Melanoma treatment have been revolutionized since 2010 by the development of immune checkpoint inhibitors, and, for BRAF-mutated melanoma, targeted therapies based on BRAF and MEK inhibitors, which ...is a model of effective targeted therapy in cancer. However, patients with BRAF wild type cannot benefit for such treatments. In this review, we will focus on the current clinical development of targeted therapies beyond BRAF, in NRAS-mutated and KIT-altered melanoma.
In NRAS-mutated melanoma, targeted therapies based on MEK inhibition are being developed as monotherapy or in combination with MAPK, PI3K or CDK4/6 inhibitor. Targeted therapies of KIT-altered melanoma patients is based in KIT inhibitor (mostly imatinib, nilotinib), although for both melanoma subtypes, results are for now disappointing as compared with BRAF and MEK inhibitors in BRAF-mutated melanoma.
Combined therapeutic targeted strategies are awaited in NRAS-mutated and KIT-altered melanoma and could provide additional benefit.
Tailoring clinical trial methods and design according to drug class and gathering systematically long‐term real‐life clinical data from national early access programs might be options to improve the ...reliability of drug development in metastatic melanoma.
Better understanding of the biology of BRAF-mutated melanoma has led to the development of highly effective therapy, BRAF and MEK inhibitors, targeting abnormally activated protein kinases for ...patient with BRAF-mutated melanoma. The purpose of this article was to review the recent published data on BRAF and MEK inhibitors in melanoma in the metastatic, adjuvant and neoadjuvant setting to facilitate the management of melanoma patients in clinical practice.
The spectacular outcomes of targeted therapy in advanced melanoma patients have led to their development in the adjuvant setting with substantial improvements in recurrence-free and overall survival. The neoadjuvant strategy is already used in many cancers to decrease tumor load, improve resectability and prevent relapse. Targeted therapy in the neoadjuvant setting is a therapeutic approach being explored in subsequent studies.
We hope that this review will help clinicians to manage melanoma patients in routine practice.
Abstract Aims and background With the recent emergence of immunotherapies and novel targeted treatments for advanced and metastatic melanoma such as selective B-Raf inhibitors and checkpoint ...inhibitors, the treatment landscape in Europe has changed considerably. The aim of this review was to provide an overview of current treatment pathways in Europe for the treatment of advanced melanoma, unresectable stage III–IV. Methods A literature search of four databases was conducted to identify publications reporting on the treatment patterns of advanced and metastatic melanoma (stage III–IV) in European populations. Results Seven full-text publications and two conference abstracts reported on observational studies of melanoma treatment practices in France, Italy and the United Kingdom. Treatment patterns were identified for two time periods: 2005–2009 and 2011–2012. Common treatments reported for both periods included chemotherapy with dacarbazine, fotemustine or temozolomide. The main differences between the two periods were the introduction and prescription of immunotherapy ipilimumab and targeted therapy vemurafenib between 2011 and 2012. Across the three countries studied, the types of treatments prescribed between 2005 and 2009 were relatively similar, however, with noticeable differences in the frequency and priority of administration. Conclusion Treatment practices for advanced melanoma vary markedly across different European countries and continue to evolve with the introduction of new therapies. The results of this review highlight a considerable evidence gap with regards to recent treatment patterns for advanced melanoma in Europe, especially post-2011 after the introduction of novel therapeutic agents, and more recently with the introduction of programmed cell death 1 inhibitors.
Abstract
Background
Although the PI3K/AKT/mTOR pathway is one of the most altered pathways in human tumours, therapies targeting this pathway have shown numerous adverse effects due to positive ...feedback paradoxically activating upstream signaling nodes. The somewhat limited clinical efficacy of these inhibitors calls for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer.
