Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2506-2506 ◽  
Author(s):  
Maxime Chenard-Poirier ◽  
Martin Kaiser ◽  
Kevin Boyd ◽  
Priya Sriskandarajah ◽  
Anastasia Constantinidou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Single Agent ◽  
Braf Inhibitor ◽  
Response Assessment ◽  
Mek Inhibitor ◽  
Solid Tumours ◽  
Tumour Regression ◽  
Wide Range ◽  
Braf Mutant

2506 Background: RO5126766 is a potent RAF and MEK inhibitor with activity in xenografts models of RAS and RAF-mutated cancers. We present data from the RAS/RAF-mutated advanced solid tumor cohort and the initial results for the multiple myeloma (MM) cohort. Methods: Patients with KRAS, NRAS or BRAF-mutant tumours were treated with RO5127566 using a novel schedule:4mg twice weekly in 4-week cycles. For MM patients, it was given 3 weeks out of 4 and co-administration of weekly dexamethasone was authorised. Response assessment was completed using RECIST 1.1 criteria for solid tumours and the International Myeloma Working Group (IMWG) criteria were used for MM. Results: A total of 20 patients with solid tumours (10 NSCLC, 5 gynaecological cancers and 5 miscellaneous cancers) and 1 MM patients were evaluable. Among the 10 KRAS-mutant NSCLC patients, tumour regression was seen in 6/10 (60 %), of which 3/10 (30 %) were partial responses. Two of these patients had maintained response for over 1 year and one patient is still on study after 30 cycles. Of the gynaecological cancers, 3/5 patients (60%) achieved a partial response ( KRAS-mutant endometrial and ovarian cancer and BRAF-mutant ovarian). Of these patients, 1 of the KRAS mutants had received 2 previous lines of MEK inhibitors and the BRAF mutant had previously received a BRAF inhibitor. In the miscellaneous group, 4 patients with colorectal cancer (2 BRAF and 2 NRAS) and 1 patient with NRAS-mutant melanoma were treated and none responded. Two patients with MM have been treated so far (1 KRAS, 1 KRAS+NRAS). The one evaluable patient has had an IMWG partial response (PR) after 1 cycle (FLC-λ from 324 mg/L to 161mg/L, ratio 0.03 to 0.08) without concomittant dexamethasone. This patient was previously treated with an immunomodulatory drug, a proteasome inhibitor and two ASCTs. Conclusions: RO5126766 has shown exciting preliminary activity across a wide range of RAS- and RAF-mutated malignancies, with significant response rates in lung and gynaecological cancers. To our knowledge, the PR seen in our MM patient represents one of the first responses to a single-agent RAF/MEK inhibitor in multiple myeloma in a trial context. Clinical trial information: NCT02407509.

scholarly journals Systemic Therapy for Melanoma: ASCO Guideline

2020 ◽  
Vol 38 (33) ◽  
pp. 3947-3970 ◽  
Author(s):  
Rahul Seth ◽  
Hans Messersmith ◽  
Varinder Kaur ◽  
John M. Kirkwood ◽  
Ragini Kudchadkar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Systemic Therapy ◽  
Cutaneous Melanoma ◽  
Meta Analysis ◽  
Mek Inhibitor ◽  
Wild Type ◽  
Additional Information ◽  
Metastatic Setting ◽  
Wide Range ◽  
Braf Mutant

PURPOSE To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS ASCO convened an Expert Panel and conducted a systematic review of the literature. RESULTS A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma. RECOMMENDATIONS In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF-mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines .

scholarly journals Response to Ipilimumab/Nivolumab Rechallenge and BRAF Inhibitor/MEK Inhibitor Rechallenge in a Patient with Advanced Metastatic Melanoma Previously Treated with BRAF Targeted Therapy and Immunotherapy

2020 ◽  
Vol 2020 ◽  
pp. 1-6 ◽  
Author(s):  
Caitlyn N. Myrdal ◽  
Srinath Sundararajan
Keyword(s):  
Targeted Therapy ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Optimal Sequencing ◽  
The Right

