Search

Purpose: The influence of the transcriptional and immunologic context of mutations on therapeutic outcomes with targeted therapy in cancer has not been well defined. BRAF V600E–mutant (BM) colorectal cancer comprises two main transcriptional subtypes, BM1 and BM2. We sought to determine the impact of BM subtype, as well as distinct biological features of those subtypes, on response to BRAF/MEK/EGFR inhibition in patients with colorectal cancer. Patients and Methods: Paired fresh tumor biopsies were acquired at baseline and on day 15 of treatment from all consenting patients with BM colorectal cancer enrolled in a phase II clinical trial of dabrafenib, trametinib, and panitumumab. For each sample, BM subtype, cell cycle, and immune gene signature expression were determined using RNA-sequencing (RNA-seq), and a Cox proportional hazards model was applied to determine association with progression-free survival (PFS). Results: Confirmed response rates, median PFS, and median overall survival (OS) were higher in BM1 subtype patients compared with BM2 subtype patients. Evaluation of immune contexture identified greater immune reactivity in BM1, whereas cell-cycle signatures were more highly expressed in BM2. A multivariate model of PFS incorporating BM subtype plus immune and cell-cycle signatures revealed that BM subtype encompasses the majority of the effect. Conclusions: BM subtype is significantly associated with the outcome of combination dabrafenib, trametinib, and panitumumab therapy and may serve as a standalone predictive biomarker beyond mutational status. Our findings support a more nuanced approach to targeted therapeutic decisions that incorporates assessment of transcriptional context.

BACKGROUND: Current treatment outcomes for patients with recurrent HGG are poor, with median progression-free survival (PFS) and overall survival (OS) of 2.5 and 7.5 months, respectively. Dabrafenib (BRAF inhibitor) + trametinib (MEK inhibitor) resulted in an intracranial overall response rate (ORR) of 58% in BRAF V600–mutated melanoma brain metastases. Dabrafenib + trametinib was evaluated as treatment for patients with BRAF V600E–mutated HGG. METHODS: In this phase 2, open-label trial (NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including HGG, received continuous dabrafenib (150 mg BID) + trametinib (2 mg QD) until unacceptable toxicity, disease progression, or death. For the HGG cohort, eligible patients had histologically confirmed recurrent or progressive WHO grade 3 or 4 glioma and had prior treatment with radiotherapy and first-line chemotherapy or concurrent chemoradiation therapy. The primary endpoint was investigator-assessed ORR by RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. RESULTS: Thirty-seven patients with HGG had enrolled at data cutoff (3 January 2018). Median age was 42 years, 31 of 37 patients were evaluable for response. Investigator-assessed confirmed ORR was 26% (8/31; 95% CI, 12%-45%), including 1 complete response (CR). Six of 8 responses were ongoing at data cutoff. Five of 8 responding patients had a DOR of ≥ 12 months. Median PFS was 1.9 months (95% CI, 1.7–18.5). Median OS was 11.7 months (95% CI, 6.4-not reached). Adverse events (AEs) in patients with HGG included fatigue (35%), headache (30%), and rash (24%). Grade 3/4 AEs included neutropenia (8%) and fatigue (5%). Biomarker analyses are ongoing and will be presented. CONCLUSIONS: Dabrafenib + trametinib demonstrated promising efficacy in patients with BRAF V600E-mutated recurrent/refractory HGG, as 1 patient had a CR, and most responders had a prolonged DOR.

Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism. Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428–43. ©2018 AACR. See related commentary by Janku, p. 389. See related article by Hazar-Rethinam et al., p. 417. This article is highlighted in the In This Issue feature, p. 371

