Targeting RAF1 gene fusions with MEK inhibition in metastatic melanoma.

The biological and clinical relevance of gene fusions in melanoma is unknown. Reports and preclinical data have suggested that tumor cells with specific rearrangements such as RAF1 gene fusions could be therapeutically targeted. To investigate the relevance of targeted therapy in patients with melanoma harboring RAF1 gene fusions, we reviewed records of 1268 melanoma patients with targeted sequencing data at the Dana-Farber Cancer Institute.

Nivolumab maintenance improves overall survival of patients with advanced melanoma who experience severe immune-related adverse events on nivolumab plus ipilimumab.

Background: The combination of ipilimumab and nivolumab is a highly effective treatment for metastatic cutaneous melanoma. However, immune-related adverse events (irAEs) are common, often necessitating treatment interruption and the use of immunosuppressive agents. There is no data on the impact of resuming nivolumab on survival following recovery from the irAE and completion of immunosuppressive treatment.

Is There a Current Role for Combination Chemotherapy or High-Dose Interleukin 2 in Melanoma?

Immune checkpoint inhibition and targeted therapies have revolutionized the treatment of melanoma. However, chemotherapy and interleukin 2 (IL-2) therapy may still have a role in the later-line treatment of patients who do not have durable responses to other treatments. Chemotherapy can work transiently in patients whose disease has progressed on immune checkpoint inhibitors and for whom there are no appropriate targeted therapy options.

Sargramostim for Prophylactic Management of Gastrointestinal Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy for Cancer.

Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations.

Multicenter Evaluation of Radiation and Immune Checkpoint Inhibitor Therapy in Mucosal Melanoma and Review of Recent Literature.

Purpose: Optimal integration of local therapy and systemic immune therapy for patients with mucosal melanoma (MM) is uncertain. We evaluated treatment patterns and outcomes following radiation therapy (RT) in combination with immune checkpoint inhibition (ICI) in MM.

Methods And Materials: Thirty-seven patients with localized (n = 32, 87%) or node-positive (n = 5, 14%) MM were treated across 4 institutions with RT to the primary tumor with or without oncologic resection (n = 28, 76%) and ICI from 2012 to 2020.

Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study.

Background: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.

Methods: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma.

Ziv-aflibercept plus pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment.

Background: Vascular endothelial growth factor is associated with reduced immune response and impaired anti-tumor activity. Combining antiangiogenic agents with immune checkpoint inhibition can overcome this immune suppression and enhance treatment efficacy.

Methods: This study investigated the combination of ziv-aflibercept anti-angiogenic therapy with pembrolizumab in patients with advanced melanoma resistant to anti-PD-1 treatment.

Immunomodulator use, risk factors and management of flares, and mortality for patients with pre-existing rheumatoid arthritis after immune checkpoint inhibitors for cancer.

Objective: To investigate immunomodulator use, risk factors and management for rheumatoid arthritis (RA) flares, and mortality for patients with pre-existing RA initiating immune checkpoint inhibitors (ICI) for cancer.

Methods: We performed a retrospective cohort study of all patients with RA meeting 2010 ACR/EULAR criteria that initiated ICI for cancer at Mass General Brigham or Dana-Farber Cancer Institute in Boston, MA (2011-2022). We described immunomodulator use and changes at baseline of ICI initiation.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of melanoma, version 3.0.

Since the first approval for immune checkpoint inhibitors (ICIs) for the treatment of cutaneous melanoma more than a decade ago, immunotherapy has completely transformed the treatment landscape of this chemotherapy-resistant disease. Combination regimens including ICIs directed against programmed cell death protein 1 (PD-1) with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) agents or, more recently, anti-lymphocyte-activation gene 3 (LAG-3) agents, have gained regulatory approvals for the treatment of metastatic cutaneous melanoma, with long-term follow-up data suggesting the possibility of cure for some patients with advanced disease. In the resectable setting, adjuvant ICIs prolong recurrence-free survival, and neoadjuvant strategies are an active area of investigation.

Mortality and immune-related adverse events after immune checkpoint inhibitor initiation for cancer among patients with pre-existing rheumatoid arthritis: a retrospective, comparative, cohort study.

Background: Patients with pre-existing rheumatoid arthritis initiating immune checkpoint inhibitors for cancer might be at risk of increased mortality, rheumatoid arthritis flares, and other immune-related adverse events (AEs). We aimed to determine whether pre-existing rheumatoid arthritis was associated with higher mortality and immune-related AE risk in patients treated with immune checkpoint inhibitors.

