Rilvegostomig Elicits Responses in CPI-Naive NSCLC, Irrespective of PD-L1 TPS Status

Jeroen Hiltermann, MD, PhD

Single-agent rilvegostomig elicited durable responses and showcased favorable tolerability in patients with metastatic non­–small cell lung cancer (NSCLC) without prior exposure to checkpoint inhibitors (CPIs), according to data from the phase 1/2 ARTEMIDE-01 study (NCT04995523) presented during the 2024 IASLC World Conference on Lung Cancer.¹

When the agent was given at a dose of 750 mg every 3 weeks in those with a PD-L1 tumor proportion score (TPS) of 1% to 49% (n = 31), it induced an overall response rate (ORR) of 29% (95% CI, 14.2%-48.0%) with 38.7% continuing treatment at the time of data cutoff. The median duration of response (DOR) was 6.4 months (95% CI, 4.2-not calculable [NC]); of the 9 confirmed responders, 5 were still in response at the time of data cutoff. The median progression-free survival (PFS) was 6.0 months (95% CI, 2.7-8.4).

Those with a PD-L1 TPS of 50% or higher who received the drug at 750 mg every 3 weeks (n = 34) experienced an ORR of 61.8% (95% CI, 43.6%-77.8%) with 70.6% still on treatment at cutoff. Although the data are immature, the median DOR was 10.3 months (95% CI, 8.2-NC); of 17 confirmed responders, 14 were still in response. Although the PFS data were also immature with only 38.2% events, the median PFS was 10.2 months (95% CI, 6.3-NC).

When rilvegostomig was given at a dose of 1500 mg every 3 weeks to those with a PD-L1 TPS of 50% or higher (n = 30), it induced an ORR of 36.7% (95% CI, 19.9%-56.1%). Data were immature for DOR and PFS in this group, and both were NC. Of the 9 confirmed responders in this group, all were still responding to treatment at the time of the presentation.

“Rilvegostomig monotherapy showed encouraging preliminary responses and durable responses in CPI-naive metastatic NSCLC across PD-L1 strata,” Jeroen Hiltermann, MD, PhD, of the University of Groningen, Universitar Medisch Centrum Groningen, in Groningen, Netherlands, said in an oral presentation of the data. “The efficacy data was even stronger when central PD-L1 testing was being done and when patients were chemotherapy naive. Rilvegostomig was well tolerated with no grade 4 or higher treatment-related adverse effects [AEs], a low discontinuation rate, and low rates of grade 3 immune-mediated AEs.”

Rilvegostomig is a bispecific, humanized IgG1 antibody that inhibits both PD-1 and TIGIT with a high affinity to both, permitting cooperative receptor binding with the goal to enhance antitumor immunity, Hiltermann said. He added that the agent has an engineered triple-mutant Fc domain with a reduced function to avoid unwanted depletion by Fc-mediated antibody-dependent cell cytotoxicity or antibody-dependent cellular phagocytosis.

Preclinical data indicated that rilvegostomig enhanced antitumor activity in a humanized mouse tumor model vs anti­–PD-1 treatment alone or anti–PD-1 and an anti-TIGIT combined. Previously, the agent demonstrated safety and efficacy in patients with advanced NSCLC whose disease was resistant to CPIs.

At the conference, Hiltermann shared data with the agent in patients with CPI-naive metastatic NSCLC and a PD-L1 TPS of 1% to 49% or at least 50%.

Parts C and D of the first-in-human study enrolled patients with stage IV NSCLC who had not received CPIs. They had to have a life expectancy of at least 12 weeks at the time of enrollment, have at least 1 measurable lesion by RECIST 1.1 criteria, and acceptable bone marrow, liver, and kidney function.² Patients had received up to 1 previous chemotherapy regimen for metastatic disease.¹ Those in part C had a PD-L1 TPS of 1% or higher and those in part D had a TPS of 50% or higher.

Those enrolled to part C were given the agent at 750 mg every 3 weeks. Others were randomly assigned 1:1 to part D1 or D2 where they received the agent at 750 mg or 1500 mg, respectively, every 3 weeks. The primary end points of the study are investigator-assessed ORR by RECIST 1.1 criteria and safety. Secondary end points include DOR and PFS.

“This was a regular cohort of metastatic NSCLC patients and there were no clear differences [in baseline characteristics] between the cohorts,” Hiltermann noted.

