Pembrolizumab (pembro) plus dabrafenib (dab) and trametinib (tram) in BRAFV600E/K-mutant melanoma: Long-term follow-up of KEYNOTE-022 parts 1, 2, and 3.
Abstract:9516 Background: KEYNOTE-022 (NCT02130466) was a phase 1/2 study of pembro + dab + tram or pembro + tram in patients (pts) with unresectable stage III/IV melanoma (parts 1-3) or solid tumors (parts 4 and 5). In previous analyses of pts with BRAFV600E/K -mutant melanoma, pembro + dab + tram was shown to have manageable safety in parts 1-3, albeit with a higher incidence of TRAEs in part 3, and substantially improved PFS, DOR, and OS vs placebo + dab + tram in part 3, although the primary end point of a statist… Show more
“…Triple therapy in the first line obtained encouraging results in ongoing phase III trials in advanced resectable melanoma. Pembrolizumab + dabrafenib + trametinib improved PFS, duration of response (DOR), and OS compared with placebo + dabrafenib + trametinib ( 29 ), and atezolizumab + vemurafenib + cobimetinib prolonged PFS and provided a clinically meaningful benefit in median DOR compared with placebo + vemurafenib + cobimetinib ( 30 ) in patients with BRAF V600E/K-mutant melanoma. Based on such results, this study will evaluate the neoadjuvant treatment with ICB and targeted therapy followed by adjuvant treatment with atezolizumab (an anti-PD-L1).…”
BackgroundFollowing the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma.MethodsThe study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) cobimetinib 60 mg once daily from day 1 to 21 and from day 29 to 42; and (4) atezolizumab 840 mg for two cycles (day 22 and day 43).Patients will be randomized to three different arms: A) BRAF-mutated patients will receive over 6 weeks (1) + (3); B) BRAF-mutated patients will receive over 6 weeks (2) + (3) + (4); C) BRAF wild-type patients will receive over 6 weeks (3) + (4). All patients will also receive atezolizumab 1200 mg every 3 weeks for 17 cycles after surgery and after a second screening period (up to 6 weeks).DiscussionNeoadjuvant therapy for regional metastases may improve operability and outcomes and facilitate the identification of biomarkers that can guide further lines of treatment. Patients with clinical stage III melanoma may especially benefit from neoadjuvant treatment, as the outcomes of surgery alone are very poor. It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival.Clinical trial registrationeudract.ema.europa.eu/protocol.htm, identifier 2018-004841-17.
“…Triple therapy in the first line obtained encouraging results in ongoing phase III trials in advanced resectable melanoma. Pembrolizumab + dabrafenib + trametinib improved PFS, duration of response (DOR), and OS compared with placebo + dabrafenib + trametinib ( 29 ), and atezolizumab + vemurafenib + cobimetinib prolonged PFS and provided a clinically meaningful benefit in median DOR compared with placebo + vemurafenib + cobimetinib ( 30 ) in patients with BRAF V600E/K-mutant melanoma. Based on such results, this study will evaluate the neoadjuvant treatment with ICB and targeted therapy followed by adjuvant treatment with atezolizumab (an anti-PD-L1).…”
BackgroundFollowing the increased survival of patients with metastatic melanoma thanks to immunotherapy and targeted therapy, neoadjuvant approaches are being investigated to address the unmet needs of unresponsive and intolerant patients. We aim to investigate the efficacy of neoadjuvant plus adjuvant combined or sequenced vemurafenib, cobimetinib and atezolizumab in patients with high-risk, resectable BRAF-mutated and wild-type melanoma.MethodsThe study is a phase II, open-label, randomized non-comparative trial in patients with stage IIIB/C/D surgically resectable, BRAF-mutated and wild-type melanoma, with three possible treatments: (1) vemurafenib 960 mg twice daily from day 1 to 42; (2) vemurafenib 720 mg twice daily from day 1 to 42; (3) cobimetinib 60 mg once daily from day 1 to 21 and from day 29 to 42; and (4) atezolizumab 840 mg for two cycles (day 22 and day 43).Patients will be randomized to three different arms: A) BRAF-mutated patients will receive over 6 weeks (1) + (3); B) BRAF-mutated patients will receive over 6 weeks (2) + (3) + (4); C) BRAF wild-type patients will receive over 6 weeks (3) + (4). All patients will also receive atezolizumab 1200 mg every 3 weeks for 17 cycles after surgery and after a second screening period (up to 6 weeks).DiscussionNeoadjuvant therapy for regional metastases may improve operability and outcomes and facilitate the identification of biomarkers that can guide further lines of treatment. Patients with clinical stage III melanoma may especially benefit from neoadjuvant treatment, as the outcomes of surgery alone are very poor. It is expected that the combination of neoadjuvant and adjuvant treatment may reduce the incidence of relapse and improve survival.Clinical trial registrationeudract.ema.europa.eu/protocol.htm, identifier 2018-004841-17.
“…Even so, it is noteworthy that there may be a group of patients for whom triple therapy is more effective. The characteristics of the patient groups that benefited from triple therapy in the COMBI-i study were not consistent with the subgroup analysis of KEYNOTE022 (16). As more data is gathered in the future and further post-hoc analyses are reported, it may be possible to predict which patients will benefit from triple therapy.…”
“…Given the limitations seen in both immune checkpoint inhibitors (ICIs) and targeted therapies, combination therapy of ICIs with BRAF/MEK inhibitors has been further developed. The KEYNOTE-022 phase I/II trial evaluated the addition of pembrolizumab to dabrafenib and trametinib in patients with unresectable or metastatic melanoma in parts 1–3 and solid tumors in parts 4–5 [ 54 ]. Reports from the long-term follow-up of melanoma patients with BRAFV600E/K mutations were presented in 2022 [ 54 ].…”
Section: Combinations Of Braf/mek Inhibitors With Immunotherapymentioning
The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. Constitutive activation of this pathway by BRAF mutations can cause downstream activation of kinases, leading to uncontrolled cellular growth and carcinogenesis. Therefore, inhibition of BRAF and the downstream substrate MEK has been shown to be effective in controlling tumor growth and proliferation. Over the last decade, several BRAF and MEK inhibitors have been investigated, ranging from primarily melanoma to various cancer types with BRAF alterations. This subsequently led to several Food and Drug Administration (FDA) approvals for BRAF/MEK inhibitors for melanoma, non-small cell lung cancer, anaplastic thyroid cancer, colorectal cancer, histiocytosis neoplasms, and finally, tumor-agnostic indications. Here, this comprehensive review will cover the developments of BRAF and MEK inhibitors from melanomas to tumor-agnostic indications, novel drugs, challenges, future directions, and the importance of those drugs in personalized medicine.
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