Gareth Rivalland

Update on Mucin-1 immunotherapy in cancer: a clinical perspective

Introduction: Mucin 1 (MUC1) is particularly well suited as a cancer immunotherapy target due to the elevated protein expression and aberrant forms associated with malignancy. A variety of therapeutic strategies have been explored, including antibodies intended to induce cancer cell destruction, and vaccinations with peptides, tumor extracts, and gene expression systems. Areas covered: MUC1 immunotherapeutic strategies have included vaccination with peptide sequences, glycan molecules, viruses, and dendritic cells, monoclonal antibodies and monoclonal antibody conjugates. Here we review the relevant clinical trials in each field of immunotherapy with particular focus on large and recently published trials. Expert opinion: Long clinical experience in the trial setting has reduced concerns of immunotherapy associated toxicities and inappropriate immune responses, with the main limitation (common to many experimental approaches) being a lack of clinical efficacy. However, there have been sufficient treatment-associated responses to justify continued pursuit of MUC1 targeted immunotherapies. The focus now should be on application to the relevant cancers under appropriate circumstances and combination with the emerging non-specific immunotherapy approaches such as the PD-1 pathway inhibitors.

Digital PCR of genomic rearrangements for monitoring circulating tumour DNA

Identifying circulating tumour DNA (ctDNA) for monitoring of cancer therapy is dependent on the development of readily designed, sensitive cancer-specific DNA markers. Genomic rearrangements that are present in the vast majority of cancers provide such markers.Tumour DNA isolated from two fresh-frozen lung tumours underwent whole genome sequencing. Genomic rearrangements were detected using a new computational algorithm, GRIDSS. Four genomic rearrangements from each tumour were chosen for further study using rearrangement-specific primers. Six of the eight rearrangements tested were identified as tumour-specific, the remaining two were present in the germline. ctDNA was quantified using digital PCR for the tumour genomic rearrangements in patient blood. Interestingly, one of the patients had no detectable ctDNA either prior to or post surgery although the rearrangements were readily detectable in the tumour DNA.This study demonstrates the feasibility of using digital PCR based on genomic rearrangements for the monitoring of minimal residual disease. In addition, whole genome sequencing provided further information enabling therapeutic choices including the identification of a cryptic EGFR exon 19 deletion in one patient and the identification of a high somatic mutation load in the other patient. This approach can be used as a model for all cancers with rearranged genomes.

Combination approaches in NSCLC involving immune checkpoint inhibitors

Immune checkpoint inhibition has been proven to be highly efficacious in NSCLC and associated with durable responses in a limited number of patients. Chemotherapy and targeted therapies, which have also expanded rapidly in this field lead to high response rates and improved survival although inevitably resistance occurs and hence treatment failure. There is increasing evidence showing that chemotherapy and targeted therapy interplay with the immune system including exerting effects on tumor cells and the host immune cells. Naturally combining both of these treatment modalities to induce cytotoxic effects on tumor cells to release tumor antigens and priming of the immune system should in turn lead to enhanced anticancer activity. This review will explore some of the preclinical rationale and clinical trial data we have to date on combining various systemic therapies with immunotherapies.

Brief Report: Pembrolizumab as palliative immunotherapy in malignant pleural mesothelioma

Introduction: There is no approved second‐line treatment for malignant pleural mesothelioma (MPM). On the basis of promising early results, pembrolizumab was used off‐label in Switzerland and Australia. We investigated outcomes in association with clinicopathological features and expression of programmed death ligand 1 (PD‐L1). Methods: Registry data in Australia and Switzerland were pooled. Patient characteristics, including age, sex, histological subtype, and previous treatments were captured. Outcomes were assessed locally. PD‐L1 expression was categorized as negative (<5%), intermediate (5%‐49%), and high (≥50%). Results: A total of 93 patients (48 from Switzerland and 45 from Australia) were treated; 68 patients (73%) had epithelioid MPM, and 67 (72%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab was the second‐line treatment in 48 of 93 patients (52%). PD‐L1 expression results were available for 66 patients (71%). Most (68%) were negative, 18% were intermediate, and 14% were high for PD‐L1 expression. In the full cohort, the overall response rate (ORR) was 18%, the median progression‐free survival (mPFS) was 3.1 months, and the median overall survival was 7.2 months. In patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 and only one previous systemic treatment (n = 35), the ORR was 37%, the mPFS was 3.7 months, and the median overall survival was 10.2 months. The nonepitheloid histological subtype showed an improved ORR (24% versus 16% [p = 0.54) and mPFS (5.6 versus 2.8 months [p = 0.02]). Compared with intermediate and negative PD‐L1 expression, high PD‐L1 expression was associated with an improved ORR (44% versus 42% versus 11% [p = 0.01]) and mPFS (6.2 versus 3.9 versus 2.7 months [p = 0.04]). Toxicity was as expected. Conclusion: These real‐world data demonstrate similar response rates but inferior survival compared with those in early‐phase trials. High PD‐L1 expression and nonepitheloid histological subtype were associated with greater activity. Anti–PD‐L1 immunotherapy is a reasonable second‐line therapy in patients with MPM.

Standard of care in immunotherapy trials: Challenges and considerations

ABSTRACT The success of immunotherapeutics over the past decade has fundamentally altered the therapeutic landscape in melanoma and non-small cell lung (NSCLC) cancer care. Multiple clinical trials have confirmed significant improvements in survival with a variety of immunotherapeutic strategies. The careful and appropriate selection of standard of care (SOC) therapies is key to the successful design and interpretation of these trials. To date immunotherapeutic trials have used best supportive care, matched placebo, chemotherapy, targeted therapy or, more recently, established immunotherapeutics in melanoma clinical trials as SOCs. Each of these SOC choices has a fundamental impact on the selection and validity of response assessment criteria and clinical endpoints. As yet there is no established approach, thus new data must be interpreted with an understanding of the limitations of the current paradigm. Additionally, the pace of development has mandated the use of novel clinical trial designs, answering multiple therapeutic questions simultaneously and designed to expedite regulatory approval. This review addresses the most important challenges in the selection of SOC in immunotherapeutic trials and the current and future challenges in trial design.