Introduction/Background*Pembrolizumab conferred a 57% objective response rate (ORR) in patients with mismatch repair deficient (MMRd) advanced endometrial cancer (EC). However, the majority of patients with advanced disease have no specific molecular profile (NSMP) tumours or p53-abnormal (p53abn). We hypothesized that pembrolizumab with an inducer of immunogenic cell death such as doxorubicin could improve clinical responses and survival in all EC molecular subtypes.
Methodology The TOPIC study (NCT03276013) was an investigator-initiated, single-arm, multi-centre, phase II study in patients with recurrent/metastatic EC who received one prior line of platinum-based chemotherapy. Patients received doxorubicin 60 mg/m2 IV every 3 weeks for up to 9 cycles in combination with pembrolizumab 200 mg IV every 3 weeks up to 36 cycles, or until progression or toxicity. Tumour samples were analysed before treatment. Immunohistochemistry was performed for mismatch repair proteins and p53. Single-gene sequencing was used to detect polymerase-ɛ (POLE) exonuclease domain mutations. Primary outcome was progression-free survival rate at 6 months (PFS6). Subgroups were assessed relative to the primary outcome, ORR, median overall survival (OS), and 18-months OS rate.
Result(s)*Molecular classification could be determined in 44 out of 48 patients included. As defined in the protocol, carcinosarcoma patients (n=6) were considered an exploratory cohort and were excluded from this analysis. In the non-carcinosarcoma cohort (n=38) median age was 66 years (range 37–80). Five (11.4%) patients were MMRd, 10 (22.7%) NSMP and 23 (52.3%) p53abn. No patient with POLE-mutated tumour was enrolled. Fifty-eight patients had endometroid EC, 42% serous carcinoma. Histologic grade at diagnosis: grade 1, 12.2%; grade 2, 21.1% and grade 3, 44.6%. Median follow-up at data cut-off was 19.1 months. Overall PFS6 was 59.3% (95%CI 45.4%-77.6%) with a median PFS of 6.5 months. Efficacy data according to patients’ molecular subtype are shown (see table 1). Overall, the NSMP subtype showed the better efficacy results (PFS6 of 78% and 40% ORR).
Conclusion*Pembrolizumab plus doxorubicin exhibited promising antitumor activity in women with advanced EC after failure to platinum therapy, even in those patients that were not MMRd.
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