Little is known about the optimal sequencing of targeted therapy and immunotherapy in the treatment of patients with BRAFV600-mutated metastatic melanoma. BRAF/MEK inhibition often has the benefit of rapid disease regression; however, resistance is frequently seen with long-term use. Treatment with immune checkpoint inhibitors offers the potential for long-term response but displays a lower rate of objective response. The benefit of synergy between therapies is apparent; however, there is limited data regarding optimal sequencing in the treatment of advanced melanoma. We present the case of a 62-year-old gentleman with advanced BRAFV600-mutated melanoma who followed an unconventional treatment path. After progressing on single-agent vemurafenib, he had response to multiple modalities of immunotherapy before progression. After, he had a substantial response to multiple BRAF/MEK inhibitor rechallenges before developing resistance. The patient is now stable after a retrial of combination immunotherapy. Our case illustrates that with the right sequencing of therapy, meaningful clinical responses can be elicited with rechallenging of targeted therapy and immunotherapy in metastatic melanoma.

Achievements and Challenges of Molecular Targeted Therapy in Melanoma

2015 ◽  
pp. 177-186 ◽  
Author(s):  
Ryan Sullivan ◽  
Patricia LoRusso ◽  
Scott Boerner ◽  
Reinhard Dummer
Keyword(s):  
Tumor Suppressor ◽  
Mapk Pathway ◽  
Single Agent ◽  
Braf Inhibitor ◽  
Clinical Trial Data ◽  
Great Majority ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Loss Of Function ◽  
Early Clinical Trial

The treatment of melanoma has been revolutionized over the past decade with the development of effective molecular and immune targeted therapies. The great majority of patients with melanoma have mutations in oncogenes that predominantly drive signaling through the mitogen activated protein kinase (MAPK) pathway. Analytic tools have been developed that can effectively stratify patients into molecular subsets based on the identification of mutations in oncogenes and/or tumor suppressor genes that drive the MAPK pathway. At the same time, potent and selective inhibitors of mediators of the MAPK pathway such as RAF, MEK, and ERK have become available. The most dramatic example is the development of single-agent inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) and MEK (trametinib, cobimetinib, binimetinib) for patients with metastatic BRAFV600-mutant melanoma, a subset that represents 40% to 50% of patients with metastatic melanoma. More recently, the elucidation of mechanisms underlying resistance to single-agent BRAF inhibitor therapy led to a second generation of trials that demonstrated the superiority of BRAF inhibitor/MEK inhibitor combinations (dabrafenib/trametinib; vemurafenib/cobimetinib) compared to single-agent BRAF inhibitors. Moving beyond BRAFV600targeting, a number of other molecular subsets—such as mutations in MEK, NRAS, and non-V600 BRAF and loss of function of the tumor suppressor neurofibromatosis 1 ( NF1)—are predicted to respond to MAPK pathway targeting by single-agent pan-RAF, MEK, or ERK inhibitors. As these strategies are being tested in clinical trials, preclinical and early clinical trial data are now emerging about which combinatorial approaches might be best for these patients.

A Multicenter, Single-Arm, Open-Label Study To Evaluate the Efficacy and Safety of Single-Agent Lenalidomide in Patients with Relapsed and Refractory Multiple Myeloma; Prelininary Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1565-1565 ◽  
Author(s):  
Paul Richardson ◽  
Sundar Jagannath ◽  
Mohamad Hussein ◽  
James Berenson ◽  
Seema Singhal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Stable Disease ◽  
Single Agent ◽  
Phase 2 ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Multicenter Phase ◽  
Best Response

