No standard treatment has been defined yet for second- or third-line systemic treatment of advanced, recurrent endometrial cancer. The phase 2 NSGO-PALEO/ENGOT-EN3 trial shows that treatment with letrozole and palbociclib provides a clinically meaningful improvement in progression-free survival (PFS) with manageable toxicity, meriting further phase 3 investigation.
Advanced, recurrent endometrial cancer is a dismal prognosis. Carboplatin and paclitaxel is considered to be the first-line systemic treatment of choice. However, no standard treatment had been defined yet for second- line or third-line systemic treatment. Response rates for chemotherapy, TKIs, immune checkpoint inhibitors, and aromatase inhibitors proved to be low. Evidence from several preclinical and phase 1 clinical studies suggest treatment with a CDK4/6 inhibitor could be effective in patients with advanced, metastatic, oestrogen receptor (ER)-positive endometrial cancer.
The NSGO-PALEO/ENGOT-EN3 trial is a (small) randomised phase 2 trial that included 77 patients with primary stage 4 or relapsed ER-positive endometrial cancer who had one or more previous lines of therapy. Prior surgery, radiation therapy, chemotherapy or ≤1 line of endocrine therapy (MPA/megestrol acetate) was permitted. Patients were 1:1 randomised to receive letrozole (2.5 mg) plus placebo or letrozole plus palbociclib (125 mg) until progression. The primary endpoint was PFS. Dr Mansoor Mirza (Rigshospitalet, Copenhagen, Denmark, presented the first results of the trial .
Letrozole plus palbociclib significantly improved PFS compared with letrozole plus placebo: median PFS was 8.3 months versus 3.0 months (HR 0.56, P=0.041). The secondary endpoint, disease control rate at 24 weeks, was also in favour of letrozole plus palbociclib: 64% versus 38%. Treatment-emergent grade 3/4 adverse events were significantly more frequent with letrozole plus palbociclib compared with letrozole plus placebo: neutropenia 42% versus 0%; anaemia 8% versus 3%. Patient-reported outcomes were similar in the 2 treatment arms. Palbociclib was discontinued for adverse events in 25% of the patients on palbociclib and letrozole was discontinued in 19% of the patients on palbociclib versus 11% of the patients on placebo. Based on these results, Dr Mirza concluded that the letrozole plus palbociclib combination demonstrated clinically meaningful improvement in PFS with manageable toxicity, meriting further phase 3 investigation.
- Mirza MR, et al. A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO / ENGOT-EN3 trial. ESMO 202 Virtual, abstract LBA28.