Early On-Treatment Assessment of T Cells, Cytokines, and Tumor DNA with Adaptively Dosed Nivolumab + Ipilimumab: Final Results from the Phase 2 ADAPT-IT Study.

Purpose: The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported.

Adaptive Dosing of Nivolumab + Ipilimumab Immunotherapy Based Upon Early, Interim Radiographic Assessment in Advanced Melanoma (The ADAPT-IT Study).

Purpose: Nivolumab + ipilimumab (nivo + ipi) is highly efficacious but has high toxicity. Standard treatment in advanced melanoma is four doses of nivo + ipi followed by nivo alone. Whether four doses of nivo + ipi are needed is unclear.

Combining Panitumumab With Anti-PD-1 Antibody in Cutaneous Squamous Cell Carcinoma of the Head and Neck After Inadequate Response to Anti-PD-1 Antibody Alone.

Anti-epidermal growth factor receptor (EGFR) antibodies and anti-programmed cell death 1 protein (PD-1) antibodies have been used separately to treat metastatic cutaneous squamous cell carcinoma (cSCC). While two anti-EGFR antibodies have similar clinical activity, cetuximab is administered weekly, whereas panitumumab is administered every two weeks. This report details findings using panitumumab in combination with anti-PD-1 antibody in patients with relapsed refractory cSCC.

Challenges in assessing the clinical utility and economic value of immune checkpoint inhibitor therapies of Cancer.

Advances in the immunotherapy of cancer have prolonged survival for cancer patients, but the clinical and financial impact of treatments must be considered in determining the overall clinical utility and economic value of therapeutic agents. Quality-adjusted life years and incremental cost-effectiveness ratios are clinical and economic metrics that can be used to evaluate the value of immune checkpoint inhibitors. This Commentary provides perspective on the limitations, benefits, and potential enhancement of this approach to support value-based medicine.

Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAF Mutated Papillary Thyroid Cancer: Two Case Reports.

Background: A multi-institutional, randomized phase II trial of continuous dosing of dabrafenib with or without trametinib is ongoing in metastatic thyroid cancer. Preclinical evidence and emerging clinical experience in other cancers support evaluating intermittent dosing of these two agents to achieve more durable response, while being better tolerated and more cost effective.

Patients: Two consecutive patients with symptomatic, metastatic radioactive iodine-resistant BRAF mutated papillary thyroid cancer and poor performance status were treated initially with dabrafenib 150 mg twice daily plus trametinib 2 mg once daily, first in continuous daily dosing, then in a five-week-on and three-week-off schedule.

Melanoma brain metastasis: overview of current management and emerging targeted therapies.

The high rate of brain metastasis in patients with advanced melanoma has been a clinical challenge for oncologists. Despite considerable progress made in the management of advanced melanoma over the past two decades, improvement in overall survival has been elusive. This is due to the high incidence of CNS metastases, which progress relentlessly and which are only anecdotally responsive to systemic therapies.

Phase I study of the selective Aurora A kinase inhibitor MLN8054 in patients with advanced solid tumors: safety, pharmacokinetics, and pharmacodynamics.

This phase I trial examined the safety, pharmacokinetics, and pharmacodynamics of MLN8054, an oral, selective, small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received increasing doses of MLN8054 in 28-day cycles until dose-limiting toxicity (DLT) was seen in ≥2 of 3-6 patients in a cohort. For the 10-mg and 20-mg cohorts, treatment was administered once daily on days 1 to 5 and 8 to 12.

Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors.

Purpose: Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase.

Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma.

Background: Glycoprotein-96, a non-polymorphic heat-shock protein, associates with intracellular peptides. Autologous tumor-derived heat shock protein-peptide complex 96 (HSPPC-96) can elicit potent tumor-specific T cell responses and protective immunity in animal models. We sought to investigate the feasibility, safety, and antitumor activity of HSPPC-96 vaccines prepared from tumor specimens of patients with metastatic melanoma.

A randomized phase 2 study of erlotinib alone and in combination with bortezomib in previously treated advanced non-small cell lung cancer.

Introduction: This phase 2 study was conducted to determine the efficacy and safety of erlotinib alone and with bortezomib in patients with non-small cell lung cancer (NSCLC).

Methods: Patients with histologically or cytologically confirmed relapsed or refractory stage IIIb/IV NSCLC were randomized (1:1; stratified by baseline histology, smoking history, sex) to receive erlotinib 150 mg/d alone (arm A; n = 25) or in combination with bortezomib 1.6 mg/m2, days 1 and 8 (arm B; n = 25) in 21-day cycles.

A randomized phase III trial of biochemotherapy versus interferon-alpha-2b for adjuvant therapy in patients at high risk for melanoma recurrence.

The objective of this study was to compare the clinical benefit of biochemotherapy and interferon-alpha-2b (IFN) as adjuvant therapy. Biochemotherapy has higher response rates than other regimens in patients with metastatic melanoma. We conducted a randomized phase III study comparing the clinical benefit of biochemotherapy and IFN as adjuvant therapy.

Changes in pERK1/2 and pAKT expression in melanoma lesions after imatinib treatment.

Response to treatment with imatinib mesylate has been associated in preclinical models with the inhibition of two signaling pathways that promote cellular survival - the phosphatidylinositol 3-kinase/AKT pathway and the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) pathway. We sought to evaluate the extent of inhibition of these two pathways in metastatic melanoma specimens from patients treated with imatinib. Metastatic melanoma tumor samples were obtained before and during the second week of imatinib treatment from patients enrolled in a phase II study.

Analysis of protein tyrosine kinases expression in the melanoma metastases of patients treated with Imatinib Mesylate (STI571, Gleevec).

