Combined BRAF Inhibition Research Articles

Encorafenib and cetuximab with/without binimetinib therapies for patients with BRAF -mutated metastatic colorectal cancer with prognostic factors: The BEETS trial (JACCRO CC-18).

164 Background: BRAF inhibitor combination therapies, triplet (encorafenib, binimetinib and cetuximab) and doublet (encorafenib and cetuximab), have been approved for BRAF -mutated metastatic colorectal cancer (mCRC) in Japan. The treatment with triplet is recommended for patients (pts) with clinical prognostic factors according to the sub-group analysis of the BEACON CRC trial. However, it is unclear whether the treatment strategy is useful. We therefore conducted a study on the use of combination therapy with triplet or doublet based on observational study that accumulated real world data. Methods: The BEETS trial was a multicenter observational study to prospectively evaluate the efficacy and safety of BRAF inhibitor combination therapy as a 2nd- or 3rd-line treatment in pts with BRAF -mutated mCRC in clinical practice [UMIN000045530]. Two hundred pts were assigned to either triplet or doublet therapy based on the physician’s choice. The primary endpoint was overall survival (OS). The secondary endpoints included overall response rate (ORR), disease control rate, progression-free survival (PFS), and safety. The exploratory analysis was performed to evaluate the efficacy of triplet and doublet therapies in all pts and pts with clinical prognostic factors (PS1, 3 or more metastatic sites, elevated CRP value, or primary tumor present) using inverse probability weighting (IPW) analysis based on propensity scores to account for potential cofounding factors. Results: Among 203 pts enrolled from Oct 2021 to Nov 2023, 195 pts were evaluable (median age 67 years old, 52% male, ECOG PS 0/1/2 55%/39%/6%, no. of prior regimens 1/2 85%/15%, right-sided primary 61%, MSI-high 7%, triplet regimen 57%). Median OS was 13.2 months (95%CI 11.4-17.4) with 1y-survival rate of 53%, and median PFS was 4.9 months. Comparing the triplet and doublet using IPW, the median OS and PFS were comparable between the two treatments (triplet vs. doublet; 16.0 months vs. 13.6 months [HR 0.88, 95%CI 0.53-1.48] and 5.7 months vs. 4.8 months [HR 0.87, 95%CI 0.59-1.28]). In 139 pts with any prognostic factors, median OS and 1y-survival rate were 13.2 months vs. 9.6 months [HR 0.80, 95%CI 0.45-1.43] and 54% vs. 42%, median PFS and ORR were 5.3 months vs. 4.2 months [HR 0.75, 95%CI 0.48-1.19] and 34% vs. 42%, in the triplet vs. doublet therapy, respectively. Conclusions: Our study demonstrated that BRAF inhibitor doublet therapy is a reasonable treatment for BRAF -mutated mCRC. However, triplet therapy may be a clinically useful for pts with clinical prognostic factors. Clinical trial information: UMIN000045530 .

Updates on hairy cell leukemia (HCL) and HCL-like disorders

Hairy cell proliferations represent very different entities. They include hairy cell leukemia in its classic form (HCL), a well-defined entity, but also the variant form of HCL (LT-V ou HCL-V), whose presentation is far from HCL and whose prognosis is poorer. Other hairy cell proliferations include splenic red pulp lymphoma (SDRPL) and splenic marginal zone lymphomas (SMZL) with circulating villous cells. In this article, we emphasize the novelties concerning the different recent biological aspects of HCL, including the unusual clinical presentations but also the importance for the diagnosis of the detection of the BRAFV600E mutation, a molecular marker of the disease, and the presence of other non-canonical mutations that should be identified because of the contraindication to the use of BRAF inhibitors. Finally, the presence of a non-mutated profile of immunoglobulin heavy chains (IGHV), observed in 20% of cases, is associated with a poor prognosis. We also provide guidance in characterizing other hairy cell proliferations when examining the blood smear. The first-line treatment of HCL has recently changed and immunochemotherapy combining cladribine plus rituximab has become the gold standard. In relapsed or refractory forms, other treatments should be discussed in a multidisciplinary consultation meeting and combine BRAF inhibitors with anti-CD20 antibodies, BTK inhibitors or Bcl-2 inhibitors. The choices should be discussed according to the patient's profile but also their biological profile.

