KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in <i>BRAF</i>-mutant melanoma

Ferrucci, Pier Francesco; Giacomo, Anna Maria Di; Vecchio, Michele Del; Atkinson, Victoria; Schmidt, Henrik; Schachter, Jacob; Queirolo, Paola; Long, Georgina V.; Stephens, Rosalie; Svane, Inge Marie; Lotem, Michal; Abu-Amna, Mahmoud; Gasal, Eduard; Ghori, Razi; Diede, Scott J.; Croydon, Elizabeth; Ribas, Antoni; Ascierto, Paolo A.

doi:10.1136/jitc-2020-001806

Cited by 141 publications

(146 citation statements)

References 27 publications

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“…It could not meet its primary endpoint of improved median PFS, although a trend to a longer PFS with pembrolizumab (median PFS 16.0 months compared to 10.3 months with placebo) was reported. An updated analysis of KEYNOTE 022 at 24-month follow-up showed the triplet potential as a treatment option for patients with BRAF -mutant advanced melanoma ( 90 ). 24-month PFS rates were 41% with pembrolizumab versus 16.3% with placebo; mOS was not reached with pembrolizumab versus 26.3 months with placebo (HR: 0.64; 95% CI: 0.38–1.06).…”

Section: Treatment Of Stage Iii/iv Non-resectable Melanomamentioning

confidence: 99%

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Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy

2021

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Melanoma is the most fatal skin cancer. In the early stages, it can be safely treated with surgery alone. However, since 2011, there has been an important revolution in the treatment of melanoma with new effective treatments. Targeted therapy and immunotherapy with checkpoint inhibitors have changed the history of this disease. To date, more than half of advanced melanoma patients are alive at 5 years; despite this breakthrough, approximately half of the patients still do not respond to treatment. For these reasons, new therapeutic strategies are required to expand the number of patients who can benefit from immunotherapy or combination with targeted therapy. Current research aims at preventing primary and acquired resistance, which are both responsible for treatment failure in about 50% of patients. This could increase the effectiveness of available drugs and allow for the evaluation of new combinations and new targets. The main pathways and molecules under study are the IDO inhibitor, TLR9 agonist, STING, LAG-3, TIM-3, HDAC inhibitors, pegylated IL-2 (NKTR-214), GITR, and adenosine pathway inhibitors, among others (there are currently about 3000 trials that are evaluating immunotherapeutic combinations in different tumors). Other promising strategies are cancer vaccines and oncolytic viruses. Another approach is to isolate and remove immune cells (DCs, T cells, and NK cells) from the patient’s blood or tumor infiltrates, add specific gene fragments, expand them in culture with growth factors, and re-inoculate into the same patient. TILs, TCR gene transfer, and CAR-T therapy follow this approach. In this article, we give an overview over the current status of melanoma therapies, the clinical rationale for choosing treatments, and the new immunotherapy approaches.

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Section: Treatment Of Stage Iii/iv Non-resectable Melanomamentioning

confidence: 99%

“…G3–5 AEs occurred in 58.3% of the pembrolizumab group versus 25% of the placebo group. The most common G3–5 trAEs were pyrexia (10.0% versus 3.3%), increased aspartate aminotransferase (6.7% versus 3.3%), and increased γ-glutamyl transferase (6.7% versus 5.0%) ( 90 ).…”

Section: Treatment Of Stage Iii/iv Non-resectable Melanomamentioning

confidence: 99%

Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy

2021

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“…Tx-related adverse events (TRAEs) grade ≥ 3 occurred in 55% vs 33% of pts treated with spartalizumb arm versus placebo. TRAEs leading to discontinuation of all 3 study drugs occurred in 12% vs 8% of pts in the two arms, respectively [37].…”

Section: Discussionmentioning

confidence: 94%

Cautious Addition of Targeted Therapy to PD-1 Inhibitors after Initial Progression of BRAF Mutant Metastatic Melanoma on Checkpoint Inhibitor Therapy