Background: Protein tyrosine kinase (PTK) inhibition has been identified as a promising strategy in the development of new selective therapies, targeting the signaling pathways in melanoma progression. Gleevec, a novel class of anti-tumor drugs, may have a potential therapeutic benefit in melanoma, which involves abnormal activation of abl, c-kit, and platelet-derived growth factor (PDGF) tyrosine kinases.

Methods: Tumor biopsies from 13 patients with metastatic melanoma were screened by immunohistochemistry for PTK [c-kit, C-abl, Abl-related gene (ARG), PDGF receptor-alpha (PDGFR-alpha) and PDGFR-beta] expression before and after being treated with Gleevec @ 400 mg bid for 2 weeks.

Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy.

Background: Systemic treatment of metastatic melanoma is largely ineffective and alternative approaches are needed. Imatinib mesylate is an oral tyrosine kinase inhibitor that targets bcr-Abl, c-kit, platelet-derived growth factor receptor (PDGFR)-alpha, and PDGFR-beta, leading to remarkable clinical responses in several cancers. Signal transduction via c-kit, PDGFR-alpha, and PDGFR-beta has been demonstrated in malignant melanoma.

Pilot study of high-dose, concurrent biochemotherapy for advanced melanoma.

Background: Durable complete response rates ranging from 5% to 20% have been reported in association with biochemotherapy for patients with metastatic melanoma, with response rates on the low end of this range being observed in trials that used lower doses and less intense treatment schedules. In the current study, the authors addressed the feasibility of increasing the doses of agents used in concurrent biochemotherapy.

Methods: Three patients with metastatic melanoma were enrolled at each of six concurrent biochemotherapy dose levels.

Phase II evaluation of paclitaxel by short intravenous infusion in metastatic melanoma.

In four clinical trials in mostly chemotherapy-naive patients with metastatic melanoma, paclitaxel was found to be effective with a response rate of 16%. In vitro studies have shown that following exposure of cancer cells to paclitaxel for 1 h, sensitivity to repeat paclitaxel doses decreased markedly at 48-72 h and returned at 120 h. In this phase II study we assessed the efficacy of paclitaxel at a dose of 90 mg/m per day given intravenously over 80 min on days 1, 5 and 9 every 3 weeks, initially in two groups of 14 patients with metastatic choroidal and non-choroidal melanoma.

Biochemotherapy in patients with metastatic anorectal mucosal melanoma.

Background: Patients with metastatic anorectal melanoma generally have an unfavorable prognosis, but no effective systemic therapy has been reported.

Methods: The authors retrospectively evaluated the medical records of all patients with metastatic anorectal melanoma treated with biochemotherapy between January 1991 and December 2001 at the University of Texas M. D.

Imatinib mesylate inhibits platelet-derived growth factor receptor phosphorylation of melanoma cells but does not affect tumorigenicity in vivo.

Platelet-derived growth factor (PDGF) and its cognate receptor are widely expressed on melanomas. Coexpression of the growth factor and receptor suggests their role in autocrine or paracrine growth mechanisms. Imatinib mesylate was previously reported to have specific activity in inhibiting select tyrosine kinase receptors, including PDGF and c-Kit.

Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array.

Background: It has been proposed that melanoma progression involves a multistep process from benign nevi (BN), dysplastic nevi (DN), radial and vertical growth phase melanoma (MM) to metastatic melanoma (MMM). Protein tyrosine kinases (PTKs) may participate in this progression.

Methods: Tissue microarray blocks of 89 melanocytic lesions were evaluated by immunohistochemistry for the expression of selected PTKs: c-kit, c-abl, abl-related gene (ARG), platelet-derived growth factor receptors alpha (PDGFR-alpha) and beta (PDGFR-beta).

Phase II evaluation of temozolomide in metastatic choroidal melanoma.

Temozolomide (Temodar) has demonstrated clinical activity against melanoma equivalent to that of intravenous dacarbazine (DTIC). Phase I clinical studies have shown that low dose chronic administration of temozolomide permits the delivery of higher dose intensities than a 5 day dose schedule. Temozolomide is hydrolysed to its active metabolite monomethyltriazenoimidazole carboxamide (MTIC) upon absorption from the gastrointestinal tract, while DTIC is inactive until it is metabolized in the liver to MTIC.

Phase I trial of subcutaneous recombinant human interleukin-2 in patients with metastatic melanoma.

Background: Interleukin-2 (IL-2) has activity in metastatic melanoma when given in high doses by the intravenous (IV) route, but its side effects and effectiveness when given in intermediate to high doses by the subcutaneous (SC) route have not been studied adequately. This study sought to determine the maximum tolerated dose (MTD) of IL-2 administered once daily by the SC route.

Methods: Outpatients with progressive metastatic melanoma after chemotherapy were enrolled in a Phase I trial of IL-2 administered SC daily for 5 days per week for 4 consecutive weeks, repeated at 6-week intervals.

Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial.

Purpose: The addition of cytokines to chemotherapy has produced encouraging results in advanced melanoma. In this phase III trial, we compared the effects of chemotherapy (cisplatin, vinblastine, and dacarbazine [CVD]) with those of sequential biochemotherapy consisting of CVD plus interleukin-2 and interferon alfa-2b.

Patients And Methods: Metastatic melanoma patients who had not previously received chemotherapy were stratified by prognostic factors and given chemotherapy or biochemotherapy.

Phase II trial of 9-nitrocamptothecin (RFS 2000) for patients with metastatic cutaneous or uveal melanoma.

The camptothecin derivative 9-nitrocamptothecin (9-NC) has demonstrated clinical activity in patients with ovarian and pancreatic carcinomas. Preclinical studies have shown promising activity of 9-NC for melanoma. We have thus conducted a phase II clinical trial of 9-NC for patients with metastatic cutaneous and uveal melanoma.