Clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials.

3101 Background: The Dutch Drug Rediscovery Protocol (DRUP, NCT02925234) and the Australian Cancer Molecular Screening and Therapeutic (MoST, ACTRN12616000931471) Program are similar non-randomized, multi-drug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic pre-treated cancer patients with tumors harboring Cyclin D-CDK4/6 pathway alterations that were treated with CDK4/6 inhibitors palbociclib or ribociclib as monotherapy. Methods: Eligible adult patients had therapy-refractory solid malignancies with one of the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoints for this combined analysis were clinical benefit, defined as confirmed objective response or stable disease (SD) ≥16 weeks, and safety. Results: Among 139 enrolled patients 33 tumor types were represented, with glioblastoma multiforme (18%), sarcoma (13%), non-small cell lung cancer (9%) and pancreatic cancers (9%) being most common; 116 patients received palbociclib and 23 received ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15% (17 cases of SD ≥16 weeks). Median progression-free survival was 4 months (95% CI 3-5 months) and median overall survival 5 months (95% CI 4-6 months). No unexpected toxicity was observed for either drug. Additional driver alterations were identified in 98% and 77% of patients based on whole genome sequencing (WGS) and sequencing next generation sequencing (NGS) analysis at baseline, respectively (Most common in WGS: TP53 (45%), KRAS (25%), PTEN (15%), SMAD4 (15%). Most common in NGS: TP53 (21%), EGFR (17%), TERT promoter (15%), KRAS (11%). Conclusions: Results show minimal clinical activity of palbociclib and ribociclib monotherapy in patients with pre-treated cancers harboring cyclin D-CDK4/6 pathway alterations. Our findings indicate that single agent use of palbociclib or ribociclib is not recommended. Furthermore, we demonstrate that merging data from similar precision oncology trials is feasible. This finding is especially relevant in the context of precision oncology, with rare molecular subsets and/or cancer histologies. Clinical trial information: NCT02925234 .