A retrospective observational study of patients with melanoma prescribed combined BRAF and MEK inhibitors in a real‐world treatment setting in Japan

AbstractObjectiveThis study aimed to describe patients with melanoma initiating treatments with dabrafenib plus trametinib (Dab + Tram) or encorafenib plus binimetinib (Enco + Bini) in a real‐world setting in Japan.MethodsData were extracted from the Japanese Medical Data Vision (MDV) insurance claims database. Patients diagnosed with melanoma between 2012 and 2021 and prescribed with Dab + Tram or Enco + Bini were included in three cohorts: non‐adjuvant Dab + Tram, adjuvant Dab + Tram, and Enco + Bini. Data were extracted on patient characteristics at treatment initiation. During follow‐up, all changes in melanoma treatments were documented. Treatment adherence was determined as the proportion of prescription days covered (PDC) and treatment dose intensity as the relative dose intensity (RDI).ResultsSixty‐seven patients were included in the non‐adjuvant Dab + Tram cohort (55 first‐line treatments), seven in the adjuvant Dab + Tram cohort (six first‐line treatments), and 16 in the Enco + Bini cohort (four first‐line treatments). The mean age was 61.3 ± 13.5 years and 56.1% were men. Twenty‐seven patients with non‐adjuvant Dab + Tram or Enco + Bini in first line (45.8%) switched to a second line. The median treatment duration was 11.8 months for Dab + Tram and 8.1 months for Enco + Bini. A PDC ≥ 80% was observed for 85.7% of patients with adjuvant Dab + Tram, 68.7% for non‐adjuvant Dab + Tram, and 75.0% for Enco + Bini. Median RDI was 1.0 for adjuvant Dab + Tram, 0.9 for non‐adjuvant Dab + Tram, and 0.6 for Enco + Bini.ConclusionDab + Tram is used consistently with clinical practice guidelines in the adjuvant setting, but adherence in the non‐adjuvant setting is suboptimal, as is the prescribed dose of Enco + Bini. Prescribers should ensure that these therapies are used in an optimal way to improve outcomes in melanoma.

Triple combination of vemurafenib, cobimetinib, and atezolizumab in real clinical practice in the Russian Federation: results of the A1 cohort of the ISABELLA study.

Among several treatment options for BRAF-mutant metastatic melanoma, a combination of BRAF inhibitor, MEK inhibitor, and anti-PDL1 antibody seems to be a new emergent approach recently registered in the Russian Federation. It is still not clear which patient population benefits more from this simultaneous use of three drugs instead of its sequencing. This study aimed to evaluate patients' characteristics treated in real practice in 14 Russian regions by triple combination and to analyze their outcomes depending on biomarkers (PD-L1 expression). This was a part (cohort A1) of a prospective non-interventional study of clinical outcomes and biomarkers in patients with skin melanoma. Patients were included in cohort A1 if combination treatment with vemurafenib (vem) + cobimetinib (cobi) + atezolizumab (atezo) was initiated no earlier than 12 weeks (84 days) prior to written informed consent to participate in this study. The index event was the initiation of therapy with all three drugs vem + cobi + atezo (i.e., triple combination). The primary efficacy endpoint of the study was the 24-month overall survival (OS), defined as the time from the index date to the date of death from any cause. If the patient did not experience an event, the OS will be censored at the date of the last contact. Objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) in the Intention to treat (ITT) population, in biomarker positive population, and in population with brain metastases were also evaluated. Quality of life questionnaires were pre-planned by protocol if it was a part of routine practice. Adverse events were also collected. Between March 2021 and May 2023, 59 patients were enrolled in 19 centers from 14 regions of Russia. Thirty-one of 59 (52.4%) patients had central nervous system metastases, and 18 of 31 (58.4%) were symptomatic. Forty of 59 patients (68%) received the triple combination as the first-line treatment. The median follow-up period was 16.83 [95% confidence interval (CI) 13.8-19.8] months. The mean duration of therapy with this regimen was 9.95 months (95% CI 7.48-13.8). ORR was 55.1%; progression as the best outcome was seen in 16.3%. The median DoR was 12.95 months (95% CI 11.0-14.8 months), with a median of 20.3 months (95% CI 9.1-31.5 months) when triple therapy was administered in the first-line treatment. In patients with brain metastases (N = 31), ORR was 45.1%; the median DoR was 12.95 (95% CI 11.0-14.8 months). The median PFS in the entire population was 13.6 months (95% CI 8.6-18.6); the 24-month PFS was 22%. The estimated median OS in the entire population was 15.8 months (95% CI NA); 24-month OS was 45% (95% CI 0.32-0.64). In multivariate Cox regression model, biomarkers of interest [lactate dehydrogenase, Programmed cell death ligand-1 (PD-L1)] did not have statistically significant impact on PFS, OS, or DoR probably due to high data missing rate. No unexpected adverse events were reported. Grades 3-4 AEs were seen in 23 of 59 patients (38%) with most common were skin and liver toxicity. Triple combination of atezolizumab, vemurafenib, and cobimetinib had proven its efficacy and tolerability in real settings. No impact of potential predictive biomarkers was seen (NCT05402059).

