Prognostic markers and tumour growth kinetics in melanoma patients progressing on vemurafenib

Abstract

The BRAF inhibitor vemurafenib is an effective drug in patients with BRAF mutant metastatic melanoma, but resistance occurs after a median of 6 months. The anti-CTLA4-antibody, ipilimumab, is a standard first-line and second-line treatment option in Europe, with a median time to response of 2-3 months, but some patients show rapid clinical deterioration before that. The aim of this analysis was to identify prognostic markers for survival after failure of vemurafenib treatment to identify patients who have a sufficient life expectancy to respond to new immunotherapy treatments. We retrospectively analysed 101 consecutive unselected patients treated with vemurafenib for metastatic melanoma at a single institution. The association between clinical parameters and death within 3 months after cessation of vemurafenib (n=69) was assessed by binary logistic and Cox regression. Of the patients, 45% died within 3 months of progression on vemurafenib. Elevated baseline serum lactate dehydrogenase, absence of normalization of serum lactate dehydrogenase on vemurafenib therapy, performance status of at least 2 at progression and time from primary tumour to metastatic disease less than 5 years were identified as poor prognostic markers. In an exploratory tumour growth kinetics analysis (n=16), we found that following cessation of vemurafenib, approximately a third each showed a stable, decelerated or accelerated rate of tumour growth. Patients with these poor prognostic markers are unlikely to have sufficient life expectancy to complete ipilimumab treatment after failure with vemurafenib. Consideration needs to be given to the elective use of immunotherapy before patients become resistant to vemurafenib. This requires prospective randomized evaluation. Our tumour growth kinetics analysis requires confirmation; however, it may suggest that intermittent vemurafenib treatment should be investigated in clinical trials.

Myeloid Cells That Impair Immunotherapy Are Restored in Melanomas with Acquired Resistance to BRAF Inhibitors

“…Tumors with alternate resistance mechanisms will require further study to determine if MDSC recruitment is a general feature of resistance, or whether it applies only to resistance driven by MAPK pathway reactivation. As clinical studies are underway to determine how and when to optimally integrate immunotherapies for inhibitor treated patients (19,38), our findings indicate that MDSC depleting drugs may restore vulnerability to immune checkpoint blockade therapies. The efficacy of this approach might be altered in a setting of resistance to combined BRAFi and MEKi, as MEKi has been shown to improve immunotherapeutic effectiveness (17), but can also directly inhibit T cell function (39).…”

Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma

“…Anecdotal case series of patients with advanced V600 BRAF -mutant melanoma suggest that rechallenge with a MAPKi, after previous evidence of disease progression and a brief drug holiday, can lead to clinical benefits, including objective tumor regression and enhanced life quality (11–16). More recently, a prospective clinical trial demonstrated that, following an interval of at least 12 weeks since disease progression and off MAPKi, rechallenge with BRAFi+MEKi led to 32% partial responses and 40% disease stabilization (17).…”

Switching to Immune Checkpoint Inhibitors upon Response to Targeted Therapy; The Road to Long-Term Survival in Advanced Melanoma Patients with Highly Elevated Serum LDH?

“…The value of sequencing targeted therapy prior to treatment with ICI in patients with initial elevated LDH has not been investigated thus far. Previous retrospective reports revealed that normalization of LDH while on targeted therapy was associated with ipilimumab cycle completion [18,19]. In another study on 101 advanced melanoma patients with decreased serum LDH after BRAF inhibitor treatment who completed all courses of ipilimumab, showed a significantly longer OS compared to those who did not (median OS 12.7 months vs. 1.2 months) [20].…”