Search

PURPOSE Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4–blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600-mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. PATIENTS AND METHODS In a phase III trial, patients with treatment-naive BRAFV600-mutant metastatic melanoma were randomly assigned to receive either combination nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1, and at disease progression were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D). The primary end point was 2-year overall survival (OS). Secondary end points were 3-year OS, objective response rate, response duration, progression-free survival, crossover feasibility, and safety. RESULTS A total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rank P = .010). Step 1 progression-free survival favored arm A ( P = .054). Objective response rates were arm A: 46.0%; arm B: 43.0%; arm C: 47.8%; and arm D: 29.6%. Median duration of response was not reached for arm A and 12.7 months for arm B ( P < .001). Crossover occurred in 52% of patients with documented disease progression. Grade ≥ 3 toxicities occurred with similar frequency between arms, and regimen toxicity profiles were as anticipated. CONCLUSION Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

Combination programmed cell death protein 1/cytotoxic T-cell lymphocyte-4-blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients withIn a phase III trial, patients with treatment-naiveA total of 265 patients were enrolled, with 73 going onto step 2 (27 in arm C and 46 in arm D). The study was stopped early by the independent Data Safety Monitoring Committee because of a clinically significant end point being achieved. The 2-year OS for those starting on arm A was 71.8% (95% CI, 62.5 to 79.1) and arm B 51.5% (95% CI, 41.7 to 60.4; log-rankCombination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.

Objective To select optimal therapies based on the detection of actionable genomic alterations in tumor samples is a major challenge in precision medicine. Methods We describe an effective process (opened December 1, 2017) that combines comprehensive genomic and transcriptomic tumor profiling, custom algorithms and visualization software for data integration, and preclinical 3-dimensiona ex vivo models for drug screening to assess response to therapeutic agents targeting specific genomic alterations. The process was applied to a patient with widely metastatic, weakly hormone receptor positive, HER2 nonamplified, infiltrating lobular breast cancer refractory to standard therapy. Results Clinical testing of liver metastasis identified BRIP1, NF1, CDH1, RB1, and TP53 mutations pointing to potential therapies including PARP, MEK/RAF, and CDK inhibitors. The comprehensive genomic analysis identified 395 mutations and several structural rearrangements that resulted in loss of function of 36 genes. Meta-analysis revealed biallelic inactivation of TP53, CDH1, FOXA1, and NIN, whereas only one allele of NF1 and BRIP1 was mutated. A novel ERBB2 somatic mutation of undetermined significance (P702L), high expression of both mutated and wild-type ERBB2 transcripts, high expression of ERBB3, and a LITAF-BCAR4 fusion resulting in BCAR4 overexpression pointed toward ERBB-related therapies. Ex vivo analysis validated the ERBB-related therapies and invalidated therapies targeting mutations in BRIP1 and NF1. Systemic patient therapy with afatinib, a HER1/HER2/HER4 small molecule inhibitor, resulted in a near complete radiographic response by 3 months. Conclusion Unlike clinical testing, the combination of tumor profiling, data integration, and functional validation accurately assessed driver alterations and predicted effective treatment.

Chronic lymphocytic leukemia (CLL) is a malignant B-cell disorder that remains a largely incurable disease. We and others have previously shown that angiogenesis is important in the pathogenesis of CLL. Sorafenib is a small molecule signal transduction inhibitor that exhibits anti-tumor activity through a number of mechanisms including blocking of the Raf/MEK/ERK pathway and inhibition of receptor tyrosine kinases involved in angiogenic signaling such as the VEGF receptors. The data presented here are correlative studies performed on a Phase 2 clinical trial designed to measure the overall response rate to oral doses of sorafenib in CLL patients who have failed previous nucleoside analog therapy (alone or in combination with alkylating agents) or monoclonal antibody therapy. Each cycle consisted of 400 mg of sorafenib administered orally twice a day for 28 days. Treatment continued until any of the withdrawal criteria (unacceptable toxicity, disease progression, patient’s decision to withdraw) were reached. Peripheral blood samples for correlative studies were obtained before initiation of therapy, after 12 weeks (beginning of cycle 4) and after 24 weeks (beginning of cycle 7), or when the patient went off-study for any indication. In these studies, we specifically focused on examining VEGF and the VEGF receptors VEGFR-1 (flt-1), VEGFR-2 (KDR), VEGFR-3 (flt-4), neuropilin-1 and neuropilin-2. These molecules were analyzed at the transcript level by RT-PCR and at the protein level by western blotting or ELISA. In addition we examined plasma levels of IL-8 by ELISA, since IL-8 has been recently shown to be an important mediator of cell survival and angiogenesis in CLL. Specimens were analyzed from a total of five patients. Plasma IL-8 levels were markedly decreased in all three patients who underwent therapy beyond 12 weeks. The two patients went off study at or before 12 weeks did not show any decrease in IL-8 levels. No decrease was noted between the pre-treatment and post-treatment plasma concentrations of VEGF for any of the patients. No consistent change in cellular expression was observed between the pre-treatment and post-treatment samples for VEGF, VEGFR-1, VEGFR-2 or VEGFR-3. Neuropilin-1 expression was decreased or absent in the post therapy samples in patients who received therapy beyond 12 weeks, while no change in expression was seen in the two patients who went off study at or before 12 weeks. Neuropilin-2 expression was not detected in any of the samples. These results suggest that sorafenib suppresses angiogenic pathways by inhibiting secretion of IL-8 and expression of neuropilin-1. Additional studies and samples are needed to confirm these interesting findings, and to further delineate the anti-angiogenic effects of sorafenib in CLL.