Current Systemic Therapies for Melanoma

Palathinkal, Darren M.; Sharma, Timmie R.; Koon, Henry; Bordeaux, Jeremy S.

doi:10.1097/01.dss.0000452626.09513.55

Cited by 32 publications

(43 citation statements)

References 107 publications

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“…Using vermurafinib, a BRAF-inhibitor, in patients with BRAF-mutated melanoma for instance, resulted in significantly improved overall and progression-free survival (67)(68)(69). Also other members of recently (2013) approved drugs such as dabrafenib and Trametinib showed promising results in phase III trials so that the portfolio of systemic targeted drugs which can be used as standard therapy for metastatic melanoma has been expanded considerably (70).…”

Section: Discussionmentioning

confidence: 99%

Malignant melanoma brain metastases: Treatment results and prognostic factors - a single-center retrospective study

Ostheimer

Bormann

Fiedler

et al. 2015

International Journal of Oncology

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Abstract. The brain is one of the most frequent locations of metastasis in malignant melanoma. We aimed to identify prognostic factors for overall survival (OS) and local tumor control (LC) in patients with malignant melanoma metastasized to the brain treated by multimodal therapy. All patients diagnosed with malignant melanoma brain metastases between 1992 and 2011 at a single center were registered (n=100, 65% male, 35% female). OS and LC of individual brain metastases were retrospectively analyzed. Subgroup analyses was performed in patients with multiple brain metastasis (n=35) and LC per lesion (n=72) was evaluated in 37 patients. Median age was 57 (27-81) years. Fifty-three percent of patients had 1-2 brain metastases, 47% had >2 and 71% presented with additional extracranial metastases. Primary treatment included systemic therapy alone (temozolomide/fotemustine, 14%), local therapy (surgery and/or stereotactic radiotherapy, 25%), whole-brain radiotherapy (WBRT, 10%), combined WBRT and systemic therapy (18%), local therapy plus WBRT (5%) and combination of local and systemic therapy (8%). Three percent received a tri-modal therapy (WBRT, local and systemic therapy) and 17% refused treatment. Median follow-up in surviving patients was 32 (4-222) months, median OS in all patients 3.9 months (1-year survival 21.4%). Local therapy (p<0.001), systemic therapy (p=0.002), number of brain metastases and primary therapy including a local therapy (p<0.001) were significantly associated with OS. In the subgroup with multiple brain metastases (n=35), a trend (p=0.058) for improved OS after initial treatment with WBRT plus systemic therapy was noted (median OS 3.8 months) and use of these two modalities over the course of the disease was significantly associated with OS (p=0.007). The best LC per single lesion (n=37) could be achieved by combination of local with systemic therapy (p=0.011). Number of brain metastases, extracranial metastases and use of local therapy are independent prognostic factors in melanoma metastatic to the brain. LC and OS can be improved by combining local with systemic treatment. In patients with multiple brain metastases, WBRT plus systemic therapy provides superior OS.

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Section: Discussionmentioning

confidence: 99%

Malignant melanoma brain metastases: Treatment results and prognostic factors - a single-center retrospective study

Ostheimer

Bormann

Fiedler

et al. 2015

International Journal of Oncology

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“…6 Beginning in 2011, the treatment landscape for metastatic melanoma changed with the approval of novel immunotherapies, such as ipilimumab (Yervoy®), and targeted therapies, such as vemurafenib (Zelboraf®), dabrafenib (Tafinlar®), and trametinib (Mekinist®), all of which improved overall survival benefit. 6–11 In 2014, two additional immunotherapies, pembrolizumab (Keytruda®) and nivolumab (Opdivo®) were approved for the treatment of unresectable or metastatic melanoma. Both treatments were associated with improvements in progression-free survival (PFS), overall survival (OS), and overall objective responses.…”

Section: Introductionmentioning

confidence: 99%

Cost-Effectiveness of Nivolumab-Ipilimumab Combination Therapy Compared with Monotherapy for First-Line Treatment of Metastatic Melanoma in the United States

