Pfizer Halts Phase III PALLAS Trial of Ibrance as Adjuvant Therapy in Early Breast Cancer Due to Futility

News Event

Today, Pfizer announced that its CDK4/6 inhibitor Ibrance was recommended for termination in a Phase III clinical trial evaluating post-surgical maintenance therapy for patients with early-stage breast cancer, due to the slim likelihood of success. The trial, named PALLAS, enrolled 5,796 patients with HER2-negative, hormone receptor (HR)-positive breast cancer. It compared two years of Ibrance combined with standard therapy followed by three years of standard therapy against five years of continuous standard therapy, assessing their impact on the incidence of metastatic breast cancer. The results showed that adding Ibrance did not prolong invasive disease-free survival (iDFS). Ibrance is one of the primary growth drivers for Pfizer. Had the PALLAS trial succeeded, it was expected to capture an additional 150,000 patients in major Western markets. As these patients would require at least two years of maintenance therapy, this represented a significant revenue opportunity. Pfizer has another similar maintenance therapy trial, Penelope-B, currently underway, targeting patients with HR-positive, HER2-normal breast cancer. If successful, this trial could reach 60,000 patients in major Western markets. This news dashed hopes for significant growth in this broad market segment, causing Pfizer’s stock to drop 7% today and wiping out billions in market capitalization.

Drug Source Analysis

CDK4/6 inhibitors represent a significant breakthrough in the treatment of breast cancer. The three major competing drugs—Ibrance, Kisqali, and Verzenio—have all been granted Breakthrough Therapy Designation by the FDA. Although Ibrance was first synthesized as early as 2001, this mechanism initially received little attention. One reason is that oncology was not as prominent two decades ago as it is today. That era was characterized by the dominance of blockbuster drugs, with large pharmaceutical companies such as Pfizer focusing more on medications for hyperglycemia and hyperlipidemia. Secondly, Ibrance was one of the products acquired by Pfizer through its acquisition of Wyeth; however, at the time, all attention was centered on the blockbuster drug Lipitor, leaving these peripheral assets largely unexamined. In 2007, preclinical studies demonstrated activity in breast cancer, prompting Pfizer to initiate its first Phase II clinical trial in 2009. This Phase II trial significantly prolonged progression-free survival (PFS) in patients with advanced metastatic breast cancer, leading Pfizer to immediately increase its investment. Novartis and Eli Lilly also aggressively advanced their own CDK programs. Eli Lilly appeared to bypass Phase II and proceed directly to Phase III trials.

Ibrance became the first CDK4/6 inhibitor to reach the market, sequentially obtaining approvals for use in combination with letrozole as first-line therapy for HER2-negative, HR-positive patients, and in combination with fulvestrant for second-line treatment, thereby establishing itself as the leader in this mechanism of action. The product generated $5 billion in sales last year. However, to date, Ibrance has only demonstrated a significant prolongation of progression-free survival (PFS); it has missed the overall survival (OS) endpoint in several Phase II and III clinical trials. In the 2018 PALOMA-3 trial, which evaluated the combination with fulvestrant in the same second-line population, it missed statistical significance by a narrow margin. Although Kisqali and Verzenio have subsequently demonstrated survival benefits in premenopausal and postmenopausal populations, respectively, and Novartis and Eli Lilly are by no means insignificant players in the industry, the sales of these two products last year were each only about one-tenth of those of the market leader, Ibrance. This underscores the first-mover advantage enjoyed by the pioneer product from the leading pharmaceutical company.

Expanding the use of anticancer drugs from late-stage tumors to earlier lines of therapy is a common strategy. The most successful example is the third-generation EGFR inhibitor Tagrisso, which has not only secured approvals across all lines of treatment for advanced metastatic lung cancer but also demonstrated an 83% reduction in the risk of progression in maintenance therapy, positioning it as a potential blockbuster drug. Horizontal expansion into other indications is also a major growth pathway for oncology drugs, as seen with the multiple indications approved for PD-1 inhibitors. However, the expansion of CDK4/6 inhibitors into other tumor types, such as lung cancer, has faced challenges. G1 previously attempted to leverage CDK inhibitors to protect dividing cells from chemotherapy-induced damage by arresting the cell cycle, but the results were mediocre. This may be because CDK4/6 inhibition does not necessarily sustain long-term blockade of cell division, and chemotherapy may not selectively target only dividing cells as traditionally assumed. The growth rate of patient tumor cells is typically lower than that of blood cells and far slower than that of cell lines cultured in the laboratory. The precise mechanisms underlying the efficacy of oncology drugs remain highly complex.