Large-vessel vasculitis possibly induced by BRAF and MEK inhibitors for BRAF V600E positive lung adenocarcinoma.

The combination therapy of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors is approved for treating patients with BRAF V600E-positive tumours, including melanoma and lung cancer. Several case reports indicated autoimmune side effects associated with the use of BRAF and MEK inhibitors. Still, the effects of these drugs on the immune system were not fully elucidated. Here, we report a patient with large-vessel vasculitis diagnosed after initiation of treatment with dabrafenib and trametinib for BRAF V600E-positive metastatic lung adenocarcinoma. She was a never-smoker woman in her early 70s who presented with a chronic cough and was diagnosed with BRAF V600E-positive metastatic lung adenocarcinoma by transbronchial lung biopsy. She was successfully treated with prednisolone and methotrexate while BRAF and MEK inhibitors were continued. We should be careful about autoimmune diseases using BRAF and MEK inhibitors.

Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.

PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.

Exposure-Response Relationships for Pralsetinib in Patients with RET-Altered Thyroid Cancer or RET Fusion-Positive Nonsmall Cell Lung Cancer.

Pralsetinib is a highly potent oral kinase inhibitor of oncogenic RET (rearranged during transfection) fusions and mutations. Pralsetinib received approval from the United States Food and Drug Administration for the treatment of patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), and received accelerated approval for the treatment of patients with RET fusion-positive thyroid cancer. Exposure-response (ER) analyses of efficacy were performed separately in patients with thyroid cancer and in patients with NSCLC, but data for all patients were pooled for the safety analysis. ER models were developed with time-varying exposure; the effect of covariates was also examined. For patients with NSCLC, a higher starting dose was associated with improved progression-free survival (PFS), but this improvement did not correlate with a higher exposure overall. Significant covariates included sex and baseline Eastern Cooperative Oncology Group (ECOG) score. For patients with thyroid cancer, a higher exposure was associated with improved PFS. Significant covariates included prior systemic cancer therapy and ECOG score. For safety, higher exposure was associated with a greater risk of grade ≥3 anemia, pneumonia, and lymphopenia. Patients with an ECOG score of ≥1 had an increased risk of grade ≥3 pneumonia. Non-White patients had a lower risk of grade ≥3 lymphopenia. ER analysis revealed that higher pralsetinib exposure was associated with improved PFS in thyroid cancer, but not in NSCLC. However, a higher starting dose (ie, 400 vs ≤300 mg daily) was correlated with better PFS for all indications. Higher exposure was also associated with an increased risk of grade ≥3 adverse events (AEs); however, the overall incidence of these events was acceptably low (≤20%). This analysis supports the use of a 400 mg starting dose of pralsetinib, allowing for dose reduction in the event of AEs.

A phase 1 study of triple-targeted therapy with BRAF, MEK, and AKT inhibitors for patients with BRAF-mutated cancers.

BACKGROUND: Aberrant PI3K/AKT signaling in BRAF-mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF-mutated solid tumors (ClinicalTrials.gov identifier NCT01902173). METHODS: Patients with BRAF V600E/V600K-mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose-limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. RESULTS: Twenty-seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor-resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib. CONCLUSIONS: Concomitant inhibition of both the MAPK and PI3K-AKT pathways for the treatment of BRAF-mutated cancers was well tolerated, leading to objective responses, but higher level drug-drug interactions affected exposure to dabrafenib and its metabolites.

Outcomes in patients with BRAFV600-mutated melanoma and brain metastases at baseline treated with dabrafenib plus trametinib.

