A window-of-opportunity phase II COLIBRI study demonstrates the acceptability and safety of a double immune checkpoint blockade (ICB) with nivolumab plus ipilimumab in the neoadjuvant setting pre-chemoradiation followed by nivolumab monotherapy as maintenance therapy post-chemoradiation in patients with locally advanced cervical squamous cell carcinoma.
Using multiplex-immunofluorescence (multi-IF) tissue imaging or high-throughput genomic sequencing, expansion of CD8-positive (including proliferative ones), elevated CD8-positive/FOXP3-positive ratio and HOT signature score were significantly increased after neoadjuvant double ICB. Both the CD8-positive/FOXP3-positive ratio defined by multi-IF and the HOT score correlated with response to treatment. These data, combined with ongoing translational research, support further studies with neoadjuvant sequencing strategies to evaluate ICB in this setting. The findings were reported by Prof. Isabelle Ray-Coquard of the Centre Léon Bérard, University Claude Bernard Lyon 1 in Lyon, France at 2023 ASCO Annual Meeting on 3 June in Chicago, IL, US.
Prof. Ray-Coquard explained that locally advanced cervical carcinoma remains an unmet therapeutic need, with more than 40% rate of recurrence despite treatment with the standard of care chemoradiation. Common prognostic factors include FIGO stage, pathological tumour type, lymphovascular space invasion. A high tumour CD8-positive/FOXP3-positive cell ratio is associated with better clinical outcome after neoadjuvant chemotherapy in patients with cervical carcinoma.
ICB provides survival benefit for patients with cervical carcinoma in the recurrent setting. However, durvalumab in combination with and following chemoradiation, did not significantly improved progression-free survival (PFS) in patients with high-risk locally advanced cervical carcinoma compared with chemoradiation alone in CALLA study. Alternative neoadjuvant ICB and differential sequencing of radiation and ICB are worth exploring.
Inclusion criteria for COLIBRI, a study organised by GINECO, were women aged at least 18 years with histologically confirmed cervical (adeno)squamous carcinoma, locally advanced (FIGO 2018) stage IB3-IVA, ECOG performance status of 0 or 1. It is a single arm pilot study.
Primary objective is to measure the CD8-positive/FOXP3-positive lymphocyte ratio in pre- versus post-ICB treatment biopsies in patients treated with neoadjuvant combination of nivolumab plus ipilimumab, before standard chemoradiation. Primary endpoint is CD8-positive/FOXP3-positive Treg cell relative change between pre- and post-ICB biopsies by multi-IF tissue imaging.
Secondary objectives are evolution of the immune microenvironment before and after chemoradiation and at progression multi-IF and high-throughput genomic sequencing, objective response rate by RECIST v1.1 criteria before and after chemoradiation and at end of treatment for local tumour and global response, correlation between clinical activity assessment and biological changes of the immune microenvironment, safety, PFS and overall survival (OS) at 3 years, other exploratory translational research on immune microenvironment and HPV molecular signatures.
HOT signature gene list included CCL19, CCR2, CCR4, CCR5, CD27, CD40LG, CD8A, CXCL10, CXCL11, CXCL13, CXCL9, CXCR6, FASLG, FGL2, GZMA, GZMH, IDO1, IFNG, IRF8, LAG3, LYZ, MS4A1, PDCD1, TBX21, TLR7, TLR8.
Assuming a standard deviation of 14 units, 40 patients were enrolled providing a 95% confidence interval with a precision of 5 units around the mean estimation of the CD8-positive/FOXP3-positive relative change of lymphocytes from pre- to post-treatment biopsies. Depending on the distribution of the ratio, Student paired t-tests or Wilcoxon signed rank tests were used to compare pre- and post-treatment biopsies. Association between multi-IF or high-throughput genomic sequencing data and the tumoural responses was assessed using Wilcoxon Mann-Whitney or Fisher exact tests. p values less than 0.05 were considered to indicate statistical significance in all tests.
Patients received 1 cycle of nivolumab 3 mg/kg on days 1 and 15 plus ipilimumab 1 mg/kg on day 1 before starting chemoradiotherapy plus brachytherapy. After chemoradiotherapy, patients could continue nivolumab in maintenance 480 mg total dose every 28 days for 6 months. In total, 40 patients were treated. There were no new or unexpected side effects. Grade ≥3 side effects related to ICB occurred in 3 patients.
multi-IF data of the 28 evaluable patients revealed an increase of total CD8-positive cells (Wilcoxon, p = 0.009), proliferating CD8-positive cells (p = 0.002) and CD8-positive/FOXP3-positive ratio (p = 0.03) between baseline and before chemoradiation. In the 37 patients evaluable by high-throughput genomic sequencing, a significant increase of expression of the CD8A gene (paired t-test, p = 2.2e-05) and the HOT score (paired t-test, p = 3.1e-06) was observed after ICB.
A rate of complete response at end of treatment was 82.5% (33 of 40 patients) and additionally partial responses were recorded in 4 of 40 patients (40%). Global response was 81% in patients with FIGO I/II and 74% in patients with FIGO III/IV stage. Four patients (10%) had progressive disease at end of maintenance of whom 3 patients with FIGO IIIC. Four patients have no change before/after ICB for CD8-positive infiltrate, CD8-positive/FOXP3-positive ratio, cold HOT score.
The study team expects clinical endpoints of PFS and OS in 2025 and as further perspective to evaluate the neighborhood of CD8-positive and FOXP3-positive immune cells and spatial localisation of TLS, DCs, MPs and PD-L1 expression, to analyze gene expression profiles, to analyze the systemic immune response by characterising the phenotype and activation status of immune cells and anti-HPV T-cell response, to characterise HPV molecular status, integration sites and viral genes deletion to correlate with prognosis and response to ICB and to analyze HPV ctDNA to correlate HPV ctDNA kinetics with treatment response.
The authors concluded that very high rate of complete responses on primary tumour 6 months post-chemoradiation suggests favourable clinical outcomes. These data indicate that neoadjuvant nivolumab plus ipilimumab is safe and orchestrates de novo immune responses in cervical squamous cell carcinoma.
Prof. Catheryn Yashar of the University of California San Diego, who discussed the findings of this study that evaluated neoadjuvant nivolumab plus ipilimumab for one cycle before standard chemoradiation and where the patients can continue nivolumab for 6 months, pointed out that the use of surrogate markers for ICB may be valuable when designing studies. There are many factors to consider when combining immunotherapy with other therapies to design the optimal sequencing.
The study was funded by Bristol-Myers Squibb.
Reference
Ray-Coquard OL, Kaminsky-Forrett M-C, Ohkuma R, et al. In situ immune impact of nivolumab + ipilimumab combination before standard chemoradiation therapy (RTCT) for FIGO IB3-IVA in patients (pts) with cervical squamous carcinoma: COLIBRI trial, a GINECO study. J Clin Oncol 41, 2023 (suppl 16; abstr 5501).