Association of NRAS Mutation With Clinical Outcomes of Anti-PD-1 Monotherapy in Advanced Melanoma: A Pooled Analysis of Four Asian Clinical Trials

Abstract

BackgroundAnti-PD-1 monotherapy is the standard therapy for advanced melanoma patients, including those with NRAS mutations. The influence of NRAS mutation on immunotherapy, especially in noncutaneous melanoma, is largely uncharacterized.Materials and MethodsWe analyzed clinical data of four clinical trials for advanced melanoma patients treated with anti-PD-1 monotherapy between 2016 and 2019. The impact of NRAS mutation on efficacy and outcome of immunotherapy were analyzed in cutaneous and noncutaneous groups separately.ResultsA total of 206 patients were assessed, including 92 cutaneous melanoma patients with 12 NRAS mutations and 114 noncutaneous melanoma patients with 21 NRAS mutations. In cutaneous melanoma, the response rates of NRAS mutant patients were lower than patients without NRAS mutations (9.5% vs. 23.9%), the median progression-free survival (PFS) and median overall survival (OS) were shorter for patients with NRAS mutations, although without significant difference for OS (P=0.081). In noncutaneous melanoma, the response rates were 0 and 13.7% for NRAS mutant and wild-type patients, the median PFS were 3.6 months (95% CI: 0.9-6.3) and 4.3 months (95%CI: 2.9-5.7) (P=0.015), and the median OS were 10.8 months (95% CI: 1.5-20.1) and 15.3 months (95% CI: 13.2-17.4) (P=0.025), respectively. In multivariate analysis, NRAS mutation, along with ECOG performance score and LDH level, was negatively associated with both PFS (HR 1.912, P=0.044) and OS (HR 2.210, P=0.025) in noncutaneous melanoma.ConclusionIn advanced Asian melanoma treated with anti-PD-1 monotherapy, NRAS mutant patients had lower response rates and poorer prognoses compared to wild-type patients, especially in noncutaneous subtypes.

Atezolizumab plus Bevacizumab in Patients with Unresectable or Metastatic Mucosal Melanoma: A Multicenter, Open-Label, Single-Arm Phase II Study

“…Patient demographics and baseline clinical characteristics are summarized in Table 1 . The median age (range) was 61 ( 33 –73) years, most patients had an ECOG PS of 0 [32/43 (74.4%)], and 23 (53.5%) patients had metastatic disease. The median baseline sum of diameters of target lesion was 36.3 mm (range 10.0–217.0).…”

“…In a previous study, NRAS mutations were found to be associated with better outcomes in patients with metastatic melanoma ( 31 ), while another study showed that NRAS mutations had no impact on the outcomes of immunotherapy ( 32 ). However, in a pooled analysis of four clinical trials conducted in Asia, NRAS mutations were associated with worse outcomes of immunotherapy ( 33 ). Therefore, the effect of NRAS on the efficacy of immunotherapy is unknown and needs to be verified in large-scale prospective studies.…”

Molecular underpinnings of exceptional response in primary malignant melanoma of the esophagus to anti-PD-1 monotherapy

“…We previously retrospectively analyzed the association of NRAS mutation status with the clinical outcomes of anti-PD-1 monotherapy in advanced melanoma, which showed that the PFS and OS of patients with NRAS mutation were shorter than those of patients without NRAS mutation in cutaneous and acral/mucosal melanoma. 38 Kirchberger et al also reported that survival is less favorable in immune checkpoint inhibitor-treated patients with NRAS mutation. 39 Therefore, the high mutation frequency of RAS family might be another reason for a better response to anti-PD-1 and the highly aggressive nature of PMME compared with NEMM.…”

The Effects of Axitinib plus Tislelizumab in the Treatment of Advanced Renal Cell Carcinoma

“…The t -test in the present study revealed a significant reduction of BUN, SCR, TNF- β 1, VEGF, TIMP-1, and MMP-2 after treatment, and the use of axitinib plus tislelizumab resulted in greater reduction, indicating that axitinib combined with tislelizumab can improve renal function, probably because the interplay of these two plays a central role in reducing tumor blood supply via blocking the formation of neovascularization, so as to inhibit the proliferation and growth of VEGF, reduce the angiogenesis for tumor nutrients provision, and inhibit the occurrence and growth of tumor cells [ 20 ]. Moreover, the tislelizumab immunotherapy drug binding to PD-1 on the tumor surface stimulates lymphocyte secretion, boosts the resistance to tumor cells, attenuates or even reverses T cell disability or failure, reactivates the attack and killing ability of effector T cells, and enhances tumor resistance [ 21 ]. The action of the combination can restore the renal function accordingly.…”