Daily highlight in melanoma & other skin cancers

Reported by Dr Mireille Langouo Fontsa, Institut Jules Bordet-ULB, Brussels

In the context of the phase 2 SWOG S1801 trial, the efficacy of neoadjuvant-adjuvant administration of pembrolizumab was compared to adjuvant treatment alone, specifically focusing on the achievement of pathological complete response (pCR). In the field of breast cancer, the FDA recognizes pCR as an endpoint for drug approval in the neoadjuvant setting. While a positive pCR is associated with improved long-term outcomes, its direct correlation with Event-Free Survival (EFS), Recurrence-Free Survival (RFS), and Overall Survival (OS) has not been definitively established. Consequently, this study aimed to investigate the relationship between pCR and EFS.

In melanoma, pCR is categorized into four groups: complete response with no residual viable cells (0%) in the tumor bed, near complete response (1-10%), partial response (11-50%), and non-response (51-100%) with detectable viable cells. Analysis of the data revealed a strong concordance between pCR and both EFS and RFS. Notably, neoadjuvant treatment with pembrolizumab led to a high rate of pCR. A two-year follow-up demonstrated significantly improved RFS in patients with pCR and near complete response (pnCR), collectively termed as the major pathological response (MPR) group, compared to those with partial or no response. The study concludes that pCR could serve as a surrogate marker for predicting RFS. However, standardized training for pathological examination of these markers is essential before relying on these findings.

In a subsequent trial, the efficacy of pembrolizumab therapy, either alone or in combination with a personalized mRNA vaccine, was explored in high-risk resected melanoma patients. Building on previous research (mRNA-4157-P201/KEYNOTE-942 trial), the combination of mRNA-4157 (V940) and pembrolizumab demonstrated a clinically significant improvement in RFS and Distant Metastasis-Free Survival (DMFS). Interestingly, the analysis of circulating tumor DNA (ctDNA) status revealed that baseline ctDNA status holds prognostic value, with a negative baseline predicting better outcomes in terms of RFS and DMFS. Longitudinal ctDNA patterns were also associated with these endpoints, indicating that both patients with negative ctDNA at baseline and those with a positive ctDNA status converting to negative during treatment experienced improved outcomes. Importantly, this association remained irrespective of the BRAF status, underscoring the predictive value of ctDNA as a tool in this context.

The prevalence of brain metastasis in melanoma patients is affecting 50% of cases. A phase 1 trial investigated the concurrent intrathecal (IT) and intravenous (IV) administration of nivolumab in leptomeningeal disease, a challenging condition with limited survival benefits even with potent drugs. The trial tested the maximum dose and safety profile of 50 mg IT nivolumab in heavily pretreated patients. The safety profile of IT administration was found to be manageable, with no grade 3 adverse events observed, and a notable median OS of 7.5 months. However, further extensive trials are required to validate these findings.

Lastly, a trial explored a triplet combination therapy involving atezolizumab (PD-L1 inhibitor), bevacizumab (VEGF inhibitor), and cobimetinib (MEK inhibitor) in melanoma patients with brain metastases. The trial demonstrated increased clinical Intracranial Complete Response Rate (ICRR) and Intracranial Best Brain Response (ICBB) with a manageable safety profile. Further investigation of this triplet combination (TACo therapy) is warranted, as innovative approaches are urgently needed to overcome immunotherapy resistance in this patient population.

References:

Platel S. – Pathologic response and exploratory analyses of neoadjuvant-adjuvant versus adjuvant pembrolizumab (PEM) for resectable stage IIIB-IV melanoma from SWOG S1801. ESMO2023 – LBA48

Weber J.S. – mRNA-4157 (V940) individualized neoantigen therapy + pembrolizumab vs pembrolizumab in high-risk resected melanoma: clinical efficacy and correlates of response. ESMO2023 – LBA49

Mckean M. – ctDNA reduction and clinical efficacy of the darovasertib + crizotinib (Daro + Crizo) combination in metastatic uveal melanoma (MUM). ESMO2023 – 1081O

Glitza I. – Concurrent Intrathecal (IT) and Intravenous (IV) nivolumab (N) for melanoma (MM) patients (pts) with leptomeningeal disease (LMD). ESMO2023 – 1082O

Patel S. – ATezolizumab, bevAcizumab, and Cobimetinib (TACo) in patients (pts) with PD1 refractory melanoma brain metastases (MBM). ESMO2023 – 1085O