Clinicogenomic factors and treatment patterns among patients with advanced non-small cell lung cancer with or without brain metastases in the United States.

BACKGROUND: This retrospective, real-world study evaluated the prevalence of brain metastases, clinicodemographic characteristics, systemic treatments, and factors associated with overall survival among patients with advanced non-small cell lung cancer (aNSCLC) in the US. We also described the genomic characterization of 180 brain metastatic specimens and frequency of clinically actionable genes. MATERIALS AND METHODS: De-identified electronic health records-derived data of adult patients diagnosed with aNSCLC between 2011 and 2017 were analyzed from a US-nationwide clinicogenomic database. RESULTS: Of 3257 adult patients with aNSCLC included in the study, approximately 31% (n = 1018) had brain metastases. Of these 1018 patients, 71% (n = 726) were diagnosed with brain metastases at initial NSCLC diagnosis; 57% (n = 583) of patients with brain metastases received systemic treatment. Platinum-based chemotherapy combinations were the most common first-line therapy; single-agent chemotherapies, epidermal growth factor receptor tyrosine kinase inhibitors, and platinum-based chemotherapy combinations were used in second line. Patients with brain metastases had a 1.56 times greater risk of death versus those with no brain metastases. In the brain metastatic specimens (n = 180), a high frequency of genomic alterations in the p53, MAPK, PI3K, mTOR, and cell-cycle associated pathways was observed. CONCLUSION: The frequency of brain metastases at initial clinical presentation and associated poor prognosis for patients in this cohort underscores the importance of early screening for brain metastasis in NSCLC. Genomic alterations frequently identified in this study emphasize the continued need for genomic research and investigation of targeted therapies in patients with brain metastases.

Outcomes in Patients with FLT3-Mutated Relapsed/ Refractory Acute Myelogenous Leukemia Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib versus Salvage Chemotherapy.

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (45%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients.

Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy.

Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035.

Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia.

PURPOSE: The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated (FLT3mut) acute myeloid leukemia (AML) but seldom reduces FLT3mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3mut AML. METHODS: This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505) enrolled patients with FLT3 wild-type and FLT3mut (escalation) or FLT3mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III-defined response criteria. RESULTS: Sixty-one patients were enrolled (n = 56 FLT3mut); 64% (n = 36 of 56) of FLT3mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10-2) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3mut patients was 10.0 months. CONCLUSION: The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.

Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib.

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin.

Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial.

The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation-positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

ERK Inhibitor LY3214996-Based Treatment Strategies for RAS-Driven Lung Cancer.

RAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with KRAS-mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of RAS-mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and-equally important-to identify biomarkers for patient stratification.

Clinical Characteristics, Treatments, and Concurrent Mutations in Non-Small Cell Lung Cancer Patients With NF1 Mutations.

OBJECTIVES: Metastatic non-small cell lung cancer (mNSCLC) is characterized by complex genomic alterations. NF1 mutations may confer distinct clinical characteristics within NSCLC, and real-world evidence on concurrent mutations, treatment patterns, and health outcomes is lacking. MATERIALS AND METHODS: This retrospective study was performed in patients with mNSCLC treated in the Flatiron Health network who underwent the FoundationOne tumor-sequencing. Anticancer therapies, concurrent mutations, real-world progression-free survival (rwPFS), and overall survival (OS) were assessed. RESULTS: Of the 1663 patients, 103 patients were identified with NF1 mutation. Concurrent mutations with Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (16.5%) and epidermal growth factor receptor fusion (6.8%) were the most frequent. In patients with NF1 mutation only (n = 57), 42% were women, 86% patients had smoking history, and 70% had non-squamous cell carcinoma type. Most (51%) of the patients with NF1 mutations received a single line of therapy versus other mutations and the overall treated population (44%). Platinum-based chemotherapy was the predominant first-line therapy, with programmed cell death-1/programmed cell death-ligand-1 inhibitors as subsequent lines of therapy. The NF1 mutation only group had numerically the shortest median rwPFS (82 days) than other mutation groups. Median OS for the NF1 mutation group in first, second, and third lines of therapy was 321, 498, and 210 days, respectively. CONCLUSIONS: NF1 mutations confer distinct clinical characteristics in patients with mNSCLC. These patients may have different trajectories for progression and survival than seen for other mutations, experience less systemic therapy after first-line therapy, and may have shorter survival.

Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers.

We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.

Correction: Evaluation of ERK as a therapeutic target in acute myelogenous leukemia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

A Phase I Study of LY3009120, a Pan-RAF Inhibitor, in Patients with Advanced or Metastatic Cancer.

