Metastatic BRAF Research Articles

First-line encorafenib plus binimetinib and pembrolizumab for advanced BRAF V600-mutant melanoma: Safety lead-in results from the randomized phase III STARBOARD study

BackgroundBRAF inhibitors plus MEK inhibitors (BRAFi/MEKi) and immune checkpoint inhibitors (CPIs) are approved for BRAF V600-mutant advanced melanoma. Combinations of BRAFi/MEKi with CPIs may further improve outcomes and could offer additional treatment strategies. MethodsSTARBOARD (NCT04657991) is a phase III study with an initial safety lead-in (SLI) phase conducted to determine the recommended phase III dose (RP3D) for encorafenib in combination with binimetinib and pembrolizumab. Patients with untreated, unresectable locally advanced or metastatic BRAF V600E/K-mutant cutaneous melanoma received binimetinib 45 mg twice daily and pembrolizumab 200 mg every 3 weeks plus encorafenib 450 mg once daily (COMBO450 plus pembrolizumab) or 300 mg once daily (COMBO300 plus pembrolizumab). The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Secondary endpoints included safety, objective response, time to response, and duration of response. Progression-free survival was assessed post hoc. ResultsIn the SLI, the median follow-up duration was 19.4 months. Twenty patients received COMBO450 plus pembrolizumab and 17 received COMBO300 plus pembrolizumab. DLTs occurred in 1 of 17 DLT-evaluable patients in the COMBO450 plus pembrolizumab arm and in 2 of 17 DLT-evaluable patients in the COMBO300 plus pembrolizumab arm. No treatment-related deaths occurred in either treatment arm. The overall response rate was 65.0 % in the COMBO450 plus pembrolizumab arm and 47.1 % in the COMBO300 plus pembrolizumab arm. ConclusionThe STARBOARD SLI showed that safety across the cohorts was generally comparable to the known safety profile of each agent. The standard dose regimen of COMBO450 plus pembrolizumab was chosen as the RP3D.

Mutation-Specific CRISPR Targeting with SaCas9 and AsCas12a Restores Therapeutic Sensitivity in Treatment-Resistant Melanoma.

Background: Melanoma remains one of the most challenging cancers to treat effectively with drug resistant remaining a constant concern, primarily with activating BRAF mutations. Mutations in the BRAF gene appear in approximately 50% of patients, 90% of which are V600E. Two frontline BRAF inhibitors (BRAFi), vemurafenib and dabrafenib, are frequently used to treat unresectable or metastatic BRAF V600E melanoma. Initial response rates are high, but soon thereafter, 70-80% of patients develop resistance to treatment within a year. A major mechanism of resistance is the generation of a secondary Q61K mutation in the NRAS gene. Methods: We have developed an approach in which a CRISPR-Cas complex can be designed to distinguish between mutant genes enabling resistance to standard care in tumor cells and normal genomes of healthy cells. For the first time, we demonstrated the utility of two CRISPR-directed mutation-specific editing approaches to restore BRAFi sensitivity in BRAFV600E/NRASQ61K resistant A375 cells. Results: We utilize an AsCas12a protospacer adjacent motif site created by the NRAS Q61K mutation and the Q61K mutation in the critical seed region of an SaCas9 sgRNA for Q61K-selective targeting. We show here that both approaches allow for effective NRAS targeting of only mutated-Q61K and after CRISPR-directed Q61K-targeting, previously resistant A375 cells are re-sensitized to BRAFi treatment. Conclusion: Our data support the feasibility of the development of CRISPR-Cas therapeutic approaches to the treatment of melanoma. Successful therapeutic CRISPR-directed gene editing would enable both specific and efficient editing of a mutation-specific targeting approach eliminate concern for on- and off-target damage to the genomes of healthy cells.

INEAS's Cost-Effectiveness Analysis of Vemurafenib: Paving the Way for Value-Based Pricing in Tunisia.