BRAF mutant PD-L1 positive metastatic musculoskeletal lesions from primary lung adenocarcinoma treated with combination vemurafenib and pembrolizumab: a case report

BackgroundB-Raf mutation positivity, B-Raf mutation positivity occurrence with programmed death ligand 1 overexpression, and musculoskeletal metastasis are singly rare in non-small cell lung cancer, and even rarer is all occurring in one patient.Case presentationA Filipino 63-year-old male had B-Raf mutation positive and programmed death ligand 1 overexpressed symptomatic metastatic musculoskeletal lesions from lung adenocarcinoma treated with a BRAF inhibitor, vemurafenib, in combination with an immune checkpoint inhibitor, pembrolizumab. He exhibited significant reduction in pain and burden of musculoskeletal metastatic lesions.ConclusionAlthough a rare occurrence and known to have a poor prognosis, B-Raf mutation positive programmed death ligand 1 overexpressed lung adenocarcinoma presenting with metastatic musculoskeletal lesions can respond favorably to a combination immune checkpoint inhibitor and BRAF inhibitor medication.

Tretinoin synergistically enhances the antitumor effect of combined BRAF, MEK, and EGFR inhibition in BRAFV600E colorectal cancer.

Patients with BRAF-mutated colorectal cancer (BRAFV600E CRC) are currently treated with a combination of BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor. A fundamental problem in treating patients with BRAFV600E CRC is intrinsic and/or acquired resistance to this combination therapy. By screening 78 compounds, we identified tretinoin, a retinoid, as a compound that synergistically enhances the antiproliferative effect of a combination of BRAF inhibition and MEK inhibition with or without EGFR inhibition on BRAFV600E CRC cells. This synergistic effect was also exerted by other retinoids. Tretinoin, added to BRAF inhibitor and MEK inhibitor, upregulated PARP, BAK, and p-H2AX. When either RARα or RXRα was silenced, the increase in cleaved PARP expression by the addition of TRE to ENC/BIN or ENC/BIN/CET was canceled. Our results suggest that the mechanism of the synergistic antiproliferative effect involves modulation of the Bcl-2 family and the DNA damage response that affects apoptotic pathways, and this synergistic effect is induced by RARα- or RXRα-mediated apoptosis. Tretinoin also enhanced the antitumor effect of a combination of the BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.

Real world impact of pembrolizumab availability for deficient mismatch repair metastatic colorectal cancer.

e15569 Background: Keynote 177 was a practice changing study, with pembrolizumab versus dealers’ choice chemotherapy +/- biologic significantly improving progression free survival in patients (pts) with previously untreated deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC). A high rate (29.4%) of pembrolizumab treated pts had stopped treatment at or before first response evaluation due to progressive disease as best response. Pembrolizumab availability in routine care is anticipated to benefit individual pts otherwise treated with chemotherapy. Additional pts not fit for chemotherapy, but fit for first line (1L) pembrolizumab, may be able to receive active treatment, which could increase the dMMR mCRC population benefit. Pembrolizumab availability may also drive increased MMR testing, which may impact the proportion of pts with dMMR mCRC. Methods: We analysed data from the TRACC registry of pts with mCRC in Australia comparing patient treatment across two cohorts. The first cohort was pts diagnosed from 1/1/2015 to 31/7/2021 when immunotherapy was only available via trial, self-funding or through a limited access program and the second cohort was pts diagnosed from 1/8/2021 to 23/1/2024, following the government’s Pharmaceutical Benefits Scheme reimbursement (PBSr) of pembrolizumab as 1L treatment for dMMR mCRC. We also examined early treatment discontinuation rates for pembrolizumab treated pts after PBSr. Results: Of 2819 mCRC pts overall, 2344 (83%) had known MMR status. Of pts tested 163 (7%) were dMMR. Pts with dMMR mCRC were older (mean age 66.6 vs 62.2, p < 0.01) and had more co-morbidities (59% vs 47% for modified Charlson Comorbidity Index ≥ 3, p < 0.01). They were also more likely to have a right side primary (67% vs 31%, p < 0.01), BRAF V600E mutation (49% vs 11%, p < 0.01) and peritoneal or brain metastases (34% vs 22%, p < 0.01). Before PBSr of pembrolizumab, 85 of 117 (73%) dMMR mCRC pts received 1L treatment; 62/85 (73%) chemotherapy, 19/85 (22%) immunotherapy and 4/85 (5%) combination BRAF inhibitor and EGFR inhibitor. Following PBSr, an increased proportion (40 of 46) of dMMR mCRC pts received any 1L treatment (87% vs 73%, p = 0.05), with 1/40 (2.5%) receiving chemotherapy and 39/40 (97.5%) pembrolizumab. In a landmark analysis of these 39 pts, 12 of 19 (63%) that had started treatment ≥ 6 months ago remained on pembrolizumab. Conclusions: A high proportion of Australian pts with mCRC are undergoing dMMR testing. Increasing testing, including of more elderly pts, may increase the proportion of mCRC pts that are dMMR compared to that reported for trial populations. dMMR mCRC pts have multiple adverse prognostic features. The broad availability of pembrolizumab, such as through the Australian PBSr, looks likely to lead to an increased proportion of pts receiving any 1L therapy. Early data suggests the expected clinical benefit, with a low rate of early treatment discontinuation.

