Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected <i>BRAF</i> V600–Mutant Stage III Melanoma

Hauschild, Axel; Dummer, Reinhard; Schadendorf, Dirk; Santinami, Mario; Atkinson, Victoria; Mandalà, Mario; Chiarion-Sileni, Vanna; Larkin, James; Nyakas, Marta; Dutriaux, Caroline; Haydon, Andrew; Robert, Caroline; Mortier, Laurent; Schachter, Jacob; Lesimple, Thierry; Plummer, Ruth; Dasgupta, Kohinoor; Haas, T; Shilkrut, Mark; Gasal, Eduard; Kefford, Richard; Kirkwood, John M.; Long, Georgina V.

doi:10.1200/jco.18.01219

Cited by 217 publications

(161 citation statements)

References 21 publications

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“…This could be explained by the likely underestimation of stage IIIC disease in our study, resulting from a lack of information about the number of involved lymph nodes in a considerable number of patients. Currently, the effective novel therapies are introduced in the adjuvant setting as routine care . It is therefore likely that the survival of patients with stage III disease will significantly improve in the near future.…”

Section: Discussionmentioning

confidence: 99%

Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population‐based study

Verver

Veldt

Akkooi

et al. 2019

Intl Journal of Cancer

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Melanoma of unknown primary (MUP) may have a different biology to melanoma of known primary, but clinical trials of novel therapies (e.g., immune checkpoint or BRAF/MEK inhibitors) have not reported the outcomes in this population. We therefore evaluated the overall survival (OS) among patients with MUP in the era of novel therapy. Data for stage III or IV MUP were extracted from a nationwide database for the period 2003–2016, with classification based on the eighth edition of the American Joint Committee on Cancer criteria. The population was divided into pre‐ (2003–2010) and post‐ (2011–2016) novel therapy eras. Also, OS in the post‐novel era was compared between patients with stage IV MUP by whether they received novel therapy. In total, 2028 of 65,110 patients (3.1%) were diagnosed with MUP. Metastatic sites were known in 1919 of 2028 patients, and most had stage IV disease (53.8%). For patients with stage III MUP, the 5‐year OS rates were 48.5% and 50.2% in the pre‐ and post‐novel eras, respectively (p = 0.948). For those with stage IV MUP, the median OS durations were unchanged in the pre‐novel era and post‐novel era when novel therapy was not used (both 4 months); however, OS improved to 11 months when novel therapy was used in the post‐novel era (p < 0.001). In conclusion, more than half of the patients with MUP are diagnosed with stage IV and the introduction of novel therapy appears to have significantly improved the OS of these patients.

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Section: Discussionmentioning

confidence: 99%

Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population‐based study

Verver

Veldt

Akkooi

et al. 2019

Intl Journal of Cancer

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“…Some preclinical models suggested that neoadjuvant therapy with clinically detectable volumes of disease would be required to induce long‐term disease control . These preclinical concerns surrounding an overt tumor microenvironment being a requirement for anti‐PD1 activity have been settled in melanoma, however, with the reporting of multiple international adjuvant therapy clinical trials of completely resected stage IIIB and IIIC (AJCCv7) and stage IV disease (Table ) . In the CheckMate 238 study (Efficacy Study of Nivolumab Compared to Ipilimumab in Prevention of Recurrence of Melanoma After Complete Resection of Stage IIIB/IIIC or Stage IV Melanoma) of stage III and IV melanoma (stages IIIB and IIIC, resected stage IV; AJCCv7), nivolumab demonstrated superiority to ipilimumab in terms of both relapse‐free survival (RFS) and toxicity profile.…”

Section: Role Of Anti‐pd1 Therapy In Melanomamentioning

confidence: 99%

“…The combination of dabrafenib and trametinib has also been evaluated as adjuvant therapy in the COMBI‐AD trial (A Phase III Randomized Double Blind Study of Dabrafenib [GSK2118436] in Combination With Trametinib (GSK1120212) Versus Two Placebos in the Adjuvant Treatment of High‐Risk BRAF V600 Mutation‐Positive Melanoma After Surgical Resection), treating patients with resected stage III disease (Table ). Long‐term RFS data have now been reported and, at a median follow‐up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), the 4‐year RFS rates were 54% (95% CI, 49%‐59%) in the dabrafenib plus trametinib arm and 38% (95% CI, 34%‐44%) in the placebo arm, respectively (hazard ratio [HR], 0.49; 95% CI, 0.40‐0.59). The estimated cure rate was 54% (95% CI, 49%‐59%) in the dabrafenib plus trametinib arm compared with 37% (95% CI, 32%‐42%) in the placebo arm.…”

Section: The Role Of Targeted Therapy In Braf‐mutant Melanomamentioning

confidence: 99%

“…20 These preclinical concerns surrounding an overt tumor microenvironment being a requirement for anti-PD1 activity have been settled in melanoma, however, with the reporting of multiple international adjuvant therapy clinical trials of completely resected stage IIIB and IIIC (AJCCv7) and stage IV disease (Table 1). [21][22][23][24][25] In the CheckMate 238 study (Efficacy Study of Nivolumab Compared to Ipilimumab in Prevention of Recurrence of Melanoma After Complete Resection of Stage IIIB/IIIC or Stage IV Melanoma) of stage III and IV melanoma (stages IIIB and IIIC, resected stage IV; AJCCv7), nivolumab demonstrated superiority to ipilimumab in terms of both relapse-free survival (RFS) and toxicity profile. Similarly, in the KEYNOTE-054 study (Study of Pembrolizumab [MK-3475] Versus Placebo After Complete Resection of High-Risk Stage III Melanoma, pembrolizumab demonstrated superiority to placebo in patients with completely resected stage III melanoma (stages IIIA, IIIB, and IIIC; AJCCv7).…”