Abstract INTRODUCTION: Lenalidomide (REVLIMID®; CC-5013) is a novel, orally active immunomodulatory drug under investigation for the treatment of multiple myeloma (MM). Phase 1 dose-escalation studies in patients (pts) with relapsed and refractory MM determined that the maximum tolerated dose (MTD) of lenalidomide was 25 mg/day, based upon myelosuppression encountered beyond 28 days, which was manageable with growth factor support and dose reduction. In a multicenter phase 2 study to determine optimal dose and schedule, 102 pts with relapsed or refractory MM were randomized to receive lenalidomide at either 15 mg bid (n=34) or 30 mg qd (n=68), for 21 days every 4 wks. Both treatment arms showed significant activity with manageable toxicity. An increased incidence of cytopenia was noted in the 15-mg bid group and thus the 30 mg qd schedule was taken forward. METHODS: The objective of this multicenter, phase 2, open-label study (CC-5013-MM-014) was to further evaluate the effectiveness and safety of single-agent lenalidomide administered at a dose of 30 mg qd for 21 days every 28 days (28-day cycle) in pts with relapsed and refractory MM. Eligible patients included those who had received prior thalidomide, bortezomib, or SCT. RESULTS: 222 pts were enrolled into the study. All patients had received at least 2 prior anti-myeloma treatments, including bortezomib (41%), thalidomide (80%), and SCT (44%). Table 1 shows Best Response data, excluding patients in whom responses were not evaluable (n=10). Partial response or better occurred in 25% of patients and SD or better in 71%. Time to Progression was a median of 22.4 wks (range 1.8– 66 wks). The median survival has not been reached (the lower bound of the 95% CI exceeds 15 months). The most common treatment-related AEs (those reported in ≥10% of patients overall) included upper respiratory tract infection, neutropenia and thrombocytopenia. AEs that most frequently led to dose reduction or interruption by percentage of cases were neutropenia (40%), thrombocytopenia (23%), fatigue (5%), and anemia (5%). CONCLUSION: Oral lenalidomide in relapsed and refractory MM patients achieved PR+CR in 25%, stable disease or better in 71%, a median TTP of approximately 6 months and a median survival that has not been reached. Toxicity has been manageable with a very low incidence of DVT and minimal treatment-emergent neuropathy. Table 1. Best Response Best Response* n (%) *Excluding patients not evaluable (n=10); CR=complete response and PR=partial response (EBMT criteria) ≥PR (CR + PR) 53 (25) Stable disease 152 (71)

Influence of Cytogenetics in Patients with Relapsed and Refractory Multiple Myeloma (MM) Treated with Carfilzomib (CFZ).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1827-1827 ◽  
Author(s):  
Andrzej Jakubowiak ◽  
Luhua Wang ◽  
Robert Z Orlowski ◽  
Sundar Jagannath ◽  
David Siegel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Single Agent ◽  
Entire Group ◽  
Fish Analysis ◽  
Advisory Committees ◽  
Minor Response

Abstract Abstract 1827 Poster Board I-853 Background It is now well established that cytogenetic abnormalities can affect the responses to therapies in multiple myeloma (MM) patients. Bortezomib, used alone or in combination with other agents, has been shown to overcome the adverse impact of several common unfavorable cytogenetic features. More recently, responses with lenalidomide and dexamethasone have been reported in patients with some types of unfavorable cytogenetics. Carfilzomib (CFZ) is a novel proteasome inhibitor that has demonstrated single agent activity in relapsed and/or refractory MM patients. The objective of this analysis was to provide the first preliminary information on the influence of cytogenetics in patients (pts) with relapsed and/or refractory MM treated with CFZ. Methods We evaluated 79 pts treated on two single agent CFZ studies (PX-171-003 and PX-171-004) in relapsed and/or refractory myeloma in which metaphase cytogenetics and/or FISH analysis for del 13q, t(4:14), and t(14;16) chromosomal abnormalities were available. Metaphase cytogenetics was conducted for all pts in the analysis; fluorescence in situ hybridization (FISH) results were available for 28 of the 79 pts. Twenty-one pts with relapsed and refratory MM (PX-171-003) and 58 pts with relapsed or refractory MM (PX-171-004) received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 in a 28-day cycle for up to 12 cycles. For this analysis, responders were defined as pts who achieved at least a Minor Response (MR) [MR + Partial Response (PR) + Very Good Partial Response (VGPR) + Complete Response (CR)] by IMWG and EBMT criteria. Results The median age of analysed pts was 63 yrs and 100% of pts were relapsed, with 70% refractory to their last therapy. Analysis of their histories demonstrated prior thalidomide treatment in 75% of pts, prior lenalidomide treatment in 57%, prior bortezomib treatment in 55%, and prior stem cell transplantation in 84%. The response rate (≥MR) for the entire group of patients was 40.5%. Twenty three of 79 pts had at least one of the abnormalities. The presence of del 13q, t(4;14), or t(14;16) did not significantly change the response rates, with 43.5% of pts with one or more abnormalities responding compared to 39.3% with none. The median time to progression (TTP) for all patients in this analysis was 203 days. The TTP for pts with one or more of the abnormalities was 195 days and was not significantly different from the TTP of 208 days for pts with none of the abnormalities (Figure; P > 0.05). Conclusion In this preliminary analysis, CFZ showed comparable activity in relapsed and relapsed/refractory MM with del 13q and/or t(4:14), and/or t(14;16) versus none of these abnormalities, with ≥MR in 43.5% vs. 39.3% of patients, and a TTP of 195 vs. 208 days, respectively. Updated efficacy data and TTP data will be presented at the meeting. Disclosures Jakubowiak: Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Wang:Proteolix, Inc.: Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Kukreti:Celgene: Honoraria. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. McDonagh:Proteolix: Research Funding. Vallone:Proteolix, Inc.: Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix: Research Funding.

