Sintilimab Plus Anlotinib Improves Responses, PFS Vs Chemotherapy in Untreated NSCLC

The combination of sintilimab and anlotinib (AL3818) elicited improved responses and progression-free survival (PFS) compared with chemotherapy in previously untreated patients with metastatic non–small cell lung cancer (NSCLC), according to preliminary data from the phase 2 SUNRISE trial (NCT04124731).¹

Findings presented at the 2022 ESMO Congress showed that evaluable patients treated with sintilimab plus anlotinib (n = 40) achieved an investigator-assessed overall response rate (ORR) of 50% (95% CI, 33.8%-66.2%) by RECIST v1.1 criteria compared with 32.6% (95% CI, 19.1%-48.5%) in those given chemotherapy (n = 43). Notably, 1 patient in the experimental arm experienced a complete response compared with none in the control arm; the partial response rates were 47.5% and 32.6%, respectively.

“This new chemotherapy-free combination of sintilimab and anlotinib could be a potential option for future first-line treatment of metastatic NSCLC,” presenting study author Baohui Han, MD, PhD, of the Respiratory Department, at Chest Hospital Affiliated to Shanghai Jiao Tong University in Shanghai, China, and colleagues, wrote in the presentation.

In previously reported data from a phase 1 trial (NCT03628521), sintilimab plus anlotinib generated an ORR of 72.7% and a disease control rate (DCR) of 100% in previously untreated patients with advanced NSCLC.2Additionally, the median PFS was 15.0 months (95% CI, 8.3–not reached); the 18- and 24-month PFS rates were 45.9% and 26.2%, respectively. The estimated 12-month overall survival (OS) rate achieved with the doublet was 95.5%.

SUNRISE was the first randomized trial to compare the combination with chemotherapy in this population. The open-label, multicenter trial enrolled patients aged between 18 and 75 years with metastatic stage IV NSCLC who did not receive prior systemic treatment for metastatic disease. Patients were required to have an ECOG performance status of 0 or 1. Those with EGFR, ALK, and ROS1 mutations were not permitted.

Patients were randomly assigned 1:1 to receive 200 mg of intravenous (IV) sintilimab on day 1 plus 12 mg of oral anlotinib on days 1 to 14 of every 21-day cycle, or platinum-doublet chemotherapy once every 3 weeks for 4 to 6 cycles, plus pemetrexed maintenance.

Treatment continued until progressive disease, intolerable toxicity, patient withdrawal, or death. Patients who experienced progressive disease in the chemotherapy arm were permitted to cross over to receive 200 mg of IV sintilimab once every 3 weeks.

Stratification factors included histology (squamous vs nonsquamous) and PD-L1 expression (at least 1% or less than 1%). ORR served as the trial’s primary end point. Secondary end points consisted of DCR, PFS, OS, and safety.

The median age in the investigative and control arms was 64 years (range, 33-75) and 65 years (range, 45-75), respectively. Most patients were male (83.7% vs 76.1%), had an ECOG performance status of 1 (100.0% vs 95.7%), were current/former smokers (52.4% vs 52.2%), and had nonsquamous histology (53.5% vs 54.3%).

Regarding PD-L1 expression, 62.8% and 65.2% of patients, respectively, had an expression of at least 1%; 37.2% and 34.8% of patients, respectively, had an expression of less than 1%. In the combination arm, 24.0% of patients had brain metastases and 8.0% of patients had liver metastases; in the chemotherapy arm, those rates were 6.7% and 3.3%, respectively.

Additional data showed that the median duration of response was 16.3 months (95% CI, 11.3–not estimable) in the sintilimab/anlotinib arm compared with 6.2 months (95% CI, 1.6-13.2) in the chemotherapy arm. Sintilimab plus anlotinib resulted in a median PFS of 10.8 months (95% CI, 8.02-19.25) vs 5.7 months (95% CI, 3.48-6.93) with chemotherapy (HR, 0.40; 95% CI, 0.25-0.74; P = .002).

Regarding safety, any-grade treatment-related adverse effects (TRAEs) occurred in 74.4% of patients in the sintilimab/anlotinib arm vs 87.0% in the chemotherapy arms. Grade 3 or higher TRAEs were reported in 11.6% and 43.5% of patients, respectively.

Immune-related TRAEs of any grade and grade 3 or higher occurred in 46.5% and 4.7% of patients in the sintilimab/anlotinib group, respectively; those rates in the chemotherapy arm were 4.3% and 0%, respectively. Any-grade serious TRAEs were reported in 14.0% of patients in the sintilimab/anlotinib group, including 7.0% of patients who experienced grade 3 or higher serious TRAEs. In the chemotherapy arm, rates of any-grade and grade 3 or higher serious TRAEs were 19.6% and 15.2%, respectively.

TRAEs led to treatment discontinuation, interruption, or death in 0%, 20.9%, and 0% of patients in the sintilimab/anlotinib, respectively; those rates were 4.3%, 28.3%, and 2.3%, respectively, in the chemotherapy arm.

The most common TRAEs in the sintilimab/anlotinib arm were hypothyroidism, hyponatremia, and increased aspartate aminotransferase. No unexpected TRAEs were observed in either arm.

References

1. Han B, Chu T, Yu Z, et al. Sintilimab plus anlotinib versus platinum-based chemotherapy as first-line therapy in metastatic NSCLC (SUNRISE): an open label, multi-center, randomized, phase 2 study. Ann Oncol. 2022;33(suppl 7):S1423-S1424. doi:10.1016/j.annonc.2022.08.059
2. Chu T, Zhong R, Zhong H, et al. Phase 1b study of sintilimab plus anlotinib as first-line therapy in patients with advanced NSCLC. J Thorac Oncol. 2021;16(4):643-652. doi:10.1016/jtho.2020.11.026