BACKGROUND: Brain metastases (BM) and lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN) are associated with poor prognosis in patients with melanoma. Although treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have demonstrated long-term clinical benefit in patients with melanoma, data on their efficacy in patients with BM are limited. METHODS: DESCRIBE Italy is an observational, retrospective, real-world study evaluating dabrafenib plus trametinib in 499 patients with BRAFV600-mutant stage III unresectable or stage IV melanoma from various sites across Italy. Here, we analyzed the clinical outcomes for the subgroup of patients receiving first-line treatment and presenting with BM at diagnosis and assessed the impact of predictive factors such as LDH levels and the presence of other metastases on median progression-free survival (mPFS). RESULTS: Overall, 325 evaluable patients were on first-line therapy and are the focus of this analysis; of these, 76 patients (23.4%) had BM at baseline. mPFS was lower for patients with BM at baseline compared with overall patients (8.7 months vs 9.3 months, respectively). Patients with BM at diagnosis and LDH >ULN had a considerably shorter mPFS compared with patients with LDH ⩽ULN (5.3 months vs 9.9 months, respectively). mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively). CONCLUSIONS: Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced BRAFV600-mutated melanoma and BM at baseline, supporting its use in this population with poor outcomes.

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial.

BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (≥20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: NCT02034110 .

Comparative analysis of adjuvant therapy for stage III BRAF-mut melanoma: A real-world retrospective study from single center in China.

BACKGROUND: BRAF V600 mutation is the most common oncogenic alternation in melanoma and is visible in around 50% of cutaneous and 10%-15% of acral or mucosal subtypes. Currently, immunotherapy with anti-PD-1 blockade and dual-targeted therapy with Dabrafenib plus trametinib (D + T) target therapy have been approved as adjuvant therapies for Stage III melanoma with BRAF V600 mutation. According to their phase III clinical trials, 3-year recurrence-free survival (RFS) is around 60% for both types of treatment. However, early disease control was slightly more effective with targeted therapy than immunotherapy. With different drug approval deadlines in China, anti-PD1 monotherapy, D + T combination, and Vemurafenib (V) monotherapy have all been used in real clinical practice as adjuvant settings for stage III BRAF-mut melanoma in recent years. We conducted this retrospective study to evaluate the efficacy of different treatments in the Chinese melanoma population. METHODS: Patients who underwent radical surgery and were diagnosed as Stage III melanoma harboring BRAF V600 mutation by pathological report were retrospectively identified at Fudan University Shanghai Cancer Center from January 2017 to December 2021. Patients with mucosal melanoma, or with follow-up of <6 months, or receiving other adjuvant treatment were excluded. Pearson's chi-squared test or Fisher's exact test was performed for univariable analysis of the different adjuvant groups. Log-rank analysis was used to identify prognostic factors for relapse-free survival (RFS). RESULTS: Ninety-three patients with resected stage III melanoma with BRAF V600E mutation were identified in our study, including 25 patients receiving adjuvant anti-PD-1 immunotherapy (PD-1), 25 receiving adjuvant D + T, 23 receiving V, and 20 patients with observation-only (OBS). There were no statistical differences between treatment groups in baseline characteristics including age, gender, subtypes, primary thickness, ulceration, and nodal involvement. Median relapse-free survival (RFS) time was not reached in the D + T group, 15 months in the V group, 15 months in the PD-1 group, and 10 months in the OBS group, respectively. Compared to OBS, all three other groups showed a tendency to benefit from RFS, while only D + T achieved a statistical difference (p = 0.002). However, compared to D + T, anti-PD-1 monotherapy also showed significantly worse relapse control (p = 0.032). CONCLUSIONS: For Chinese stage III melanoma with BRAF mutation, both novel targeted therapy and immunotherapy showed potential benefits in relapse-free survival compared to observation only. Dual-targeted D + T therapy may still be the best choice for adjuvant therapy because anti-PD-1 monotherapy has failed to report equivalent efficacy in real-world practice.

Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy.

The event-free survival of pediatric low-grade gliomas is poor, and patients often require multiple treatment strategies. While MEK and RAF inhibitors are efficacious in early-phase trials, not all patients respond, and many experience progression following completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. We report our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system tumors. Two of four patients using this combination therapy experienced severe thromboembolic events, necessitating discontinuation of therapy. This combination requires further investigation, and we urge caution if used.

Effects of short-term treatment with vibegron for refractory nocturnal enuresis.