For those in part C, the median age was 65.5 years (range, 41-79); 23.5% of patients were female. Most patients were Asian (70.6%), and more than half had an ECOG performance status of 1 (61.8%). Moreover, 47.1% of patients had squamous histology, 14.7% were never smokers, and 32.4% had prior chemotherapy. Patients had brain (14.7%), liver (17.6%), and bone (14.7%) metastases. Regarding local PD-L1 TPS, 91.2% had a status ranging from 1% to 49% and 8.8% had a status of at least 50%.

For those in part D1, the median patient age was 69.0 years (range, 48-78) and 29.0% were female. The majority were Asian (67.7%), 61.3% had an ECOG performance status of 1, 22.6% had squamous disease, 3.2% were never smokers, and 9.7% previously had chemotherapy. Twenty-nine percent of patients had brain metastases, 29.0% had bone metastases, and 6.5% had liver metastases. For those in part D2, the median patient age was 68.0 years (range, 52-85) and 29.0% were female. Moreover, 61.3% were Asian, 64.5% had an ECOG performance status of 1, 38.7% had squamous histology, 9.7% were never smokers, and 6.5% had prior chemotherapy. Patients had brain (22.6%), liver (16.1%), and bone (38.7%) metastases.

“There are two things I would like to point out. The first is that PD-L1 testing was being done locally and for part C, it appeared that 91% of patients had PD-L1 of 1% to 49% as opposed to part D where per protocol all patients had TPS of 50% [or higher],” Hiltermann noted. “Prior chemotherapy was allowed in this study, with a higher prevalence in part C.”

Investigators sought to determine whether testing for PD-L1 centrally or having received chemotherapy would impact response outcomes. Within the group of patients with a PD-L1 TPS of 1% to 49%, the ORR was higher, at 38.1% in those who were chemotherapy naive (n = 21). Moreover, the ORR was 34.8% in this group when PD-L1 was tested centrally (n = 23). Within the group of patients with a TPS of 50% or higher, those who were chemotherapy naive (n = 31) had a higher ORR of 67.7%. When PD-L1 was tested centrally (n = 22), the ORR was higher at 68.2%.

“Furthermore, we have some translational data that may explain the underlying biology of why we find these ORRs…You can see that patients having a partial response tended to have a higher level of activated CD8-positive T cells as compared [with] patients having stable disease or progressive disease,” Hiltermann said. “When we compared that to a historical control of durvalumab [Imfinzi], this response [was higher.] The proportion of responders having an increase in activation [of CD8] of 20% [or higher] from baseline, was [57%.1] for rilvegostomig 750 mg responders vs [16.1%] for the historical control [responders].”

Rilvegostomig had a favorable safety profile, with almost all AEs being low grade, manageable, and reversible. No grade 4 or 5 effects were reported. Notably, no clear safety difference was observed between the doses of 750 mg or 1500 mg. Only 2 grade 3 or higher immune-mediated AEs were reported. A low rate of patients discontinued rilvegostomig due to treatment-related AEs (4.2%).

The most common treatment-related AEs experienced by 5% or more of patients included hypothyroidism, increased alanine aminotransferase, increased aspartate aminotransferase, myalgia, hypercholesterolemia, increased lipase, pruritus, hypertriglyceridemia, diarrhea, fatigue, increased gamma-glutamyl transferase, pyrexia, reduced appetite, hyperthyroidism, hyperuricemia, vomiting, constipation, and rash.

“Randomized data from this trial support the 750 mg every 3 weeks to move forward as the recommended phase 2 dose for registrational studies,” Hiltermann concluded. He added that ongoing phase 3 studies include TROPION-Lung10 (NCT06357533), in which rilvegostomig given at 750 mg every 3 weeks will be tested together with datopotamab deruxtecan as first-line treatment in patients with advanced nonsquamous NSCLC and a PD-L1 TPS of 50% or higher.

Disclosures: Dr Hiltermann disclosed having commercial interest in relation to Roche, Bristol Myers Squibb, and AstraZeneca in that research funding was received from ineligible companies.

References

1. Hiltermann J, Izumi H, Cho BC, et al. Efficacy and safety of rilvegostomig, an anti-PD-1/TIGIT bispecific, for CPI-naïve metastatic NSCLC with PD-L1 1-49% or ≥50%. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, California. Abstract OA11.03.
2. A study of AZD2936 anti-TIGIT/​anti-PD-1 bispecific antibody in participants with advanced or metastatic NSCLC (ARTEMIDE-01). ClinicalTrials.gov. Updated August 1, 2024. Accessed September 9, 2024. https://clinicaltrials.gov/study/NCT04995523