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n = 15), nausea (n = 12), dermatitis acneiform (n = 10), decreased appetite (n = 7), and maculopapular rash (n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.

ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine.

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAF- and KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

Phase I Study of LY2940680, a Smo Antagonist, in Patients with Advanced Cancer Including Treatment-Naïve and Previously Treated Basal Cell Carcinoma.

Purpose: The purpose of this study was to determine a recommended phase II dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer.Experimental Design: This was a phase I, multicenter, open-label study of oral LY2940680. The maximum tolerable dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naïve and previously hedgehog (Hh)-inhibitor-treated patients with basal cell carcinoma (BCC) were enrolled.Results: Eighty-four patients were treated (dose escalation, n = 25; dose confirmation, n = 19; and BCC dose expansion, n = 40). Common treatment-emergent adverse events were dysgeusia [41 (48.8%)], fatigue [40 (47.6%)], nausea [38 (45.2%)], and muscle spasms [34 (40.5%)]. Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested that all doses were biologically active [inhibition median of 92.3% (80.9% to 95.7%)]. All clinical responses (per RECIST 1.1) were in patients with BCC (n = 47); the overall and estimated response rate was 46.8% (95% confidence interval, 32.1%-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh treatment-naïve (11/16) patients.Conclusions: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh treatment-naïve patients. Clin Cancer Res; 24(9); 2082-91. ©2018 AACR.

Loss of epigenetic regulator TET2 and oncogenic KIT regulate myeloid cell transformation via PI3K pathway.

Mutations in KIT and TET2 are associated with myeloid malignancies. We show that loss of TET2-induced PI3K activation and -increased proliferation is rescued by targeting the p110α/δ subunits of PI3K. RNA-Seq revealed a hyperactive c-Myc signature in Tet2-/- cells, which is normalized by inhibiting PI3K signaling. Loss of TET2 impairs the maturation of myeloid lineage-derived mast cells by dysregulating the expression of Mitf and Cebpa, which is restored by low-dose ascorbic acid and 5-azacytidine. Utilizing a mouse model in which the loss of TET2 precedes the expression of oncogenic Kit, similar to the human disease, results in the development of a non-mast cell lineage neoplasm (AHNMD), which is responsive to PI3K inhibition. Thus, therapeutic approaches involving hypomethylating agents, ascorbic acid, and isoform-specific PI3K inhibitors are likely to be useful for treating patients with TET2 and KIT mutations.

Mouse PDX Trial Suggests Synergy of Concurrent Inhibition of RAF and EGFR in Colorectal Cancer with BRAF or KRAS Mutations.

Purpose: To evaluate the antitumor efficacy of cetuximab in combination with LSN3074753, an analog of LY3009120 and pan-RAF inhibitor in 79 colorectal cancer patient-derived xenograft (PDX) models.Experimental Design: Seventy-nine well-characterized colorectal cancer PDX models were employed to conduct a single mouse per treatment group (n = 1) trial.Results: Consistent with clinical results, cetuximab was efficacious in wild-type KRAS and BRAF PDX models, with an overall response rate of 6.3% and disease control rate (DCR) of 20.3%. LSN3074753 was active in a small subset of PDX models that harbored KRAS or BRAF mutations. However, the combination treatment displayed the enhanced antitumor activity with DCR of 35.4%. Statistical analysis revealed that BRAF and KRAS mutations were the best predictors of the combinatorial activity and were significantly associated with synergistic effect with a P value of 0.01 compared with cetuximab alone. In 12 models with BRAF mutations, the combination therapy resulted in a DCR of 41.7%, whereas either monotherapy had a DCR of 8.3%. Among 44 KRAS mutation models, cetuximab or LSN3074753 monotherapy resulted in a DCR of 13.6% or 11.4%, respectively, and the combination therapy increased DCR to 34.1%. Molecular analysis suggests that EGFR activation is a potential feedback and resistant mechanism of pan-RAF inhibition.Conclusions: MAPK and EGFR pathway activations are two major molecular hallmarks of colorectal cancer. This mouse PDX trial recapitulated clinical results of cetuximab. Concurrent EGFR and RAF inhibition demonstrated synergistic antitumor activity for colorectal cancer PDX models with a KRAS or BRAF mutation. Clin Cancer Res; 23(18); 5547-60. ©2017 AACR.

Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study.

