Clinico-molecular predictors of exceptional response to immune checkpoint inhibitors (ICI) in metastatic cervical cancer (mCC).

5539 Background: Metastatic cervical cancer (mCC) constitutes a global health challenge, despite preventive efforts like HPV vaccination, with imputable 342,000 deaths in 2020. Immunotherapies with Immune checkpoint inhibitors (ICI) have been assessed in the context of recurrent or mCC. Only 15% of patients with PDL1+ mCC respond to ICI, however responses can be prolonged. We aimed to describe outcomes for long-term responders (LTR) versus non long-term responders (NLTR) to ICI, and identify clinico-molecular predictors for LTR. Methods: We conducted a retrospective review of all patients with mCC treated with an ICI at Institut Gustave Roussy (IGR). Patients were classified as LTR if they had a complete response (CR) / partial response (PR) / stable disease (SD) maintained for ≥12 months (mo) and as NLTR if progressed <12mo after ICI initiation. Cox regression analysis was performed to identify factors significantly associated with LTR (vs NLTR) and expressed as an odds ratio (OR). For a subset (43/106 patients), genomic analyses were performed using large panel next generation sequencing done at IGR within specific trials: STARTRK (NCT02097810) and STING (NCT04932525) on a tumor sample. Results: Between 01/2015 and 09/2023, 106 patients with mCC were treated with an ICI at the IGR. 20 patients (19%) were classified as LTR and 86 as NLTR (81%). 93% of patients received ICI without chemotherapy (2 LTR and 6 NLTR). After a median follow-up of 42mo, median PFS was not-reached in LTR versus 3.5mo for NLTR. Among the 20 LTR, 11 pts were in sustained complete response with a median of 22mo (range 2-55mo) since ICI discontinuation. Neither body mass index, performance status, LDH, neutrophil/lymphocyte ratio nor number of prior lines were predictive of LTR vs NLTR. A multivariate regression analysis identified 3 clinical factors significantly associated with LTR: oligo-metastatic (OR=11.4; p 0.006), lymph node metastases only (OR=8.2; p 0.02) and progression outside of irradiated fields (OR=5.9; p 0.03). With regards to molecular features, neither TMB nor MMR status were predictive, however PIK3CA mutations were significantly more frequent in LTR, found in 90% (vs 27% of NLTR) and PBMR1 mutations found exclusively in LTR, while NLTR presented with higher rates of STK11 alterations. Conclusions: Although responses to ICI in mCC remain rare (<20% patients), they are associated with impressive outcomes (median PFS>3.5 years) with a significant proportion disease-free months to years after ICI discontinuation suggesting some may be cured. Certain clinico-molecular features are strongly associated with LTR and may allow the selection of patients for ICI.