Efficacy and Safety of Sintilimab Plus Anlotinib for PD-L1-Positive Recurrent or Metastatic Cervical Cancer: A Multicenter, Single-Arm, Prospective Phase II Trial

Abstract

Purpose: No combined immunotherapy and antiangiogenic therapy have been investigated in exclusively programmed death-ligand 1 (PD-L1)-positive advanced cervical cancer (CA). We investigated the efficacy and safety of sintilimab plus anlotinib as second-line or later therapy for PD-L1-positive recurrent or metastatic (R/M) CA.

Patients and methods: Patients with PD-L1-positive (Combined Positive Score ≥ 1) R/M CA who progressed after at least one prior systemic chemotherapeutic regimen or could not tolerate chemotherapy were eligible for the phase II trial. The patients received 200 mg sintilimab once on day 1 and 10 mg anlotinib once daily on days 1-14 every 3 weeks. The primary end point was investigator-confirmed objective response rate (ORR) per RECIST v1.1. Secondary end points included progression-free survival (PFS), overall survival, and disease control rate. Biomarkers were explored.

Results: Forty-two patients were enrolled. The ORR was 54.8% (95% CI, 38.7 to 70.2). In 39 efficacy-evaluable patients, the ORR was 59.0% (95% CI, 42.1 to 74.4); the disease control rate was 94.9% (95% CI, 82.7 to 99.4). The median PFS was 9.4 months (95% CI, 8.0 to 14.6). The median overall survival was not reached. Furthermore, 85.8% of the patients experienced treatment-related adverse events. The most frequent treatment-related adverse events were hypothyroidism (33.3%), elevated aspartate aminotransferase levels (21.4%), and hypertension (19.0%). Patients with altered PIK3CA, PI3K-AKT signaling, or KMT2D had a higher ORR, whereas those with altered STK11 and/or JAK2 had a significantly shorter PFS.

Conclusion: Sintilimab plus anlotinib as second-line or later therapy is efficacious and safe for patients with advanced CA who have failed prior chemotherapy.

FIG 1.

Antitumor activity. (A) Duration of responses of patients in the ITT population. The length of each bar represents the duration of treatment of each patient. (B) Best percentage change from baseline in target lesion size. The dashed line at –30% change represents the cutoff for PR or SD per RECIST v1.1. The Kaplan-Meier curves of (C) PFS and (D) OS in the ITT population. (E) The Kaplan-Meier curves of PFS of patients stratified by squamous versus non-SCC of the cervix. CPS, Composite Positive Score; CR, complete response; EOT, end of treatment; ITT, intention-to-treat; non-SCC, nonsquamous cell carcinoma of the cervix; NR, not reached; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; SCC, squamous cell carcinoma of the cervix.

FIG 2.

Boxplots showing the median CPS (A) of PD-L1 in the efficacy-evaluable patients stratified by best response (CR or PR v SD or PD). (B) Treatment response of efficacy-evaluable patients stratified by TMB (high v low). (C) The Kaplan-Meier curves of PFS of efficacy-evaluable patients stratified by TMB (high v low). TMB high was defined as ≥ 7 Muts/Mb, and TMB low was defined as < 7 Muts/Mb. CPS, Composite Positive Score; CR, complete response; HR, hazard ratio; Muts, mutations; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TMB, tumor mutational burden.

FIG 3.

(A) OncoPrint of functional driver mutations in 41 patients with cervical cancer. Genes altered in at least three patients are shown. Rows represent genes, and columns represent samples. Glyphs and color coding are used to summarize distinct genomic alterations including mutations, copy number alterations (amplifications and homozygous deletions), and changes in gene expression, best response, immunotherapy line, age, HPV, TPS and CPS coverage, PFS and PFS status, and TMB. (B) Treatment response of patients with altered versus wild-type PIK3CA (left) or PI3K-AKT (middle). Alteration status of the PI3K-AKT signaling pathway in patients with SCC and non-SCC (right). (C) Treatment response of patients with mutated versus wild-type KMT2D. (D) The Kaplan-Meier curves of PFS of efficacy-evaluable patients stratified by the alteration status of STK11 (left), JAK2 (middle), and STK11 or JAK2 (right). CPS, Composite Positive Score; CR, complete response; HPV, human papilloma virus; Mut, mutant; non-SCC, nonsquamous cell carcinoma of the cervix; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; SCC, squamous cell carcinoma; TMB, tumor mutational burden; TPS, tumor proportion score; WT, wild-type.