HIMALAYA Trial Examines Treatment-Emergent ADAs for Durvalumab in HCC Regimens

Investigators conducting the Phase 3 HIMALAYA global trial of durvalumab in unresectable hepatocellular carcinoma (uHCC) found that patients were at low risk of developing antidrug antibodies (ADAs) to the STRIDE regimen of a single priming dose of tremelimumab followed by regular interval durvalumab, as well as to durvalumab alone.

The HIMALAYA study revealed that the STRIDE regimen significantly improved overall survival of patients with uHCC vs sorafenib. Because reported rates of treatment-emergent ADAs vary from 1.5% for pembrolizumab to 54.1% for atezolizumab across indications, the study team sought to determine if STRIDE or monotherapy with durvalumab also posed the risk of ADA development.

The investigators conducted secondary analyses to assess the presence of ADAs to D and T at baseline, prior to the first study dose; they repeated the analyses once during treatment and once after treatment discontinuation. Participants who were ADA-positive at any visit were also tested for the presence of neutralizing antibodies (nAbs).

Patients with a positive post-baseline sample only or with an ADA titer that increased more than 4-fold following treatment were considered to have treatment-emergent ADAs. Patients with no positive sample for ADAs at any visit were classified as ADA negative.

“The frequency of ADAs to D [durvalumab] was similar in the STRIDE (T+D) and D arms: 8.2% (24/294) and 7.1% (20/282) of pts [patients], respectively, were ADA+ to D; 3.1% (9/294) and 2.8% (8/282) of pts, respectively, were TE-ADA+ to D; and 1.7% (5/294) and 0.7% (2/282) of pts, respectively, had nAbs to D,” the authors wrote in a poster presentation for the ASCO 2023 ASCO Gastrointestinal Cancers Symposium.

In the STRIDE arm, the authors reported, 15.9% (29/182) of patients were ADA+ to tremelimumab, 11.0% (20/182) exhibited treatment-emergent ADAs to tremelimumab, and 4.4% (8/182) of patients had nAbs to the drug. “Although the number of pts was small, in the STRIDE arm, ORR was 11.1% (1/9) in pts TE-ADA+ to D, 35.0% (7/20) in pts TE-ADA+ to T and 23.9% (94/393) in the full analysis set (FAS).”

In the durvalumab arm, the ORR was 25.0% (2/8) among patients positive for treatment-emergent ADA to the drug and 18.5% (72/389) in the full analysis set. Overall survival for patients who were positive for treatment-emergent ADAs and nAbs to D or T in the D and STRIDE arms was consistent with the full analysis set. In both arms, treatment-related and Grade 3/4 treatment-related adverse event rates were not increased in the ADA+ vs ADA- groups and were generally consistent with the overall population.

Overall, the rates of treatment-related-ADAs and nAbs to both durvaluman and tremelimumab  were low (≤11%). “The presence of ADAs did not appear to impact clinical efficacy or safety of STRIDE or D monotherapy in the small number of ADA+ pts. These results support a low risk of ADAs for STRIDE or D in uHCC,” the investigators concluded.

—Rebecca Mashaw

Reference:

Crysler OV, Yarchoan M, Furuse J. Presence and impact of antidrug antibodies (ADAs) to tremelimumab (T) or durvalumab (D) in the phase 3 HIMALAYA study of unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2023; 41 (suppl 4; abstr 551)

DOI: 10.1200/JCO.2023.41.4_suppl.551

Clinical trial information: NCT03298451.