BACKGROUND: Long-term nocturnal enuresis treatment leads to stress and lowered self-esteem for children and their parents. This study evaluated the short-term effectiveness and safety of vibegron (50 mg) for children with refractory nocturnal enuresis. METHODS: A retrospective cohort study of children with therapy-resistant enuresis was conducted using data for July to December 2019. Enuresis frequency was recorded during 30 days before and after additional vibegron administration with prior treatment. We assessed the treatment effectiveness based on enuresis frequencies between before and after treatment with vibegron 50 mg. Statistical evaluation was performed using a paired t-test. RESULTS: Among 29 children receiving vibegron, 14 (48.3%) exhibited a partial or complete response to the drug. Enuresis frequencies (mean ± standard deviation [SD]) were, respectively, 15.8 ± 9.2 and 9.5 ± 9.6 before and after treatment with vibegron during the observed 30 days. A statistically significant reduction in enuresis frequency was found (p < 0.001). Moreover, maximum mean±SD morning urine of 200 ± 62.9 mL before treatment with vibegron changed to 232 ± 76.6 mL after treatment. A significant increase in voiding volume in the early morning was found (p < 0.05). No drug-related severe adverse event was found. CONCLUSION: Short-term treatment with vibegron is safe and effective for children with refractory enuresis.

Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia.

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.

A distinct four-value blood signature of pyrexia under combination therapy of malignant melanoma with dabrafenib and trametinib evidenced by an algorithm-defined pyrexia score.

Pyrexia is a frequent adverse event of BRAF/MEK-inhibitor combination therapy in patients with metastasized malignant melanoma (MM). The study's objective was to identify laboratory changes which might correlate with the appearance of pyrexia. Initially, data of 38 MM patients treated with dabrafenib plus trametinib, of which 14 patients developed pyrexia, were analysed retrospectively. Graphical visualization of time series of laboratory values suggested that a rise in C-reactive-protein, in parallel with a fall of leukocytes and thrombocytes, were indicative of pyrexia. Additionally, statistical analysis showed a significant correlation between lactate dehydrogenase (LDH) and pyrexia. An algorithm based on these observations was designed using a deductive and heuristic approach in order to calculate a pyrexia score (PS) for each laboratory assessment in treated patients. A second independent data set of 28 MM patients, 8 with pyrexia, was used for the validation of the algorithm. PS based on the four parameters CRP, LDH, leukocyte and thrombocyte numbers, were statistically significantly higher in pyrexia patients, differentiated between groups (F = 20.8; p = <0.0001) and showed a significant predictive value for the diagnosis of pyrexia (F = 6.24; p = 0.013). We provide first evidence that pyrexia in patients treated with BRAF/MEK-blockade can be identified by an algorithm that calculates a score.

Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial.

Background: Oncogenic BRAF mutations are commonly found in advanced differentiated thyroid cancer (DTC), and reports have shown efficacy of BRAF inhibitors in these tumors. We investigated the difference in response between dabrafenib monotherapy and dabrafenib + trametinib therapy in patients with BRAF-mutated radioactive iodine refractory DTC. Methods: In this open-label randomized phase 2 multicenter trial, patients aged ≥18 years with BRAF-mutated radioactive iodine refractory DTC with progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 13 months before enrollment were eligible. Patients were randomly assigned to receive dabrafenib alone or dabrafenib + trametinib. The primary endpoint was objective response rate by modified RECIST (minor response of -20% to -29%, partial and complete response) within the first 24 weeks of therapy. Trial Registration Number: NCT01723202. Results: A total of 53 patients were enrolled. The objective response rate (modified RECIST) was 42% (11/26 [95% confidence interval {CI} 23-63%]) with dabrafenib versus 48% (13/27 [CI 29-68%]) with dabrafenib + trametinib (p = 0.67). Objective response rate (RECIST 1.1) was 35% (9/26 [CI 17-56%]) with dabrafenib and 30% (8/27 [CI 14-51%]) with dabrafenib + trametinib. Most common treatment-related adverse events included skin and subcutaneous tissue disorders (17/26, 65%), fever (13/26, 50%), hyperglycemia (12/26, 46%) with dabrafenib alone and fever (16/27, 59%), nausea, chills, fatigue (14/27, 52% each) with dabrafenib + trametinib. There were no treatment-related deaths. Conclusions: Combination dabrafenib + trametinib was not superior in efficacy compared to dabrafenib monotherapy in patients with BRAF-mutated radioiodine refractory progressive DTC.