Main body
Recent studies have shown the central role of mTOR complex 2 (mTORC2) as a pro‐tumourigenic factor of the PI3K/AKT/mTOR pathway in a number of cancers. SIN1/MAPKAP1 is a major partner of mTORC2, acting as a scaffold and responsible for the substrate specificity of the mTOR catalytic subunit. Its overexpression promotes the proliferation, invasion and metastasis of certain cancers whereas its inhibition decreases tumour growth in vitro and in vivo. It is also involved in epithelial‐mesenchymal transition, stress response and lipogenesis. Moreover, the numerous interactions of SIN1 inside or outside mTORC2 connect it with other signaling pathways, which are often disrupted in human tumours such as Hippo, WNT, Notch and MAPK.
Conclusion
Therefore, SIN1's fundamental characteristics and numerous connexions with oncogenic pathways make it a particularly interesting therapeutic target. This review is an opportunity to highlight the tumourigenic role of SIN1 across many solid cancers and demonstrates the importance of targeting SIN1 with a specific therapy.
Despite the poor prognosis associated with melanoma brain metastases (BM), data concerning these patients and their inclusion in clinical trials remains scarce. We report here the efficacy results of ...a subgroup analysis in patients with BRAFV600-mutant melanoma and BM treated with BRAF and MEK inhibitors dabrafenib (D) and trametinib (T).
This phase IIIb single-arm, open-label, multicenter, French study included patients with unresectable stage IIIc or IV BRAFV600-mutant melanoma with or without BM. The present analysis focuses on patients with BM. Response rates were determined clinically and/or radiologically as per standard clinical practice. Progression-free survival (PFS) was estimated using the Kaplan Meier analysis and modelled with multivariate Cox regression model. Risk subgroups were identified using an exponential regression tree analysis. Significance was set at p < 0.05.
Between March 2015 and November 2016, 856 patients were included and 275 (32%) patients had BM. Median PFS was 5.68 months (95% confidence interval CI, 5.29–6.87). Significant independent factors associated with shorter PFS were ECOG ≥1, elevated serum lactate dehydrogenase (LDH), ≥3 metastatic sites, and non-naïve status. The binary-split classification and regression tree modelling identified baseline LDH and ECOG status as major prognostic factors.
This is to date the largest, close to real-world, study in advanced BRAFV600-mutant melanoma patients with BM treated with D+T. ECOG >1, ≥3 metastatic sites and elevated LDH were associated with shorter PFS, a finding previously demonstrated only in patients without BM. Further studies are warranted to determine the optimal treatment sequence in this population.
•This is the largest cohort of patients with BRAF V600-mutant melanoma and with brain metastases.•The results confirm the clinical activity of trametinib + dabrafenib in these patients.•LDH, Eastern Cooperative Oncology Group, number of metastatic sites and naïve/non-naïve status were associated with progression-free survival.
Melanoma brain metastases (MBMs) are historically associated with poor prognosis. Radiation therapy is conventionally associated with a high local control rate. Development of targeted therapy and ...immunotherapy has improved overall survival (OS) and intracranial response rate, but about 50% of patients failed to respond to these novel therapies. The objective of this study was to assess the impact of combined radiotherapy (cRT) on overall survival in a large multicenter real-life prospective cohort of patients with MBM treated with immunotherapy or targeted therapy.
Clinical data from 262 patients with MBM were collected via MelBase, a French multicentric biobank prospectively enrolling unresectable stage III or IV melanoma. Two groups were defined: patients receiving cRT (cRT group) or not receiving cRT (no-cRT group). Primary end-point was OS. Propensity score weighting was used to correct for indication bias.
Among the 262 patients, 93 (35%) received cRT (cRT group). The patients were treated with immunotherapy in 69% and 60% and with targeted therapy in 31% and 40% of the cRT and no-cRT groups, respectively. With a median follow-up of 6.9 months, median OS was 16.8 months and 6.9 months in the cRT and no-cRT groups, respectively. After propensity score weighting, cRT was associated with longer OS (hazard ratio = 0.6, 95% confidence interval: 0.4–0.8; p=0.007). Median OS after ponderation was 15.3 months and 6.2 months in the cRT and no-cRT groups, respectively.
This study shows that cRT may be associated with a significant decrease of 40% in the risk of death in patients with MBM treated with systemic therapy.