The Tunisian Health Technology Assessment (HTA) body, INEAS, conducted a cost-effectiveness analysis (CEA) of vemurafenib in the treatment of locally advanced or metastatic BRAF V600-mutated melanoma. The objective of this analysis was to enable the use of value-based pricing as a new approach to price negotiation. This study was part of a broader HTA report that was prepared in response to a joint request from the regulatory authorities and the CNAM, Tunisia's compulsory insurance scheme. Our analysis was based on a probabilistic Markov cohort model that calculated the costs and quality-adjusted life years (QALY) associated with vemurafenib compared to the standard of care from a public payer perspective. The CEA indicated that vemurafenib provides a gain of 0.38 life years (1.78 vs. 1.4) for an incremental cost of USD 101,106.62 from the perspective of the main public payer (CNAM). This study revealed an incremental cost-effectiveness ratio (ICER) of 163,311.40 USD/QALY and 163,911.46 USD/QALY, respectively, from the CNAM and public health facilities' perspectives. Vemurafenib cannot be considered cost-effective in terms of what has normally been considered a reasonable willingness to pay (WTP) in Tunisia. A significant price reduction would be necessary to bring the incremental cost-effectiveness ratio to an acceptable level.

O6-1 Post-hoc analysis of TRAEs observed in a phase 2 study of encorafenib + binimetinib in metastatic BRAF V600-mutated TC

O6-1 Post-hoc analysis of TRAEs observed in a phase 2 study of encorafenib + binimetinib in metastatic BRAF V600-mutated TC

Relative dose intensity of first-line triplet chemotherapy in metastatic colorectal cancer

PurposeRelative dose intensity (RDI) is a measurement of chemotherapy (CT) dose defined as the actual dose received divided by the standard calculated dose during a set period. The study objective was to assess the impact of a RDI ≥ 80% on response and survival of patients treated in first line CT by FOLFOXIRI or FOLFIRINOX ± Bevacizumab (BV) for an unresectable metastatic colorectal cancer (mCRC). Materials and methodsIt was a retrospective, non-interventional, multicenter study calculating RDI from the first cycles of CT to the first CT-scan evaluation (CT-scan1). Objective response and disease control rates (ORR and DCR), progression-free survival (PFS) and overall survival (OS) were compared between patients with RDI ≥ 80% and <80% and results were adjusted for age, gender, ECOG, tumor location, number of metastatic sites, RAS and BRAF status, the CT regimen, the use of BV, the delay from C1 to CT scan1. ResultsAmong 152 screened patients, 100 met inclusion criteria, with a mean (± standard deviation) age at 59.0 (± 10.7) years. The ECOG performance status was 0–1 in 96 (96%) patients; metastases were synchronous in 95 (95%), RAS and BRAF were mutated in 60 (60%) and 22 (22%), respectively. ORR was observed in 51 (51%) at CT-scan1 with median PFS and OS of 10.5 and 21.9 months, respectively. A RDI ≥ 80% was observed in 44 (44%) patients without impact on ORR (ORa: 1.04, 95% CI: 0.37 to 2.89, p = 0.94) but was significantly associated to improved PFS and OS with HRa 0.50 (95%CI: 0.29 to 0.87, p = 0.013) and 0.52 (95% CI: 0.29 to 0.91, p = 0.023), respectively. ConclusionOur results suggest a low level of FOLFOXIRI or FOLFIRINOX +/- BV exposure in first-line mCRC is associated with a significant trend on PFS and OS.

Updated results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with EC-naïve metastatic BRAF V600E colorectal cancer (CRC) in the phase 1b/2 HERKULES-3 study.

3517 Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Patients (pts) with metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) have dramatically poorer survival rates than those with non-BRAF V600E mutated CRC, highlighting the need for novel therapies. The combination of a BRAF plus EGFR inhibitor is approved for the treatment of pts with BRAF V600E mCRC; however, objective response occurs in only 20% of pts. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. ERAS-007 alone or in combination with encorafenib and cetuximab (EC) showed promising in vitro and in vivo activity in BRAF V600E CRC models, supporting investigation of the potential clinical benefit of ERAS-007 + EC in pts with BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety, tolerability, PK, and preliminary clinical activity of the combination of ERAS-007 + EC in pts with EC-naïve BRAF V600E CRC. Results: As of 30 November 2023, 19 (EC-naïve and EC-pretreated) pts have been dosed with ERAS-007 100 mg twice daily-once a week (BID-QW) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥25% of pts were dermatitis acneiform (52.6%); nausea and fatigue (47.4% each); diarrhea (42.1%); constipation, headache, and hematuria (31.6% each); and vomiting, anemia, and infusion-related reaction (26.3% each). There were no Grade 4 TEAEs. One pt suffered a Grade 5 unrelated event of respiratory failure. There were no Grade 3 treatment-related AEs that occurred in more than 1 pt. There were no ERAS-007-related AEs that led to discontinuation of ERAS-007. Of the 19 pts, 11 were EC naïve and 10 of 11 were efficacy evaluable. In the EC naïve efficacy evaluable pts, the ORR was 40% with 3 of the 4 responses confirmed. The maximum duration of response is &gt; 15 months; updated data will be presented. Conclusions: ERAS-007 100 mg BID-QW in combination with EC was safe and well tolerated with preliminary evidence of promising clinical activity. These results support continued evaluation of this combination in EC naïve pts with BRAF V600E CRC. Clinical trial information: NCT05039177 .