Phase 1b Evaluation of the Safety and Efficacy of a 30-Minute IV Infusion of Carfilzomib In Patients with Relapsed and/or Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3024-3024 ◽  
Author(s):  
Kyriakos Papadopoulos ◽  
David Samuel diCapua Siegel ◽  
Seema B. Singhal ◽  
Jeffrey R. Infante ◽  
Edward A. Sausville ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Peripheral Blood ◽  
Research Funding ◽  
Mononuclear Cells ◽  
Single Agent ◽  
Proteasome Inhibition ◽  
Response Assessment ◽  
Phase 2 ◽  
Peripheral Blood Mononuclear ◽  
Phase 1B

Abstract Abstract 3024 Background: Carfilzomib (CFZ) is a novel, highly selective, epoxyketone proteasome inhibitor. In two separate Phase 2 trials in patients (pts) with relapsed and/or refractory (R/R) multiple myeloma (MM), single-agent CFZ administered as an IV bolus over 1–10 minutes has demonstrated durable activity at 20/27 mg/m2 and is well-tolerated with no clinically significant cumulative toxicity. In rats, significantly improved tolerability of CFZ was obtained following administration as a 30 min infusion as compared to a rapid IV bolus. Notably, a dose of 48 mg/m2 via IV bolus resulted in 50% lethality, compared to minimal toxicity without lethality at the same dose via a 30 min infusion. The reduced toxicity with 30-min infusion may reflect the role of Cmax (45 μM for bolus vs. 1.5 μM for infusion), since proteasome inhibition in blood and tissue was equivalent in both groups. Here we report on the results of administration of CFZ as a 30-minute IV infusion in a Phase 1b study in pts with R/R MM. The goals of this study are to determine the maximum recommended dose for infusion, safety, efficacy, pharmacokinetics (PK), and pharmacodynamic (PD) parameters. Methods: This Phase 1b trial is enrolling pts with R/R MM after ≥2 prior treatment failures. CFZ is given as a 30-minute IV infusion on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C) until progression. Dosing in all cohorts is initiated at 20 mg/m2 for the first two doses, with subsequent escalation to 36, 45, 56, or 70 mg/m2. Dose escalation follows standard 3+3 rules. Dexamethasone (4 mg for doses up to 45 mg/m2) is given prior to each infusion, with 8 mg given at higher doses. Responses by IMWG Uniform Response Criteria are measured at every C. Plasma samples for PK analysis and peripheral blood samples for PD analysis were obtained from pts at C1D1 (20 mg/m2) and C2D1 (all dose cohorts). Results: To date, 16 pts with R/R MM have been enrolled in the Phase 1b infusion study (4 at 36 mg/m2; 3 at 45 mg/m2; 7 at 56 mg/m2 and 2 at 70 mg/m2). Pts have remained on study for a median of 4 cycles (range 1–13+). Dose Limiting Toxicity (DLT) was observed in both pts treated at 70 mg/m2: reversible Grade (G) 3 renal failure in one pt within 24-hours following his first dose at 70 mg/m2 (C1D8); reversible G3 fatigue with fevers 4 days following four doses of 70 mg/m2 (C1 D20). Both pts were successfully rechallenged and continue on treatment. Seven patients have started dosing at 56 mg/m2; to date, one DLT (reversible G3 hypoxia with fevers) was observed. Thirteen pts are evaluable for efficacy (2 pts withdrew prior to 1st response assessment; 1 pt is too early to assess). Responses, time on study and prior regimens are detailed in the following table. Preliminary PK analysis demonstrates that the Cmax with 30-minute infusion is lower than obtained with a 5–10 minute IV bolus of the same dose. Inhibition of proteasome activity in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) was >80% at 20 mg/m2 and >90% at 36 mg/m2 and above. Common adverse events (AEs) with CFZ delivered as a 30-minute infusion have included fatigue, fevers, myalgias, diarrhea, nausea, thrombocytopenia, and reversible elevations in serum creatinine. There have been no episodes of worsening of baseline peripheral neuropathy or hepatotoxicity. Conclusions: In pts with R/R MM, single-agent CFZ as 30-minute IV infusion is both active and well-tolerated at doses ≥36 mg/m2; the dose level of 56 mg/m2 is being expanded as the recommended phase 2 dose on this schedule. Responses were seen in 8 out of 13 evaluable MM pts, including three VGPRs in pts who had received 5–7 prior regimens. Similar to animal studies, improved safety outcomes in MM patients can be achieved with near complete proteasome inhibition when CFZ is administered as a 30-minute infusion. An additional schedule of CFZ using weekly dosing (30-minute infusion for 5 weeks out of every 6) will be investigated in this trial. Disclosures: Papadopoulos: Onyx Pharmaceuticals: Consultancy, Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Gordon:Onyx Pharmaceuticals: Research Funding. Kauffman:Onyx Pharmaceuticals: Employment. Woo:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Bui:Onyx Pharmaceuticals: Employment. Hannah:Onyx Pharmaceuticals: Consultancy.

