Sintilimab/Anlotinib Produces Meaningful Responses in PD-L1+ Recurrent or Metastatic Cervical Cancer

Pipeline Report | <b>Pipeline Report: March 2022</b>

The addition of anlotinib to sintilimab appeared to be efficacious and safe when used as a second- or later-line treatment in patients with PD-L1–positive, recurrent or metastatic cervical cancer.

The addition of anlotinib (AL3818) to sintilimab (Tyvyt) appeared to be efficacious and safe when used as a second- or later-line treatment in patients with PD-L1–positive, recurrent or metastatic cervical cancer, according to data from a prospective phase 2 trial published in the Journal of Clinical Oncology.1

Among 42 patients in the intent-to-treat (ITT) population, the confirmed overall response rate (ORR) was 54.8% (95% CI, 38.7%-70.2%). Two patients (4.8%) experienced a complete response (CR), 50% had a partial response (PR), and 33.3% had stable disease. The median time to response in this population was 1.7 months (95% CI, 1.4-2.8).

Additionally, 39 efficacy-evaluable patients achieved a confirmed ORR of 59.0% (95% CI, 42.1%-74.4%) with this approach, which included a CR rate of 5.1% and a PR rate of 54.8%. Furthermore, 35.9% of patients in this population achieved stable disease.

“To our knowledge, this is the first study to prospectively evaluate the combination of immunotherapy plus antiangiogenic therapy in exclusively PD-L1–positive patients with advanced cervical cancer,” lead study author Qin Xu, MD, of the Departments of Gynecology at Fujian Medical University Cancer Hospital, and colleagues, wrote in the paper. “In our study, sintilimab plus anlotinib as a second-line or later therapy for patients with advanced cervical cancer has exhibited promising efficacy and an acceptable safety profile. Notably, 60% of our patients had 2 or more prior recurrences, suggesting that this drug combination holds promise for heavily pretreated cervical cancer.”

Platinum-based chemotherapy in combination with antiangiogenic therapy remains the preferred frontline treatment approach for patients with recurrent or metastatic cervical cancer.2 However, for those who develop resistance to platinum-based chemotherapy, no standard-of-care regimens are available for use in the second-line or later setting, and prognosis remains poor for these patients with advanced disease.3

Other clinical trials have investigated the use of immunotherapy in patients with recurrent or metastatic cervical cancer, although none have exclusively investigated the approach of immunotherapy plus antiangiogenic therapy specifically in patients with PD-L1–positive disease. To fill this gap, investigators involed in this prospective trial sought to examine sintilimab, a selective anti–PD-1 monoclonal antibody, in combination with anlotinib, a multikinase inhibitor.

The open-label, single-arm trial enrolled adult patients between the ages of 18 years and 75 years with pathologically confirmed PD-L1-positive recurrent or metastatic cervical cancer, defined as a combined positive score of 1 or more. PD-L1 expression was assessed by immunohistochemistry.

Other eligibility criteria included having received at least 1 prior line of systemic therapy or intolerance to chemotherapy, at least 1 measurable lesion per RECIST v1.1 criteria, acceptable organ function, and an ECOG performance status of 0 or 1. Notably, patients who received anlotinib therapy or other anti–PD-1 antibodies targeting PD-1 or PD-L1 were excluded.

Study participants received 200 mg of intravenous (IV) sintilimab on day 1 every 3 weeks, plus 10 mg of oral anlotinib given once daily on days 1 through 14 per cycle. Treatment continued until disease progression, intolerance, death, withdrawal, or start of a new antitumor therapy. Dose modification of sintilimab was not permitted. Notably, patient who experienced intolerable adverse effects (AEs) that caused delay or discontinuation of 1 drug were allowed to continue treatment on the other.

The primary end point of the study was ORR, which was defined by the percentage of investigator-confirmed CRs or PRs. Key secondary end points included progression-free survival (PFS), overall survival (OS), and disease control rate (DCR).