COLUMBUS 7-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600E/K-mutant melanoma

BackgroundTreatment with encorafenib plus binimetinib and encorafenib monotherapy is associated with improved progression-free survival (PFS) and overall survival (OS) compared with vemurafenib in patients with BRAF V600E/K-mutant metastatic melanoma. We report results from the 7-year analysis of COLUMBUS part 1 (NCT01909453) at 99.7 months (median duration between randomization and data cutoff). Methods577 patients with locally advanced unresectable or metastatic BRAF V600E/K-mutant melanoma who were treatment-naive or progressed after first-line immunotherapy were randomized 1:1:1 to encorafenib 450 mg once daily (QD) plus binimetinib 45 mg twice daily (BID) (n = 192), vemurafenib 960 mg BID (n = 191), or encorafenib monotherapy 300 mg QD (n = 194). No prior BRAF/MEK inhibitor was allowed. ResultsSeven-year PFS and OS rates (95 % CI) were 21.2 % (14.7–28.4 %) and 27.4 % (21.2–33.9%) in the encorafenib plus binimetinib arm and 6.4 % (2.1–14.0 %) and 18.2 % (12.8–24.3 %) in the vemurafenib arm, respectively. Median melanoma-specific survival (95 % CI) was 36.8 months (27.7–51.5 months) in the encorafenib plus binimetinib arm and 19.3 months (14.8–25.9 months) in the vemurafenib arm. Thirty-four long-term responders (complete/partial response ongoing at 7 years) were identified across arms. ConclusionsThis is the longest follow-up from a phase III trial of BRAF/MEK inhibitor combination in BRAF V600E/K-mutant metastatic melanoma. Safety results were consistent with the known tolerability profile of encorafenib plus binimetinib. Results support the long-term efficacy and known safety of encorafenib plus binimetinib in this population and provide new insights on long-term responders. Interactive data visualization is available at the COLUMBUS dashboard (https://clinical-trials.dimensions.ai/columbus7/).

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial

No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.

Effectiveness, safety and utilization of cobimetinib and vemurafenib in patients with BRAF V600 mutant melanoma with and without cerebral metastasis under real-world conditions in Germany: the non-interventional study coveNIS.

Cobimetinib/vemurafenib combination therapy is approved for treatment of adults with unresectable or metastatic BRAF V600 mutated malignant melanoma (mM). The non-interventional post-authorisation safety study coveNIS collected real-world data on cobimetinib/vemurafenib treatment focussing on overall survival (OS), safety and utilization. MM patients with brain metastases are usually excluded from clinical studies. coveNIS observed 2 cohorts: mM patients without (Cohort A) and with cerebral metastases (Cohort B), aiming to close the data gap for the latter population. A direct comparison of the 2 cohorts was not intended. The primary effectiveness objective was OS; the safety objective was the incidence of all and of serious adverse events (AEs). Secondary objectives included progression-free survival (PFS), time to development of cerebral metastasis (Cohort A) and time to central nervous system relapse (Cohort B). All statistical analyses were descriptive. Between 2017 and 2021, 95 patients were included (Cohort A: 54, Cohort B: 41 patients) at 32 sites in Germany. Median OS was 21.6 months in Cohort A, 7.4 months in Cohort B. Median PFS was 6.9 months in Cohort A, 5.2 months in Cohort B. The proportion of patients experiencing any AEs was 83.3% (Cohort A) and 87.8% (Cohort B). The two most common AEs in Cohort A were 'diarrhoea' (37%), 'vomiting' (20.4%) and 'pyrexia' (20.4%); in Cohort B 'diarrhoea' (36.6%) and 'fatigue' (22%). In conclusion, the OS rates in Cohort A and Cohort B of coveNIS are in line with the OS data from other trials with BRAF/MEK inhibitors for mM. No new safety signals were observed.

