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29th September 2022
RP2 oncolytic mono-therapy has been shown in a phase 1 study to provide an objective response in a small number of patients as well as in combination with nivolumab according to findings presented at the recent European Society for Medical Oncology congress.
RP2 oncolytic therapy involves genetically engineered viruses designed to target and kill cancer cells while sparing normal cells and activating the host immunity to recognise and attack the tumour. The current RP2 therapy makes use of the herpes simplex virus (HSV) and which acts as a multifaceted gene therapy vector, carrying genes encoding immunostimulatory molecules in its genome. The oncolytic effect of HSV and the inflammatory response that the virus stimulates provide a one-two punch at attacking tumours. The first oncolytic virus therapy to be approved by the FDA in 2015 was T-VEC for the treatment of patients with metastatic melanoma that cannot be surgically removed. T-VEC was also approved by the EMA in 2016. As well as killing tumour cells, RP2 oncolytic therapy induces production of human granulocyte-macrophage colony-stimulating factor (GM-CSF) which has been shown to promote anti-tumour immunity in mice and humans. It also leads to the production of anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) antibody-like molecule since CTLA-4 indirectly facilitates tumour progression by restraining host anti-tumoral immunity. Consequently, blockage of CTLA-4 function promotes immune-mediated tumour regression.
In the phase 1 open-label trial discussed at the congress, PR2 was used as both mono-therapy and combined with nivolumab in a cohort of 30 patients with nivolumab given at a dose of 240 mg twice weekly for 4 months from the second RP2 dose, then 480 mg every four weeks for 20 months. Patient’s response to treatment were assessed using the modified RECIST v1.1.
RP2 oncolytic therapy outcomes
All patients involved in the trial had advanced cancers which had failed to respond to, or were not eligible for, standard of care options.
An objective response with RP2 mono-therapy was seen in 3 of 9 patients and which included 1 complete response for longer than 15 months in a patient with mucoepidermoid carcinoma, one partial response for over 18 months in oesophageal cancer with liver metastases and a partial response in uveal melanoma with liver metastases that progressed at 15 months. Objective responses with RP2 and nivolumab were seen in 44.4% of those with cutaneous melanoma, 25% in uveal melanoma and 33% in squamous cell carcinoma of the head and neck.
Immuno-histochemistry analysis of the tumour site revealed a robust increase in CD8 T cell influx, PD-L1 expression, and an increase in the CD8/foxp3+ cell ratio. Clinical responses were independent of baseline CD8 T cell infiltration, PD-L1 expression levels, and prior anti-PD-1 therapy status.
In a statement on the Institute for Cancer Research site, study leader Professor Kevin Harrington said ‘our study shows that a genetically engineered, cancer-killing virus can deliver a one-two punch against tumours – directly destroying cancer cells from within while also calling in the immune system against them.’ He added that ‘our initial trial findings suggest that a genetically engineered form of the herpes virus could potentially become a new treatment option for some patients with advanced cancers – including those who haven’t responded to other forms of immunotherapy. I am keen to see if we continue to see benefits as we treat increased numbers of patients.’
21st January 2022
The combination of relatlimab-nivolumab has been shown to improve progression-free survival to a greater extent that nivolumab alone in patients with metastatic or unresectable melanoma, compared to nivolumab alone. This was the conclusion of a Phase II-III trial by researchers from the Department of Melanoma Medical Oncology, University of Texas, US.
The prognosis for patients with advanced melanoma is poor, with 5-years survival rates of 5-19%, depending on the location and the number of metastases. Nevertheless, over the past decade, there have been improvements in survival for such patients, after the introduction of drugs such as ipilimumab (an anti–cytotoxic T-lymphocyte–associated antigen 4 monoclonal antibody) and anti–programmed death 1 agents such as nivolumab. In fact, studies suggest that the combination of ipilimumab and nivolumab, can produce a median overall survival of more than 60.0 months, compared to 36.9 months with nivolumab and 19.9 months ipilimumab mono-therapy respectively.
Lymphocyte Activation Gene – 3 (LAG-3) is an immune checkpoint molecule that regulates both T-cell activation and homeostasis and is up-regulated in melanoma. In addition, it has been found that both LAG-3 and programmed cell death 1 (PD-1) act synergistically to regulate T-cell function to promote tumour immune escape. Consequently, the use of relatlimab (an antibody that binds to LAG-3) and nivolumab (a PD-1 inhibitor), has showed promising anti-tumour activity, including a durable objective responses in patients with melanoma that relapsed after, or was found to be refractory to PD-1 inhibition.
For the present study, the US team used relatlimab-nivolumab as a fixed-dose combination, compared to nivolumab alone in patients with previously untreated metastatic or unresectable melanoma. They included patients 12 years of age and older, with previously untreated, histologically confirmed, unresectable stage III or IV melanoma. In phase 2–3, double-blind trial, included patients were randomised 1:1 to 160 mg of relatlimab and 480 mg of nivolumab or 480 mg of nivolumab, with both therapies administered in a single 60-minute intravenous infusion every 4 weeks. The primary end point of the study was progression-free survival assessed according to RECIST, version 1.1.
A total of 714 patients with a mean age of 63 years (41.7% female) were randomised to either relatlimab-nivolumab (355) or nivolumab alone.
The median progression-free survival interval was 10.1 months with relatlimab–nivolumab and 4.6 months with nivolumab, giving a hazard ratio (HR) for progression or death of 0.75 (95% CI 0.62 – 0.92, p = 0.006). After 12 months, progression-free survival was 47.7% with relatlimab–nivolumab and 36% with nivolumab.