Clinical Predictors of Survival in Patients With BRAFV600-Mutated Metastatic Melanoma Treated With Combined BRAF and MEK Inhibitors After Immune Checkpoint Inhibitors.

Prospective and between trial comparisons indicate that first-line treatment with immune checkpoint inhibitors improves survival outcomes compared to first-line therapy with combined BRAF and MEK inhibitors in metastatic melanoma containing BRAFV600E/K mutations. Long-term outcomes for BRAF/MEK inhibition after progression on immunotherapy have not been reported. Moreover, clinical variables associated with outcome from treatment with combined BRAF/MEK inhibition were previously identified in the first-line setting but have not been investigated when targeted therapies are administered after progression on immune therapy. We performed a retrospective single institution analysis of 40 metastatic melanoma patients receiving combined BRAF/MEK inhibitors after progression on an anti-PD-1 or ipilimumab plus nivolumab to assess response rate by RECIST 1.1, progression-free and overall survival (PFS and OS). Pretreatment clinical variables were analyzed for association with OS. Ipilimumab/nivolumab was the first-line immunotherapy regimen in 39 patients (97.5%), and BRAFV600E/K mutations were present in 33 (83%) and 7 (17%) patients, respectively. The median OS from start of BRAF/MEK inhibitors was 20.3 months (1.73-106.4+, 95% CI of median 13.3-30.7). Clinical characteristics associated with worse survival prior to starting BRAF/MEK inhibitors included age > 60 years (median OS 14 vs. 28 months; HR 2.5; 95% CI 0.91-6.87, P = .023), ECOG-PS > 2 (median OS 7 vs. 33 months; HR 2.89; 95% CI 0.78-10.76, P = .018), and presence of bone metastases (median OS 9 vs. 52 months; HR 3.17; 95% CI 1.33-7.54, P = .002). These associations with shorter survival maintained their significance on multivariate analysis. If confirmed in larger cohorts, the identified prognostic variables can be used for stratification of patients in future randomized trials.

Ezrin Inhibition Overcomes Acquired Resistance to Vemurafenib in BRAFV600E-Mutated Colon Cancer and Melanoma Cells In Vitro.

Despite the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach. Bioinformatic analysis of obtained proteomics data indicated actin-cytoskeleton linker protein ezrin as a highly ranked protein significantly associated with vemurafenib resistance whose overexpression in the resistant cells was additionally confirmed at the gene and protein level. Ezrin inhibition by NSC305787 increased anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant cells in an additive manner, which was accompanied by downregulation of CD44 expression and inhibition of AKT/c-Myc activities. We also detected an increased ezrin expression in vemurafenib-resistant melanoma cells harbouring the BRAFV600E mutation. Importantly, ezrin inhibition potentiated anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant melanoma cells in a synergistic manner. Altogether, our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying the BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers.

Impressive clinical response following combined BRAF and MEK inhibition in a low-grade serous ovarian carcinoma patient with a BRAF V600E mutation

Introduction: Low-grade serous ovarian cancer (LGSOC) accounting for less than 10% of all serous ovary cancers. The chemoresistance inherent to this type of ovarian cancer narrows the therapeutic options, especially in the recurrent setting. It is thought that the mitogen-activated protein kinase (MAPK) pathway plays a significant role in the pathogenesis of these tumours, and about 2 to 20% of LGSOC harbour a BRAF mutation. 
 Case report: We present a case report of a 58-year-old woman with LGSOC FIGO stage IIIC who presented recurrence of the tumor process after total abdominal hysterectomy and systemic treatment. Thereafter, she underwent molecular profiling, which revealed a BRAF V600E mutation; accordingly, the patient was administered dabrafenib and trametinib combination therapy. The patient noted significant clinical improvement with normalization of CA 125 and radiological partial response. To date, the patient still maintains partial response, with good treatment tolerance and performance status ECOG 0/1 and good quality of life. 
 Conclusions: LGSOC represents the challenge that is managing a rare cancer with scarce therapeutic options. Given the prevalence of BRAF mutations in this type of tumour, it might be relevant to consider genetic testing. It may provide new treatment opportunities for patients with a known chemoresistant tumour, by identifying potential actionable targets and avoid potential toxicities associated with chemotherapy. Here we demonstrate that impressive clinical responses can be achieved in BRAF mutated LGSOC treated with combined BRAF and MEK inhibitor treatment.