Cost-effectiveness analysis of encorafenib and binimetinib combination as first-line treatment for metastatic or unresectable &lt;i&gt;BRAF&lt;/i&gt; V600-mutated metastatic melanoma in Russia

Objective: to perform a cost-effectiveness analysis of using encorafenib and binimetinib combination in the first-line therapy for metastatic or unresectable BRAF V600-mutated melanoma in the Russian Federation. Material and methods. The comparators included “dabrafenib + trametinib” combination and vemurafenib monotherapy, which are listed in the Russian clinical guidelines and the Vital and Essential Drugs List. Since “encorafenib and binimetinib” combination demonstrated superior overall response rate compared to “dabrafenib + trametinib” and vemurafenib monotherapy, the method of cost-effectiveness analysis was used. We developed a disease progression model based on data from the COLUMBUS randomized control trial and published network meta-analysis. The model was used to calculate the direct medical costs associated with the considered alternatives over a 3-year modeling horizon. We compared the incremental cost-effectiveness ratio for “encorafenib + binimetinib” vs. “dabrafenib + trametinib” to the same ratio calculated for “dabrafenib + trametinib” vs. vemurafenib monotherapy.Results. Mean costs of using “encorafenib + binimetinib” combination over a 3-year period, considering the discontinuation of treatment as the disease progresses, was 6,547,693.07 rubles. Meanwhile, it was 5,962,742.52 rubles for “dabrafenib + trametinib” and 2,581,781.45 rubles for vemurafenib monotherapy. The incremental cost-effectiveness ratio of “encorafenib + binimetinib” vs. “dabrafenib + trametinib” was 3,846,818.71 rubles per 1 patient with a response to therapy. This was 85.14% lower than the same ratio estimated for “dabrafenib + trametinib” vs. vemurafenib monotherapy (25,890,022.64 rubles per 1 patient with a response to therapy).Conclusion. The “encorafenib + binimetinib” combination is a cost-effective treatment method for patients with unresectable or metastatic BRAF V600-mutated melanoma in the Russian Federation.

1117P Overall survival (OS) in patients with metastatic BRAF V600-mutant melanoma treated with encorafenib plus binimetinib (ENCO+BINI): Comparing real-world vs clinical trial data

1117P Overall survival (OS) in patients with metastatic BRAF V600-mutant melanoma treated with encorafenib plus binimetinib (ENCO+BINI): Comparing real-world vs clinical trial data

Fertility, teratogenicity, and contraception during therapy with BRAF/MEK inhibitors

Targeted mutation-based therapy with BRAF and MEK inhibitors has become an integral part of systemic therapy for metastatic melanoma in the advanced setting and for the adjuvant therapy of melanoma in stageIII after complete resection. Due to the increased chances of survival and early use in the adjuvant situation, fertility preservation as well as aspects of teratogenicity and pregnancy are increasingly relevant in patients who are often still young. To communicate the published and study-based information on fertility preservation, teratogenicity and pregnancy under therapy with BRAF and MEK inhibitors. Summaries of product characteristics as well as studies and case reports on BRAF and MEK inhibitors published in PubMed were used as sources of information. There are no specific preclinical studies or experience in humans on fertility, teratogenicity, and contraception with targeted therapy. Recommendations can only be derived from toxicity studies and individual case reports. Patients should be offered counseling on the options for fertility-protective measures before starting targeted therapy. Due to unclear teratogenicity, adjuvant melanoma therapy with dabrafenib and trametinib should not be initiated in pregnant patients. In the advanced metastatic situation, BRAF and MEK inhibitors should only be given after extensive interdisciplinary education and counselling of the pregnant patient and her partner. Patients should be informed about the need for adequate contraception during targeted therapy.

Encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for unresectable locally advanced or metastatic BRAF V600-mutant melanoma: Results from STARBOARD safety lead-in (SLI).