Diverse Mechanisms of Vemurafenib Resistance in BRAF-Mutant Hairy Cell Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 449-449 ◽  
Author(s):  
Jae H Park ◽  
Stephen S. Chung ◽  
Benjamin Durham ◽  
Young Rock Chung ◽  
Sasinya Scott ◽  
...  
Keyword(s):  
Research Funding ◽  
De Novo ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Genomic Analysis ◽  
Response Assessment ◽  
Advisory Board ◽  
Braf V600e ◽  
Kras Mutations ◽  
Braf Mutant

Abstract Background: We previously reported potent anti-tumor activity of the oral BRAF inhibitor vemurafenib in patients with relapsed or refractory BRAF mutant hairy cell leukemia (HCL) (Park et al. ASH 2014). According to the study design, patients whose disease relapsed following the initial treatment were allowed to be re-treated with vemurafenib. Here we report the clinical outcome of patients who were retreated with vemurafenib at relapse following initial treatment, as well as the result of genomic analysis that provided an insight into mechanisms of resistance to BRAF inhibition in HCL. Patients and Methods: Patients with BRAF mutant HCL who were refractory or resistant to purine analogs, or who had ≥2 relapses with an indication for treatment (ANC ≤1.0, HGB ≤10, or PLT ≤100K) were enrolled. Eligible patients received vemurafenib 960mg twice daily for 3 months. Bone marrow (BM) evaluations were performed after 3 months to assess response. Patients with partial (PR) or complete response (CR) with detectable minimal residual disease were allowed to receive vemurafenib for up to 3 additional months. After a maximum of 6 months of therapy, patients were observed with monthly CBC. At disease relapse with peripheral blood (PB) counts low enough to meet the initial eligibility criteria, re-treatment with vemurafenib was allowed until disease progression or unacceptable toxicity. Serial PB and/or BM samples were collected for targeted next-generation sequencing analysis of a 300-gene panel to detect contributors to resistance and genes collaborating with BRAF mutations in HCL. Results: 26 patients have been enrolled. 2 patients discontinued treatment before response assessment: 1 patient due to primary refractory disease to vemurafenib and 1 patient due to grade 3 photosensitivity. 24 patients completed at least 3 months of treatment, and therefore are available for efficacy evaluations. Of the 24 evaluable patients, all patients achieved response (10 CR and 14 PR) with the overall response rate of 100% when assessed after 3 months of vemurafenib. With the median follow up of 11.7 months (range, 1.3 - 25.4 months), 7 patients experienced disease relapse (3 previous CR and 4 PR). Of the 7 relapse patients, 6 met re-treatment criteria and restarted vemurafenib. 4 of the 6 patients regained response (all PR) with complete hematologic recovery and remain on therapy. 