“A pooled analysis of four clinical trials of nivolumab (Opdivo) in advanced melanoma, reported by Larkin et al in JAMA Oncology, suggested similar response rates in patients with BRAF V600 mutant and BRAF wild-type disease.
“The retrospective analysis included data from adult patients with unresectable stage III or stage IV melanoma from four clinical trials. Nivolumab was given at 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg every 2 weeks until disease progression, treatment discontinuation due to adverse events, withdrawal, or end of study, with 83% of patients receiving the 3 mg/kg dose. Overall, 72% of patients in the BRAF mutant group had received prior BRAF inhibitor therapy. A total of 73% of patients in the BRAF wild-type group and 86% in the mutant group had received at least two prior therapies for advanced disease.
“The investigators concluded, ‘The results of this retrospective analysis suggest that nivolumab has similar efficacy and safety outcomes in patients with wild-type or mutant BRAF, regardless of prior BRAF inhibitor or ipilimumab treatment.’ “
The gist: A drug called XL888 has shown promise for people with unresectable stage III/IV BRAF V600 mutation-positive melanoma. It was tested in a clinical trial with volunteer patients. It is hoped that XL888 could help prevent resistance to the drug vemurafenib (aka Zelboraf). In the trial, a combination of XL888 and vemurafenib was safely given to patients. The patients showed good response to the treatment.
“Exelixis, Inc. (EXEL) today announced preliminary results from a phase 1 investigator-sponsored trial (IST) evaluating the safety and activity of XL888, an Exelixis-discovered small molecule oral inhibitor of Heat Shock Protein 90 (HSP90), in combination with vemurafenib in patients with unresectable stage III/IV BRAF V600 mutation-positive melanoma. Safety and efficacy results support the further investigation of 90 mg of XL888 twice weekly (BIW) and vemurafenib 960 mg twice daily (BID) in additional studies that would include a third agent.
“The trial results were presented today by Keiran Smalley, Ph.D., an investigator on the trial and an associate professor at H. Lee Moffitt Cancer Center, Tampa, Florida, in a late-breaking oral presentation session at the Society for Melanoma Research 2014 International Congress, which is taking place November 13-16, 2014, in Zurich, Switzerland. Based on these results, as well as findings from coBRIM, the phase 3 pivotal trial of cobimetinib, an Exelixis-discovered MEK inhibitor, and vemurafenib in previously untreated metastatic melanoma patients with a BRAF V600 mutation, the Moffitt Center plans to initiate a phase 1b IST of the triple combination of vemurafenib, cobimetinib, and XL888 in a similar patient population.
“ ‘The BRAF inhibitor vemurafenib is active in BRAF-mutated malignant melanoma, but development of resistance is common. Preclinical studies led by Keiran Smalley, Ph.D. suggested that most BRAF inhibitor resistance mechanisms involve proteins that are clients of HSP90, and the preclinical evaluation of XL888 showed that it is highly active in vemurafenib-resistant melanoma models,’ said Jeffrey Weber, MD, Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center and Research Institute in Tampa, FL. ‘The current phase 1 data show that both drugs can be given together, and compelling initial response results suggest potential cooperative activity.’ “
Guerreschi P, Scalbert C, Qassemyar A, Kluza J, et al. Melanoma Res. Jul 10, 2013.
“Recently, the BRAF V600 inhibitor, vemurafenib, has revolutionized the therapeutic management of metastatic melanoma. However, adverse effects and the onset of resistance are frequently observed, limiting the efficacy of this treatment. Patient-derived tumor xenografts (PDTX) engrafted in immunocompromised mice have been proposed as valuable preclinical models that can predict clinical response to treatments. Here, we established a PDTX model of BRAF V600E melanoma useful for testing the efficacy of vemurafenib. First, we validated the stability of the model that was similar to the original tumor with respect to histology, immunohistochemistry, mutational status, and fluorine-18 fluorodeoxyglucose ([F]FDG)-PET/computed tomography (CT). Next, the sensitivity of the xenografts to vemurafenib was determined by tumor growth inhibition and decreased in standardized uptake value on [F]FDG-PET/CT. Finally, this result, using personalized PDTX, allowed successful rechallenge with vemurafenib in a patient who was administered a lower dose of vemurafenib because of the onset of adverse events. Overall, we found that PDTX provides ‘real-time’ results in an animal that phenocopies the biology and expected vemurafenib responses of the tumor in a patient with BRAF V600E melanoma. Thus, this ‘coclinical’ trial using PDTX can help guide vemurafenib treatment for metastatic melanoma.”
Kaplon J, Zheng L, Meissl K, Chaneton B, et al. Nature. May 19, 2013.
“Here we show, by metabolic profiling and functional perturbations, that the mitochondrial gatekeeper pyruvate dehydrogenase (PDH) is a crucial mediator of senescence induced by BRAFV600E, an oncogene commonly mutated in melanoma and other cancers…”
Callahan, M, Rampal, R ... Levine, RL, Chapman, PB. NEJM. Dec. 13, 2013.
Vemurafenib, a selective RAF inhibitor, extends survival among patients with BRAF V600E–mutant melanoma. Vemurafenib inhibits ERK signaling in BRAF V600E–mutant cells but activates ERK signaling in BRAF wild-type cells. This paradoxical activation of ERK signaling is the mechanistic basis for the development of RAS-mutant squamous-cell skin cancers in patients treated with RAF inhibitors. This study reports the accelerated growth of a previously unsuspected RAS-mutant leukemia in a patient with melanoma who was receiving vemurafenib. Exposure to vemurafenib induced hyperactivation of ERK signaling and proliferation of the leukemic cell population, an effect that was reversed on drug withdrawal.