Cdk4/6 Inhibitor PD 0332991 Demonstrates Cell Cycle Inhibition Via FLT-PET Imaging and Tissue Analysis in Patients with Recurrent Mantle Cell Lymphoma
Authors: Leonard John P. , LaCasce Ann , Smith Mitchell R , Noy Ariela , Yap Jeffrey T , Van den Abbeele Annick D , Yu Jian Q , Chen-Kiang Selina , Ely Scott A , Vallabhajosula Shankar , Chirieac Lucian R , Larson Steven M , Shapiro Geoffrey I , Schoder Heiko 
Published: April 2020

Abstract
Mantle cell lymphoma (MCL) carries an unfavorable prognosis and requires new treatment strategies. The associated t(11;14) chromosomal translocation results in enhanced cyclin D1 expression and cyclin D-dependent kinase (Cdk) activity to promote cell cycle progression. PD 0332991, a specific, potent Cdk4/6 inhibitor causes G1 arrest in MCL cell lines by blocking Cdk4/6-specific phosphorylation of Rb on serine 807–811 (pSRb). We report a translational evaluation of PD 0332991 in MCL patients. A phase Ib, multicenter trial is exploring safety and pharmacodynamic effects of PD 0332991 via 18F-labeled fluorodeoxyglucose (FDG) and fluorothymidine (FLT) positron emission tomography (PET) imaging and pSRb/cell cycle biomarker analyses pre-treatment and on day 21. The maximum standardized uptake value (SUVmax) was calculated in up to 10 lesions per patient and the summed SUVmax of all lesions calculated for each patient. Enrollment has been completed as planned with 16 patients receiving PD 0332991 125 mg orally once daily, 21 of every 28 days. Mean age was 66 years (range [r], 40–80), 81% were male, 70% had stage IV disease, with a median of 3 prior regimens (r, 1–8). Currently there are 8 patients with stable disease and ongoing treatment up to 40 weeks, while 8 patients have progressed. Correlative studies have been extensively employed to demonstrate proof of mechanism. Of 10 patients evaluable for PET analyses, mean change in SUVmax for FLT-PET and FDG-PET was −54.0% (r, −3.0 to −80.4%) and −23.9% (r, 7.6 to −73.3%), respectively.
Among five pre- and post-treatment biopsy samples analyzed, marked reductions of 52–100% in the percentage of pSRb were noted in day 21 biopsies (p=0.011); in contrast total Rb was maintained or was reduced by a much lesser degree than pSRb (n=5; p=0.109). Additionally, among a total of eight paired samples, six demonstrated reductions in Ki67 staining post-treatment (r, 48–97%, including the five samples with reduced pSRb staining). Two additional paired samples did not demonstrate reduced Ki67 staining post-treatment. Nonetheless, the overall reduction in Ki67 post-treatment among the eight samples reached statistical significance (p=0.036). In 7/8 of cases, the degree of Ki67 reduction post-treatment correlated with the reduction in FLT-PET SUVmax (R2 = 0.62). Principal toxicities that have been observed thus far include grade 3/4 events of neutropenia and grade 3 thrombocytopenia. In patients with MCL, PD 0332991 is well tolerated with manageable toxicities. Collectively these data demonstrate that PD 0332991 inhibits Cdk4/6, leading to reduced cell proliferation (reflected in reductions in FLT-PET SUVmax, Ki 67 status and pSRb/cell cycle biomarker analyses). As Cdk4 and Cdk6 are direct and specific targets of PD 0332991, these data provide proof of mechanism of action of PD 0332991 in patients by using cyclin D1 dependent MCL as a disease model and inform combination treatment approaches.
Research Funding: Supported in part by a grant from the Lymphoma Research Foundation.