2 patients discontinued re-treatment before response assessment: 1 patient due to grade 2 photosensitivity and fatigue, and 1 patient due to resistant disease with refractory cytopenia and a rapid increase in splenomegaly. Targeted genomic analysis in 20 patients pre-vemurafenib revealed at least 1 somatic alteration coexisting with the BRAF V600E mutation in every patient, including deletion of 7q in more than half of patients and recurrent mutations in MLL3 and MED12 (Figure). Genomic analysis of the patient with de novo resistance to vemurafenib identified a missense mutation in IRS1 (Insulin Receptor Substrate 1; IRS1 P1201S) in addition to the BRAF V600E mutation. Functional characterization of the IRS1 P1201S mutation in vitro revealed potent induction of MAP kinase and PI3K-AKT signaling by the IRS1 mutant relative to wildtype, consistent with prior knowledge that IRS1 activates both MAP kinase and PI3K-AKT signaling. These data suggest that bypass activation of ERK and parallel activation of the AKT pathway contributed to de novo vemurafenib resistance. In the patient with acquired resistance to vemurafenib, genetic analysis of pretreatment, remission and relapse PB mononuclear cells revealed emergence of 2 separate, activating subclonal KRAS mutations at relapse. The mutations in KRAS were not seen at pretreatment or at remission. Activating RAS mutations are well known mediators of vemurafenib resistance in BRAF V600E-mutant malignancies, and, in this case, the detection of KRAS mutations coincided with clinical relapse and insensitivity to vemurafenib. Conclusions: Despite high response rates after a short course of vemurafenib in most patients, we observed de novo and acquired resistance to vemurafenib. Serial genomic analysis revealed ERK-dependent and independent mechanisms of BRAF inhibitor resistance in HCL. Our data provide the first insights into genetic mechanisms of RAF inhibitor resistance in HCL and suggest combinatorial therapeutic strategies that may have a role in the therapy of HCL. Figure 1. Figure 1. Disclosures Park: Amgen: Consultancy; Juno Therapeutics: Other: Advisory Board, Research Funding; Genentech: Research Funding. Off Label Use: Vemurafenib in HCL. Stone:Agios: Consultancy; AROG: Consultancy; Juno: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Celator: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding. Rai:Nash Family Foundation: Research Funding; Karches Family Foundation: Research Funding; Nancy Marks Family Foundation: Research Funding; Leon Levy Foundation: Research Funding. Altman:Seattle Genetics: Other: Advisory board; Ariad: Other: Advisory board; Spectrum: Other: Advisory board; Novartis: Other: Advisory board; BMS: Other: Advisory board; Astellas: Other: Advisory board; assistance with abstract preparation. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.

Summary of treatment-emergent renal events from patients treated with single-agent carfilzomib from four phase II studies in relapsed and/or refractory multiple myeloma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18569-e18569 ◽  
Author(s):  
R Donald Harvey ◽  
Sagar Lonial ◽  
Priti Patel ◽  
Leanne McCulloch ◽  
Ruben Niesvizky ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Renal Dysfunction ◽  
Single Agent ◽  
Safety Data ◽  
Lower Grade ◽  
Phase Ii Studies ◽  
Wide Range ◽  
Grade 3 ◽  
And Shifts

