Anlotinib/Sintilimab Combo Confers Long-Term OS Benefit in Advanced Cervical Cancer

The combination of anlotinib (AL3818) and sintilimab (Tyvyt) was found to provide a long-term survival benefit to patients with previously treated advanced cervical cancer, according to data from a phase 2 study (ChiCTR1900023015) presented during the 2022 ASCO Annual Meeting.¹

At a median follow-up of 13.0 months (range, 0.03-24.8), 18 (42.9%) patients experienced overall survival (OS) events. The median OS experienced with the doublet was 17.4 months (95% CI, 12.4–not reached [NR]). Moreover, the 12-month OS rate was 71.8% (95% CI, 59.0%-87.4%), and the 24-month OS rate was 49.1% (95% CI, 34.5%-69.9%).

“Additional investigations in larger randomized controlled trials are warranted in the future,” lead study author Qin Xu, MD, of Fujian Cancer Hospital, and colleagues, wrote in a poster on the data.

Developed in China, anlotinib is a novel oral molecular RTK inhibitor. The agent targets VEGFR1, VEGFR3, VEGFR2/KDR, PDGFR-α, c-Kit, and FGFRs 1–3, and inhibits tumor angiogenesis and tumor cell proliferation. Investigators hypothesize that anlotinib could hit more targets than that other RTK inhibitors, such as pazopanib (Pazopanib), sunitinib (Sutent), and sorafenib (Nexavar).² Sintilimab, an investigational PD-1 inhibitor, was approved in China for the treatment of relapsed/refractory Hodgkin lymphoma.³

Between September 2019 and February 2021, investigators recruited 42 patients who were between the ages of 18 years and 75 years who had recurrent or metastatic cervical cancer. To be eligible for enrollment, patients needed to have received at least 1 prior platinum-based chemotherapy, they needed to have PD-L1 positivity with a combined positive score of at least 1, and an ECOG performance status of 0 or 1. Those who previously received anlotinib or another anti–PD-1/PD-L1 therapy were not permitted.

Study participants received oral anlotinib at a once-daily dose of 10 mg on days 1 to 14 of a 3-week cycle along with intravenous (IV) sintilimab at 200 mg on day 1 of each cycle.

Overall response rate (ORR) served as the primary end point of the trial. Secondary end points included OS, progression-free survival (PFS), disease-control rate (DCR), safety, and biomarker analyses.

The median patient age was 53 years (range, 36-67). At a data cutoff date of February 10, 2022, a total of 39 patients were determined to be evaluable for efficacy.

In the intention-to-treat population (n = 42), the confirmed ORR with the doublet was 54.8% (95% CI, 38.7%-70.2%), which included 3 (7.1%) complete responses (CRs) and 20 (47.6%) partial responses (PRs); 33.3% of patients achieved stable disease, and 4.7% experienced disease progression. The DCR achieved with the combination regimen was 88.1% (95% CI, 74.4%-96.0%).

In patients evaluable for efficacy (n = 39), the ORR experienced with the combination was 59% (95% CI, 42.1%-74.4%), which included a CR rate of 7.7% and a PR rate of 51.3%; 35.9% of patients achieved stable disease, and 5.1% had progressive disease. The DCR with the regimen in the efficacy-evaluable population, was 94.9%.

Moreover, the median PFS was 9.46 months (95% CI, 8.2-11.9) with anlotinib/sintilimab, and the 6-month PFS rate was 73.4% (95% CI, 60.6%-89.0%).

Data published in February 2022 indicated that this combination represented a promising option for patients with recurrent advanced endometrial cancer. From November 2019 to September 2020, investigators recruited 23 women who received at least 1 platinum-based chemotherapy and who had at least 1 measurable lesion per RECIST criteria to a phase 2 trial (ChiCTR1900023015).⁴

Oral anlotinib was administered at 12 mg daily from days 1 to 14 in each 21-day cycle in addition to IV sintilimab, which was administered at 200 mg every 3 weeks. Treatment continued until disease progression, death, or unacceptable toxicity.

The primary end point of the trial was ORR, and secondary end points included duration of response (DOR), DCR, PFS, OS, and safety.

Results from the therapeutic evaluation showed that the incidence of CR, PR, stable disease, and progression disease was 17.4%, 56.5%, 17.4% and 8.7% respectively, which translated to an ORR of 73.9% (95%CI, 51.6%-89.8%) and a DCR of 91.3% (95%CI, 72.0%-98.9%). Additionally, the median PFS with the regimen was 12.8 months (95% Cl, 4.8-NR).

Responses were ongoing in 8 patients of 22 evaluable patients at the time of data cutoff. Notably, the DOR reached 16 months in 1 patient, and the shortest time to response was under 2 months. Compared with baseline measurements, 3 patients on the study had residual lymph nodes smaller than 10 mm following treatment with anlotinib plus sintilimab, 1 patient had immune-related stable disease, and 1 patient experienced progression of non-target lesions.

The median time of the first response was 1.5 months (range, 0.7-12.8), and the median PFS was not reached with the regimen.

References

1. Xu Q, Chen C, Sun Y, et al. Overall survival results from a phase II trial of anlotinib plus sintilimab in patients with recurrent advanced cervical cancer. J Clin Oncol. 2022;40(suppl 16) 5536. doi:10.1200/JCO.2022.40.16_suppl.5536
2. Li S. Anlotinib: A novel targeted drug for bone and soft tissue sarcoma. Front Oncol. 2021;11:664853. doi:10.3389/fonc.2021.664853
3. Deng M. The approval of sintilimab for classical Hodgkin’s lymphoma: views and perspectives of anti-PD-1/PD-L1 antibodies in China. 2019;2(2):54-55. doi:10.1093/abt/tbz005
4. Wei W, Ban F, Huang Y, et al. Anlotinib plus sintilimab in patients with recurrent advanced endometrial cancer: a prospective open-label, single-arm, phase II clinical trial. Ann Oncol. 2021;32(suppl 5):S762. doi: 10.1016/j.annonc.2021.08.1241