Comparative Efficacy of Combination Immunotherapy And Targeted Therapy in the Treatment of
            <i>BRAF</i>
            -mutant Advanced Melanoma: A Matching-Adjusted Indirect Comparison

Atkins, Michael B.; Tarhini, Ahmad A.; Rael, M; Gupte-Singh, Komal; O'Brien, Elliott; Ritchings, Corey; Rao, Sumati; McDermott, David F.

doi:10.2217/imt-2018-0208

Cited by 30 publications

(32 citation statements)

References 24 publications

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“…For example, in a recent matching-adjusted indirect comparison, clinical outcomes with nivolumab plus ipilimumab were compared with dabrafenib plus trametinib or vemurafenib plus cobimetinib combination treatments in patients with BRAF-mutant advanced melanoma. 47 After adjusting for differences in baseline characteristics, PFS and response outcomes were similar among the treatments; but, beyond 12 months of treatment, nivolumab plus ipilimumab improved OS compared with targeted therapy. This suggests that the survival benefit with combination immunotherapy emerges later and may be more durable than with targeted therapies.…”

Section: Discussionmentioning

confidence: 88%

Evolving impact of long-term survival results on metastatic melanoma treatment

Michielin

Atkins

Koon

et al. 2020

J Immunother Cancer

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Melanoma treatment has been revolutionized over the past decade. Long-term results with immuno-oncology (I-O) agents and targeted therapies are providing evidence of durable survival for a substantial number of patients. These results have prompted consideration of how best to define long-term benefit and cure. Now more than ever, oncologists should be aware of the long-term outcomes demonstrated with these newer agents and their relevance to treatment decision-making. As the first tumor type for which I-O agents were approved, melanoma has served as a model for other diseases. Accordingly, discussions regarding the value and impact of long-term survival data in patients with melanoma may be relevant in the future to other tumor types. Current findings indicate that, depending on the treatment, over 50% of patients with melanoma may gain durable survival benefit. The best survival outcomes are generally observed in patients with favorable prognostic factors, particularly normal baseline lactate dehydrogenase and/or a low volume of disease. Survival curves from melanoma clinical studies show a plateau at 3 to 4 years, suggesting that patients who are alive at the 3-year landmark (especially in cases in which treatment had been stopped) will likely experience prolonged cancer remission. Quality-of-life and mixture-cure modeling data, as well as metrics such as treatment-free survival, are helping to define the value of this long-term survival. In this review, we describe the current treatment landscape for melanoma and discuss the long-term survival data with immunotherapies and targeted therapies, discussing how to best evaluate the value of long-term survival. We propose that some patients might be considered functionally cured if they have responded to treatment and remained treatment-free for at least 2 years without disease progression. Finally, we consider that, while there have been major advances in the treatment of melanoma in the past decade, there remains a need to improve outcomes for the patients with melanoma who do not experience durable survival.

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Section: Discussionmentioning

confidence: 88%

Evolving impact of long-term survival results on metastatic melanoma treatment

Michielin

Atkins

Koon

et al. 2020

J Immunother Cancer

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“…Current treatment options for unresectable stage III and stage IV disease (5) include BRAF-targeted therapies for patients that have BRAF-mutant melanomas, and ICIs with anti-PD-1 alone or in combination with anti-CTLA-4. However, durable response is only seen in a minority of patients, and the optimal sequencing of therapies and the selection of the most effective first-line therapy, remain controversial (6,7). The CheckMate 067 trial demonstrated that the combination ipilimumab and nivolumab resulted in superior long-term survival outcomes compared with either nivolumab or ipilimumab monotherapy, with a 5-year overall survival of 52% (8).…”

Section: Introductionmentioning

confidence: 99%

Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy

Marsavela

Lee

Calapre

et al. 2020

Clinical Cancer Research

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Purpose: We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment. Experimental Design: Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first-(n ¼ 32) or second-line (n ¼ 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (n ¼ 66). An external validation cohort included 128 patients commencing ICI therapies in the first-(N ¼ 77) or second-line (N ¼ 51) settings. Results: In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07-0.53; P < 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22-0.83; P ¼ 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti-PD-1 monotherapy, relative to those treated with combination anti-CTLA-4/anti-PD-1 inhibitors. Conclusions: Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-na€ ve patients with high ctDNA may preferentially benefit from combined ICIs.

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“…Considering an additional subgroup analysis from CheckMate 067 showing a 64% survival rate in all patients with normal baseline LDH and less than three organ sites with metastases, it is likely that combined ICB might show a 5-year survival rate > 64% in BRAF -mutated patients showing additional favorable baseline characteristics. Although these results should be interpreted with great caution, an indirect comparison by Atkins et al showed improved survival outcome in BRAF -mutated melanoma patients receiving ipilimumab plus nivolumab compared with V + C and D + T [ 52 ]. This is also supported by indirectly comparing the 5-year landmark OS rates of COMBI-v/d and CheckMate 067 (34% vs. 60%).…”

Section: Summary/discussionmentioning

confidence: 99%

Long-Term Outcomes in BRAF-Mutated Melanoma Treated with Combined Targeted Therapy or Immune Checkpoint Blockade: Are We Approaching a True Cure?

2020

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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 longterm outcome.

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Comparative Efficacy of Combination Immunotherapy And Targeted Therapy in the Treatment of BRAF -mutant Advanced Melanoma: A Matching-Adjusted Indirect Comparison

Cited by 30 publications

References 24 publications

Evolving impact of long-term survival results on metastatic melanoma treatment

Evolving impact of long-term survival results on metastatic melanoma treatment

Circulating Tumor DNA Predicts Outcome from First-, but not Second-line Treatment and Identifies Melanoma Patients Who May Benefit from Combination Immunotherapy

Long-Term Outcomes in BRAF-Mutated Melanoma Treated with Combined Targeted Therapy or Immune Checkpoint Blockade: Are We Approaching a True Cure?

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