BACKGROUND: Hairy cell leukemia is a rare, indolent, B-cell lymphoproliferative disease characterized by the BRAF V600E mutation in 90% to 100% of patients. Few treatment options are available for patients who progress on first-line therapy with a purine analogue and/or rituximab. The efficacy of combined BRAF and MEK inhibition is well established in BRAF V600-mutated melanoma, non-small cell lung cancer, and anaplastic thyroid cancer. Here we report interim results of treatment with the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in patients with recurrent/refractory BRAF V600E-mutated HCL. METHODS: In this phase 2, open-label trial (ROAR; NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including HCL, received continuous dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) until unacceptable toxicity, disease progression, or death. For the HCL cohort, eligible patients had histologically confirmed HCL (according to WHO classification) that was refractory to first-line treatment with a purine analogue or relapsed after ≥ 2 prior lines of treatment. The presence of a BRAF V600E mutation was assessed locally and confirmed by a central laboratory. The primary endpoint was investigator-assessed overall response rate (ORR) based on criteria adapted from NCCN guidelines. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Minimal residual disease (MRD) status was assessed by flow cytometry in both peripheral blood and bone marrow aspirates. For complete response (CR) without MRD, both peripheral blood and bone marrow aspirate samples had to be negative. RESULTS: At the data cutoff (January 3, 2018), 43 patients with HCL had enrolled. Median age was 67 years (range, 40-81) and 38 (88%) were male. Twenty-one patients (49%) had received ≥ 4 prior treatments. At the time of data cutoff, 35 patients (81%) remained on study treatment, 5 (12%) in follow-up; 2 (5%) had withdrawn from study (loss to follow-up and consent withdrawal [n = 1 each]), and 1 (2%) had died. Eight patients had discontinued therapy due to adverse events (AEs; 5 [12%]), study withdrawal (2 [5%]), or disease progression (1 [2%]). Median time on study treatment was 17 months (range, 1-39). Among 41 patients evaluable for response, the investigator-assessed confirmed ORR was 78% (32/41; 95% CI, 62%-89%) with 20 (49%) having CR, (6 [15%] CR without MRD and 14 [34%] CR with MRD), and 12 (29%) partial response. All responses were ongoing at the data cutoff; 16 (50%) responses were lasting ≥ 18 months. PFS and OS rates at 12 months were both 97.6% (95% CI, 83.9%-99.7%). The most common AEs in patients with HCL were pyrexia (67%), chills (51%), hyperglycemia (44%), nausea (44%), peripheral edema (42%), cough (40%), and fatigue (40%). Grade 3/4 AEs were reported in 49% of patients, with the most common (> 5%) being hyperglycemia (9%), anemia (7%), and neutropenia (7%). AEs led to dose reduction and treatment interruption in 42% and 56% of patients, respectively. AEs led to permanent discontinuation in 5 patients (12%; headache and malaise [n = 1]; pyrexia, chills and palmar-plantar erythrodysesthesia syndrome [n = 1]; fat necrosis [n = 1]; hyperglycemia and pancreatic adenocarcinoma [n = 1]; Hodgkin lymphoma [n = 1]). CONCLUSIONS: Dabrafenib + trametinib was well tolerated and demonstrated a high rate of durable responses in patients with heavily pretreated recurrent/refractory BRAF V600E-mutated HCL. Disclosures Kreitman: NIH: Patents & Royalties: Co-inventor on the NIH patent for Moxetumomab Pasudotox. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blay:Roche: Honoraria, Other: Non-financial support, Research Funding; Novartis: Honoraria, Other: Non-financial support, Research Funding. Wainberg:Merck: Consultancy; EMD Serono: Consultancy; Lilly: Consultancy; Five Prime: Consultancy; Novartis: Consultancy. Stein:Novartis: Other: Patient documentation fees; GSK: Other: Patient documentation fees. Willenbacher:Merck: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Honoraria, Other: Steering board, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau. Burgess:Novartis: Employment. Mookerjee:Novartis: Employment. Subbiah:Roche/Genentech: Research Funding; LOXO: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Bayer: Research Funding.

6023 Background: ATC is a rare, aggressive malignancy with a dismal prognosis. Median overall survival (OS) is < 6 mo. Combined BRAF and MEK inhibition is efficacious in BRAF V600–mutated melanoma and lung cancer. One-fourth of ATCs harbor activating BRAF V600E mutations; thus, D (BRAF inhibitor) + T (MEK inhibitor) was evaluated as a treatment for pts with BRAF V600E–mutated ATC. Methods: In this phase 2, open-label trial (NCT02034110), pts with BRAF V600E mutations in 9 rare tumor types, including ATC, received continuous D (150 mg BID) + T (2 mg QD) until unacceptable toxicity, disease progression, or death. Eligible pts had advanced or metastatic cancer with no standard-of-care treatment options. The primary endpoint was investigator-assessed overall response rate (ORR). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), OS, and safety. We report data from the ATC cohort. Results: 16 pts with BRAF V600E–mutated ATC had evaluable data with a median follow-up time of 47 wk (range 4-120 wk). BRAF V600E mutations were centrally confirmed in 15/16 pts. Median age was 72 y; all 16 pts had undergone prior tumor radiation and/or surgery and 6/16 pts (38%) had received ≥1 prior line of systemic therapy. Investigator-assessed confirmed ORR was 69% (11/16; 95% CI, 41%-89%), with 7/11 responses ongoing at the time of data cut. The Bayesian estimate of ORR was 69% (95% credible interval, 47%-87%) with a 100% probability that this ORR exceeded the 15% historical RR. Median DOR, PFS, and OS were not estimable due to insufficient progression and death events. Kaplan-Meier estimates of DOR, PFS, and OS at 12 mo were 90%, 79%, and 80%, respectively. The safety population comprised 100 pts enrolled in 7/9 histologies. Among all pts, 92% had an AE. Common AEs of any grade for all histologies were fatigue (38%), pyrexia (37%), and nausea (35%). In the ATC cohort, the most common grade 3/4 events were hyponatremia (19%), pneumonia (13%), and anemia (13%). Conclusions: D+T combination therapy significantly improved outcomes in ATC with a favorable safety profile. This regimen represents a clinically meaningful therapeutic advance for pts with advanced/metastatic BRAF V600–mutated ATC. Clinical trial information: NCT02034110.

TPS2604Background: Combination D + T is approved for the treatment of BRAF V600E/K–mutant unresectable or metastatic melanoma. BRAF V600E mutations have also been identified in some rare cancers, including anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, nonseminomatous germ cell tumor, hairy cell leukemia (HCL), World Health Organization (WHO) grade I/II glioma, WHO grade III/IV glioma, multiple myeloma, and adenocarcinoma of the small intestine. US incidence rates of these rare tumors range from 0.07 to 6.3 per 100,000, with BRAF V600E mutation frequency ranging from 3% in high-grade glioma to 90% in HCL. Therefore, the ROAR study is underway in pts with these 9 rare BRAF-mutant cancers to assess the safety and efficacy of D + T combination therapy. Methods: This international, multicenter, open-label phase 2 study (NCT02034110) uses a Bayesian hierarchical statistical design that increases study power by borrowing information across histology cohorts based on the emergin...