Abstract 677P
Background
Loss of p16 expression is a poor prognostic marker in SCCHN. Palbociclib is a selective inhibitor of CDK4/6 by blocking Rb phosphorylation and has radiosensitizing activity in preclinical studies. Addition of palbociclib to cetuximab and radiotherapy provides a strong rationale to improve efficacy of treatment in locally advanced SCCHN, especially in p16-negative SCCHN.
Methods
This was a phase I study (NCT03024489) designed to determine the maximum tolerated dose (MTD) and toxicity of palbociclib, cetuximab, and IMRT, using a classical 3+3 design. Palbociclib was escalated from 75 to 125 mg/d for 21 day-on and 7 day-off for 2 cycles. Cetuximab was administered at 400 mg/m2 IV on day -7 and then 250 mg/m2 weekly for 7 weeks. IMRT was delivered for a total dose of 70 Gy for 33-35 fractions. MRI and PET scans pre- and post-treatment was used to evaluate preliminary efficacy.
Results
A total of 27 eligible patients were enrolled. Oropharynx (41%) and hypopharynx (30%) were the most common primary site. All patients presented with advance stages (III 37%, IVa 33%, and IVb 30%). In the dose escalation cohort (n=13), a DLT, febrile neutropenia, was observed in 1 of 7 patients who received 125 mg of palbociclib, thus MTD was not achieved. The palbociclib 125 mg was selected for a p16-negative SCCHN expansion cohort (n=14). All patient completed IMRT as planned with median duration of 48 days. Two patients (7%) had IMRT interruption. Table: 677P
| Toxicity (gr 1-2/3-4) and preliminary efficacy | N = 27 (%) |
| Neutropenia | 3 (11) / 3 (11) |
| Anemia | 2 (7) / 3 (11) |
| Thrombocytopenia | 2 (7) / 1 (4) |
| Febrile neutropenia | 0 / 2 (7) |
| Mucositis | 11 (41) / 13 (48) |
| RT dermatitis | 18 (67) / 6 (22) |
| Acneiform rash | 25 (93) / 1 (4) |
| Diarrhea | 7 (26) / 1 (4) |
| Increased AST | 4 (15) / 1 (4) |
| Increased ALT | 4 (15) / 1 (4) |
| Fatigue | 15 (56) / 1 (4) |
| Constipation | 14 (52) / 0 |
| Dry mouth | 7 (26) / 0 |
| Fever | 7 (26) / 0 |
| ORR by RECIST 1.1 (n=24) CR PR SD PD | 23 (96.3) 10 (42) 13 (54) 0 1 (4) |
| Mean percent changes of PET/CT scan (n=23) SUV max MTV TLG | -68% -61% -80% |
| Pattern of recurrence overall locoregional distant | 12 (44) 7 (26) 5 (19) |
| Median survival (months) DFS 2-yr DFS OS 2-yr OS | 28 74% 112 44% |
Conclusions
This is the first prospective study evaluated a CDK 4/6 inhibitor in combination with radiotherapy. The recommended phase 2 dose of palbociclib was 125 mg/d. The combination was well tolerated with promising preliminary efficacy. Molecular biomarkers involving the Rb/CDK4/6 pathways are being explored.
Clinical trial identification
NCT03024489, Jan 2017.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Pfizer.
Disclosure
N. Ngamphaiboon: Financial Interests, Personal, Invited Speaker: Roche, MSD, Novartis, Merck; Financial Interests, Personal, Advisory Board: MSD, Novartis, Bayer, AstraZeneca, Elli Lilly; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Invited Speaker: MSD, Roche, Exelixis, RAPT therapeutics, BeiGene, Boehringer Ingelheim Pharmaceuticals; Non-Financial Interests, Other, Safety Monitoring Committee (SMC): Boehringer Ingelheim Pharmaceuticals. T. Siripoon: Financial Interests, Institutional, Principal Investigator: Roche. All other authors have declared no conflicts of interest.