George Lau, MD, FRCP, FAASLD, chairman, senior consultant, Gastroenterology and Hepatology, the Humanity and Health Medical Group, discusses clinical implications for the use of dual checkpoint inhibition in HCC based on an analysis of immune-related adverse effects (IrAEs) seen with the single tremelimumab regular interval durvalumab (STRIDE) regimen in the phase 3 HIMALAYA trial (NCT03298451).

An exploratory post hoc analysis evaluated the frequency and timing of irAEs in relation to treatment with tremelimumab (Imjudo) plus durvalumab (Imfinzi) in patients with unresectable hepatocellular carcinoma (HCC), Lau begins.

Safety data from the initial read-out of the HIMILAYA trial showed that both the STRIDE regimen and the monotherapy had a manageable safety profile. However, the safety profile of the STRIDE regimen is differentiated from other available immune checkpoint inhibitor (ICI) combinations, necessitating an investigation of when and how long immune-related toxicities occurred during the treatment course.

Of the original 1171 patients enrolled on the study, safety was assessed in those who had received 1 or more doses of tremelimumab (Imjudo) plus durvalumab (Imfinzi) at 300 and 500 mg, respectively, or were given durvalumab alone. IrAEs were defined as AEs of special interest associated with drug exposure and wereconsistent with an immune-mediated mechanism of action for which no alternate etiology was clear. The frequency of irAEs and category of AEs were recorded at several time points after treatment initiation, with a data cut off of August 27, 2021.

Results presented at the 2023 ASCO Annual Meeting

 demonstrated that any-grade irAEs occurred more frequently with the STRIDE regimen vs durvalumab alone. However, the majority of irAEs associated with the STRIDE regimen occurred within the first 3 months of treatment, were low grade, and were manageable, Lau states.

Moreover, the timing and severity of toxicities in the STRIDE group were comparable between the combination and monotherapy groups, despite the higher frequency of toxicities seen with the STRIDE regimen. This outcome was also consistent with previous studies of dual ICI therapy vs single-agent ICIs.

These data have addressed a major concern regarding whether a dual checkpoint inhibitor regimen for patients with HCC would overaugment immune responses and lead to worsened irAEs, Lau concludes.

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George Lau, MD, FRCP, FAASLD, discusses clinical implications for the use of dual checkpoint inhibition in HCC based on an analysis of immune-related adverse effects seen with the STRIDE regimen in the phase 3 HIMALAYA trial.
 

Dr Lau on the Temportal Patterns of irAEs Associated With the Stride Regimen in HCC

George Lau, MD, FRCP, FAASLD, chairman, senior consultant, Gastroenterology and Hepatology, the Humanity and Health Medical Group, discusses the association between immune-related adverse effects (irAEs) and overall survival (OS) for patients with unresectable hepatocellular carcinoma (HCC) enrolled on the phase 3 HIMALAYA trial (NCT03298451).

At the 2023 ASCO Annual Meeting, investigators presented information on an exploratory analysis of the trial

, revealing that patients treated the combination of durvalumab (Imfinzi) plus tremelimumab (Imjudo) experienced manageable and low-grade irAEs. Additionally, those who experienced irAEs achieved a numerical improvement in OS.

The median OS in patients who developed an irAE was 23.2 months (95% CI, 19.1-32.4) vs 14.1 months (95% CI, 11.6-17.9) in those patients who did not experience an irAE (HR, 0.727; 95% CI, 0.557-0.948). Moreover, the 6-months OS rates for patients who did and did not experience irAEs were 81.3% (95% CI, 75.1%-88.0%) vs 77.1% (95% CI, 72.1%-82.5%), respectively, and the 12-month OS rates were 69.1% (95% CI, 61.8%-77.2%) vs 55.2% (95% CI, 49.4%-61.8%), respectively.

Prior data from the trial showed that durvalumab/tremelimumab led to a 22% reduction in the risk of death vs sorafenib (Nexavar; HR, 0.78; 95% CI, 0.66-0.92; 

supported the FDA approval of the combination

 for the treatment of adult patients with HCC. However, one of the concerns of using 2 immune checkpoint inhibitors—specifically with a high dose of tremelimumab—was that the combination could lead to overactivation of the immune system and irAEs, Lau explains.

The OS difference based on the development of irAEs was similar for patients who were treated with durvalumab monotherapy, Lau expands. The median OS for those treated with durvalumab monotherapy who developed an irAE was 17.8 months (95% CI, 13.8-25.1) vs 16.5 months (95% CI, 13.1-19.4) for those who did not develop an irAE, Lau concludes.

George Lau, MD, FRCP, FAASLD, discusses the association between immune-related adverse effects and overall survival for patients with unresectable hepatocellular carcinoma enrolled on the phase 3 HIMALAYA trial.


George Lau, MD, FRCP, FAASLD

Articles

Dr Lau on the Temportal Patterns of irAEs Associated With the Stride Regimen in HCC

Dr Lau on the Association of irAEs and OS in the HIMALAYA Study in HCC