Evidence of synergy with combined BRAF-targeted therapy and immune checkpoint blockade for metastatic melanoma.
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ABSTRACT:
SUBMITTER: Cooper ZA
PROVIDER: S-EPMC4292518 | biostudies-other | 2014 Oct
REPOSITORIES: biostudies-other
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Project description:Approximately 50% of all melanomas harbor an activating BRAF mutation. In patients suffering from an advanced melanoma with such a somatic alteration, combined targeted therapy with a BRAF and MEK inhibitor can be applied to significantly increase the survival probability. Nevertheless, resistance mechanisms, as well as negative predictive biomarkers (elevated lactate dehydrogenase levels, high number of metastatic organ disease sites, brain metastasis), remain a major problem in treating melanoma patients. Recently, a landmark overall survival (OS) rate of 34% after 5 years of combined targeted therapy in treatment-naïve patients was reported. On the other hand, patients harboring a BRAF mutation and receiving first-line immune checkpoint blockade with ipilimumab plus nivolumab showed a 5-year OS rate of 60%. As indicated by these data, long-term survival can be reached in melanoma patients but it remains unclear if this is equivalent to reaching a true cure for metastatic melanoma. In this review, we summarize the recent results for combined targeted therapy and immunotherapy in advanced melanoma harboring an activating BRAF mutation and discuss the impact of baseline characteristics on long-term outcome.
| S-EPMC7371660 | biostudies-literature
Project description:BRAF-targeted therapy results in objective responses in the majority of patients; however, the responses are short lived (∼6 months). In contrast, treatment with immune checkpoint inhibitors results in a lower response rate, but the responses tend to be more durable. BRAF inhibition results in a more favorable tumor microenvironment in patients, with an increase in CD8(+) T-cell infiltrate and a decrease in immunosuppressive cytokines. There is also increased expression of the immunomodulatory molecule PDL1, which may contribute to the resistance. On the basis of these findings, we hypothesized that BRAF-targeted therapy may synergize with the PD1 pathway blockade to enhance antitumor immunity. To test this hypothesis, we developed a BRAF(V600E)/Pten(-/-) syngeneic tumor graft immunocompetent mouse model in which BRAF inhibition leads to a significant increase in the intratumoral CD8(+) T-cell density and cytokine production, similar to the effects of BRAF inhibition in patients. In this model, CD8(+) T cells were found to play a critical role in the therapeutic effect of BRAF inhibition. Administration of anti-PD1 or anti-PDL1 together with a BRAF inhibitor led to an enhanced response, significantly prolonging survival and slowing tumor growth, as well as significantly increasing the number and activity of tumor-infiltrating lymphocytes. These results demonstrate synergy between combined BRAF-targeted therapy and immune checkpoint blockade. Although clinical trials combining these two strategies are ongoing, important questions still remain unanswered. Further studies using this new melanoma mouse model may provide therapeutic insights, including optimal timing and sequence of therapy.
| S-EPMC4097121 | biostudies-literature
Project description:BACKGROUND:Uveal melanoma (UM) is highly refractory to treatment with dismal prognosis in advanced stages. The value of the combined checkpoint blockade with CTLA-4 and PD-1 inhibition in metastatic UM is currently unclear. METHODS:Patients with metastatic or unresectable UM treated with ipilimumab in combination with a PD-1 inhibitor were collected from 16 German skin cancer centers. Patient records of 64 cases were analyzed for response, progression-free survival (PFS), overall survival (OS), and safety. Clinical parameters and serum biomarkers associated with OS and treatment response were determined with Cox regression modelling and logistic regression. RESULTS:The best overall response rate to combined checkpoint blockade was 15.6% with 3.1 and 12.5% complete and partial response, respectively. The median duration of response was 25.5?months (range 9.0-65.0). Stable disease was achieved in 21.9%, resulting in a disease control rate of 37.5% with a median duration of the clinical benefit of 28.0?months (range 7.0-65.0). The median PFS was 3.0?months (95% CI 2.4-3.6). The median OS was estimated to 16.1?months (95% CI 12.9-19.3). Regarding safety, 39.1% of treated patients experienced a severe, treatment-related adverse event according to the CTCAE criteria (grade 3: 37.5%; grade 4: 1.6%). The most common toxicities were colitis (20.3%), hepatitis (20.3%), thyreoiditis (15.6%), and hypophysitis (7.8%). A poor ECOG performance status was an independent risk factor for decreased OS (p?=?0.007). CONCLUSIONS:The tolerability of the combined checkpoint blockade in UM may possibly be better than in trials on cutaneous melanoma. This study implies that combined checkpoint blockade represents the hitherto most effective treatment option available for metastatic UM available outside of clinical trials.
