Perspectives from AACR 2018: Advances of immunotherapy for the treatment of melanoma

Speaker: Stéphane Champiat

Stéphane Champiat reports the findings presented at AACR 2018, in particular the results from a phase III study of pembrolizumab in adjuvant treatment of melanoma, and results from a phase Ib study of Toll-like receptor 9 (TLR-9) agonist in melanoma resistant to anti-PD-1 therapy.

The phase III adjuvant trial, published simultaneously in the NEJM, randomised 1019 patients with stage III resectable melanoma who were treated either by pembrolizumab 200 mg flat dose IV every 3 weeks up to a maximum of 18 doses for a year, compared to placebo.

Primary endpoint was recurrence-free survival (RFS) and efficacy data is in favour of the pembrolizumab arm with a hazard ratio of 0.57; at 18 months RFS rate was 71% for the pembrolizumab arm compared to 53%. The benefit is observed regardless of PD-L1 and BRAF status.

In terms of toxicity there is no new signal observed. The toxicity profile is immune related, the treatment seems to be less toxic than what have been seen with CTLA-4 inhibition or interferon, and comparable with other anti-PD-1 drugs. The most frequent toxicities are fatigue, rash and thyroid dysfunction. There was one toxicity-related death in a patient who suffered from myositis, which underlines a need to be cautious with immune-related adverse events.

Implications of these findings are that pembrolizumab is now an option for adjuvant treatment in melanoma. It is an additional option to nivolumab that has shown superiority compared to ipilimumab, but also the dabrafenib/trametinib study that showed a benefit in the adjuvant setting in patients with BRAF mutated melanoma. We need more studies to compare these different options to find out what to use in the clinical practice.

This study has an interesting design: In a second part, patients having a recurrence of their disease will be unblinded and cross over to the pembrolizumab arm. In a couple of years it will be interesting to see the results from that part and if pembrolizumab at relapse shows the same benefit as in the adjuvant setting.

The second important study that was presented was a phase Ib study that included so far 69 patients. Most patients (91%) were progressing after anti-PD-1 therapy. A TLR-9 agonist (CMP-001) was administered weekly at the beginning and then every three weeks combined with pembrolizumab.

In terms of efficacy, overall response rate of 22% with 2 complete responses is very promising, with acceptable and manageable toxicity (flu-like syndrome, injection site pain, hypotension).

Translational studies of CD8 and PD-1 immunohistochemistry have shown an increase of CD8 infiltration and PD-1 expression after treatment, and also an increased immune signature. These findings are associated with the mechanism of action of intra-tumoral TLR-9 agonist.

These results are very encouraging for melanoma patients progressing on anti-PD-1 who have acquired resistance, but also for patients with primary resistance to immunotherapy, as such intra-tumoral injection may prime the immune system to trigger a prolonged response.

The extension cohort is ongoing and hopefully we'll continue to see similar results in terms of efficacy.

These results in melanoma are interesting for other tumour types and this type of strategy of intra-tumoral injection with innate agonist is potentially very interesting for “cold” tumours which are not responding to anti-PD-1 therapy.

Abstracts:

  • Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma. Results from the EORTC 1325-MG/Keynote 054 phase III trial. (CT001) A.M.M. Eggermon
    http://www.nejm.org/doi/full/10.1056/NEJMoa1802357
  • Results of a phase Ib study of intratumoral toll-like receptor 9 agonist in combination with pembrolizumab in subjects with advanced melanoma resistant to PD-1 inhibition. (CT144) M. Mihem