9531 Background: BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi) (eg, enco + bini) and immune checkpoint inhibitors (CPIs) (eg, pembro) are approved for patients (pts) with BRAF V600-mutant metastatic melanoma. Combinations of BRAFi + MEKi with CPIs further improve outcomes and may offer additional treatment strategies. STARBOARD (NCT04657991) is an ongoing randomized, double-blinded, placebo-controlled, phase 3 study of enco + bini + pembro vs pembro in pts with unresectable locally advanced or metastatic BRAF V600-mutant cutaneous melanoma. Here we present the SLI results. Methods: Key inclusion criteria were histologically confirmed unresectable/metastatic BRAF V600E/K-mutant cutaneous melanoma and ≤1 prior systemic therapy for unresectable/metastatic disease. Pts received enco 450 mg QD + bini 45 mg BID + pembro 200 mg IV Q3W (COMBO450+P) or enco 300 mg QD + bini 45 mg BID + pembro 200 mg IV Q3W (COMBO300+P). The primary objective was to identify the recommended phase 3 dose (RP3D). The primary endpoint was dose-limiting toxicity (DLT) incidence; secondary endpoints included safety, objective response rate (ORR), time to response (TTR), and PFS (post hoc). Results: 20 pts received COMBO450+P and 17 COMBO300+P (cutoff: Dec 2, 2022). See table for baseline characteristics. 1 pt had a DLT with COMBO450+P: Grade (G) 3 drug-induced liver injury with concurrent G4 ALT increase and G3 bilirubin increase that resolved. 2 pts had DLTs with COMBO300+P: 1 with G3 rheumatoid arthritis flare and 1 with inability to receive drug due to G4 arthralgia, G4 back pain, G4 pyrexia, G3 chills, G3 headache, G3 paranesthesia, and G3 maculopapular rash. Drug-related AEs led to permanent discontinuation in 4, 5, and 6 pts for enco, bini, and pembro, respectively. 1 pt in the COMBO300+P arm died &lt;28 days after discontinuing all study treatments due to disease progression. See table for antitumor activity data. Conclusions: Safety across cohorts was comparable and consistent with the known safety profile of each agent. Both regimens were generally tolerable; COMBO450+P was chosen as the RP3D based on the totality of the safety data. The phase 3 portion of STARBOARD is ongoing. Clinical trial information: NCT04657991 . [Table: see text]

A randomized trial of consolidation-targeted adjuvant therapy with encorafenib and cetuximab versus usual care for patients with stage II/III BRAF V600E colon cancer: Alliance for Clinical Trials in Oncology A022004.

TPS3641 Background: Patients with mismatch repair proficient (pMMR) BRAF V600E mutant high-risk stage II (T4) or stage III colon cancer have a substantial risk of recurrence despite standard adjuvant therapy. In patients with metastatic BRAF V600E mutant colorectal cancer, the combination of the RAF inhibitor encorafenib and the EGFR inhibitor cetuximab has been shown to improve overall and progression-free survival compared to standard therapy after at least one prior line of therapy. This study will evaluate if this combination improves disease-free survival (DFS) in patients with resected BRAF V600E mutant pMMR/microsatellite stable (MSS) high-risk stage II (T4) or stage III colon cancer after standard adjuvant therapy. Methods: The study has a seamless phase II/III design, enrolling a maximum of 394 patients. BRAF mutation status can be determined locally or submitted for central testing in trial pre-screening. Eligible patients will be randomized 1:1 to usual surveillance versus 6 months of treatment with encorafenib (300mg oral daily) plus cetuximab (500mg/m2 intravenous every 14 days). Stratification factors are adjuvant chemotherapy regimen (FOLFOX versus CAPOX), duration of adjuvant therapy (3 months versus &gt; 3 months), tumor stage (T4N0 versus T1-3N1 versus T4N1/TanyN2), and ctDNA marker status (detectable versus undetectable) at randomization. Adjuvant therapy must be completed at most 8 weeks prior to registration. For the phase II component, in the ctDNA detectable cohort, the primary endpoint will be ctDNA clearance rate at 6 months, and, in the ctDNA undetectable cohort, the primary endpoint will be 6-month ctDNA recurrence-free survival, where events consist of death, recurrence, or ctDNA positivity. The primary endpoint of the phase III component is DFS, and secondary endpoints are overall survival, adverse events, and alternative DFS calculated from the date of primary resection, rather than date of study randomization. Patient reported symptoms (PRO-CTCAE) will be collected and analyzed as an exploratory endpoint, and serial blood banking will support future correlative studies. The trial will proceed to the phase III portion if either of the two endpoints in the phase II cohorts is statistically superior in patients receiving encorafenib plus cetuximab. The phase III study sample size will provide 80% power at a one-sided α of 0.05 to detect an approximately 10% improvement in the three-year DFS rate, assuming 68% in the control arm. Two interim analyses will be performed for DFS endpoint. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org . U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); Pfizer, Eli Lilly; Clinicaltrials.gov ID: NCT05710406. Clinical trial information: NCT05710406 .