| S-EPMC6854774 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) therapy provides remarkable clinical gains and has been very successful in treatment of melanoma. However, only a subset of patients with advanced tumors currently benefit from ICB therapies, which at times incur considerable side effects and costs. Constructing predictors of patient response has remained a serious challenge because of the complexity of the immune response and the shortage of large cohorts of ICB-treated patients that include both 'omics' and response data. Here we build immuno-predictive score (IMPRES), a predictor of ICB response in melanoma which encompasses 15 pairwise transcriptomics relations between immune checkpoint genes. It is based on two key conjectures: (i) immune mechanisms underlying spontaneous regression in neuroblastoma can predict melanoma response to ICB, and (ii) key immune interactions can be captured via specific pairwise relations of the expression of immune checkpoint genes. IMPRES is validated on nine published datasets1-6 and on a newly generated dataset with 31 patients treated with anti-PD-1 and 10 with anti-CTLA-4, spanning 297 samples in total. It achieves an overall accuracy of AUC = 0.83, outperforming existing predictors and capturing almost all true responders while misclassifying less than half of the nonresponders. Future studies are warranted to determine the value of the approach presented here in other cancer types.
| S-EPMC6693632 | biostudies-literature
Project description:Background: Immune checkpoint- and targeted therapy have dramatically improved the therapeutic landscape in the management of BRAF mutation positive metastatic melanoma. However, pending the results of clinical trials, not only is it currently unclear whether immune checkpoint- or targeted therapy should be commenced up front, but the optimal time for changing treatment, specifically to prevent resistance whilst maintaining disease control, is unknown. Methods: We retrospectively identified eleven patients with BRAF V600 mutated metastatic melanoma who commenced targeted therapy between 11/2012 and 12/2017 in our center. In 5 cases the decision was made to "electively" switch to immune checkpoint therapy (elective group) following the development of a complete or partial response. In the remaining 6 cases the initial "reactive" switch was necessitated by disease progression or the development of intolerable side-effects (reactive group). Results: Overall, the elective cohort had a more favorable course in terms of overall survival (1,003 vs. 827 days), and 80% of the patients remain alive, in contrast to 17 % of the patients in the reactive group. However, it should be borne in mind that multiple switches due to disease progression were undertaken and this undoubtedly also impacted upon overall survival. Conclusion: Elective switching from targeted to immune checkpoint therapy was associated with a better outcome in terms of survival, at least in everyday clinical practice. It remains unclear whether the choice of initial therapy confers long-term survival and disease-control advantages and this should be addressed in prospective studies.
| S-EPMC6928141 | biostudies-literature
Project description:Patients with BRAF V600 (BRAF) mutated metastatic melanoma are eligible for therapy with both immune checkpoint inhibitors and targeted therapies, making treatment choice a complex decision. The present study aimed to describe patterns of treatment with immunotherapy and targeted therapy and BRAF testing in patients with metastatic melanoma presumed to have BRAF mutations (BRAF+) in the years following the approval of the newer generation of immune checkpoint inhibitors and targeted therapies (2014-2016). Two large US commercial claims databases [Truven Health Analytics MarketScan and IQVIA Real-World Data Adjudicated Claims - USA (IQVIA RWD Adjudicated Claims - USA)] were used. Patients were presumed BRAF+ if they received at least 2 lines of therapy of which at least 1 included targeted therapy. Sequence of lines of therapy and regimens used in first (1L), second (2L), and third (3L), as well as timing of BRAF testing by sequence of therapy were described. In the Truven sample (n=162), targeted therapy was used by 66% in 1L and by 54% in 2L, and 62% had a BRAF test; in the IQVIA RWD Adjudicated Claims - USA sample (n=247), targeted therapy was used by 62% in 1L and by 50% in 2L, and 68% had a BRAF test. Among those with a claim for a BRAF test prior to 1L, over two-thirds were initiated on targeted therapy. These findings suggest that the rate of BRAF testing remained low in the years following the approval of BRAF-targeted regimens for metastatic disease. Given the recently approved adjuvant treatment options for stage III melanoma, improving the rates of BRAF testing becomes increasingly important.