BACKGROUND: Myelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib. 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved the primary endpoint of 35% or more reduction in spleen volume from baseline assessed by MRI or CT. Furthermore, more than 50% of patients discontinue ruxolitinib treatment after 3-5 years. On the basis of this unmet need, we investigated the efficacy and safety of fedratinib, a JAK2-selective inhibitor, in patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis. METHODS: This single-arm, open-label, non-randomised, phase 2, multicentre study, done at 31 sites in nine countries, enrolled adult patients with a current diagnosis of intermediate or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis, found to be ruxolitinib resistant or intolerant after at least 14 days of treatment. Other main inclusion criteria were palpable splenomegaly (≥5 cm below the left costal margin), Eastern Cooperative Oncology Group performance status of 2 or less, and life expectancy of 6 months or less. Patients received oral fedratinib at a starting dose of 400 mg once per day, for six consecutive 28-day cycles. The primary endpoint was spleen response (defined as the proportion of patients with a ≥35% reduction in spleen volume as determined by blinded CT and MRI at a central imaging laboratory). We did the primary analysis in the per-protocol population only (patients treated with fedratinib, for whom a baseline and at least one post-baseline spleen volume measurement was available) and the safety analysis in all patients receiving at least one dose of fedratinib. This trial was registered with ClinicalTrials.gov, number NCT01523171. FINDINGS: Between May 8, 2012, and Aug 29, 2013, 97 patients were enrolled and received at least one dose of fedratinib. Of 83 assessable patients, 46 (55%, 95% CI 44-66) achieved a spleen response. Common grade 3-4 adverse events included anaemia (37 [38%] of 97 patients) and thrombocytopenia (21 [22%] of 97), with 18 (19%) patients discontinuing due to adverse events. Seven (7%) patients died during the study, but none of the deaths was drug related. Suspected cases of Wernicke's encephalopathy in other fedratinib trials led to study termination. INTERPRETATION: This phase 2 study met its primary endpoint, suggesting that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis might achieve significant clinical benefit with fedratinib, albeit at the cost of some potential toxicity, which requires further evaluation. Fedratinib development in this setting is currently being assessed. FUNDING: Sanofi.

A first-in-human phase 1 study of a hepcidin monoclonal antibody, LY2787106, in cancer-associated anemia.

BACKGROUND: Hepcidin plays a central role in iron homeostasis and erythropoiesis. Neutralizing hepcidin with a monoclonal antibody (mAb) may prevent ferroportin internalization, restore iron efflux from cells, and allow transferrin-mediated iron transport to the bone marrow. This multicenter, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of a fully humanized mAb (LY2787106) with high affinity for hepcidin in cancer patients with anemia. METHODS: Thirty-three patients with hepcidin levels ≥5 ng/mL received LY2787106 either every 3 weeks (19 patients, dose range 0.3-10 mg/kg) (part A) or weekly (14 patients, dose 10 mg/kg) (part B). LY2787106 PK/PD markers of iron and hematology biology were measured. RESULTS: LY2787106 clearance (32 mL/h) and volume of distribution (7.7 L) were independent of dose and time, leading to a dose-proportional increase in concentration with dose. Consistent dose-dependent increases in serum iron, and transferrin saturation were seen at the 3 and 10 mg/kg dose levels, typically peaking within 24 h after LY2787106 administration and returning to baseline by day 8. CONCLUSIONS: Our findings indicate that LY2787106 was well tolerated in cancer patients with anemia and that targeting the hepcidin-ferroportin pathway by neutralizing hepcidin resulted in transient iron mobilization, thus supporting the role of hepcidin in iron regulation. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01340976.

Impact of allogeneic hematopoietic cell transplant in patients with myeloid neoplasms carrying spliceosomal mutations.

Molecular predictors of outcome are increasingly important in determining optimal therapy for myeloid neoplasms. Mutations in the spliceosomal genes (U2AF1 and SRSF2) predict for poor outcomes in myelodysplastic syndromes (MDS) and related diseases. We investigated the effect of hematopoietic cell transplant (HCT) on the negative prognostic impact of U2AF1 and SRSF2 mutations. In total, 122 patients with MDS (30%), acute myeloid leukemia (51%), myeloproliferative neoplasms (MPN) (11%), and MDS/MPN (8%) receiving a HCT from 2003 to 2012 were evaluated for mutations in U2AF1 and SRSF2 by direct sequencing. Median time of follow up was 24 months (range 0.46-110). SRSF2 mutations were detected in 11 (10%) patients and U2AF1 in 3 (3%) patients. There were no significant differences in baseline characteristics between mutated and wild-type (WT) patients. Patients carrying SRSF2 and U2AF1 mutations had similar overall survival (P = 0.84), relapse mortality (P = 0.50), and non-relapse mortality (P = 0.72) compared to WT patients. However, taking into account disease status and cytogenetics in a subset of AML patients, SRSF2 and U2AF1 mutations were associated with worse survival (HR 3.71, P = 0.035).