Samlowski

Adajar

2021

Preprint

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Background: Virtually all metastatic melanoma patients who progress after initial treatment with PD-1 or CTLA-4 directed antibodies will die of their disease. Salvage options are urgently needed. It is theoretically attractive to combine immunotherapy with targeted agents in progressing patients with BRAF mutation positive melanoma, but the toxicity of combined treatment has proven challenging. We have observed striking responses with the cautious addition of low doses of targeted therapy to PD-1 antibody treatment at the time of disease progression following initial immunotherapy. This allowed conversion of a significant number of rapidly progressing patients to durable complete responses in BRAF mutant melanoma. Results: We therefore performed a retrospective analysis of our large patient database and identified 23 patients who progressed on initial checkpoint inhibitor treatment, who subsequently had cautious addition of BRAF±MEK inhibitor therapy to PD-1 antibody treatment. We found an objective response rate of 55% in second line therapy, with a median progression-free survival of 33.4 months and median overall survival of 34.1 months, with 40% of patients in remission over 3 years. Ten of 12 responding patients were able to discontinue all therapy and continue in unmaintained remission. Toxicity of this approach was generally manageable (only 21.7 % grade 3-5 toxicity). There was 1 early sudden death for unknown reasons in a responding patient. Conclusions: Our results suggest that 2nd line therapy with PD-1 inhibitors plus BRAF±MEK inhibitors has substantial activity and manageable toxicity. This treatment can induce additional durable complete responses after failure of initial immunotherapy of metastatic melanoma. These remarkable results suggest further evaluation be performed of sequential checkpoint inhibitor therapy with cautious addition of targeted therapy in appropriate patients.

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“…Screening of the full-text citations resulted in the exclusion of studies that did not fulfill the inclusion criteria (n=14); did not show adequate data (n=7); not randomized clinical studies (n=1) or in the early stage of clinical trials without uploaded results (n=15). Finally, five randomized clinical trials (RCTs) were included in our meta-analysis (20,21,(24)(25)(26))and details about selection of studies were schematically shown in Figure 1.…”

Section: Included Trials and Studiesmentioning

confidence: 99%

Triple Combination Therapy With PD-1/PD-L1, BRAF, and MEK Inhibitor for Stage III–IV Melanoma: A Systematic Review and Meta-Analysis

et al. 2021

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Triple combination of anti-PD-1/PD-L1 immunotherapy and anti-BRAF plus anti-MEK targeted therapy is a promising antitumor strategy and is increasingly being used in clinical trials. To evaluate the safety and efficacy of triple combination of PD-1/PD-L1, BRAF, and MEK inhibition in patients diagnosed with stage III-IV melanoma, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). The PubMed, EMBASE, and Cochrane Library were searched for all studies published from inception to January 2021. The progression free survival (PFS), overall survival (OS), overall response rate (ORR), and risk of adverse events (AEs) were extracted by two independent investigators and pooled hazard ratio (HR) or risk ratio (RR) with 95% CI were determined using the random-effects model for data synthesis. Overall, five randomized controlled trials encompassing 1,266 patients with stage III-IV melanoma were selected. Triple combination therapy significantly improved PFS (HR = 0.71; 95% CI = 0.59 to 0.86; P = 0.0005) and 2-year OS (RR = 1.12; 95% CI = 1.03 to 1.23; P = 0.01), but had no impact on ORR (RR = 1.09; 95% CI = 0.91 to 1.30; P = 0.37) when compared with controlled treatment group. In addition, triple combination therapy was associated with increased risks of hypothyroidism, arthralgia, myalgia, ALT increased, AST increased, asthenia, and pyrexia compared with control group. Triple combination therapy of PD-1/PD-L1, BRAF, and MEK inhibition achieved better survival benefits but had higher incidence of some adverse events over two-drug combination or monotherapy. Further randomized controlled clinical trials are needed to verify our results.Systematic Review RegistrationPROSPERO 2021 CRD42021235845 Available from https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021235845.

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KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma

Cited by 141 publications

References 27 publications

Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy

Therapeutic Advancements Across Clinical Stages in Melanoma, With a Focus on Targeted Immunotherapy

Cautious Addition of Targeted Therapy to PD-1 Inhibitors after Initial Progression of BRAF Mutant Metastatic Melanoma on Checkpoint Inhibitor Therapy

Triple Combination Therapy With PD-1/PD-L1, BRAF, and MEK Inhibitor for Stage III–IV Melanoma: A Systematic Review and Meta-Analysis

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