Targeting AMP kinase in melanoma: A phase I trial of phenformin with dabrafenib/trametinib.

9536 Background: AMP-activated protein kinase (AMPK) can phosphorylate BRAF and block its activation of MEK. AMPK is activated by biguanides such as metformin and phenformin (phen). Preclinical data indicated that phen can enhance the effects of BRAF inhibitors (BRAFi) in sensitive and BRAFi-resistant melanoma (mel) cell lines whereas metformin does not. Phen also can decrease myeloid-derived suppressor cells (MDSCs) enhancing immune reactivity against mel. For these reasons, we designed a phase I trial combining phen with dabrafenib/trametinib (dab/tram) in patients (pts) with metastatic BRAF V600-mutated mel. Methods: Bulk phen was provided by the Division of Cancer Treatment and Diagnosis of the National Cancer Institute under a materials transfer agreement. Phen was encapsulated at the Pharmaceutical Product Facility at MSKCC under cGMP procedures and used under an IND held by MSKCC. Eligible pts had metastatic BRAF V600-mutated mel. For the dose-escalation phase, prior BRAFi therapy was allowed. A 3+3 dose escalation design was used starting at a phen dose of 50 mg bid and standard dosing of dab/tram (150 mg bid/2 mg qd). Subsequent planned dose levels were 100 mg bid, 200 mg bid, and 300 mg bid with de-escalation to intermediate doses for toxicity. Plasma PK samples were collected and assayed by MRI Global Inc using a validated, GLP-compliant, HPLC-MS/MS assay. PBMC were collected to measure circulating MDSCs. At the recommended phase 2 dose (RP2D), we planned to treat 10 BRAFi-naïve pts. Results: We accrued 18 patients from March 2017 through December 2019. Dose-escalation to 200 mg bid was not tolerable nor was 150 mg bid. Therefore, we determined 100 mg bid to be the RP2D and accrued 2 patients on the dose expansion cohort before further accrual became impossible due to the COVID-19 pandemic. The most common toxicities were gastrointestinal – nausea, vomiting, anorexia, and transaminase and alkaline phosphatase elevation – accounting for 9 DLTs. Two patients were hospitalized due to lactic acidosis. There were also constitutional/inflammatory and skin/mucosal adverse events thought to be related to dab/tram. Weight loss was seen in most patients (median 3.7% at week 8) thought to be related to phen. There were 8 PRs and 2 CRs. Responses were observed in 2/7 pts who had received prior therapy with BRAFi. One CR lasted &gt; 1 year. There were 8/11 (73%) responders among the BRAFi-naïve pts. At the RP2D of 100 mg bid, day 8 median phen plasma level was 73.4 ng/ml (range 32.8-253.2). At the the 50 mg bid dose level, it was 40.8 ng/ml (range 29.7-110.2). MDSC could be analyzed from the 150 mg bid and 200 mg bid dose levels (N = 7 pts). In all but 1 pt, MDSCs decreased while on phen. Conclusions: We observed 10/18 (55.5%) total responses with 2/7 among previously treated pts. Circulating MDSCs decreased on treatment. Phen at 100 mg bid can be combined safely with dab/tram and should be explored in future randomized phase II trials. Clinical trial information: NCT03026517 .

Preliminary results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with metastatic BRAF V600E mutated colorectal cancer (CRC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers).

