C. Robert

Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma

BACKGROUND Combination therapy with the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib improved survival in patients with advanced melanoma with BRAF V600 mutations. We sought to determine whether adjuvant dabrafenib plus trametinib would improve outcomes in patients with resected, stage III melanoma with BRAF V600 mutations. METHODS In this double‐blind, placebo‐controlled, phase 3 trial, we randomly assigned 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations to receive oral dabrafenib at a dose of 150 mg twice daily plus trametinib at a dose of 2 mg once daily (combination therapy, 438 patients) or two matched placebo tablets (432 patients) for 12 months. The primary end point was relapse‐free survival. Secondary end points included overall survival, distant metastasis–free survival, freedom from relapse, and safety. RESULTS At a median follow‐up of 2.8 years, the estimated 3‐year rate of relapse‐free survival was 58% in the combination‐therapy group and 39% in the placebo group (hazard ratio for relapse or death, 0.47; 95% confidence interval [CI], 0.39 to 0.58; P<0.001). The 3‐year overall survival rate was 86% in the combination‐therapy group and 77% in the placebo group (hazard ratio for death, 0.57; 95% CI, 0.42 to 0.79; P=0.0006), but this level of improvement did not cross the prespecified interim analysis boundary of P=0.000019. Rates of distant metastasis–free survival and freedom from relapse were also higher in the combination‐therapy group than in the placebo group. The safety profile of dabrafenib plus trametinib was consistent with that observed with the combination in patients with metastatic melanoma. CONCLUSIONS Adjuvant use of combination therapy with dabrafenib plus trametinib resulted in a significantly lower risk of recurrence in patients with stage III melanoma with BRAF V600E or V600K mutations than the adjuvant use of placebo and was not associated with new toxic effects. (Funded by GlaxoSmithKline and Novartis; COMBI‐AD ClinicalTrials.gov, NCT01682083; EudraCT number, 2012‐001266‐15.)

Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Netherlands Cancer Institute, Division of Medical Oncology, Amsterdam, The Netherlands; Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; Department of Medicine, Dermatology Unit, Gustave Roussy Cancer Campus, Villejuif, France; Department of Pathology, Aberdeen University Medical School & Aberdeen Royal Infirmary, Aberdeen, UK; Oncology Department, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland; Royal Marsden Hospital NHS Foundation Trust, London, UK; Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital of Heidelberg, Heidelberg, Germany

Elevated Levels of BRAFV600 Mutant Circulating Tumor DNA and Circulating Hepatocyte Growth Factor Are Associated With Poor Prognosis in Patients With Metastatic Melanoma

PurposeWe performed a retrospective exploratory analysis to evaluate the prognostic and predictive effect of two circulating biomarkers, BRAFV600 mutant circulating tumor DNA (ctDNA) and circulating hepatocyte growth factor (cHGF), in metastatic melanoma.Materials and MethodsThis study evaluated patients from BRIM-3, a phase III trial comparing vemurafenib and dacarbazine in 675 patients with BRAFV600 mutated advanced melanoma. ctDNA was measured using droplet digital polymerase chain reaction, and cHGF was measured by enzyme-linked immunosorbent assay. Overall survival (OS) was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were estimated using Cox proportional hazards modeling. Partitioning analysis was used to group patients into risk categories.ResultsPatients with elevated levels of baseline BRAFV600 ctDNA had significantly shorter median OS than those with undetectable levels of ctDNA (vemurafenib arm, 9.9 v 21.4 months, respectively, and dacarbazine arm: 6.1 v 21.0 months, respect...

New Era in the Management of Melanoma Brain Metastases

The remarkable advances in the systemic therapy of metastatic melanoma have now extended the 1-year overall survival rate from 25% to nearing 85%. Systemic treatment in the form of BRAF-targeted therapy and immunotherapy is slowly but surely proving its efficacy in the treatment of metatstatic brain metastases (MBM). Single-agent BRAF inhibitors provide an intracranial response rate of 25% to 40%, whereas the combination of BRAFi/MEKi leads to responses in up to 58%. However, the durability of responses induced by BRAFi/MEKi seems to be even shorter than in extracranial disease. On the other hand, single-agent ipilimumab provides comparable clinical benefit in MBMs as it does in extracranial metastases. Single-agent PD-1 anitbodies induce response rates of approximately 20%, and those responses appear durable. Similarly the combination of CTLA-4+ PD-1 antibodies induces durable responses at an impressive rate of 55% and is safe to administer. Although the local treatment approaches with radiation and surgery remain important and are critically needed in the management of MBM, systemic therapy offers a new dimension that can augment the impact of those therapies and come at a potentially lower cost of neurocognitive impairment. Considerations for combining those modalities are direly needed, in addition to considering novel systemic combinations that target mechanisms specific to MBM. In this report, we will discuss the underlying biology of melanoma brain metastases, the clinical outcomes from recent clinical trials of targeted and immunotherapy, and their impact on clinical practice in the context of existing local therapeutic modalities.

Dermatologic Side Effects of Systemic Anticancer Therapy

Skin, hair, and nails are almost always modified by systemic cancer therapies. These changes can sometimes result in severe adverse events, but most of the patients present with light and moderate skin side effects. Nevertheless, these xaddermatologic manifestations can significantly impact patients’ quality of life, especially in the case of new targeted agents that are sometimes prescribed continuously over long periods of time.

Immunotherapy of Melanoma: A New Era

After decades of phase III trials failing to demonstrate an impact on survival by cytokine-based regimens and the lack of progress in the development of therapeutic vaccines in patients with metastatic melanoma, novel ways of modulating the immune system by monoclonal antibodies have changed the landscape. For the first time a clinically important and statistically significant impact on survival by a systemic therapy in advanced metastatic melanoma patients has been developed. Immunotherapy has finally established itself and is here to stay. The impact of ipilimumab-based immunotherapy in patients with advanced melanoma is a new corner stone for many subsequent developments. Other novel monoclonal antibodies are being developed and substantial hope is emerging that these developments may be able to provide a future for the so far stagnant development of effective therapeutic vaccines in metastatic disease.