Tran

McDowell

et al. 2017

JMCP

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BACKGROUND The approval of new immunotherapies has dramatically changed the treatment landscape of metastatic melanoma. These survival gains come with trade-offs in side effects and costs, as well as important considerations to third-party payer systems, physicians, and patients. OBJECTIVE Develop a Markov model to determine the cost-effectiveness of nivolumab, ipilimumab, and nivolumab-ipilimumab combination as first-line therapy in metastatic melanoma while accounting for differential effectiveness in PD-L1 positive and negative patients. METHODS A three-state Markov model (‘PD-L1 positive stable disease’, ‘PD-L1 negative stable disease’, and ‘Progression and/or Death’) was developed using a US societal perspective with a lifetime time horizon of 14.5 years. Transition probabilities were calculated from progression-free survival data reported in the CheckMate-067 trial. Costs were expressed in 2015 US dollars and were determined using national sources. Adverse event (AE) management was determined using immune-related AE (irAE) data from CheckMate-067, irAE management guides for nivolumab and ipilimumab, and treatment guidelines. Utilities were obtained from published literature, using melanoma-specific studies when available, and were weighted based on incidence and duration of irAEs. Base case, one-way sensitivity, and probabilistic sensitivity analyses were conducted. RESULTS Nivolumab-ipilimumab combination therapy is not the cost effective choice ($454,092 per progression-free quality-adjusted-life-year [PFQALY]) compared to nivolumab monotherapy in our base case analysis at a willingness-to-pay threshold of $100,000/PFQALY. Both combination therapy and nivolumab monotherapy were cost-effective choices compared to ipilimumab monotherapy. PD-L1 positive status, utility of nivolumab and combination therapy, and medication costs contributed the most uncertainty to the model. In a population of 100% PD-L1 negative patients, nivolumab was still the optimal treatment but combination therapy had an improved ICER of $295,903/PFQALY. Combination therapy became dominated by nivolumab when 68% of the sample was PD-L1 positive. In addition, the cost of ipilimumab would have to decrease to <$21,555 per dose for combination therapy to have an ICER <$100,000/PFQALY, and to <$19,151 (a 42% reduction) to be more cost-effective than nivolumab monotherapy. CONCLUSIONS Nivolumab-ipilimumab combination therapy is not cost-effective compared to nivolumab monotherapy, which is the most cost-effective option. Professionals in managed care settings should consider the pharmacoeconomic implications of these new immunotherapies as they make value-based formulary decisions and future cost-effectiveness studies are completed.

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“…Until recently, metastatic melanoma patients have had a 5-year survival rate of less than 20% (2) and systemic therapy showed only minimal effect (3). With the currently approved immune checkpoint inhibitors against CTLA-4 and PD-1, 10% to 40% of all metastatic melanoma patients have long-term benefit and survival rates seem to improve (4).…”

Section: Introductionmentioning

confidence: 99%

T-cell Landscape in a Primary Melanoma Predicts the Survival of Patients with Metastatic Disease after Their Treatment with Dendritic Cell Vaccines

et al. 2016

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Tumor-infiltrating lymphocytes appear to be a predictor of survival in many cancers, including cutaneous melanoma. We applied automated multispectral imaging to determine whether density and distribution of T cells within primary cutaneous melanoma tissue correlate with survival of metastatic melanoma patients after dendritic cell (DC) vaccination. CD3þ T cell infiltration in primary tumors from 77 metastatic melanoma patients was quantified using the ratio of intratumoral versus peritumoral T-cell densities (I/P ratio). Patients with longer survival after DC vaccination had stronger T-cell infiltration than patients with shorter survival in a discovery cohort of 19 patients (P ¼ 0.000026) and a validation cohort of 39 patients (P ¼ 0.000016). I/P ratio was the strongest predictor of survival in a multivariate analysis including M substage and serum lactate dehydrogenase level. To evaluate I/P ratio as a predictive biomarker, we analyzed 19 chemotherapy-treated patients. Longer survival times of DC-vaccinated compared with chemotherapytreated patients was observed for high (P ¼ 0.000566), but not low (P ¼ 0.154) I/P ratios. In conclusion, T-cell infiltration into primary melanoma is a strong predictor of survival after DC vaccination in metastatic melanoma patients who, on average, started this therapy several years after primary tumor resection. The infiltration remains predictive even after adjustment for late-stage prognostic markers. Our findings suggest that the I/P ratio is a potential predictive biomarker for treatment selection.

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Current Systemic Therapies for Melanoma

Abstract: Despite new developments, there remains a significant need for better therapies with improved long-term efficacy and decreased toxicity.

Cited by 32 publications

References 107 publications

Malignant melanoma brain metastases: Treatment results and prognostic factors - a single-center retrospective study

Malignant melanoma brain metastases: Treatment results and prognostic factors - a single-center retrospective study

Cost-Effectiveness of Nivolumab-Ipilimumab Combination Therapy Compared with Monotherapy for First-Line Treatment of Metastatic Melanoma in the United States

T-cell Landscape in a Primary Melanoma Predicts the Survival of Patients with Metastatic Disease after Their Treatment with Dendritic Cell Vaccines

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