•This is a prospective multicenter observational cohort of advanced melanoma.•Propensity scores are used to limit confusion and selection bias.•Combined radiotherapy (cRT) increased overall survival in patients with brain metastases.•cRT and systemic therapy decreased the risk of death by 40%.•cRT and new systemic therapies may be synergistic.
Real-life populations are more heterogeneous than those included in prospective clinical studies. In cancer patients, comorbidities and co-medications favor the appearance of severe adverse effects ...which can significantly impact quality of life and treatment effectiveness. Most of tyrosine kinase inhibitors (TKI) have been developed with flat oral dosing exposing patients to the risk of poor adherence due to side effects. Additionally, genetic or physiological factors, differences in diet, and drug-drug interactions can lead to inter-individual variability affecting treatment outcomes and increasing the risk of adverse events. Knowledge of the different factors of variability allows individualized patient management. This review examines the effects of adherence, food intake, and pharmaceutical form on the pharmacokinetics of oral TKI, as well as evaluating pharmacokinetics considerations improving TKI management. Concentration-effectiveness and concentration-toxicity data are presented for the selected TKI, and a simple therapeutic drug monitoring schema is outlined to help individualize dosing of oral TKI.
•Flat oral dosing of TKI takes no consideration of heterogeneity among cancer patients and can promote non-adherence.•Genetic or physiological factors, diet, and drug–drug interactions lead to PK variability.•Use of exposure–effect data to individualize treatment can ensure optimized outcomes and reduced toxicity.•Therapeutic drug monitoring can help to further individualize dosing of oral TKI.
A multitude of TKI has been developed and approved targeting various oncogenetic alterations. While these have provided improvements in efficacy compared with conventional chemotherapies, resistance ...to targeted therapies occurs. Mutations in the kinase domain result in the inability of TKI to inactivate the protein kinase. Also, gene amplification, increased protein expression and downstream activation or bypassing of signalling pathways are commonly reported mechanisms of resistance. Improved understanding of mechanisms involved in TKI resistance has resulted in the development of new generations of targeted agents. In a race against time, the search for new, more potent and efficient drugs, and/or combinations of drugs, remains necessary as new resistance mechanisms to the latest generation of TKI emerge. This review examines the various generations of TKI approved to date and their common mechanisms of resistance, focusing on TKI targeting BCR-ABL, epidermal growth factor receptor, anaplastic lymphoma kinase and BRAF/MEK tyrosine kinases.
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•BCR-ABL, EGFR, ALK and BRAF/MEK tyrosine kinases are implicated in various cancers•Mechanisms of resistance to targeted TKI include kinase domain mutations and downstream signal pathway activation•New-generation TKIs are effective against TK mutant and can overcome resistance involving other pathways
Sonidegib, a hedgehog pathway inhibitor, is indicated for treatment of locally advanced basal cell carcinoma, based on the results of the BOLT study. However, to date, no real-world study of ...sonidegib has been reported. An observational, retrospective, single-centre study (PaSoS study) was conducted. The primary objective was to evaluate the efficacy of sonidegib for treatment of locally advanced basal cell carcinoma in a real-world setting. Secondary objectives included modalities of use, tolerability, tumour evolution, and management after discontinuation. A total of 21 patients treated with sonidegib were included from March 2018 to January 2021. The median follow-up was 18.7 months and median exposure 7.0 months. Objective response (OR) rate was 81.0% (n = 17) including 6 (29%) patients with a complete response (CR). Disease control rate was 100%. First tumour response was rapid, with a median time of 2.3 months. Nine (43%) patients underwent surgery after sonidegib discontinuation, and no relapse was observed. All the patients experienced at least 1 adverse event (AE). Muscle spasms were the most frequent AE (n = 14; 67%), followed by dysgeusia (n = 8; 38%) and alopecia (n = 12; 57%). The efficacy and safety profile of sonidegib in this first-to-date real-life trial are consistent with prior results. Overall, real-world evidence corroborated sonidegib efficacy and tolerability as a first-line treatment for locally advanced basal cell carcinoma.
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