Understanding resistance in V600E BRAF advanced colon cancer treated with BRAF inhibitors plus anti-EGFR antibodies +/- MEK inhibitors: The URBAN study.

3587 Background: The combination of BRAF inhibitors (BRAFi) plus anti-EGFR antibodies is a new standard of care in V600E BRAF mutated (mut) metastatic colorectal cancer (mCRC). Nevertheless, resistance develops during the target therapy (TT). We designed the URBAN study, a translational prospective project, in order to identify possible primary and acquired resistance mechanisms. Methods: Patients (pts) with V600E BRAF mut mCRC treated with BRAFi + anti-EGFR +/- MEK inhibitors at Veneto Institute of Oncology were enrolled. Clinical data and liquid biopsy at baseline and progression were collected. The ctDNA derived from plasma was analyzed by the AVENIO expanded kit, a hybridization capture sequencing-based 77 genes pan-cancer assay contained in NCCN Guidelines. Survival outcomes were calculated using Kaplan–Meier curves, log-rank tests and univariate Cox regression models were also performed. The study is exploratory and no formal hypothesis has been postulated. Results: Forty consecutive V600E BRAF mut mCRC pts were enrolled. Median age was 63 years (42-77), 47.5% of pts were males. Right CRC were 65% and 20% were MSI-H. Only 5% of pts received TT after second line; doublet regimen was administered in 60% of pts while triplet in 40%. According to the mPFS of doublet arm in the BEACON trial (4.2 months, mo), our population was divided in responder (R), 24 (60%), and non-responder (NR), 16 (40%). In R vs NR group, mPFS was 9 vs 3.2 mo while mOS was 21.6 vs 10.7 mo, respectively. The V600E BRAF mut was detected in 85% of the pre-treatment plasma samples without statistically significant differences in the genomic alterations between R and NR groups, but there was a higher frequency of MET and EGFR amplification in NR group. At progression, the mutation of BRAF was lost in 2 cases in R group. After receiving TT, the most common acquired mutations involved RAS genes: 16 pts (40%) acquired at least one activating mutation in KRAS and/or NRAS. Among these, 9 pts showed multiple mutations of the same RAS gene probably due to both intra- and inter-lesional heterogeneities; none of these pts had MSI-H mCRC. We found a higher number of RAS and MAP2K1 acquired mutations in NR and a trend to acquire EGFR amplification in R group. Inactivating mutations in RFN43 gene was observed in 2 cases in R group. These data did not reach statistical significance, probably due to the low number of cases. Interestingly, 37% of NR pts acquired three or more molecular alterations vs 13% in R group. Furthermore, a higher number of genetic alterations was acquired in pts treated with doublet vs triplet regimen. Conclusions: This prospective, observational molecular profiling study provided further evidences to support the use of ctDNA in capturing the dynamic somatic mutational spectrum in V600E BRAF mut mCRC and to identify potential mechanisms of resistance to TT. An expansion of study population is ongoing.

Efficacy and safety of encorafenib-based regimens in colorectal cancer: A systematic review of clinical trials.

e15600 Background: BRAF gene mutation is present in 10% of the world’s 3rd common cancer, i.e., colorectal cancer (CRC). Constitutive activation of the mitogen-activated protein kinase pathway (MAPKP) results from this mutation, abnormal activation of MAPKP, inhibiting apoptosis and enhancing proliferative activity. In this systematic review, we will assess the efficacy of encorafenib (a BRAF inhibitor) based regimens in CRC. Methods: We followed PRISMA guidelines to conduct this systematic review. A literature search was performed on PubMed, Embase, and Clinicaltrials.gov with mesh terms, ‘’Colorectal Neoplasms’’ and “Proto-Oncogene Proteins B-raf” from the inception of data till 01/05/2023. We screened 4572 articles and included 1 randomized clinical trial (RCT, N = 665), and 4 non-randomized trials (nRCTs, N = 175), measuring the efficacy of encorafenib (E) based regimens in BRAF V600-mutated CRC. Results: In 4 clinical trials (N = 840), 246 patients treated with a double regimen and 373 treated with a triple regimen of E. In 2 clinical trials (N = 319), triple therapy of E + C + Binimetinib showed an overall response rate (ORR) of 47.8% and 26% in the untreated metastatic CRC (mCRC) and phase III randomized trial triple regimen arm, respectively. A recent trial on triple therapy of E + C + nivolumab (N) showed an ORR of 45% with overall survival (OS) and progression-free survival (PFS) of 11.4 and 7.3 months, respectively. In 1 randomized trial (N = 665), ORR improved from 2% in the control arm to 26% and 20% in triple and double regimens, respectively, which was mainly partial response (PR) with complete response (CR) of 4-5% in both groups. The OS was 9 and 8.4 months with a hazard ratio (HR) for death vs. control of 0.52; (95% confidence interval [CI], 0.39 to 0.70; P < 0.001) and 0.60; (95% CI, 0.45 to 0.79; P < 0.001) in the triple and dual regimen, respectively. In 1 trial of dose escalation study, alpelisib (A) was added to E + C and the addition of this third drug showed minimal changes in the ORR from 18 to 19%, and PFS improved from 3.7 to 4.2 months. (Table 1). Conclusions: A combination of BRAF inhibitors with anti-EGFR monoclonal antibodies showed a clinically significant increase in antitumor activity in BRAF-mutated mCRC compared to standard therapy. The addition of MEK/PI3K inhibitor as a third drug to E + C also showed some improvement in ORR and PFS. Triple therapy with E + C + N was also effective and tolerated well by the microsatellite stable (MSS) BRAF mutated mCRC population. Randomized trials are needed. [Table: see text]

