A Signal-seeking Phase Iia Trial of Palbociclib in Advanced Cancers With Cell Cycle Pathway Alterations – A Substudy of the Molecular Screening and Therapeutics (Most) Program

Abstract

\n BACKGROUND: The D-type cyclin and cyclin dependent kinase 4/6 (CDK) complex phosphorylates retinoblastoma protein, thereby driving cell cycle progression. This process is blocked by inhibitors of CDK4/6. As part of the Molecular Screening and Therapeutics program, this phase IIa trial tested the clinical activity of CDK4/6 inhibitor monotherapy in tumors with cell cycle pathway alterations.PATIENTS AND METHODS: Eligible patients ≥ 18 years old, with advanced or metastatic solid cancers, along with amplification of CDK4/6, CCND1/2/3, or loss of function alterations in CDKN2A were recruited. The primary objective of this signal-seeking trial was to evaluate the clinical activity of palbociclib – a composite of objective responses and the ratio of time to progression (TTP) on palbociclib, to TTP on treatment preceding trial entry.RESULTS: Ten patients had CDK4/CDK6 or Cyclin D1 amplifications, six patients had CDKN2A deletions. After a median follow-up of 35 months, there were no objective responses. Seven patients had stable disease and one had non-complete response/non-progressive disease (non-CR/non-PD) based on evaluation of a non-target lesion. Two of these seven patients maintained stable disease for at least 6 months, as did the patient with non-CR/non-PD. Median PFS and OS were 3.5 and 11.0 months respectively. No unexpected toxicities were observed. Translational correlates yielded strategies for targeting cell cycle interactions with other molecular pathways and the immune system.CONCLUSION: Palbociclib monotherapy was not associated with any objective responses, but stable disease lasting at least 6 months was observed in 19% of patients. There was no clear relationship with alteration type or histotype. The signals of immune activation provide insights into the design of future trials, with a combination approach adding checkpoint blockade to CDK4/6 inhibition.