FROM NATURE
Desmoplastic melanoma, a rare chemotherapy-resistant cutaneous malignancy, appears to be particularly responsive to immunotherapy with inhibitors of programmed death 1 (PD-1) or PD ligand 1 (PD-L1), investigators found.
Of 60 patients with desmoplastic melanoma (DM) treated with pembrolizumab (Keytruda), nivolumab (Opdivo), or an experimental PD-L1 inhibitor (BMS 936559) and followed for a median of 22 months, 42 (70%) had an objective response to immunotherapy, including 19 patients (32%) with a complete response (CR), and 38% with a partial response, reported Antoni Ribas , MD, PhD, of the University of California, Los Angeles, and colleagues.
“Our data suggest that DM, and probably the non-DM NF1 subtype arising from sun-exposed areas, have a high response rate to PD-1 blockade therapy because they have a more dynamic preexisting adaptive immune response,” they wrote in Nature .
Desmoplastic melanoma is frequently a consequence of DNA damage to cells exposed to ultraviolet light. The malignancy is characterized by spindle-shaped melanoma cells in dense, fibrous stroma. It is known to be resistant to conventional chemotherapy, and although DM tumors typically have high mutational loads, they generally lack driver mutations that could be treated with targeted agents, the investigators noted.
Nonetheless, the mutational burden of DM tumors may make them good candidates for immune checkpoint inhibitor therapy.
“As recognition of neoantigens that result from somatic nonsynonymous mutations is associated with improved clinical responses to anti–PD-1 and anti–PD-L1 therapy, we hypothesized that patients with DM might respond well to anti–PD-1 or anti–PD-L1 therapies, owing to their high mutational load,” Dr. Ribas and colleagues wrote.
To support their hypothesis, they identified 60 patients with DM from a retrospective review of pathology records on 1,058 patients with advanced melanoma treated with a PD-1 or PD-L1 inhibitor at 10 international sites from 2011 through 2016. Four of the patients had received the CTLA-4 inhibitor ipilimumab (Yervoy) in addition to anti–PD-1 agents.
Of the 60 patients, 35 (58%) had markers for a poor prognosis, either extrapulmonary visceral metastases or elevated lactate dehydrogenase levels.
The objective response rates were as noted before. Of the 23 patients with partial responses, 9 had tumor progression, whereas no patients with a CR had progression.
When the investigators looked at whole-exome sequencing results on 17 of the patients, they saw a high frequency of nonsynonymous mutations – in this instance, a change in the amino acid sequence of proteins from cytosine to thymine – “as part of a strong signature of ultraviolet light–induced DNA damage that is common to cutaneous melanoma.”
The most common driver mutations were in NF1, seen in 14 of the 17 cases. In contrast, targetable mutations in BRAF or RAS were absent.
Immunohistochemistry comparisons of samples from 19 cases of DM with 13 non-DM melanomas showed that the DM tumors had a significantly higher proportion of PD-L1–positive cells in the tumor parenchyma (P = .004). DM cells from invasive tumor margins showed increased CD8 cell density PD-L1 expression.
“Therefore, patients with advanced desmoplastic melanoma derive substantial clinical benefit from PD-1 or PD-L1 immune checkpoint blockade therapy, even though desmoplastic melanoma is defined by its dense desmoplastic fibrous stroma. The benefit is likely to result from the high mutational burden and a frequent preexisting adaptive immune response limited by PD-L1 expression,” Dr. Ribas and colleagues wrote.
The study was funded in part by the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, National Institutes of Health grants, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund. The authors reported having no competing financial interests.
SOURCE: Ribas A et al. Nature. 2018 Jan 10. doi: 10.1038/nature25187 .