The authors concluded that their data support the role of dual checkpoint inhibition over mono-therapy and establish relatlimab–nivolumab as a potential new treatment option for patients with previously untreated metastatic or unresectable melanoma.
Tawbi HA et al. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. New Eng J Med 2022
19th November 2021
Atezolizumab and nivolumab have been found to prolong overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC) cancer say researchers from Hoffmann-La Roche, Basel, Switzerland. NSCLC accounts for 85% of all lung cancers although nearly 40% of patients are diagnosed at stage 4, which has a poor prognosis, warranting systemic therapy. Treatment of NSCLC can be achieved with platinum-based chemotherapy although many patients relapse and in such cases, mono-therapy with the chemotherapeutic agent, docetaxel, has been found to be effective.
In recent years it has been discovered that developing tumours are capable of evading the immune system by avoiding checkpoint signals designed to prevent uncontrolled activation of T lymphocytes. Monoclonal antibodies including nivolumab and atezolizumab, work to either inhibit checkpoint PD-1 surface receptors (nivolumab) or its ligand, PD-L1 (atezolizumab) thereby blocking these receptors and signals, enabling the immune system to combat the tumour. Although both monoclonal antibodies are approved for use in NSCLC, there is a lack of head-to-head studies comparing these two agents even in comparison to docetaxel.
For the present study, researchers examined real-world studies contained within the US nationwide electronic health record, in which patients with advanced NSCLC and prior platinum-based therapy, who had been started on either atezolizumab, nivolumab or docetaxel. They included adults (18 years and over) diagnosed with locally advanced and/or metastatic NSCLC, none of whom had been previously treated with one of the three agents. The team also only included patients with at least 6 months of follow-up data and set the primary endpoint as overall survival.
In total, 3336 patients were included in the analysis with 206 receiving atezolizumab, 500 docetaxel and 2630 nivolumab. Patients in the atezolizumab and nivolumab groups were of a similar mean age, 68.3 and 67.3 years respectively while those in the docetaxel group were slightly younger with a mean age of 65.6 years.
Compared to docetaxel, use of atezolizumab was associated with a significantly longer survival (adjusted hazard ratio, aHR = 0.79, 95% CI 0.64 – 0.97, p = 0.02) even among those with different cancer stages. In contrast, the adjusted hazard ratio for atezolizumab compared with nivolumab was 1.07 (95% CI 0.89 – 1.28, p = 0.47) and this did not differ between patients at different cancer stages. However, the authors recognised that their analysis may not have been sufficiently powered to detect a difference between these two treatments.
The authors concluded that their real-world data suggested that atezolizumab and nivolumab produced a longer overall survival than docetaxel among those who had failed to respond to platinum-based chemotherapy.
Ramagopalan S et al. Comparative Effectiveness of Atezolizumab, Nivolumab, and Docetaxel in Patients With Previously Treated Non–Small Cell Lung Cancer. JAMA Netw Open 2021
25th October 2021
Nivolumab represents a treatment that might be beneficial for patients with malignant mesothelioma was the conclusion of a study by a team from the Mesothelioma Research Programme, University of Leicester, Leicester, UK. Malignant mesothelioma is a cancer which mainly affects the tissue that cover each lung (pleural mesothelioma) and leads to around 2,700 cases each year in the UK. In the majority of cases, pleural mesothelioma is caused by exposure to asbestos although it can take 10 to 50 years to emerge after exposure, which helps explain why over half of cases occur in those aged over 75. Prognosis for mesothelioma cancer is poor, with many patients living less than one year and it has 5-year overall survival of only 5%.
Malignant mesotheliomas express the protein PD-L1 which is the ligand for PD-1 and the binding of the two on the surface of T cells inactivates the cell. Nivolumab is a PD-1 immune checkpoint inhibitor which blocks this PD-1 to PD-L1 binding and has been shown to be a promising therapy in malignant mesothelioma. However, to date, there have been no randomised, double-blind trials of mono-therapy with checkpoint inhibitors in patients with relapsed mesothelioma after platinum-based chemotherapy. As a result, the mesothelioma research team established the CheckpOiNt Blockage For the Inhibition of Relapsed Mesothelioma (CONFIRM) trial, to evaluate the efficacy of nivolumab on overall survival and progression-free survival in those with progressive disease after a single course of platinum-based chemotherapy.
Included patients were adults (> 18 years of age) with histologically confirmed pleural or peritoneal mesothelioma and who had radiological evidence of disease progression. Participants were randomised 2:1 (nivolumab:placebo) and given nivolumab at a dose of 240 mg every 2 weeks until disease progression, withdrawal from treatment or for a maximum of 12 months, depending on which came first. The co-primary endpoints were progression-free survival and overall survival.
A total of 332 participants with malignant mesothelioma were included and randomised to nivolumab or placebo. The median age of participants allocated to nivolumab as 70 years (76% female) and the median duration of follow-up was 11.6 months.
The median progression-free survival was 3 months in the nivolumab and 1.8 months in the placebo groups (hazard ratio, HR = 0.67, 95% CI 0.53 – 0.85, p = 0.0012). The proportion of participants with progression-free survival at 1 year was 14.2% and 7.2% in the nivolumab and placebo groups respectively.
The median overall survival was 10.2 vs 6.9 months (nivolumab vs placebo), giving a hazard ratio of 0.69 (95% CI 0.52 – 0.91). The proportion of patients surviving 1 year one year was also higher in the nivolumab group (43.4% vs 30.1%, nivolumab vs placebo).
Serious adverse events occurred in 41% of patients in the nivolumab group and 44% of patients in the placebo group and there were no treatment-related deaths in either group.
The authors reported that they will continue to monitor patients and that a final and updated analysis will be published in due course.