr. Debu Tripathy of Anderson hopes to see a survival advantage of 2-3 months. According to the RBC survey, if Trodelvy's survival advantage reaches 2 months, 75% of doctors are willing to use Trodelvy.

Dr. Hope Rugo, principal investigator of the TROPiCS-02 trial and director at the UCSF Helen Diller Family Comprehensive Cancer Center, believes that the existing data is sufficient to support the use of Trodelvy for treating this heavily pretreated patient population. Dr. Hope Rugo noted, "In these patients with very limited treatment options, a clinically meaningful and significant reduction in the risk of disease progression or death was observed. Trodelvy will be an important potential treatment option for these patients in the future."

Gilead also stated that it plans to meet with the U.S. FDA in the near future to discuss the data. However, industry analysts remain pessimistic about Trodelvy's potential in HR+/HER2- diseases, not only because the TROPiCS-02 data was weaker than expected. Another reason is that at the ASCO Annual Meeting, AstraZeneca/Daiichi Sankyo showcased breakthrough results of their HER2-targeted antibody-drug conjugate Enhertu in treating HER2-low breast cancer. The HER2-low group includes HR+ patients, which means there is patient overlap between Enhertu and Trodelvy. On average, 39% of HR+/HER2- patients surveyed by RBC met the HER2-low criteria for Enhertu.

Reference Source:

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