e18569 Background: Patients (pts) with multiple myeloma (MM) are vulnerable to renal injury and impairment both from their disease and treatment-related adverse events (AEs). Carfilzomib (CFZ) is a selective proteasome inhibitor with proven efficacy in MM. Safety data have been compiled from over 700 pts who have received single-agent CFZ. All were pretreated and included individuals with varying degrees of renal function, including hemodialysis pts. Herein we present an analysis of the incidence and severity of CFZ treatment-emergent renal events from 526 pts in four phase 2 trials. Methods: Pts from the 003-A0, 003-A1, 004, and 005 trials were included in this analysis. In all studies, CFZ was dosed on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). Doses were 20 mg/m2 in C1 for all studies escalating to 27 mg/m2 in C2 per individual protocol, except 005 (15 mg/m2 in C1, 20 mg/m2 in C2, and 27 mg/m2 in C3). Renal AEs—the incidence, frequency, and resolution of episodes of worsening renal function, defined minimally as a doubling of serum creatinine from baseline—and shifts in other laboratory parameters were tabulated and summarized based on NCI CTCAE v.3 criteria. Results: The majority of pts (71%) had renal dysfunction (CrCl <50 mL/min) at baseline. Overall, 87% experienced no significant worsening of renal function during the course of treatment. Transient worsening was reported in 31 pts (6%) with a median duration of 1.4 weeks and a median of 1.0 episode per patient; non-transient worsening was reported in 37 pts (7%) with 8 (2%) of those permanently discontinuing treatment due to a renal dysfunction AE. 38 patients (7.2%) experienced Grade 3/4 acute renal failure, of which 31 were Grade 3. The percentage of patients in 003-A0, 003-A1, and 004 whose creatinine levels shifted to Grade 3 or 4 from any lower grade was <5%. Results from 005 showed no major PK differences in pts with a wide range of renal function. Conclusions: Treatment-emergent renal events resulting in CFZ discontinuation were uncommon. Based on the findings from this cross trial analysis, CFZ dose and schedule need not be adjusted in pts with baseline renal dysfunction, including pts on hemodialysis.

Type II RAF inhibition predicts superior ERK suppression compared to type I RAF inhibition in different BRAF mutant types recurrently found in lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23154-e23154
Author(s):  
Philippe Giron ◽  
Amir Noeparast ◽  
Sylvia De Brakeleer ◽  
Ulrike De Ridder ◽  
Erik Teugels ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Line ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Expression Vectors ◽  
Type I ◽  
Type Ii ◽  
Braf Mutations ◽  
Braf Mutant ◽  
Mutant Braf

e23154 Background: Somatic driver BRAF mutations account for 6-8% of lung cancers. As opposed to melanoma in which V600E mutant BRAF predominates, the majority of lung cancer-derived BRAF mutations are non-V600. Yet, the efficacy of RAF-inhibitors and the possible resistance mechanisms in non-V600 BRAF mutant cells remain to be uncovered. Recently, we have shown that non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of type I RAF inhibitor Dabrafenib and a MEK inhibitor Trametinib. As a single agent, Dabrafenib shows only weak suppression of mutant BRAF-induced ERK signaling; moreover it can induce ERK paradoxical activation in CRAF overexpressing cells. Methods: Several recombinant BRAF expression vectors were generated by performing site-directed mutagenesis. We compared the effects of Dabrafenib and a type II RAF inhibitor (AZD-628) at clinically relevant dose as single agents or in combination with MEK inhibitor Trametinib on ERK activity in HEK293T cells expressing several tumor-derived BRAF mutants and a non-V600 BRAF mutant lung cancer cell line (H1666). Viability and caspase3/7 activation assays were performed using the H1666 cell line model. Results: In contrast to Dabrafenib, AZD-628 does not induce paradoxical ERK activation in CRAF expressing cells. Increased CRAF expression desensitizes BRAF-mutant expressing cells to Dabrafenib but not to AZD-628. Notably, AZD-628 has superior ERK-inhibitory effect in HEK293T cells co-expressing several different BRAF-mutants with CRAF and in H1666 cells. Combination of Trametinib and AZD-628 has superior MEK-inhibitory and pro-apoptotic effect in H1666 cells compared to combined Trametinib/Dabrafenib. Moreover, upon down titration of the RAF inhibitors with a steady dose of Trametinib, AZD-628 resulted in overall stronger effect on viability compared to Dabrafenib. Conclusions: In our in vitro model, we obtained strong indications that at conventional doses, type II RAF-inhibitor AZD628 is superior to type I RAF-inhibitor Dabrafenib in combination with MEK inhibitor Trametinib for the treatment of non-V600 BRAF mutant lung cancer.

