‘Winner of 3-way war among CDK-inhibitor breast cancer drugs will come out in 5 years'

A heated debate is going on whether to view the three CDK4/6 inhibitors – Ibrance, Kisqali, and Verzenio -- in treating breast cancer as the same drug group or as individual drug groups.

These CKD (cyclin-dependent kinase)4/6 inhibitors are said to have changed the treatment paradigm of HR+ (hormone receptor-positive)/HER2- (human epithelial cell growth factor receptor 2 negative) breast cancer.

At the San Antonio Breast Cancer Symposium (SABCS) 2022 last Friday, Dr. Ruth O’Regan of the Wilmot Cancer Research Institute at Rochester University and Dr. Debra Patt of the Texas Oncology held a debate with the theme of “Are all CKD4/6 inhibitors the same or different?”

Both experts agreed that clinical data on the three drugs is insufficient but made opposite interpretations.

Dr. O’Regan focused on the individuality of CDK4/6 inhibitors.

“Because each of the three drugs’ molecular structure and efficacy is different, we can replace one with another or must do so at times,” she said.

According to Dr. O’Regan, the mOS (median value of overall survival) of Pfizer’s Ibrance (palbociclib) stood at 53.9 months in the PALOMA-2 study, showing no significant difference with the place group’s 51.2 months and failing to prove it improves survival compared to the letrozole monotherapy group. However, Kisqali’s mOS was 58.7 months in the MONALEESA-7 study, superior to the control group’s 48.0 months.

O’Regan admitted the effective comparison of the three drugs is difficult. “MONALEESA-7 study was conducted on premenopausal patients to prove the two analytical standards of progression-free survival (PFS) and OS,” she said. “Meanwhile, Verzenio was the only CDK4/6 inhibitor among the three to conduct a clinical trial on patients with brain metastasis combined with elascestrant. Likewise, the three are attempting clinical trials of different characteristics.”

Acknowledging that she cannot refute the point that all CDK4/6 inhibitors are the same, Dr. O’Regan said, “However, we are far short of data. We will need another five years or so to answer many questions on the three inhibitors.”

However, Dr. Patt agreed with Dr. O’Regan, saying, “We still have almost no data.” However, she refuted her colleague, saying, “The real problem is how far we can infer from the data we have.”

According to Patt, the data on the differences in safety and drug fastness among the three is larger than the data on their relative efficacy.

The most common side effects in all three drugs are neutrophil reduction, diarrhea, and dose reduction, but each has a different toxic profile. The neutrophil reduction was a relative rate in Kisqali and Ibrance, and diarrhea was more common in Verzenio. The dose reduction due to abnormal response ranged widely, from 31 percent in the MONALEESA-7 study to 50 percent in the MONALEESA-2 study in the case of Kisqali. Ibrance reported a similarly wide range, from 36 percent in the PALOMA-2 study to 43 percent in the MONARCH-3 study.

Because of the difference in drug tolerance, Verzenio, unlike the other two, can be administered continuously without a pause but should be administered twice daily. Ibrance and Kisqali should be administered once for 21 consecutive days before having a seven-day rest.

“It is important that we have three inhibitors like these,” Dr. Patt said. “There are differences among them, but patients pick one or another depending on their circumstances. If there is no drug for specific patients, we can always replace it with another.”

All major international guidelines, including the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), currently recommend the three CDK4/6 inhibitors of Ibrance, Kisqali, and Verzenio as the preferred treatment of the “Catetory1” grade for HR+/HER2- breast cancer.