Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib ± cobimetinib: a pooled analysis of four clinical trials

Ascierto, Paolo A.; Ribas, Antoni; Larkin, James; McArthur, Grant A.; Lewis, Karl D.; Hauschild, Axel; Flaherty, Keith T.; McKenna, Edward; Zhu, Qian; Mun, Yong; Dréno, Brigitte

doi:10.1186/s12967-020-02458-x

Cited by 10 publications

(9 citation statements)

References 30 publications

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“…Similar proportions of patients across these studies received subsequent anticancer treatment with immunotherapy or further targeted therapy. Although the extent to which long-term OS is influenced by subsequent treatment is unclear, recent analyses suggest that patients who progress following treatment with BRAF and/or MEK inhibitors derive an OS benefit from subsequent treatment with immunotherapy or additional targeted therapy (12). Identification of subgroups of patients likely to achieve long-term treatment benefit is important to inform treatment decisions in the management of patients with metastatic melanoma.…”

Section: Discussionmentioning

confidence: 99%

5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation–Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study

Ascierto

Dréno

Larkin

et al. 2021

Clinical Cancer Research

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123

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Purpose:The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAF V600 mutation-positive advanced melanoma. We report long-term followup of coBRIM, with at least 5 years since the last patient was randomized.Experimental Design: Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily).Results: 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports.Conclusions: Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAF V600 mutation-positive advanced melanoma.Research.

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Section: Discussionmentioning

confidence: 99%

5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation–Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study

Ascierto

Dréno

Larkin

et al. 2021

Clinical Cancer Research

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123

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“…Another important consideration is that our analysis simplified our treatment variations by categorising them into major groups. We did not distinguish different types of immunotherapies or targeted therapies, either in monotherapies or combination therapies as well as with or without surgical metastasectomy or radiotherapy, nor evaluated the sequence of different treatments given, which past studies had reported variations in survival outcomes 42–48 . Furthermore, while we excluded ocular melanoma, which is highly resistant to systemic therapies and typically treated differently, we did not further analyse the differences in prognosis among other melanoma subtypes due to our limited sample size and data regarding the primary tumours.…”

Section: Discussionmentioning

confidence: 99%

Clinical predictors of survival in real world practice in stage IV melanoma

Archer

Yip

et al. 2022

Cancer Reports

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Background and Aim While studies continually identify new clinical prognostic factors in stage IV melanoma, the introduction of targeted and immunotherapies have revolutionised the prognosis of advanced melanoma since 2011. The study aims to investigate the prognostic significance of past and newly identified clinical factors in a contemporary cohort. Methods A retrospective analysis of The Canberra Hospital melanoma database identified 161 patients with Stage IV melanoma between 2011 and 2017. Survival was analysed by demographics and clinical factors with chi‐square tests to determine significance. Logistic binary regression was performed to test the independence of the clinical factors on predicting the survival outcome. Results Overall, the 3‐month, 6‐month, 9‐month, and 12‐month stage IV melanoma survival rate of our cohort was 79%, 67%, 55%, and 45%, respectively. Age, sex, and BRAF mutation status were found to have no impact on survival, whereas M1d category of the American Joint Committee on Cancer (AJCC) staging (8th edition), neutrophil‐lymphocyte ratio (NLR) >3, elevated serum LDH, more than three metastatic sites, brain metastases, poorer Eastern cooperative oncology group (ECOG) status were associated with poorer survival. Binary logistic regression test identified AJCC staging, NLR (cutoff score 3), LDH, and brain metastases as independent prognostic factors. Conclusion Most clinical factors investigated in this study were found to have a statistically significant impact on survival, with AJCC (8th edition) staging M1a‐M1d, NLR (cutoff score 3), LDH, and brain metastases identified as independent prognostic factors in stage IV melanoma from a contemporary cohort treated with targeted therapies and immunotherapies.

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“…However, it has been reported that BRAF/MEKi therapy might also affect the tumor microenvironment (TME) and improve durable tumor surveillance, thus having a long-term beneficial effect. It has been shown that these long-term effects are most likely in patients with CR to TT [ 30 ]. In particular, it has been suggested by Long and colleagues, that patients with a CR and favorable baseline characteristics, such as a lower initial tumor burden, fewer metastatic tumor sites, or normal LDH-levels, may be more likely to show a stronger and more sustained response, thus driving long-term survival [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study

Stege

Haist

Schultheis

et al. 2021

Cancers

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The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progression-free (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment (p < 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary real-world cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT.

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Impact of initial treatment and prognostic factors on postprogression survival in BRAF-mutated metastatic melanoma treated with dacarbazine or vemurafenib ± cobimetinib: a pooled analysis of four clinical trials

Cited by 10 publications

References 30 publications

5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation–Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study

5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation–Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study

Clinical predictors of survival in real world practice in stage IV melanoma

Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study

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