3557 Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) has dramatically worse survival than non-BRAF V600E mutated CRCs, and novel therapies are needed. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. The combination of a BRAF plus EGFR inhibitor (EC) is approved for the treatment of pts with BRAF V600E mCRC; however, only 20% of pts experience an objective response. ERAS-007 alone or in combination with EC showed promising in vitro and in vivo activity in BRAF V600E CRC models to support the combinatorial clinical benefit of ERAS-007+EC in BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety and tolerability of escalating doses of ERAS-007 + EC in pts with BRAF V600E CRC. Prior BRAF inhibitor and EGFR inhibitor treatment is neither required nor excluded to be enrolled in this study. Results: As of 30 November 2022, 12 patients were dosed with ERAS-007 twice daily-once a week (BID-QW) (75 and 100 mg; n = 10) or once daily once a week (QW) (150 mg; n = 2) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion once every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥20% of pts were fatigue (50%), headache (42%), constipation, diarrhea, nausea, dermatitis acneiform (33% each), and vomiting (25%). No TEAEs led to ERAS-007 discontinuation or death. Grade ≥3 TEAEs were reported in 3 pts (25%). Grade ≥3 treatment-related AEs reported in ≥ 2 patients (17%) include hypertension, headache, confusional state, and skin toxicity. Three pts (25%) died due to disease progression. No DLTs were reported. Out of 4 efficacy evaluable EC naïve pts, one confirmed partial response (PR) and one unconfirmed PR were observed. Evaluation of PK is ongoing and preliminary data will be presented. Conclusions: ERAS-007+EC in pts with BRAF V600E CRC shows acceptable preliminary safety/tolerability and evidence of clinical activity. The highest dose of ERAS-007 evaluated and cleared by the safety review committee to date is 100 mg BID-QW when combined with EC. Observed PK, toxicity, and preliminary activity support continued evaluation of this combination in pts with BRAF V600E CRC. Clinical trial information: NCT05039177 .

Combination of encorafenib and binimetinib in the treatment of patients with &lt;i&gt;BRAF&lt;/i&gt;-mutated advanced melanoma. Case report

Background. The need to use BRAF and MEK inhibitors in the treatment of patients with metastatic and/or unresectable BRAF + melanoma in certain clinical situations is beyond doubt nowadays. The medical community need more information about the new combination of targeted therapy approved in Russia, further details on the expected efficacy and tolerability, potential differences from the existing combinations.&#x0D; Aim. To present of the study results and demonstration of our experience with the new generation of targeted therapy encorafenib and binimetinib combination in the treatment of patients with metastatic and/or inoperable BRAF+ melanoma.&#x0D; Materials and methods. We present the clinical case of BRAF+ advanced melanoma patient with multiple metastases in the liver, spleen, mediastinal and abdominal lymph nodes, stomach and bones who is being treated with encorafenib and binimetinib since 2015 with the treatment efficacy and tolerability described in details, as well as the published data on the efficacy and tolerability of this combination from the pivotal phase III study COLUMBUS.&#x0D; Results. High immediate and long-term efficacy, satisfactory tolerability of encorafenib and binimetinib combination are presented. Updated data on progression-free and overall survival in the COLUMBUS study confirmed the long-term efficacy of COMBO450 therapy in patients with advanced melanoma with BRAF V600 mutation.&#x0D; Conclusion. New generation of BRAFi and MEKi combination expands options of systemic therapy for patients with metastatic and/or inoperable BRAF+ melanoma.

What is the best treatment for Anaplastic Thyroid Cancer?

The LaryngoscopeEarly View Triological Society Best Practice What is the best treatment for Anaplastic Thyroid Cancer? Kareem Al-Mulki MD, Kareem Al-Mulki MD Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A.Search for more papers by this authorRichard V. Smith MD, Corresponding Author Richard V. Smith MD [email protected] orcid.org/0000-0002-5216-6374 Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A. Send correspondence to Richard V. Smith, MD, Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY. Email: [email protected]Search for more papers by this author Kareem Al-Mulki MD, Kareem Al-Mulki MD Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A.Search for more papers by this authorRichard V. Smith MD, Corresponding Author Richard V. Smith MD [email protected] orcid.org/0000-0002-5216-6374 Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, U.S.A. Send correspondence to Richard V. Smith, MD, Department of Otorhinolaryngology—Head and Neck Surgery, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY. Email: [email protected]Search for more papers by this author First published: 03 May 2023 https://doi.org/10.1002/lary.30724 Editor's Note: This Manuscript was accepted for publication on April 15, 2023. The authors have no funding, financial relationships, or conflicts of interest to disclose. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. BIBLIOGRAPHY 1Bible KC, Kebebew E, Brierley J, et al. 2021 American Thyroid Association Guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2021; 31(3): 337- 386. 2Subbiah V, Kreitman RJ, Wainberg ZA, et al. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J Clin Oncol. 2018; 36(1): 7- 13. 3Hu S, Helman SN, Hanly E, Likhterov I. The role of surgery in anaplastic thyroid cancer: a systematic review. Am J Otolaryngol. 2017; 38(3): 337- 350. 4Kwon J, Kim BH, Jung HW, Besic N, Sugitani I, Wu HG. The prognostic impacts of postoperative radiotherapy in the patients with resected anaplastic thyroid carcinoma: a systematic review and meta-analysis. Eur J Cancer. 2016; 59: 34- 45. 5Baek SK, Lee MC, Hah JH, et al. Role of surgery in the management of anaplastic thyroid carcinoma: Korean nationwide multicenter study of 329 patients with anaplastic thyroid carcinoma, 2000 to 2012. Head Neck. 2017; 39(1): 133- 139. Early ViewOnline Version of Record before inclusion in an issue ReferencesRelatedInformation

