Pauline Corbaux

KELIM score predicts outcome in patients with platinum-resistant/refractory recurrent ovarian cancer

Intraperitoneal Nivolumab after Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy in Advanced Ovarian Cancer: A Phase I Study with Expansion Cohort

Abstract Purpose: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are expected to be synergistic with intraperitoneal (IP) immunotherapy by increasing tumor antigen expression and mutational load. We assessed the feasibility and safety of IP nivolumab following complete CRS and HIPEC in pretreated patients with recurrent ovarian cancer (ClinicalTrials.gov identifier: NCT03959761). Patients and Methods: Patients received IP nivolumab (0.5, 1, or 3 mg/kg) using a 3 + 3 dose-escalation design, starting 5 to 7 days after CRS and HIPEC. Four IP Q2W (once every 2 weeks) nivolumab infusions were planned. The primary objective was to demonstrate the feasibility of IP nivolumab based on dose-limiting toxicity. Secondary objectives were to assess changes in tolerance of CRS and HIPEC. Results: A total of 17 patients were enrolled including 10 patients in the dose escalation and 7 patients in the expansion phase. No dose-limiting toxicity was observed at any dose level in the 9 evaluable patients. Six of the 17 patients (35%) did not complete all planned infusions: 4 (23.5%) due to peritoneal catheter complications and 2 (11.8%) due to early progression. No procedure-related deaths occurred. Eleven patients (65%) experienced serious adverse events (SAE), mainly transitory grade 3 to 4 transaminase elevations (6/11) and surgery-related (9/11). Four SAEs were related to the peritoneal catheter and two to HIPEC. No SAEs/grade 3 to 4 adverse events related to IP nivolumab occurred. Conclusions: This is the first study demonstrating the feasibility of IP nivolumab in patients with relapsed advanced ovarian cancer. Further investigation at 3 mg/kg is warranted.

Survival and modelled cancer antigen-125 ELIMination rate constant K score in ovarian cancer patients in first-line before poly(ADP-ribose) polymerase inhibitor era: A Gynaecologic Cancer Intergroup meta-analysis

In patients with advanced ovarian cancer, the modelled CA-125 ELIMination rate constant K (KELIM) is an early indicator of the tumour intrinsic chemosensitivity. We assessed the prognostic and surrogate values of KELIM with respect to those of surgery outcome (based on post-operative residual lesions) in the Gynaecologic Cancer Intergroup (GCIG) individual patient data meta-analysis MAOV (Meta-Analysis in OVarian cancer) built before the emergence of poly(ADP-ribose) polymerase (PARP) inhibitors. The dataset was split into learning and validation cohorts (ratio 1:2). The individual modelled KELIM values were estimated, standardised by the median value, then scored as unfavourable (<1.0) or favourable (≥1.0). Overall survival (OS) and progression-free survival (PFS) analyses were performed with a two-step meta-analytic approach and surrogacy through a two-level meta-analytic model. KELIM was assessed in 5884 patients from eight first-line trials (learning, 1962; validation, 3922). A favourable KELIM score was significantly associated with longer OS (validation set, median, 78.8 versus 28.4 months, hazard-ratios [HR] 0.46, 95% confidence interval [CI], 0.41-0.50, C-index 0.68), and longer PFS (validation set, median 30.5 versus 9.8 months, HR 0.49, 95% CI, 0.45-0.54, C-index 0.68), as were International Federation of Gynaecology and Obstetrics (FIGO) stage and debulking surgery outcome. Three prognostic groups were identified based on the surgery outcome and KELIM score, with large differences in OS (105.1, ∼45.0, and 22.1 months) and PFS (58.1, ∼15.0, and 8.0 months). Surrogacy for OS and for PFS was not established. KELIM is an independent prognostic biomarker for survival, complementary to surgery outcome, representing a new determinant of first-line treatment success.

Identifying high-risk relapse in early-stage I to II ovarian cancer using the CA125 ELIMination rate constant K (KELIM) score: a Gynecologic Cancer InterGroup individual patient-data meta-analysis

Despite curative surgery and adjuvant chemotherapy, a significant number of early stage I to II ovarian cancers relapse. The CA125 ELIMination rate constant K (KELIM) is a pragmatic indicator of tumor intrinsic chemosensitivity in advanced epithelial ovarian cancer. We assessed the prognostic value of KELIM in patients with early-stage ovarian cancer, with respect to 5-year recurrence-free survival and overall survival, using the Meta-Analysis in Ovarian Cancer, which is the Gynecologic Cancer InterGroup individual patient-data meta-analysis of randomized trials evaluating different adjuvant chemotherapy regimens. Individual patient KELIM values were previously estimated in 5884 patients from the Meta-Analysis in Ovarian Cancer. The prognostic value of KELIM was assessed using univariable & multivariable analyses in patients with resected International Federation of Gynecology and Obstetrics stage I and II disease. Overall, 1143 patients were identified, including clear cell (46.7%); serous (23.7%); endometrioid (12.4%); and mucinous carcinomas (3.9%). In multivariable analyses, a favorable KELIM score (≥1.0) was associated with higher 5-year recurrence-free survival (68.3% vs 55.9%; HR 0.61, 95% CI 0.48 to 0.77) and 5-year overall survival (80.7% vs 72.8%; HR 0.50, 95% CI 0.36 to 0.68), as was the histological sub-type. In exploratory analyses, KELIM score was a prognostic factor regarding 5-year recurrence-free survival and overall survival across all sub-types (especially clear cell carcinoma and serous, with HR ranging from 0.45 to 0.63) with baseline CA125 ≥15 IU/L, except for mucinous histology. The pragmatic KELIM score is an independent prognostic factor in patients with a non-mucinous stage I to II ovarian cancer optimally resected and treated with adjuvant chemotherapy. KELIM may help identify the patients at higher risk of relapse and death requiring closer follow-up or treatment intensification.

Tolerance of Intraperitoneal (IP) Nivolumab After Extensive Debulking Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Patients With Advanced Ovarian Carcinoma

Spread pattern, the lack of alternative treatments, and emerging data on the activity of anti-Programmed death ligand 1 (PDL1) targeted checkpoint inhibitor therapy in gynecological cancers provide the rationale for this investigation. Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) are likely to increase the tumor-antigen expression and the mutational load. As a result, it would be interesting to combine this approach with immunotherapy. Moreover, Intraperitoneal (IP) infusion will directly target the peritoneal cavity and potentially enhance the immune response. Indeed some recent papers indicate that the peritoneum could be considered as a lymphoid organ, involving "milky spots", thus able to produce a better immune response when immunotherapy is given by IP route rather than intravenous (IV) route. The investigating team in Lyon, France is one of the major groups for HIPEC research in Europe (Pr O. Glehen et al) - Reference center for the tumors of the peritoneum (French National Cancer Institute). The aim of this study is to assess in this I/II phase study, the feasibility of extensive debulking surgery and HIPEC followed by Intraperitoneal (IP) nivolumab dose escalation in patients with advanced ovarian carcinoma.