Methods: This retrospective, comparative cohort study was conducted at the Mass General Brigham Integrated Health Care System and the Dana-Farber Cancer Institute in Boston (MA, USA).

A phase I/II study of LY3022855 with BRAF/MEK inhibition in patients with Melanoma.

BRAF/MEK targeted therapies and immune checkpoint inhibition have dramatically improved disease control and survival of patients with advanced melanoma. However, most patients do not have durable benefit from either of these therapies. BRAF targeted therapy often has a limited duration of efficacy due to the development of resistance.

Brief Communication on Pathologic Assessment of Persistent Stable Metastatic Lesions in Patients Treated With Anti-CTLA-4 or Anti-CTLA-4 + Anti-PD-1 Therapy.

Despite the wide use of immune checkpoint inhibition for the treatment of melanoma, the mechanisms leading to long-term stable disease are incompletely understood. Patients with metastatic melanoma who had received ipilimumab alone or ipilimumab plus nivolumab 2+years prior and attained at least 6 months of stable disease were identified. Positron emission tomography/computed tomography (PET/CT) was performed.

A phase I/II study of MCS110 with BRAF/MEK inhibition in patients with melanoma after progression on BRAF/MEK inhibition.

Background: Prognosis for patients with metastatic melanoma has been improved dramatically with the development of BRAF/MEK directed therapy and immune checkpoint inhibition. However, resistance to therapy remains a challenge, particularly with BRAF/MEK targeted therapy which often has a limited duration of efficacy. Pre-clinical data suggest that adding CSF1 inhibition to BRAF/MEK targeted therapy may reduce resistance and increase efficacy.

Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

Background: Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines.

Methods: Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.

Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

Background: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown.

Methods: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population.

Impact of Precision Medicine in Oncology: Immuno-oncology.

Cancer treatment has dramatically changed over the last decade with the development of immunotherapy. Therapies including immune cytokines, immune checkpoint inhibition, intratumoral therapies, and cellular therapies are already widely used in the oncology clinic. Active development continues in these areas and in the development of vaccines, bispecific therapies, and more refined cellular therapies.

Efficacy and safety of immune checkpoint inhibitors in young adults with metastatic melanoma.

Background: The integration of immune checkpoint inhibitors (ICI) for the treatment of melanoma has resulted in remarkable and durable responses. Given the potential role of immunosenescence, age may contribute to differential ICI efficacy and toxicity. While older patients have been studied in detail, outcomes from ICI in young patients (≤40 years) are not well characterised.

Effectiveness of Adjuvant Pembrolizumab vs High-Dose Interferon or Ipilimumab for Quality-of-Life Outcomes in Patients With Resected Melanoma: A Secondary Analysis of the SWOG S1404 Randomized Clinical Trial.

Importance: A key issue for the adjuvant treatment of patients with melanoma is the assessment of the effect of treatment on relapse, survival, and quality of life (QOL).

Objective: To compare QOL in patients with resected melanoma at high risk for relapse who were treated with adjuvant pembrolizumab vs standard of care with either ipilimumab or high-dose interferon α 2b (HDI).

Design, Setting, And Participants: The S1404 phase 3 randomized clinical trial was conducted by the SWOG Cancer Research Network at 211 community/academic sites in the US, Canada, and Ireland.

Immune checkpoint inhibitor gastritis is often associated with concomitant enterocolitis, which impacts the clinical course.

Background: Gastrointestinal immune-related adverse events are frequently caused by immune checkpoint inhibitors (ICIs) and often require interruption of cancer treatment. Compared with ICI colitis and enteritis, limited information exists about ICI gastritis. This study characterized clinical features and treatment outcomes of ICI gastritis.

Chemotherapy after immune checkpoint inhibitor failure in metastatic melanoma: a retrospective multicentre analysis.

Introduction: Despite remarkably improved outcomes with immune checkpoint inhibition, many patients with metastatic melanoma will eventually require further therapy. Chemotherapy has limited activity when used first-line but can alter the tumour microenvironment and does improve efficacy when used in combination with immunotherapy in lung cancer. Whether chemotherapy after checkpoint inhibitor failure has relevant activity in patients with metastatic melanoma is unknown.