Preclinical Approach to Sensitize Multiple Myeloma Cells: Combination of the MEK Inhibitor PD0325901 with ABT-737 or Mevinolin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1842-1842
Author(s):  
Maria Rosaria Ricciardi ◽  
Elisabetta Calabrese ◽  
Michele Milella ◽  
Paola Bergamo ◽  
Samantha Decandia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Growth ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Clinical Investigation ◽  
Single Agent ◽  
Mek Inhibitor ◽  
Synergistic Activity ◽  
Mitochondrial Membrane Depolarization ◽  
The Impact

Abstract Abstract 1842 Poster Board I-868 Multiple myeloma (MM) is a plasma cell malignancy incurable with existing conventional therapies. However, the increased understanding of the molecular mechanisms underlying the growth, progression and drug resistance of MM cells is allowing the development of novel therapies based on target-specific drugs. These agents have shown promising results in pre-clinical trials and some are already in early phase of clinical investigation. However, limitations of this approach are represented by the existence of cross-talking signals among different pathways which results in ineffective inhibition of a single pathway. Therefore, targeted therapy based on the multiple inhibition of key signal transduction pathways represents the present focus of translational research. We have already demonstrated (Haematologica 2008;93[suppl.2]:P195) the potent growth-inhibitory effects of the specific MEK inhibitor PD0325901 and the marked pro-apoptotic activity of the Bcl2/BclXL inhibitor ABT-737 (kindly provided by Abbott Laboratories) on MM cell lines and primary CD138+ cells from MM patients at different disease stages (smoldering, diagnosis, relapse, refractory/resistant). Since it has already been reported that the inhibitor of the mevalonate pathway, Mevinolin, strikingly induces apoptosis by regulating different pathways, including the MEK/ERK module, we aimed in the present study to analyze the impact of the simultaneous inhibition of both pathways on apoptosis and cell growth of MM cell lines and primary samples. We exposed the KMS18, KMS27 and ARH-77 MM cell lines to increasing concentrations of PD0325901 (1–100 nM) and ABT-737 (1–100 nM) or Mevinolin (1–100 μM), alone and in combination. When used as single agents the inhibition of cell-growth was dose-dependent, while if used in combination it was synergistic, with combination indexes (CI) of 0.12 and 0.15 for PD0325901 plus ABT-737 and the same plus Mevinolin, respectively (Chou-Talalay method). We then investigated the effects of these agents on apoptosis, as determined by the sub-G1 DNA peak, and found that PD0325901 mainly showed cytostatic effects, while ABT-737 and Mevinolin needed high concentrations to affect apoptosis. The simultaneous exposure to PD0325901 plus ABT-737 or Mevinolin at lower concentrations, induced apoptosis with highly synergistic effects, as demonstrated by a CI of 0.2 (KMS18) and 0.17 (KMS27) for PD0325901 plus ABT-737 and of 0.135 (KMS18) and 0.128 (KMS27) for PD0325901 plus Mevinolin. Similarly, mitochondrial membrane depolarization was greatly induced with the combination approach. Preliminary experiments performed on primary MM samples confirmed the pro-apoptotic synergistic activity of combination strategies. On the contrary, when we used the MEK-inhibitor resistant MM cell line ARH-77, the effects of ABT-737 and Mevinolin were not potentiated by MEK inhibition with PD0325901. In conclusion, we demonstrated that the simultaneous disruption of the MEK/ERK and Bcl2/BclXL or Mevalonate signalling is effective on apoptosis induction and growth inhibition of MM cells at a greater degree than single agent therapy. Additional ongoing studies on primary samples from MM patients at different stages of the disease will help to determine the feasibility and efficacy of these combinations for clinical use. Disclosures: Petrucci: Celgene: Honoraria; Janssen Cilag: Honoraria.

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