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 <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]

The possibilities of therapy of patients with metastatic colorectal cancer with <i>BRAF</i> V600E mutation. Clinical cases

Mutation in the BRAF V600E gene in metastatic colorectal cancer (CRC) occurs in 510% of cases and is a significant problem due to the aggressive course and extremely unfavorable prognosis. In recent years, new treatment options for BRAF mutated CRC have been emerging, for example, combinations of BRAF inhibitors, anti-EGFR antibodies with optional addition of MEK inhibitors. The possibility of local treatment methods is also being discussed. Objective: to evaluate the effectiveness of triple targeted therapy in BRAF-mutated metastatic colorectal cancer. On the example of 2 clinical cases of long-term treatment of patients with this molecular subtype, possible treatment options are discussed.

Sustained release hydrogel for durable locoregional chemoimmunotherapy for BRAF-mutated melanoma

The wide prevalence of BRAF mutations in diagnosed melanomas drove the clinical advancement of BRAF inhibitors in combination with immune checkpoint blockade for treatment of advanced disease. However, deficits in therapeutic potencies and safety profiles motivate the development of more effective strategies that improve the combination therapy's therapeutic index. Herein, we demonstrate the benefits of a locoregional chemoimmunotherapy delivery system, a novel thermosensitive hydrogel comprised of gelatin and Pluronic® F127 components already widely used in humans in both commercial and clinical products, for the co-delivery of a small molecule BRAF inhibitor with immune checkpoint blockade antibody for the treatment of BRAF-mutated melanoma. In vivo evaluation of administration route and immune checkpoint target effects revealed intratumoral administration of antagonistic programmed cell death protein 1 antibody (aPD-1) lead to potent antitumor therapy in combination with BRAF inhibitor vemurafenib. The thermosensitive F127-g-Gelatin hydrogel that was evaluated in multiple murine models of BRAF-mutated melanoma that facilitated prolonged local drug release within the tumor (>1 week) substantially improved local immunomodulation, tumor control, rates of tumor response, and animal survival. Thermosensitive F127-g-Gelatin hydrogels thus improve upon the clinical benefits of vemurafenib and aPD-1 in a locoregional chemoimmunotherapy approach for the treatment of BRAF-mutated melanoma.

Dose-escalation trial of combination dabrafenib, trametinib, and AT13387 in patients with BRAF-mutant solid tumors.

Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E-mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor-sensitive and BRAF inhibitor-resistant mutant cell lines. Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small-molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K-mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones. Twenty-two patients with metastatic, BRAF V600E-mutant solid tumors were enrolled using a 3+3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N=12). Dose-limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150mg twice daily, oral trametinib 2mg once daily, and intravenous AT13387 260mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval [CI], 2%-27%), a disease control rate of 47.6% (90% CI, 29%-67%), and a median overall survival of 5.1months (90% CI, 3.4-7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer. HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.

Abstract 1377: DCC-3116, a first-in-class selective inhibitor of ULK1/2 kinases and autophagy, synergizes with encorafenib and cetuximab in BRAF V600E mutant colorectal cancer models