Immune-mediated necrotizing myopathy with anti-signal recognition particle antibodies, in a patient with melanoma treated with BRAF/MEK inhibitors.

The effect of serine/threonine-protein kinase B-Raf/mitogen-activated protein kinase (BRAF/MEK) inhibitors on the immune system is not clearly described, but rare cases of autoimmune phenomena have been reported. The clinical case we present below is the first report of a necrotizing myopathy related to dabrafenib/trametinib treatment. A 48-year-old man started dabrafenib/trametinib for stage IV BRAF-V600E mutated cutaneous melanoma. After the first month, he presented with grade 3 pyrexia (Common Terminology Criteria for Adverse Events [CTCAE] v.5.0.) and increased creatinine-kinase levels. A diagnosis of immune-mediated necrotizing myopathy, antisignal recognition particle (anit-SRP) positive, was made. At disease progression, dabrafenib/trametinib was restarted, triggering a new episode of grade 2 pyrexia and myositis. Treatment was changed to encorafenib/binimetinib without repeating pyrexia or limiting creatinine-kinase elevation, presenting even a loss of anti-SRP antibodies. Given the temporal relationship, the fact that re-exposition induced a new worsening of the myopathy and the loss of the anti-SRP antibodies after changing treatment, we infer that there possibly is a clear relationship between dabrafenib/trametinib treatment and the myopathy.

Targeting wild-type TP53 using AMG 232 in combination with MAPK inhibition in Metastatic Melanoma; a phase 1 study.

BACKGROUND: Targeting the MDM2-p53 interaction using AMG 232 is synergistic with MAPK inhibitors (MAPKi) in preclinical melanoma models. We postulated that AMG 232 plus MAPKi is safe and more effective than MAPKi alone in TP53-wild type, MAPKi-naïve metastatic melanoma. METHODS: Patients were treated with increasing (120 mg, 180 mg, 240 mg) oral doses of AMG 232 (seven-days-on, 15-days-off, 21-day cycle) plus dabrafenib (D) and trametinib (T) (Arm 1, BRAFV600-mutant) or T alone (Arm 2, BRAFV600-wild type). Patients were treated for seven days with AMG 232 alone before adding T±D. Safety and efficacy were assessed using CTCAE v4.0 and RECIST v1.1 criteria, respectively. Pharmacokinetic (PK) analysis was performed at baseline and steady-state levels for AMG 232. RESULTS: 31 patients were enrolled. Ten and 21 patients were enrolled in Arm 1 and Arm 2, respectively. The most common AMG 232-related adverse events (AEs) were nausea (87%), diarrhea (77%), and fatigue (74%). Seven patients (23%) were withdrawn from the study due to AMG 232-related AEs. Three dose-limiting AEs occurred (Arm 1, 180 mg, nausea; Arm 2, 240 mg, grade 3 pulmonary embolism; Arm 2, 180 mg, grade 4 thrombocytopenia). AMG 232 PK exposures were not altered when AMG 232 was combined with T±D. Objective responses were seen in 8/10 (Arm 1) and 3/20 (Arm 2) evaluable patients. The median progression-free survival for Arm 1 and Arm 2 was 19.0 months-not reached and 2.8 months, respectively. CONCLUSION: The maximum tolerated dose of AMG 232 for both arms was 120 mg. AMG 232 plus T±D exhibited a favorable PK profile. Although objective responses occurred in both arms, adding AMG 232 to T±D did not confer additional clinical benefit.

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases.

INTRODUCTION: Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. METHODS AND MATERIALS: Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. RESULTS: 10 patients were enrolled (median age-59 [47-64], BM-5 [1-10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. CONCLUSIONS: In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.

A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors.