| S-EPMC6494034 | biostudies-literature
Project description:In the version of this article originally published, there was an error in the URL linked to by an accession code in the data availability section of the methods. The erroneous URL was: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE100351 . The correct URL is: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE115821 . The error has been corrected in the HTML and PDF versions of this article.
| S-EPMC9639231 | biostudies-literature
Project description:Melanoma is the deadliest form of skin cancer and has an incidence that is rising faster than any other solid tumor. Metastatic melanoma treatment has considerably progressed in the past five years with the introduction of targeted therapy (BRAF and MEK inhibitors) and immune checkpoint blockade (anti-CTLA4, anti-PD-1, and anti-PD-L1). However, each treatment modality has limitations. Treatment with targeted therapy has been associated with a high response rate, but with short-term responses. Conversely, treatment with immune checkpoint blockade has a lower response rate, but with long-term responses. Targeted therapy affects antitumor immunity, and synergy may exist when targeted therapy is combined with immunotherapy. This article presents a brief review of the rationale and evidence for the potential synergy between targeted therapy and immune checkpoint blockade. Challenges and directions for future studies are also proposed.
| S-EPMC4296084 | biostudies-literature
Project description:The recent advent of targeted and immune-based therapies has revolutionized the treatment of melanoma and transformed outcomes for patients with metastatic disease. The majority of patients develop resistance to the current standard-of-care targeted therapy, dual BRAF and MEK inhibition, prompting evaluation of a new combination incorporating a CDK4/6 inhibitor. Based on promising preclinical data, combined BRAF, MEK and CDK4/6 inhibition has recently entered clinical trials for the treatment of BRAFV600 melanoma. Interestingly, while BRAF- and MEK-targeted therapy was initially developed on the basis of potent tumor-intrinsic effects, it was later discovered to have significant immune-potentiating activity. Recent studies have also identified immune-related impacts of CDK4/6 inhibition, though these are less well defined and can be both immune-potentiating and immune-inhibitory. BRAFV600 melanoma patients are also eligible to receive immunotherapy, specifically checkpoint inhibitors against PD-1 and CTLA-4. The immunomodulatory activity of BRAF/MEK-targeted therapies has prompted interest in combination therapies incorporating these with immune checkpoint inhibitors, however recent clinical trials investigating this approach have produced variable results. Here, we summarize the immunomodulatory effects of BRAF, MEK and CDK4/6 inhibitors, shedding light on the prospective utility of this combination alone and in conjunction with immune checkpoint blockade. Understanding the mechanisms that underpin the clinical efficacy of these available therapies is a critical step forward in optimizing novel combination and scheduling approaches to combat melanoma and improve patient outcomes.
| S-EPMC8137893 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) therapy provides remarkable clinical gains, where melanoma is at the forefront of its success. However, only a subset of patients with advanced tumors currently benefit from these therapies, which at times incur considerable side-effects and costs. Constructing such predictors of patient’s response has remained a serious challenge due to the complexity of the immune response and the shortage of large ICB-treated patient cohorts including both omics and response data. Here we build IMPRES, a predictor of ICB-response in melanoma which encompasses 15 pairwise transcriptomics relations between immune checkpoint genes. It is based on two key conjectures: (a) immune mechanisms underlining spontaneous regression in neuroblastoma can predict ICB response in melanoma, and (b) key immune interactions can be captured via specific pairwise relations of immune checkpoint genes’ expression. IMPRES is validated on 9 published datasets1–6 and on a newly generated dataset of 31 tumor samples treated with anti-PD-1 and 10 tumor samples treated with anti-CTLA-4 (some of these are treated with both antibodies), spanning 297 samples in total. It achieves an overall accuracy of AUC=0.83, outperforming existing predictors, capturing almost all true responders while misclassifying less than half of the non-responders. Future studies are warranted to determine the value of the approach presented here in other cancer types.
2018-08-20 | GSE115821 | GEO