Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.

BACKGROUND: In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA. PATIENTS AND METHODS: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization). RESULTS: For STRIDE, durvalumab, and sorafenib, median [95% confidence interval (CI)] follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified. CONCLUSIONS: These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.

Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic.

Background: Treatment with immune checkpoint blockade (ICB) with agents such as anti-programmed cell death protein 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can result in impressive response rates and durable disease remission but only in a subset of patients with cancer. Expression of PD-L1 has demonstrated utility in selecting patients for response to ICB and has proven to be an important biomarker for patient selection. Tumor mutation burden (TMB) is emerging as a potential biomarker. However, refinement of interpretation and contextualization is required. Materials and methods: In this review, we outline the evolution of TMB as a biomarker in oncology, delineate how TMB can be applied in the clinic, discuss current limitations as a diagnostic test, and highlight mechanistic insights unveiled by the study of TMB. We review available data to date studying TMB as a biomarker for response to ICB by tumor type, focusing on studies proposing a threshold for TMB as a predictive biomarker for ICB activity. Results: High TMB consistently selects for benefit with ICB therapy. In lung, bladder and head and neck cancers, the current predictive TMB thresholds proposed approximate 200 non-synonymous somatic mutations by whole exome sequencing (WES). PD-L1 expression influences response to ICB in high TMB tumors with single agent PD-(L)1 antibodies; however, response may not be dependent on PD-L1 expression in the setting of anti-CTLA4 or anti-PD-1/CTLA-4 combination therapy. Disease-specific TMB thresholds for effective prediction of response in various other malignancies are not well established. Conclusions: TMB, in concert with PD-L1 expression, has been demonstrated to be a useful biomarker for ICB selection across some cancer types; however, further prospective validation studies are required. TMB determination by selected targeted panels has been correlated with WES. Calibration and harmonization will be required for optimal utility and alignment across all platforms currently used internationally. Key challenges will need to be addressed before broader use in different tumor types.

Histopathological and immunophenotypic features of ipilimumab-associated colitis compared to ulcerative colitis.

BACKGROUND: Use of the immune checkpoint inhibitor ipilimumab is sometimes complicated by ipilimumab-associated colitis (Ipi-AC), an immune-mediated colitis that mimics inflammatory bowel disease. OBJECTIVE: We sought to characterize the histopathologic and immunophenotypic features of Ipi-AC and to directly compare these features to ulcerative colitis (UC). METHODS: This is a retrospective cohort study of 22 patients with Ipi-AC, 12 patients with treatment-naïve UC and five controls with diarrhoea but normal endoscopic findings. Immunohistopathologic features were described, and quantitative immunohistochemistry (IHC) was performed for CD4, CD8, CD20, CD138 and FOXP3. RESULTS: Endoscopic findings in both the Ipi-AC and UC groups included ulcerated, oedematous and erythematous mucosa. Involvement of the GI tract was more diffuse in Ipi-AC. As compared to UC, a smaller proportion of Ipi-AC biopsies had basal plasmacytosis (14% for Ipi-AC vs. 92% for UC, P < 0.0001) and crypt distortion (23% for Ipi-AC vs. 75% for UC, P = 0.003), whereas Ipi-AC biopsies had more apoptotic bodies in the left colon (17.6 ± 15.3 for Ipi-AC vs. 8.2 ± 4.2 for UC, P = 0.011). Cryptitis, ulcerations and crypt abscesses were common in both groups. Biopsy specimens from Ipi-AC had a lower density of CD20-positive lymphocytes than UC (275.8 ± 253.3 cells mm-2 for Ipi-AC vs. 1173.3 ± 1158.2 cells mm-2 for UC, P = 0.022) but had a similar density of CD4, CD8, CD138 and FOXP3-positive cells. CONCLUSIONS: Ipi-AC is a distinct pathologic entity with notable clinical and histopathological differences compared to UC. These findings provide insights into the pathophysiology of immune-related adverse events (iAEs) from ipilimumab therapy.