Among all patients in the ITT population, the median age was 53 years (range, 36-67). Moreover, 2.4% of patients had FIGO stage IA disease at diagnosis, 11.9% had IB, 11.9% had IIA, 21.4% had IIB, 16.7% had IIIB, 14.3% had IIIC, 9.5% had IVB, and in 11.9% of patients, this was unknown. The median time from initial diagnosis to enrollment was 13.3 months (range, 3.6-170.5). Additionally, most patients had an ECOG performance status of 1 (85.7%) and presented with squamous cell carcinoma (SCC; 83.3%); 11.9% of patients presented with adenocarcinoma and 4.8% had adenosquamous carcinoma.

Local recurrence alone occurred in 21.4% of patients, and 16.7% of patients had local recurrence and distant metastases. The median target lesion size was 49 mm (range, 15-217). Among patients who received prior radiotherapy (92.9%), 42.9% received adjuvant radiotherapy, 38.1% underwent curative radiotherapy, and 11.9% had received palliative radiotherapy. Most (61.5%) of those patients were administered radiotherapy within 12 months of trial enrollment.

Regarding prior lines of therapy, 40.4% had received 1 prior line, 38.1% received 2 lines, and 21.4% had received 3 or more. All patients were administered prior platinum-based chemotherapy. Most (66.7%) patients had a low tumor mutational burden (TMB) of less than 7 mutations per megabase; 23.8% of patients had high TMB and 7.1% had no somatic mutation.

In the ITT population, the DCR with the combination was 88.1% (95% CI, 74.4%-96.0%). The efficacy-evaluable patients experienced a DCR of 94.9% (95% CI, 82.7%-99.4%). Additionally, 82.1% of patients experienced a reduction in lesion size from baseline.

At data cutoff, half of all enrolled patients experienced disease progression or death. The median PFS was 9.4 months (95% CI, 8.0-14.6) with this approach, and the 6-month PFS rate was 73.1% (95% CI, 60.1%-88.9%). The median OS was not yet reached (NR; 95% CI, 12.3-NR). Moreover, the estimated 12-month OS rate was 73.8% (95% CI, 59.3%-91.7%).

Notably, among efficacy-evaluable patients, those with SCC experienced a significantly higher ORR with the combination vs non-SCC patients, at 69.7% and 0%, respectively (P = .003); these patients also experienced a longer median PFS, at 11.1 months (95% CI, 8.2-NR) and 5.8 months (95% CI, 2.8-NR), respectively (P = .01).

Regarding safety, 85.8% of patients experienced at least 1 treatment-related AE (TRAE). The most common TRAEs reported with the combination included hypothyroidism (33.3%), elevated aspartate aminotransferase (21.4%), and hypertension (19.0%). Additionally, 16.7% experienced grade 3 or higher TRAEs, which included fistula (7.1%). Notably, no treatment-related deaths occurred.

Furthermore, 7.1% of patients discontinued treatment; 7.1% of discontinued anlotinib alone because due to TRAEs. Dose reduction of anlotinib due to TRAEs were required by 26.2% of patients.

N-generation sequencing revealed 31.7% of patients presented with a PIK3CA mutation, making it the most frequently altered gene. FAT1 alterations occurred in 22.0% of patients, and PRKDC (19.5%), KMT2D(17.1%), and ATR (14.6%) mutations were also observed.

“Our comprehensive genomic profiling to interrogate CA gene mutational landscape will help to provide a framework in future studies involving multiple biomarkers for molecularly stratified therapy of advanced cervical cancer,” study authors wrote. “Additional investigations in larger randomized controlled trials are warranted.”


  1. Xu Q, Wang J, Sun Y, et al. Efficacy and safety of sintilimab plus anlotinib for PD-L1–positive recurrent or metastatic cervical cancer: a multicenter, single-arm, prospective phase II trial. J Clin Oncol. Published online February 22, 2022. doi:10.1200/JCO.21.02091
  2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Cervical Cancer. Version 1.2021.
  3. Borcoman E, Le Tourneau C. Keynote-158 study, FDA granted accelerated approval of pembrolizumab for the treatment of patients with advanced PD-L1–positive cervical cancer Ann Transl Med. 2020;8(23):1611. doi:10.21037/atm-20-2656