Abstract Background: Cancer cells activate autophagy through ULK1/2 kinases as an adaptive stress response (ASR) mechanism to therapies targeting the RTK/RAS/MAPK/PI3K pathways, limiting antitumor response. BRAF signals through the MAPK pathway while EGFR signals upstream through both the MAPK and PI3K pathways, suppressing ULK1/2 kinases and autophagy. Inhibition of mutant BRAF and EGFR reverses this suppression, activating the autophagy ASR1-4. The BRAF V600E mutation occurs in ~10% of colorectal cancer (CRC) patients. Approved treatments for these patients include the BRAF V600E inhibitor encorafenib in combination with the EGFR antibody, cetuximab. Treatment with encorafenib + cetuximab (E+C) is initially successful, but drug resistance develops either through RTK/MAPK resistant mutations or ASR pathways including autophagy. DCC-3116 is a selective, investigational, potent, first-in-class inhibitor of the ULK1/2 kinases in clinical development in combination with targeted therapies that activate the autophagic ASR pathway. Herein we demonstrate ULK1/2 kinases and autophagy are activated upon treatment with E+C. A combination of E+C with DCC-3116 leads to inhibition of ULK1/2-mediated ATG13 phosphorylation (pATG13) and autophagy in vitro. In a PK/PD model, DCC-3116 inhibits E+C induced pATG13 and leads to synergistic tumor growth inhibition (TGI) in a preclinical model of BRAF V600E mutated CRC. Methods: ULK1/2 activity was measured in cells using an ELISA for the ULK substrate phospho-ATG13 (pATG13). Autophagic flux was measured by monitoring mCherry/GFP tagged LC3 in HT-29 and Colo-205 cells. Xenograft models were performed at a CRO. Results: E+C treatment led to the activation of ULK1/2 2-3-fold in BRAF V600E mutated CRC cell lines. DCC-3116 inhibited both E+C -induced and basal pATG13 with IC50 values of 80 nM and 234 nM in HT-29 and Colo-205 cells, respectively. E+C induced autophagic flux ~3-fold which was potently inhibited by DCC-3116 with IC50 values of 65 nM in HT-29 and 40 nM in Colo-205 cells. In a PK/PD model, DCC-3116 inhibited ULK1/2-mediated pATG13 induced by E+C. The combination of DCC-3116 with E+C resulted in greater TGI compared to single agent or the combination of E+C in BRAF V600E models. Conclusions: These preclinical data demonstrate that BRAF inhibitors in combination with EGFR blockade such as E+C activate ULK-mediated autophagy as an ASR resistance mechanism which can be inhibited by DCC-3116, providing the rationale to study the combination of DCC-3116 with E+C in BRAF V600E mutated CRC patients. DCC-3116 is currently in a Phase 1 clinical trial in patients with advanced solid tumors. (NCT04892017).

Abstract 5734: Designing RAF and MEK inhibitor combinations based on their biochemical properties to effectively target MAPK-driven cancers

Abstract Oncogenic alterations of the RAS/RAF/MEK/ERK signaling pathway drives growth of over 40% of human tumors, frequently due to activating mutations of components of the pathway, such as RAS or BRAF. Targeting the pathway using BRAF inhibitors (BRAFi) in combination with MEK inhibitors (MEKi) is now the standard of care for metastatic melanoma patients harboring the BRAF(V600E) mutation. However, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including those with RAS activating mutations. The effectiveness of current clinical BRAFi relies on the fact that they bind selectively and inhibit the mutationally activated monomeric form of the BRAF(V600E) kinase in tumors but not wild-type BRAF in normal tissue where BRAF signals in its dimeric form. Yet, the development of adaptive resistance, frequently due to RAF dimerization, limits BRAFi therapeutic effectiveness. Another class of BRAFi equipotent for both monomeric and dimeric BRAF have been developed, but are predicted to have lower therapeutic index due to inhibition of dimeric wild-type BRAF in normal tissues as well. Recently, we identified and characterized a novel class of BRAFi that preferentially binds and inhibits dimeric BRAF over monomeric BRAF(V600E) (i.e. RAF dimer-selective inhibitors). Furthermore, we rationally designed a combinatorial approach utilizing a BRAF monomer-selective plus a BRAF dimer-selective inhibitor plus a MEK inhibitor, that potently disrupts the BRAF/MEK complex, to maximally inhibit BRAF(V600E) signaling in tumors while retaining a broad therapeutic index. This triple combination potently suppressed tumor growth of multiple BRAF(V600E) colorectal cancer and melanoma models resistant to the current clinical BRAFi and MEKi combinations both in vitro and in vivo. To design effective therapeutic approaches for RAS-mutated tumors, we also assessed the effectiveness of RAF and MEK inhibitors belonging to diverse biochemical and structural classes, either alone or in combination in RAS-mutant tumor models and normal cells with wild-type RAS signaling. We found that RAF dimer-selective inhibitors potently antagonized MAPK signaling and growth in various RAS mutant cancer models as compared to normal cells. We found further that RAF and MEK inhibitor combinations belonging to certain biochemical classes resulted in more potent MAPK suppression in RAS-mutant tumor as compared to wild-type RAS normal cells (“therapeutic synergy”) and should be prioritized for clinical testing. In contrast, those combinations which are more potent in normal over tumor cells (“adverse synergy”) are unlikely to be clinically successful. Thus, rationally designed combinations of selected RAFi and MEKi, based on their distinct biochemical properties, can uncover new therapeutic opportunities tailored for more effective targeting of BRAF or RAS mutant tumors. Citation Format: Ana Orive-Ramos, Christos Adamopoulos, Beau Baars, Jason Lam, Ankita Punetha, Jason Huang, Vasileios I. Petrou, Stuart A. Aaronson, Poulikos I. Poulikakos. Designing RAF and MEK inhibitor combinations based on their biochemical properties to effectively target MAPK-driven cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5734.

