Background: Preclinical data demonstrate synergy between CDK4/6 inhibition and PD-L1 blockade, enhancing immune response and tumour control. This study evaluated palbociclib priming followed by the addition of avelumab in advanced solid tumours with cell cycle pathway alterations.
Methods: This single-arm phase 2 trial (ACTRN12620000568910) enrolled patients(pts) (≥18 years) with advanced cancers, ECOG 0—2. Molecular eligibility required either a CDK4/CCND1—3 gain-of-function (GoF) or CDKN2A loss-of-function (LoF)mutation. Pts received palbociclib (125 mg PO, 21/28-day cycle) alone for the first cycle, followed by palbociclib and avelumab (10 mg/kg IV q2w) until progression or unacceptable toxicity. A tumour biopsy was performed after cycle 1. The primary endpoint was 6-month PFS (PFS6) on combination therapy. Secondary endpoints included overall PFS, OS, objective tumour response (OTR), time to progression ratio TTPr (TTP2:TTP1), safety and QoL). TTPr >1.3 indicated clinical benefit. Correlative
analyses evaluated immune activation.
Results: A total of 64 pts were enrolled between March 2021 and September 2022 (32 in each of the GoF and LoF cohorts). In the GoF cohort the most common cancers were sarcomas (n=18), while pancreas cancers predominated in the LoF cohort (n=10). No confirmed OTR were observed. PFS6 was 40% (11/26; 95% CI: 0.23 to
0.57) in GoF cohort, including pts with liposarcoma (n=5), and one of each myofibroblastic, ovarian, uterine, small intestine, lung, and liver cancers. In the LoF cohort, PFS6 was 16% (4/24; 95% CI: 0.05 to 0.33), including pts with chordoma, leiomyo sarcoma, GIST, and acinar cell carcinoma. A rTTP >1.3 was observed in 50% (15/30) of GoF and 23%(6/26) of the LoF pts. Median OS was 12.7 mo for GoF and 5.6 mo for the LoF cohort. No new safety signals were identified. Correlative studies revealed immune activation markers in both blood and in tumour following cycle 1 which
were associated with clinical benefit.
Conclusions: While no objective responses were observed, the GoF cohort showed a favourable TTPr and PFS6 in rare cancers. These results support continued investigation of CDK4/6 and PD-L1 blockade in genomically selected patients.