Following Prior Immunotherapy Resistance in Advanced PD-L1+ NSCLC Rilvegostomig Shows Promise

Rilvegostomig (AZD2936), a novel PD-1 and TIGIT bispecific, showed early signs of tolerability and efficacy in patients with advanced or metastatic PD-L1–positive non–small cell lung cancer (NSCLC) following progression on at least 1 prior checkpoint inhibitor (CPI), according to new data from the phase 1/2 ARTEMIDE-01 trial (NCT04995523).

The overall response rate (ORR) with 750-mg rilvegostomig was 4.0% (95% CI, 0.5%-13.7%), which consisted entirely of partial responses (PRs). Additionally, 44.0% of patients had stable disease. At weeks 9 and 27 the disease control rates (DCR) were 48.0% and 12.0%, respectively. Rilvegostomig was well tolerated, with no dose-limiting toxicity observed and no grade 4 or 5 treatment-related adverse events (TRAEs).

Kristoffer Staal Rohrberg, MD, PhD

“The first-in-human ARTEMIDE-01 study provides promising preliminary evidence on the safety and potential efficacy of rilvegostomig, a bispecific antibody targeting PD-1 and TIGIT. Demonstrating a manageable safety profile and signs of antitumor activity in patients with advanced/metastatic NSCLC, who had previously undergone standard therapy including checkpoint inhibitors, this dual immunotherapy approach may offer a new avenue for enhancing T-cell activity and combating immunosuppression in cancer treatment,” lead investigator Kristoffer Staal Rohrberg, MD, PhD, from Rigshospitalet, University Hospital of Copenhagen, in Denmark, in a presentation of these data at the 2023 ASCO Annual Meeting.

The initial portion of the ARTEMIDE-01 study escalated the dose of rilvegostomig to find a recommended phase 2 dose (RP2D) of the agent. In this part of the study (Part A), the dose began at 70 mg (n = 4) and was escalated to 210 mg (n = 11), 750 mg (n = 22) and 1500 mg (n = 11). The RP2D dose was identified as 750 mg, which was then moved into an expansion cohort (Part B) and enrolled 32 patients. Treatment was administered every 3 weeks in both parts. Overall, across both parts, 54 patients received rilvegostomig at 750 mg. Additional expansion cohorts in earlier settings are ongoing.

In part A, the median age of patients was 65.0 years (range, 39-83), 56.3% were male, and race was primarily White (56.3%) and Asian (39.6%). The primary histology was adenocarcinoma (66.7%) and squamous (27.1%). PD-L1 expression, by tumor proportion score, was between 1% and 49% for 52.1% of patients and was 50% or more for 47.9% of patients. Most patients were current (10.4%) or former (70.8%) smokers and either had primary (37.5%) or secondary (62.5%) resistance to prior CPI.

In part B of the study, which explored the agent at the RP2D, the median age was 63.0 years (range, 41-85), and most were male (71.9%). Races consisted of White (62.5%) and Asian (37.5%). The ECOG performance score was 0 (18.8%) and 1 (81.3%) and most patients had stage IV disease (96.9%).

The histology was adenocarcinoma for 81.3% of patients and squamous for the remainder. PD-L1 expression was evenly split (50:50) between 1% to 49% and 50% or more. Most patients were current (21.9%) or former (56.3%) smokers; however, 21.9% were never smokers. Most were secondarily resistant to a CPI (62.5%). Prior CPIs included atezolizumab (Tecentriq; 10.0%), durvalumab (Imfinzi; 20.0%), nivolumab (Opdivo; 6.3%), and pembrolizumab (Keytruda; 65.0%).

Responses were observed across all dose levels. In Part A, the ORR was 4.5% (95% CI, 0.6%-15.5%). In part B, the ORR was 3.1% (95% CI, 0.1%-16.2%). All responses were PRs. Stable disease was seen for 40.9% of patients in part A and for 37.5% in part B. At week 27, the DCR was 22.7% for patients in part A and 3.1% for those in part B. At week 9, these rates were 45.5% and 40.6%, respectively. Across all dose levels, the ORR was 3.9% (95% CI, 0.8%-11.1%), which consisted entirely of PRs. The rate of stable disease was 39.5%, and the DCR was 43.4% at week 9 and 14.5% at week 27.

There was no observed dose-limiting toxicities observed and the maximum-tolerated dose was not reached. The 750-mg dose was selected based on modeling analysis and intratumoral receptor occupancy. In flow cytology analyses, doses of rilvegostomig of 210 mg or greater were found to sustain roughly 90% occupancy of PD-1 and TIGIT receptors on peripheral T cells.

Across the study, treatment was discontinued by 3.8% of patients due to an adverse event (AE), of which 2 were considered related to rilvegostomig. These TRAEs consisted of a grade 1 case of myocarditis and grade 3 acute hepatitis. Treatment-emergent AEs (TEAEs) were experienced by 87.0% of patients treated with the 750-mg dose and in 87.5% across all doses administered. TRAEs were experienced by 51.9% of those receiving 750 mg and in 46.3% of those across all doses. A grade 3 or greater TEAE was experienced by 24.1% of those receiving rilvegostomig at 750 mg and in 27.5% across all doses. Grade 3 TRAEs were seen in 7.4% of patients in the 750-mg arm and in 5.0% across all doses.

The most common grade 3 or greater TEAEs were dyspnea (3.8%), anemia (2.5%), hypercalcemia (2.5%), pleural effusion (2.5%), pneumonia (2.5%), and respiratory failure (2.5%). The most common TRAEs at the 750-mg dose were rash, lipase increases, pyrexia, infusion-related reactions, and fatigue, all of which occurred at a frequency of less than 10% each. Serious AEs were seen in 24.1% of patients in the 750-mg dose group and in 25.0% across doses, with these considered to be treatment related for 5.6% and 3.8% of patients, respectively. There were 4 deaths related to serious AEs, with none considered related to rilvegostomig.

“While the results are preliminary, the absence of dose-limiting toxicities and the disease control rate observed at 27 weeks are encouraging,” Rohrberg said. “Evaluation in checkpoint inhibitor–naïve NSCLC patients is ongoing and will further inform on the potential of rilvegostomig as a treatment for advanced NSCLC.”

The ARTEMIDE-01 study continues to enroll participants (NCT04995523). Additionally, AstraZeneca, the developer of rilvegostomig, has announced plans to initiate a phase 3 study to further explore the agent. Rilvegostomig is also being explored in various combinations for gastric cancer (NCT05702229) and in other lung cancer settings (NCT04612751).

^Reference

^{Rohrberg KS, Brandão M, Alvarez EC, et al. Safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of AZD2936, a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-experienced advanced/metastatic non-small-cell lung cancer (NSCLC): First report of ARTEMIDE-01. J Clin Oncol. 2023;41 (suppl 16):9050. doi:10.1200/JCO.2023.41.16_suppl.9050}