Section: Role Of Anti-pd1 Therapy In Melanomamentioning

confidence: 99%

“…[29][30][31] In a landmark analysis of the COMBI-D trial ( 30 A pooled analysis of phase 3 trials found that normal lactate dehydrogenase levels, <3 metastatic organ sites, and a sum of lesion dimensions <66 mm identified the best prognostic group of those receiving combination therapy, with a 3-year progression-free survival rate of 42%, suggesting durable disease control without immunotherapy for some patients with low tumor burdens. 31 The combination of dabrafenib and trametinib has also been evaluated as adjuvant therapy in the COMBI-AD trial ( 24 and, at a median follow-up of 44 months (dabrafenib plus trametinib) and 42 months (placebo), the 4-year RFS rates were 54% (95% CI, 49%-59%) in the dabrafenib plus trametinib arm and 38% (95% CI, 34%-44%) in the placebo arm, respectively (hazard ratio [HR], 0.49; 95% CI, 0.40-0.59).…”

Section: The Role Of Targeted Therapy In Braf-mutant Melanomamentioning

confidence: 99%

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Considering adjuvant therapy for stage II melanoma

Poklepovic

Luke

2019

Cancer

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Melanoma is among the few cancers that demonstrate an increasing incidence over time. Simultaneously, this trend has been marked by an epidemiologic shift to earlier stage at diagnosis. Before 2011, treatment options were limited for patients with metastatic disease, and the median overall survival was less than 1 year. Since then, the field of melanoma therapeutics has undergone major changes. The use of anti–CTLA‐4 and anti‐PD1 immune checkpoint inhibitors and combination BRAF/MEK inhibitors for patients with BRAF V600 mutations has significantly extended survival and allowed some patients to remain in durable disease remission off therapy. It has now been confirmed that these classes of agents have a benefit for patients with stage III melanoma after surgical resection, and anti‐PD1 and BRAF/MEK inhibitors are standards of care in this setting. Some patients with stage II disease (lymph node‐negative; American Joint Committee on Cancer stage IIB and IIC) have worse melanoma‐specific survival relative to some patients with stage III disease. Given these results, expanding the population of patients who are considered for adjuvant therapy to include those with stage II melanoma has become a priority, and randomized phase 3 clinical trials are underway. Moving into the future, the validation of patient risk‐stratification and treatment‐benefit prediction models will be important to improve the number needed to treat and limit exposure to toxicity in the large population of patients with early stage melanoma.

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The Changing Kinetics of Advanced Melanoma

Coit

2019

JAMA Dermatol

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The current issue of JAMA Dermatology contains 3 articles that attempt to describe some aspect of disease kinetics of selected subsets of patients with melanoma.The first of these studies, from von Schuckmann and colleagues 1 in Australia, attempts to describe factors predictive of early recurrence (within 2 years) among patients who presented for treatment of clinically localized T1b to T4b melanoma in Queensland.Patients were recruited prospectively from a number of hospital and private clinic sources. Of 1245 patients identified and invited to participate, 700 (56%) were included in the analysis. Most of the follow-up was obtained as a patient-reported binary recurrence status (yes/no) every 6 months. In the event of patients lost to follow-up, local hospital records and Queensland Cancer Registry data were reviewed. All recurrences were verified insofar as possible by medical record review. Factors identified predicting recurrence within 2 years were not surprising and included the presence of ulceration, an increased mitotic index, increasing T stage, and head and neck location. Descriptive statistics were provided comparing outcomes by the seventh and eighth editions of the AJCC Staging Manual, and describing the initial sites of recurrence.The biggest challenge in interpreting the significance of this study is the heterogeneity of the patient data set, a data set that included 442 patients with clinical T1b to T4b who did not undergo sentinel lymph node biopsy (SLNB), 213 patients with pathologic T1b to T4b who had a negative SLNB result, and 38 patients with at least stage IIIa after a positive SLNB result (the SLNB numbers do not quite add up to 700 in Table 1). This heterogeneity recalls that of the AJCC7 data set, where pathologic staging of clinically localized melanomas was not required. The A JCC8 has addressed this shortcoming by including only patients who underwent SLNB, 2 thus describing more homogeneous T-stage subsets. Excluding the patients with T1a disease, the AJCC8 data set depicted describes the dynamic kinetics of outcome in 10 466 patients with pathologic T1b to T4b melanomas. As expected, more advanced tumors generally recur more frequently and earlier. Importantly, the AJCC8 data set demonstrated that most events in this cohort of patients are expected to occur after the 2-year threshold described in the study by von Schuckmann et al, 1 with continued attrition out to at least 10 years. Thus, the second concern: the 2-year interval, although entirely practical for a prospective study such as this, may not be entirely reflective of the true biology of this heterogeneous cohort.

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Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600–Mutant Stage III Melanoma

Cited by 217 publications

References 21 publications

Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population‐based study

Treatment of melanoma of unknown primary in the era of immunotherapy and targeted therapy: A Dutch population‐based study

Considering adjuvant therapy for stage II melanoma

The Changing Kinetics of Advanced Melanoma

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