Sequential treatment with immunotherapy and BRAF inhibitors in BRAF-mutant advanced melanoma

Aya, Francisco; Fernández-Martínez, Aranzazu; Gaba, Lydia; Victoria, Iván; Tosca, M.; Pineda, Estela; Gascón, Pere; Prat, Aleix; Arance, Ana

doi:10.1007/s12094-016-1514-0

Cited by 25 publications

(22 citation statements)

References 26 publications

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“…However, other studies did not demonstrate a negative impact of previous treatment with BRAFi to subsequent immunotherapy. For instance, a recent small retrospective series of BRAF-mutated patients compared two groups of populations receiving a sequence of BRAFi followed by immunotherapy ( n = 16) or the reverse sequence ( n = 9) [ 14 ]. ORR achieved by BRAFi was not different between groups.…”

Section: Discussionmentioning

confidence: 99%

Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma

et al. 2018

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BackgroundAnti-PD-1 and BRAF-inhibitors (BRAFi) have been approved as first-line treatments in advanced melanoma. To date, no prospective data are available to give the best sequence of treatment. The objective of this study was to evaluate in real-life the efficacy of anti-PD-1 after BRAFi, ipilimumab, or chemotherapy failure.MethodsThis was a single institution cohort analysis in patients treated with anti-PD-1 right after BRAFi, ipilimumab, or chemotherapy failure. Melanoma evolution after anti-PD-1 initiation was analyzed in BRAF-mutated and BRAF wild-type patients. The efficacy of treatment was evaluated by Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Overall Survival (OS).ResultsSeventy-four patients were included: 33 wild-type and 41 BRAF-mutated melanoma. ORR to anti-PD-1 was significantly lower in BRAF-mutated patients (12.2% vs. 45.5%, p = 0.002). After anti-PD-1 initiation, the median PFS and OS was significantly shorter in the BRAF mutated group (2 vs. 5 months and 7 vs. 20 months, p = 0.001). The hazard ratio for disease progression was of 2.3 (95%CI:1.3–3.9; p = 0.003) and 2.5 (95%CI:1.3–4.5; p = 0.005) for death. Thirty-nine percent of BRAF-mutated-patients died within 3 months after anti-PD-1 initiation. Rapid death (≤3 months) was significantly higher in BRAF-mutated patients (55.2% vs. 20.0%, p = 0.014).DiscussionThis is the largest series of unselected patients treated in real-life with anti-PD-1 as second-or-higher line of treatment. Anti-PD-1 was less effective in BRAF-mutated cases as a majority of patients presented aggressive tumor evolution after BRAFi discontinuation. These data are consistent with previous studies suggesting a negative impact of BRAFi prior to immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma

et al. 2018

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“…Importantly, newer small-molecule targeted therapies may also help to enhance immunogenicity of tumors for immunotherapies or to reduce side effects of established chemo- and radiotherapy regimens. Because the combination of immunotherapy using checkpoint inhibitors with kinase inhibitors such as BRAFi for metastatic BRAF V600mut melanoma may be effective, clinical trials assessing the best sequence, dose, and duration of treatments to archive the highest response rates are currently underway (NCT02818023, NCT02130466) [ 106 ].…”

Section: Towards Algorithms For Improved Combination Therapy and Imentioning

confidence: 99%

Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies

Gatzka

2018

Cancers

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Over the last decade, the treatment of tumor patients has been revolutionized by the highly successful introduction of novel targeted therapies, in particular small-molecule kinase inhibitors and monoclonal antibodies, as well as by immunotherapies. Depending on the mutational status, BRAF and MEK inhibitor combinations or immune checkpoint inhibitors are current first-line treatments for metastatic melanoma. However, despite great improvements of survival rates limitations due to tumor heterogeneity, primary and acquired therapy resistance, immune evasion, and economical considerations will need to be overcome. Accordingly, ongoing clinical trials explore the individualized use of small-molecule drugs in new targeted therapy combinations based on patient parameters and tumor biopsies. With focus on melanoma therapy this review aims at providing a comprehensive overview of such novel alternative and combinational therapy strategies currently emerging from basic research. The molecular principles and drug classes that may hold promise for improved tumor therapy combination regimens including kinase inhibition, induction of apoptosis, DNA-damage response inhibition, epigenetic reprogramming, telomerase inhibition, redox modulation, metabolic reprogramming, proteasome inhibition, cancer stem cell transdifferentiation, immune cell signaling modulation, and others, are explained in brief. In addition, relevant targeted therapy combinations in current clinical trials and individualized treatment strategies are highlighted.

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“…It should be noted that this was retrospective study and at the time the only licensed immunotherapy was monotherapy with ipilimumab. Aya et al (8) failed to uncover any differences in overall survival in a small retrospective cohort study specifically comparing targeted then immune therapy and vice versa. However, results from prospective trials examining sequential therapy, e.g., NCT02224781 or SECOMBIT (NCT02631447) with additional checkpoint inhibitors, are eagerly anticipated.…”

Section: Discussionmentioning

confidence: 98%

“…Pending the results of ongoing clinical trials, the optimal firstline treatment strategy remains unclear and is likely to remain patient-and tumor-specific. Given the rapid response to targeted therapy, accompanied by a dramatic decrease in overall tumor load, the decision to commence targeted therapy in patients with BRAF V600 mutations may be favored in the context of symptomatic disease and the presence of adverse prognostic markers, including raised serum LDH concentrations, ECOG performance status> 1, younger patients, and those with brain and/or metastases at multiple sites (8,9). Typically, resistance to targeted therapy occurs after a median treatment time of 13 months.…”

Section: Introductionmentioning

confidence: 99%

Sequential Treatment With Targeted and Immune Checkpoint Therapy in Patients With BRAF Positive Metastatic Melanoma: The Importance of Timing?

et al. 2019

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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.

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Sequential treatment with immunotherapy and BRAF inhibitors in BRAF-mutant advanced melanoma

Cited by 25 publications

References 26 publications

Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma

Ineffective anti PD-1 therapy after BRAF inhibitor failure in advanced melanoma

Targeted Tumor Therapy Remixed—An Update on the Use of Small-Molecule Drugs in Combination Therapies

Sequential Treatment With Targeted and Immune Checkpoint Therapy in Patients With BRAF Positive Metastatic Melanoma: The Importance of Timing?

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