Selected Articles from This Issue

Highlights| March 02 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1538-8514 Print ISSN: 1535-7163 ©2023 American Association for Cancer Research2023American Association for Cancer Research Mol Cancer Ther (2023) 22 (3): 289. https://doi.org/10.1158/1535-7163.MCT-22-3-HI Related Content A commentary has been published: Venadaparib Is a Novel and Selective PARP Inhibitor with Improved Physicochemical Properties, Efficacy, and Safety A commentary has been published: Daclatasvir, an Antiviral Drug, Downregulates Tribbles 2 Pseudokinase and Resensitizes Enzalutamide-Resistant Prostate Cancer Cells A commentary has been published: A Bispecific METxMET Antibody–Drug Conjugate with Cleavable Linker Is Processed in Recycling and Late Endosomes View more A commentary has been published: Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record March 2 2023 Citation Selected Articles from This Issue. Mol Cancer Ther 1 March 2023; 22 (3): 289. https://doi.org/10.1158/1535-7163.MCT-22-3-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Combination of BRAF inhibitor and MEK inhibitor is current Standard of Care (SoC) for BRAF-mutated melanoma. However, almost all patients develop resistance to these agents and one of the resistance mechanisms is BRAF overexpression. To overcome this kind of resistance, Takano and colleagues discovered novel ATP-competitive MEK inhibitors, DS56771486 and DS03090629. These compounds tended to retain their activities in BRAF overexpressed A375 cell line whereas currently used BRAF inhibitor and MEK inhibitor got attenuated in this cell line compared to parental A375. These results indicate the potential of these compounds to overcome the resistance to current SoC in BRAF-mutated melanoma. PARP inhibitors are widely available to patients with homologous recombination deficient breast, ovarian, pancreatic, or prostate cancers. The use of current PARP inhibitors as chemo-potentiating agents have been limited due to toxicities. Lee and colleagues developed a next generation PARP inhibitor venadaparib. Molecular characteristics of venadaparib translated to superior efficacy... You do not currently have access to this content.

TRIDENTE trial: A phase II study of rechallenge with encorafenib, binimetinib, and cetuximab in patients with RAS wild-type/BRAF V600E–mutant metastatic colorectal cancer.

TPS264 Background: The BEACON CRC trial demonstrated survival benefit of combination therapy with encorafenib (ENCO) + cetuximab (CET) +/- binimetinib (BINI) in patients with RAS wild-type (WT)/ BRAF V600E mutant metastatic colorectal cancer (mCRC). However, prognosis of those patients still be poor after the refractoriness to the BEACON combination therapy. One of resistant mechanisms to BRAF inhibitor has been reported as MAPK alterations including RAS mutation, similar to those for anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC. Promising results of rechallenge therapy with anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC and with combination of BRAF inhibitor + MEK inhibitor in patients with BRAF V600 mutant melanoma suggest the treatment strategy of rechallenge therapy with the BEACON triplet therapy in patients with RAS WT/ BRAF V600E mutant mCRC. Methods: TRIDENTE trial is a multicenter phase II trial to assess efficacy and safety of rechallenge therapy with ENCO + BINI + CET in patients with RAS WT/ BRAF V600E mutant mCRC after the refractoriness to either the BEACON doublet or triplet therapy. Key eligibility criteria includes RAS WT/ BRAF V600E mutant mCRC; ≥ 20 years old; ECOG PS 0-1; refractory or intolerant to at least one fluoropyrimidine-based regimen (including irinotecan or oxaliplatin); refractory or intolerant to anti-PD-1 antibody if patients with MSI-high; history of previous combination therapy containing ENCO + CET with at least partial response by RECIST v1.1; confirmed disease progression within 4 weeks after last administration of previous ENCO; ≥ 4 months of period between the last administration of previous ENCO and the start of study treatment. Enrolled patients receive the combination therapy with ENCO (300 mg, QD), BINI (45 mg, BID), and CET (initially 400 mg/m2, and subsequently 250 mg/m2, QW) as the study treatment. Primary endpoint is the objective response rate (ORR) by investigators’ assessment in patients receiving at least one dose of study treatment. A target sample size is calculated to be 21 on the hypothesis that the threshold ORR is 3% and expected ORR is 20%, with a significant level of 5% (one-sided) and power of 80%. Secondary endpoint includes progression-free and overall survivals, disease control rate, and safety. Exploratory molecular analysis is performed using targeted next-generation sequencing in circulating-tumor DNA at the timepoints of baseline and discontinuation of study treatment. As of September 19, 2022, 8 patients have been enrolled. Clinical trial information: jRCTs031210511 .