Abstract CT069: Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma

Abstract Background BRAF V600 mutations are frequently found in metastatic melanoma. This mutation constitutively activates the MAPK pathway, which leads to melanoma progression. Patients with BRAF V600-mutant metastatic melanoma typically receive BRAF inhibitors (BRAFi) + MEK inhibitors (MEKi), such as enco + bini, or immune checkpoint inhibitors (CPIs; eg, pembro). However, these have limitations. BRAFi and MEKi may increase BRAF V600-mutant tumor sensitivity to CPIs. Previous studies reported improved progression-free survival (PFS) in patients with advanced BRAF V600-mutant melanoma receiving BRAFi + MEKi + CPI compared with targeted therapy alone. This phase 3 trial will evaluate the efficacy and safety of enco + bini + pembro vs placebo + pembro for unresectable locally advanced or metastatic BRAF V600-mutant melanoma. A safety lead-in (SLI) was built in to determine the recommended phase 3 dose (RP3D) prior to starting phase 3. Trial design STARBOARD (NCT04657991) is a randomized, double-blind, placebo-controlled, phase 3 study evaluating approximately 600 patients with BRAF V600 advanced melanoma. Patients will be stratified by prior systemic adjuvant treatment (CPI, BRAFi/MEKi, or none) and by disease stage (per AJCC 8th edition; IIIB, IIIC, IIID, IV M1a[0], and IV M1b[0] vs IV M1a[1], IV M1b[1], IV M1c[0], IV M1c[1], IV M1d[0], and IV M1d[1]). Patients must have measurable disease (per RECIST 1.1); ECOG performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function. Patients must not have received prior systemic therapy for unresectable or metastatic melanoma; adjuvant treatment with BRAFi/MEKi, anti-PD-1, or anti-CTLA-4 is permitted. Patients cannot have symptomatic brain metastases. Study treatments and end points are shown in Table 1. RP3D was established in May 2022; phase 3 enrollment began in June 2022. Table 1. Study treatments and end points Phase 3 Treatment (21-day cycle) RP3D from SLI: enco + bini + pembro Control: placebo + pembro Primary PFS (RP3D vs control; by BICR) Secondary Key: OS (RP3D vs control) Other: PFS by investigator assessment, objective response rate, duration of response, disease control rate, and time to response, all by BICR and investigator assessment, PFS2, quality of life, safety, pharmacokinetics BICR, blinded independent central review; OS, overall survival. Citation Format: Dirk Schadendorf, Reinhard Dummer, Caroline Robert, Antoni Ribas, Ryan J. Sullivan, Timothy Panella, Meredith McKean, Edgardo S. Santos, Jill Clancy, Anna Polli, Alessandra di Pietro, Paolo A. Ascierto. Randomized phase 3 study (STARBOARD) evaluating encorafenib (enco) + binimetinib (bini) + pembrolizumab (pembro) for first-line treatment of unresectable locally advanced or metastatic BRAF V600-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT069.

4-year survival and biomarkers evaluation from a phase II study of sequential immunotherapy and targeted therapy for metastatic BRAF V600-mutated melanoma (SECOMBIT)

4-year survival and biomarkers evaluation from a phase II study of sequential immunotherapy and targeted therapy for metastatic BRAF V600-mutated melanoma (SECOMBIT)