Sitravatinib Plus Tislelizumab Elicits Antitumor Activity in PD-L1+ Advanced NSCLC

Sitravatinib plus tislelizumab showed a confirmed investigator-assessed overall response rate of 30.4% in PD-L1–positive, treatment-naïve, locally advanced or metastatic squamous non–small cell lung cancer.

The combination of sitravatinib (MGCD516) and tislelizumab (BGB-A317) showed a confirmed investigator-assessed overall response rate (ORR) of 30.4% (95% CI, 13.2%-52.9%) in patients with PD-L1–positive, treatment-naïve, locally advanced or metastatic squamous non–small cell lung cancer (NSCLC), according to findings from the phase 1b SAFFRON-103 trial (NCT03666143).1

Seven of 23 patients evaluable for response had partial responses. The disease-control rate (DCR) was 78.3% (95% CI, 56.3%-92.5%). The median progression-free survival (PFS) was 5.4 months (95% CI, 2.8-8.6) and the median overall survival (OS) was not reached (NR; 95% CI, 6.7–not evaluable [NE]).

Jun Zhao, MD, with Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China, presented the findings at the 2022 World Conference on Lung Cancer.

“We found that sitravatinib in combination with tislelizumab had a manageable safety and tolerability profile in patients with PD-L1 expression­–positive, locally advanced or metastatic squamous NSCLC,” he said. “Our results also indicate promising antitumor activity with this combination treatment.”

Zhao added that investigators are currently evaluating the combination vs docetaxel for patients with advanced NSCLC who progressed on chemotherapy and an anti–PD-L1/PD-1 antibody in an ongoing phase 3 trial (NCT04921358).

Sitravatinib is a selective TKI that may have a role in reducing the number of myeloid-derived suppressor cells and regulatory T cells, promoting the expansion of antitumor cytotoxic T cells, and increasing the ratio of M1/M2 polarized macrophages. Tislelizumab is

an anti–PD-1 monoclonal antibody designed to minimize binding to FcγR on macrophages. In previous study results, tislelizumab has shown clinical activity in patients with advanced solid tumors including, squamous NSCLC.

Patients received 120 mg once daily sitravatinib daily plus 200 mg intravenous tislelizumab 200 mg every 3 weeks until unacceptable toxicity, withdrawal, or death. The primary end point

was safety/tolerability. Secondary and exploratory end points included ORR, DCR, PFS, OS, and the association between PD-L1 expression and clinical benefit.

Chinese investigators recruited 24 patients into the open-label, nonrandomized study from May 12, 2020, to February 10, 2021. Median patient age was 65 years (range, 56-71) and 22 (91.7%) patients were male. The median follow-up was 9.5 months at the November 8, 2021, data cutoff.

Twenty-one (87.5%) patients had metastatic disease and 4 (16.7%) had received prior anticancer drug therapy. Six (25.0%) patients had an ECOG performance score (PS) of 0; 18 (75.0%) had an ECOG PS of 1. Three (12.5%) patients were never smokers, 5 (20.8%) were current smokers, and 16 (66.7%) were former smokers.

In patients with a PD-L1 tumor cell positivity score of 1%-49% (n = 12), ORR was 33.3% (95% CI, 9.9%-65.1%), median PFS was 5.4 months (95% CI, 1.5-9.7) and median OS was NR (95% CI, 7.4-NE). Among those with a cell positivity score of 50% or greater (n = 11), the ORR was 27.3% (95% CI, 6.0%-61.0%), the median PFS was 4.2 months (95% CI, 0.7-NE) and the median OS was NR (95% CI, 1.1-NE).

“There were no obvious trends between tumor cell PD-L1 expression level and ORR, PFS, or OS,” Zhao said.

All 24 patients were included in the safety subset. Twenty-three (95.8%) patients experienced any-grade treatment-emergent adverse events (TEAEs) while 22 (91.7%) experienced any-grade treatment-related adverse events (TRAEs).

Investigators observed grade 3 or higher TEAEs in 66.7% of patients and serious grade 3 or higher TEAEs in 29.2%. Grade 3 or higher TRAEs occurred in 62.5% of patients while 16.7% experienced grade 3 or higher serious TRAEs.

Two (8.3%) patients experienced TEAEs leading to death.

Nine (37.5%) patients had TEAEs leading to sitravatinib discontinuation and 7 (29.2%) had TRAEs leading to sitravatinib discontinuation. Seventeen (70.8%) patients had TEAEs leading to sitravatinib dose modification and 16 (66.7%) had TRAEs requiring dose modification.

Five (20.8%) patients had TEAEs leading to tislelizumab discontinuation and 3 (12.5%) had TRAEs leading to discontinuation. Ten patients (41.7%) had TEAEs leading to sitravatinib dose modification and 10 had TRAEs requiring dose modification.

The most common TEAEs included increased aspartate aminotransferase (54.2%), followed by increased alanine aminotransferase (45.8%) and hypoalbuminemia (45.8%).

In findings presented at the 2021 AACR Annual Meeting, the sitravatinib/tislelizumab combination induced an ORR of 26% (95% CI, 15.3%-40.3%). The median duration of response was 4.7 months (95% CI, 2.83-NE) with a DCR of 77% (95% CI, 63.8%-87.7%).2

Per investigator assessment, the median PFS was 4.1 months (95% CI, 4.0-22.8) at a median follow-up of 6.9 months. The median OS was 12.9 months (95% CI, 6.2-17.0) at a median follow-up of 7.5 months.

References
1. Zhao J, Cui J, Huang D, et al. Safety and efficacy of sitravatinib + tislelizumab in patients with PD-L1+, locally advanced/metastatic, squamous NSCLC. Presented at 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract WS08.15
2. Coward J, Gao B, de Silva IP, et al. Safety/tolerability and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with advanced platinum-resistant ovarian cancer (PROC). Presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT013