Identifying safe and effective treatments for melanoma after progression on PD-1/PD-L1 inhibitor therapy is a large unmet need. The results of the phase II LEAP-004 study of the multikinase inhibitor lenvatinib plus pembrolizumab presented at the ESMO Virtual Congress 2020 revealed very encouraging results in patients with advanced melanoma (LBA44).
Patients enrolled in the study had unresectable stage III–IV melanoma and confirmed progressive disease after previous PD-1/PD-L1 therapy, including combination with anti-CTLA-4, while a minority (37%) had BRAFV600 mutation. The study authors reported an objective response rate (ORR) per RECIST v1.1 by blinded independent central review – the primary endpoint – of 21.4% (95% confidence interval [CI] 13.9–30.5) overall, and 31.0% (95% CI 15.3–50.8) in patients who had progressed on prior anti-PD-1/PD-L1 plus anti-CTLA-4 therapy. “These are very encouraging results, as resistance to checkpoint inhibitor therapy is a huge problem and we have few effective treatments to offer our melanoma patients, particularly those lacking BRAF mutations,” commented Prof. Inge-Marie Svane from Copenhagen University Hospital, Herlev, Denmark. “Another group of patients who we would be keen to offer alternative treatments for are those who have progressed on both checkpoint inhibitor and BRAF/MEK-inhibitor therapy. If a response to lenvatinib plus pembrolizumab could also be found in this group of patients, it could have a huge clinical impact. No other treatments have shown significant benefit for these patients so this would be an obvious position for this new combination,” she added.
However, survival results from LEAP-004 were difficult to interpret. Median (95% CI) progression-free survival (PFS) and overall survival (OS) were 4.2 months (3.5–6.3) and 13.9 months (10.8–not reached), respectively. Svane said, “The median PFS result is not very impressive because an improvement of 6 months or more would be considered clinically relevant. I would hope that subgroup analyses reveal which patients benefit the most from this combination so that we can tailor treatment accordingly. Grade 3–5 treatment-related adverse events (TRAEs) were reported in 45% of patients, with 7.8% discontinuing lenvatinib and/or pembrolizumab owing to TRAEs. While these results are not unexpected for a multikinase inhibitor, the hope is that this high incidence of toxicity would be balanced with durable, clinically relevant efficacy or strategies such as dose reductions to manage side-effects.”
A different approach being investigated as an anti-PD-1-based treatment option for patients with advanced melanoma involves the addition of an agent that activates an immune response against the cancer, such as Toll-like receptor 9 [TLR9] agonists.
In the final results from the ILLUMINATE-204 study of intratumoural tilsotolimod (a TLR9 agonist) plus ipilimumab in patients with advanced melanoma following progression on or after anti-PD-1 therapy, median OS was 21.0 months, overall response rate was 22.4% and median duration of response was 11.4 months, with 7/11 responses lasting ≥ 6 months (Abstract 1083MO). Efficacy was observed in injected and non-injected distant lesions. Svane commented that, “This patient group represents a very difficult-to-treat cohort and the results are promising, but the challenge will be that many patients will lack easily accessible lesions for intratumoural injection, since most patients with advanced melanoma have widespread disease. The observation that responses were achieved in non-injected and even distant lesions is essential for the clinical value of this combination therapy. Furthermore, if distant lesions can be targeted with durable responses (6 months or more), then the need for accessible lesions for treatment administration may not be such a barrier after all.”
Additionally, other immune strategies, such as the combination of pembrolizumab plus the class I selective histone deacetylase inhibitor, entinostat, are emerging, which could help overcome immune resistance. “We still have a huge challenge in terms of an effective therapy for the many melanoma patients with brain metastases,” said Svane, “but I hope that researchers will take up that challenge in the near future, as well as address the important issue of the optimal combination and sequence of treatments. At present, only one combination, ipilimumab plus nivolumab is approved, and data to guide clinicians are limited. We remain optimistic that this will change.”
Abstract and session details
Fernandez AMA et al. Lenvatinib (len) plus pembrolizumab (pembro) for advanced melanoma (MEL) that progressed on a PD-1 or PD-L1 inhibitor: initial results of LEAP-004. ESMO Virtual Congress 2020, LBA44
Proffered Paper - Melanoma and other skin tumours, 19.09.2020, h. 16.20 – 18:00, Channel 2
Haymaker C et al. Final results from ILLUMINATE-204, a phase I/II trial of intratumoral tilsotolimod in combination with ipilimumab in PD-1 inhibitor refractory advanced melanoma. ESMO Virtual Congress 2020, Abstract 1083MO
Mini Oral - Melanoma and other skin tumours, 18.09.2020