The landscape of HR+/HER2− breast cancer treatment has witnessed remarkable progress in recent years, particularly with the advent of promising advancements. Endocrine therapy has long been the cornerstone in managing HR+/HER2− metastatic breast cancer, even in cases with visceral involvement, but the emergence of CDK4/6 inhibitors has revolutionized first-line palliative treatment approaches for HR+/HER2− advanced breast cancer.

A standout among these innovations is the novel CDK4 inhibitor PF-07220060, which, when combined with endocrine therapy, has showcased not only a favorable safety profile but also robust response rates in heavily pretreated patients with HR+/HER2− metastatic breast cancer, irrespective of mutation status. 

Furthermore, updated safety data, recently presented at ASCO, shed light on the efficacy of PF-07220060 plus endocrine therapy in patients with HR+/HER2− metastatic breast cancer. The data included extended follow-up information for patients in dose-finding cohorts (Parts 1B-C) and the initial disclosure of data for patients in dose-expansion cohorts (Parts 2B-C). As of the data cutoff on November 1, 2023, 33 patients received PF-07220060 + endocrine therapy in Parts 1B-C, while 34 patients in Part 2B and 36 patients in Part 2C received PF-07220060 alongside letrozole or fulvestrant, respectively. The combination of PF-07220060 and ET was well tolerated among patients with HR+/HER2- mBC, encompassing both post-CDK4/6i and CDK4/6 -naive cohorts.

Safety and Tolerability result

Parts 1B-C cohort (PF-07220060+ letrozole /fulvestrant)

The most common treatment-related treatment-emergent adverse events were neutropenia, diarrhea, and nausea. The most common Grade 3 treatment-related TEAEs were neutropenia, leukopenia, and anemia. No Grade ≥4 treatment-related TEAES occurred, and no febrile neutropenia was observed.

Part 2B cohort (PF-07220060 + letrozole)

The most common treatment-related treatment-emergent adverse events were neutropenia, leukopenia, and anemia. The most common Grade 3 treatment-related TEAEs were neutropenia and gamma-glutamyltransferase increase. No Grade ≥4 treatment-related TEAEs occurred, and no febrile neutropenia was observed.

Part 2C cohort (300 mg BID PF-07220060 + fulvestrant)

The most common treatment-related TEAEs were neutropenia, leukopenia, and anemia. The most common Grade 3 treatment-related TEAEs were neutropenia, leukopenia, and lymphopenia. No Grade ≥4 treatment-related TEAES occurred, and no febrile neutropenia was observed. A Grade 2 treatment-related SAE of chronic gastritis occurred in 1 patient.  No patients discontinued PF-07220060 due to treatment-related TEAES.

KOL insights

“Next generation CDK4-selective inhibitor PF-07220060 shows promising activity and great treatment profile in a heavily pretreated HR+HER2-breast cancer.” –Expert Opinion.

“The using a CDK4/6 inhibitor at any point in the disease course still provides a benefit. As such, it doesn't necessarily have to be a first-line therapy; it could be reserved for second-line treatment, particularly for patients with slow-progressing or low-burden disease.” –Expert Opinion.

Conclusion-

 

In conclusion, the combination of PF-07220060 with endocrine therapy demonstrates promising tolerability and efficacy profiles among patients with HR+/HER2− metastatic breast cancer (mBC), regardless of prior exposure to CDK4/6 inhibitors. With a low incidence of Grade 3 neutropenia and other treatment-emergent adverse events (TEAEs), patients can maintain a high relative dose intensity (RDI) and potentially benefit from continuous target coverage. According to the DelveInsight analysis, the market size of HR+/HER2− Breast Cancer in the United States was USD 7,000 million in 2023. These findings highlight the promising clinical implications of PF-07220060 in addressing the needs of this patient population, potentially contributing to improved outcomes and treatment continuity in HR+/HER2− mBC management.