Norwegian biotech Ultimovacs has recently presented positive three-year data for patients with metastatic malignant melanoma treated with cancer vaccine UV1 in combination with anti-PD-1 checkpoint inhibitor pembrolizumab. The results show both promising overall survival and an effect on predictive biomarkers, which strengthens the company’s belief in UV1 as a combination treatment with today’s checkpoint inhibitors for solid tumours. BioStock contacted Espen Basmo Ellingsen, Director Medical Affairs at Ultimovacs, to find out more.

Ultimovacs is developing the universal cancer vaccine UV1, and one of the indications for which UV1 is being evaluated is metastatic malignant melanoma – the most dangerous type of skin cancer. Although immunotherapies such as checkpoint inhibitors (CPIs) have increased survival chances in skin cancer patients, the prognosis in metastatic malignant melanoma is still poor, thus lots is still to be desired in terms of treatment effect.

Consistently positive phase I data

UV1 has the potential to fill this gap, since its goal is to strengthen the patients’ own immune system in the fight against cancer. In the completed phase I study UV1-103 with a total of 30 patients, the candidate was evaluated in combination with the patient group’s standard-of-care, CPI pembrolizumab, as first-line treatment for 14 weeks. Good safety and tolerability were demonstrated in the study, thus achieving its main objective. Additionally, initial signs of clinical response continue to be evaluated, and patients are therefore followed for overall survival up to five years after the start of treatment.

The one- and two-year follow-up data showed a survival rate of 85 and 80 per cent, respectively. These are promising numbers compared to those for pembrolizumab as monotherapy, where the overall survival rate stood at 58 per cent after 24 months. Read more about this here. At the beginning of October, Ultimovacs released three-year data from the studies, which continue to indicate a promising overall survival – 71 per cent – following the treatment combination. It is worth noting that three patients did not consent to a follow-up and one patient died within the last year.

Broad potential for UV1

The positive news flow continued last week, when the company presented additional data from the study at the International Congress of the Society for Melanoma Research 2022. The data, referring to the treatment combination´s effect on biomarkers, showed a good effect in patients with low levels of PD-L1 – a predictive biomarker associated with low efficacy with pembrolizumab monotherapy and other anti-PD-1 treatments on certain tumour types. This indicates a broad potential for the treatment combination.

The analysis also included additional prognostic biomarkers that characterise tumours with low sensitivity to pembrozilumab as monotherapy. Objective responses were observed in patients with low tumour mutational burden (TMB), tumours with low neoantigen expression, as well as tumours without enrichment for the IFN-gamma gene signature. In addition, the study showed that patients who responded to the treatment did not have higher levels of tumour-infiltrating lymphocytes before treatment.

Overall, the results suggest that the treatment combination provides an effective, sustained treatment response through activation of the patients’ immune system, as well as a broad potential for UV1 as combination therapy to anti-PD1 CPIs.

Director Medical Affairs explains more

BioStock contacted Espen Basmo Ellingsen, who is Director Medical Affairs at Ultimovacs, to learn more about the results and their implications.

Espen, the three-year data presented indicate strong overall survival, although it dropped to 71 per cent from the 80 per cent two-year data. What are your thoughts around this?

– The UV1-103 study was composed of Cohorts 1 and 2. Whereas Cohort 1 consisted of twenty patients receiving a slightly lower dose of the adjuvant, Cohort 2 included ten patients receiving the full adjuvant dose. For both cohorts combined, the 1-year survival rate was 87 per cent, and the 2-year rate was 73 per cent. The longer follow-up time allowed us to report a 3-year survival rate for patients in Cohort 1, which read out at 71 per cent. When reporting data for single cohorts, missing data, on top of the fewer patients included in the analysis, can result in relatively large changes to the survival rate. Only one patient died between years 2 and 3, but since three patients were not followed beyond 2 years, the rate had dropped from 80 per cent to 71 per cent.

Do the three-year data regarding overall survival set any expectations regarding the upcoming follow-ups?

– We were very encouraged by the high objective response rates in the UV1-103 trial, with 57 per cent of patients experiencing a 30 per cent or greater reduction in their tumour size. Furthermore, 33 per cent of the patients experienced a so-called complete response, where the entire tumour mass disappears after treatment. Previous studies suggest that patients achieving partial or complete responses experience long-term benefit and extended survival time. We are therefore very optimistic that the high survival rates will continue with longer follow-up.

Based on that the combination treatment resulting in good clinical responses in patients considered less likely to respond to monotherapy checkpoint inhibition, a potential broad applicability for UV1 as a combination therapy to anti-PD1 checkpoint inhibitors is suggested. What other indications could this applicate to?

– Checkpoint inhibition is established as the standard of care across many indications. However, the treatment response rates vary considerably within and across these indications, and many tumour types are still not amenable to checkpoint inhibition. Limited responsiveness is characterised by so-called non-inflamed or “cold” tumours, where the environment is suboptimal for the patients’ immune cells. Although melanoma is generally considered a more inflamed tumour type, some patients’ tumours still exhibit markers linked to poor responsiveness to checkpoint inhibition. Encouragingly, we also observed clinical responses to the UV1/pembrolizumab combination in patients whose tumours displayed these markers. These observations lead us to believe there is a potential for UV1 to boost responses in indications characterised by the presence of these markers and in which checkpoint inhibition demonstrates limited efficacy.

– The use of checkpoint inhibitors is, for instance, in some indications, such as NSCLC (non-small cell lung cancer), restricted to certain tumour PD-L1 levels, where only higher levels are associated with clinical benefit. Based on the data from the UV1-103 trial, adding UV1 to the checkpoint inhibitor therapy may represent a viable strategy to extend efficacy to patients with lower levels of PD-L1.

Objective responses were observed in patients with low TMB, in patients with low neoantigen tumours, and in patients with tumours that were not enriched for IFN-gamma. For non-experts within the field, could you explain the clinical relevance of these data points?

– These are all tumour biopsy-based markers aimed at determining whether a patient’s immune cells can recognise and establish an immune response against the cancer cells, also known as tumour immunogenicity. Tumour mutational burden, or TMB, estimates how many mutations are present within the tumour, i.e. how many targets there are for the immune system to recognise. With higher TMB, there is an increasing likelihood of established immune responses. The neoantigen score offers a more refined approach toward the same purpose by using complex algorithms to predict whether the mutations can lead to good immune responses. The IFN-gamma gene signature relates to a critical molecule released by the immune cells during an anti-tumour response.

– In patients with immunogenic tumours, checkpoint inhibitors can release the immune responses to promote tumour cell killing. However, depending on the levels of these markers, some patients are deprived of such responses and therefore achieve limited benefit from checkpoint inhibition alone. By vaccinating with UV1, the aim is to establish novel immune responses toward the tumour, providing a new wave of immune cells that the checkpoint inhibitors can further potentiate, leading to clinical responses in patients with less immunogenic tumours.

Lastly, the study also showed that clinical responders did not have higher levels of tumour-infiltrating lymphocytes prior to treatment. What does this indicate?

– For this analysis, we took tissue biopsies and looked specifically for the number of T-cells (the key immune cells in anti-tumour immunity) present before initiating therapy. Similar to the other analyses, a high level of T-cells in the tumour can predict clinical benefit from checkpoint inhibition. We observed robust clinical responses in patients without high levels of T-cells in their tumour before therapy, indicating that the combination therapy was able to mobilize novel immune responses leading to tumour cell killing and clinical benefit for the patients.

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