Patients with advanced BRAFV600 mutant melanoma who progressed on prior treatment with BRAF-/MEK-inhibitors and programmed cell death 1 or cytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitors can benefit from retreatment with the combination of a BRAF- and a MEK-inhibitor ('rechallenge'). Hydroxychloroquine can prevent autophagy-driven resistance and improve the efficacy of BRAF-/MEK-inhibitors in preclinical melanoma models. This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600 mutant melanoma who previously progressed on prior treatment with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Following a safety lead-in phase, patients were randomized in the phase 2 part of the trial between upfront treatment with dabrafenib, trametinib and hydroxychloroquine (experimental arm), or dabrafenib and trametinib, with the possibility to add-on hydroxychloroquine at the time of documented tumor progression (contemporary control arm). Ten and four patients were recruited to the experimental and contemporary control arm, respectively. The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm, whereas no responses were observed before or after adding hydroxychloroquine in the contemporary control arm. No new safety signals were observed for dabrafenib and trametinib. Hydroxychloroquine was suspected of causing an anxiety/psychotic disorder in one patient. Based on an early negative evaluation of the risk/benefit ratio for adding hydroxychloroquine to dabrafenib and trametinib when 'rechallenging' BRAFV600mutant melanoma patients, recruitment to the trial was closed prematurely.

Clinical trial results show promise of targeting autophagy BRAF mutant melanoma.

Macroautophagy/autophagy is a resistance mechanism to targeted therapy in BRAF mutant cancers. Preclinical evidence and clinical trial data demonstrate that hydroxychloroquine (HCQ) is an effective autophagy inhibitor at clinically achievable concentrations. Here we highlight the results of a recently published single-arm phase I/II multi-institution trial of dabrafenib, trametinib, and the autophagy inhibitor HCQ (the BAMM trial) that established the safety and activity of this regimen in BRAF V600-mutant melanoma patients. Compared to the pivotal trials that led to FDA approval of dabrafenib and trametinib, the BAMM trial enrolled a high percentage of patients with elevated LDH and prior immunotherapy, reflecting the trend that poorer-prognosis patients are treated with targeted therapy in the modern era where multiple immunotherapy regimens are available for melanoma. Dabrafenib, trametinib, and hydroxychloroquine are safe and produce a high response rate (85%). Progression-free survival does not meet the pre-specified threshold for the entire cohort but looks especially promising in patients with elevated LDH and prior treatment. A national randomized study has been launched to study this regimen further in poor-prognosis BRAF V600-mutant melanoma patients.

Interstitial lung disease associated with combination therapy of dabrafenib and trametinib in metastatic BRAFV600E-mutated poorly differentiated thyroid cancer: A case report and review of the literature.

BACKGROUND: Thyroid cancer is the most common malignancy of the endocrine system, accounting for ~ 5% of all thyroid nodules and 1% of all systemic malignancies. BRAF mutations, primarily p.V600E hot spot mutations, are found in 60 - 70% of papillary thyroid cancer cases (PTC) and in 33 - 40% of fatal anaplastic thyroid cancers (ATC), also called poorly differentiated thyroid cancer. Dabrafenib was approved by the United States Food and Drug Administration (FDA) in 2018 to be applied in combination with trametinib for unresectable advanced or metastatic anaplastic thyroid cancer harboring the BRAFV600E mutation. Unfortunately, there are few reports on the pathophysiology, molecular mechanism, and risk factors of interstitial lung disease induced by combined BRAF- and MEK-targeted therapy. CASE PRESENTATION: We treated a 73-year-old man with metastatic BRAFV600E-mutated poorly differentiated thyroid cancer using the combination of dabrafenib and trametinib. Although a significant morphologic tumor response was observed in our patient using combined BRAF- and MEK-targeted therapy, he presented with non-febrile respiratory failure, and his chest computed tomography (CT) revealed bilateral reticulation and pleural effusion. Withdrawal from dabrafenib-trametinib and administration of methylprednisolone rapidly improved his respiratory status and imaging features. CONCLUSION: The mechanisms of lung disease after the combined treatment with dabrafenib and trametinib are unclear. We hypothesized that dual-targeted therapy with a BRAF inhibitor, dabrafenib, and a MEK inhibitor, trametinib, might prevent the regeneration and proliferation of fibrotic epithelium in lung disease by blocking downstream proliferative signals.

Dihydropyrimidinone-derived selenoesters efficacy and safety in an in vivo model of Aß aggregation.

In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer's Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (Aß) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 µM and after 48 h the maintenance temperature was increased to 25 ° C for Aß expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of Aß toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate Aß aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals.