Afaf Abed

Introduction: Maximal heterozygosity on the human leukocyte antigen (HLA) loci has been found to be associated with improved survival and development of immune-related adverse events (irAEs) among NSCLC patients treated with immunotherapy. Here, we investigated the effect of germline HLA-I/-II on clinical outcomes among NSCLC patients treated with first-line pembrolizumab in combination with chemotherapy. Method: We prospectively recruited patients with NSCLC who were commencing first-line pembrolizumab in combination with chemotherapy. DNA from white blood cells was used for high-resolution HLA-I/II typing. Results: Of the 65 patients recruited, 53 complied with the inclusion criteria. We did not find an association between HLA-I/-II homozygosity and clinical outcome among the studied population. However, the presence of HLA-A01 was associated with unfavourable PFS (HR = 2.32, 95%CI 1.13–4.77, p = 0.022) and worsening OS (HR = 2.86, 95%CI 1.06–7.70, p = 0.038). The presence of HLA-B27 was associated with improved PFS (HR = 0.35, 95%CI 0.18–0.71, p = 0.004) and trends toward improving OS. None of the HLA-I supertypes were associated with the development or worsening of irAEs. Conclusions: The absence of association between genomic HLA-I/-II homozygosity and clinical outcome among patients with advanced NSCLC treated with pembrolizumab in combination with chemotherapy might reflect a diminished role for HLA molecules among patients with low or no PD-L1. HLA-A01 and HLA-B27 might have a role in predicting clinical outcomes among this cohort of patients. Further studies are needed to explore biomarkers for this group of patients.

Adjuvant immunotherapy with nivolumab or pembrolizumab represents the current standard of care for resected high-risk Stage III and IV malignant melanoma. However, data on its real-world outcomes and efficacy beyond clinical trials are limited. We evaluated the data of high-risk Stage III and IV melanoma patients treated with adjuvant immunotherapy in two hospitals in Western Australia, Australia. The study involved the retrospective collection and analysis of data from 95 eligible patients treated with nivolumab or pembrolizumab. These patients were planned to receive 1 year of immunotherapy, with treatment continuing until disease recurrence, unacceptable toxicity, or voluntary withdrawal. Our evaluation focused on overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS), along with safety outcomes. The findings of our study indicated a 2-year RFS of 73%, a DMFS of 73%, and an OS of 94%. Treatment-related adverse events were observed in 63.1% of patients, with cutaneous manifestations being the most common treatment-related toxicity and gastrointestinal tract issues being the most common higher-grade immune-related adverse event. Importantly, these findings do not significantly differ from the landmark clinical trials, CheckMate-238 and KEYNOTE-054. In conclusion, adjuvant immune checkpoint inhibitor therapy administered for up to 1 year in high-risk Stage III and IV melanoma demonstrates a comparable efficacy and toxicity profile in real-world settings to that observed in the pivotal trials.

To investigate the association between skeletal muscle mass and adiposity measures with disease-free progression (DFS) and overall survival (OS) in patients with advanced lung cancer receiving immunotherapy, we retrospectively analysed 97 patients (age: 67.5 ± 10.2 years) with lung cancer who were treated with immunotherapy between March 2014 and June 2019. From computed tomography scans, we assessed the radiological measures of skeletal muscle mass, and intramuscular, subcutaneous and visceral adipose tissue at the third lumbar vertebra. Patients were divided into two groups based on specific or median values at baseline and changes throughout treatment. A total number of 96 patients (99.0%) had disease progression (median of 11.3 months) and died (median of 15.4 months) during follow-up. Increases of 10% in intramuscular adipose tissue were significantly associated with DFS (HR: 0.60, 95% CI: 0.38 to 0.95) and OS (HR: 0.60, 95% CI: 0.37 to 0.95), while increases of 10% in subcutaneous adipose tissue were associated with DFS (HR: 0.59, 95% CI: 0.36 to 0.95). These results indicate that, although muscle mass and visceral adipose tissue were not associated with DFS or OS, changes in intramuscular and subcutaneous adipose tissue can predict immunotherapy clinical outcomes in patients with advanced lung cancer.

Background We aimed to assess the impact of genomic human leukocyte antigen (HLA)-I/II homozygosity on the survival benefit of patients with unresectable locally advanced, metastatic non-small lung cancer treated by single-agent programmed cell death protein-1/programmed death ligand 1 (PD1/PDL1) inhibitors. Methods We collected blood from 170 patients with advanced lung cancer treated with immunotherapy at two major oncology centers in Western Australia. Genomic DNA was extracted from white blood cells and used for HLA-I/II high-resolution typing. HLA-I/II homozygosity was tested for association with survival outcomes. Univariable and multivariable Cox regression models were constructed to determine whether HLA homozygosity was an independent prognostic factor affecting Overall Survival (OS) and Progression Free Survival (PFS). We also investigated the association between individual HLA-A and -B supertypes with OS. Results Homozygosity at HLA-I loci, but not HLA-II, was significantly associated with shorter OS (HR=2.17, 95% CI 1.13 to 4.17, p=0.02) in both univariable and multivariable analysis. The effect of HLA-I homozygosity in OS was particularly relevant for patients with tumors expressing PDL1 ≥50% (HR=3.93, 95% CI 1.30 to 11.85, pConclusion Our results suggest that homozygosity at ≥1 HLA-I loci is associated with short OS and PFS in patients with advanced non-small cell lung cancer with PDL1 ≥50% treated with single-agent immunotherapy. Carriers of HLA-A02 supertype reported better survival outcomes in this cohort of patients.

Antibodies against programmed death-1 (PD-1), and its ligand, (PD-L1) have been approved recently for the treatment of small-cell lung cancer (SCLC). Although there are previous reports that addressed PD-L1 detection on tumour cells in SCLC, there is no comprehensive meta-analysis on the prevalence of PD-L1 expression in SCLC. We performed a systematic search of the PubMed, Cochrane Library and EMBASE databases to assess reports on the prevalence of PD-L1 expression and the association between PD-L1 expression and overall survival (OS). This meta-analysis included 27 studies enrolling a total of 2792 patients. The pooled estimate of PD-L1 expression was 26.0% (95% CI 17.0–37.0), (22.0% after removing outlying studies). The effect size was significantly heterogeneous (I² = 97.4, 95% CI: 95.5–98.5, p < 0.0001).Positive PD-L1 expression was a favourable prognostic factor for SCLC but not statistically significant (HR = 0.86 (95% CI (0.49–1.50), p = 0.5880; I² = 88.7%, p < 0.0001). Begg’s funnel plots and Egger’s tests indicated no publication bias across included studies (p > 0.05). Overall, there is heterogeneity in the prevalence of PD-L1 expression in SCLC tumour cells across studies. This is significantly moderated by factors such as immunohistochemistry (IHC) evaluation cut-off values, and assessment of PD-L1 staining patterns as membranous and/or cytoplasmic. There is the need for large size, prospective and multicentre studies with well-defined protocols and endpoints to advance the clinical value of PD-L1 expression in SCLC.