scholarly journals O85 Durable responses in anti-PD-1 refractory melanoma following intratumoral injection of a toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab

2020 ◽  
Vol 8 (Suppl 1) ◽  
pp. A2.2-A3 ◽  
Author(s):  
Mohammed Milhem ◽  
Yousef Zakharia ◽  
Diwakar Davar ◽  
Elizabeth Buchbinder ◽  
Theresa Medina ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Confidence Interval ◽  
Initial Period ◽  
Objective Response ◽  
Intratumoral Injection ◽  
Advanced Melanoma ◽  
Low Grade ◽  
Tumor Biopsy ◽  
Tlr9 Agonist ◽  
Duration Of Response

BackgroundIntratumoral (IT) injection of CMP-001, a CpG-A TLR9 agonist packaged within a virus-like particle, is designed to activate tumor-associated plasmacytoid dendritic cells, inducing an interferon-rich tumor microenvironment and anti-tumor CD8+ T cell responses.MethodsCMP-001-001 is an ongoing Phase 1b trial evaluating the safety and efficacy of CMP-001 in combination with pembrolizumab (Part 1; N = 144) or alone (Part 2; N = 23) in patients with advanced melanoma resistant to prior anti-PD-1 therapy (Tables 1). CMP-001 is administered IT into accessible lesion(s) either with, or without on-site saline dilution (table 1), and response assessed by RECIST v1.1. Monotherapy patients who progress can be rolled over onto combination therapy and continue on study. Baseline and on-therapy serum is analyzed for cytokines, and immunohistochemistry and RNA-Seq are performed on available tumor biopsies.Abstract O85 Table 1Advanced anti-PD-1 Refractory melanoma patient population by treatment allocationResultsAdverse events (AEs) attributed to CMP-001 in combination with pembrolizumab or as monotherapy consisted predominately of transient low-Grade flu-like symptoms and injection site reactions: Grade 3+ related AEs were reported in 33% of patients treated with combination therapy and 22% of patients with monotherapy.The Objective Response Rate (ORR) with undiluted CMP-001 in combination with pembrolizumab was 24% (18/75; 95% confidence interval: 15%-35% (table 1); on-site dilution of CMP-001 was associated with a substantial decrease in ORR to 12% (7/61; 95% confidence interval: 5%-22% (table 1). Three additional patients had a delayed partial response after an initial period of disease progression. Anti-tumor response was comparable between injected and uninjected lesions. The median duration of response to combination therapy has not been reached. The ORR to CMP-001 monotherapy was 22% (5/23; 95% confidence interval: 7%-44% (table 1); time from last anti-PD-1 therapy before CMP-001 was 1.5 to >20 months in responders; 3 of the patients responding to CMP-001 monotherapy achieved PR at the first evaluation, but progressed by the second evaluation.Serum and tumor biopsy translational studies in the patients receiving combination therapy supported the proposed mechanism of TLR9 activation and identified a possible association between induction of serum CXCL10 and response.ConclusionsIT CMP-001 alone and in combination with pembrolizumab appears well tolerated, can reverse resistance to anti-PD-1 therapy, and can produce deep and durable clinical responses in patients with advanced melanoma.Ethics ApprovalCMP-001-001 was centrally approved by the WCG-WIRB, WIRB approval tracking number 20152597.

304 Intratumoral injection of CMP-001, a toll-like receptor 9 (TLR9) agonist, in combination with pembrolizumab reversed programmed death receptor 1 (PD-1) blockade resistance in advanced melanoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A331-A331
Author(s):  
Mohammed Milhem ◽  
Yousef Zakharia ◽  
Diwakar Davar ◽  
Elizabeth Buchbinder ◽  
Theresa Medina ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
San Francisco ◽  
Tumor Regression ◽  
Objective Response ◽  
Primary Objective ◽  
Advanced Melanoma ◽  
Delayed Response ◽  
Open Label ◽  
Tlr9 Agonist ◽  
Duration Of Response

BackgroundTherapeutic options are limited for patients with advanced melanoma that is refractory to PD-1 blockade. This study was performed in this patient population to assess the safety and antitumor activity of CMP-001, a CpG-A TLR9 agonist packaged within a virus-like particle.MethodsPatients were eligible for this 2-part, open-label, multicenter, phase 1b study if they had metastatic/unresectable melanoma and stable disease after =12 weeks or progressive disease (PD) on/after anti-PD-1 therapy. Part 1 evaluated CMP-001 plus pembrolizumab dose-escalation and dose-expansion. Part 2 evaluated CMP-001 monotherapy. Accessible lesion(s) were injected intratumorally with CMP-001, at a polysorbate 20 (PS20) concentration of either 0.01% or 0.00167%. The Part 1 primary objective was to identify the recommended phase 2 dose (RP2D) and schedule of CMP-001 plus pembrolizumab, while the Part 2 primary objective was to assess the safety of CMP-001 monotherapy. Secondary objectives for both parts were a preliminary assessment of antitumor activity of CMP-001 plus pembrolizumab and CMP-001 monotherapy, and the overall safety profile and pharmacodynamics of the combination.ResultsIn Part 1 (N=159) and Part 2 (N=40), 93.1% and 80.0% of patients had PD as their last response to prior anti–PD-1 therapy, respectively. The most common treatment-related adverse events (TRAEs; >25%) were flu-like symptoms (Parts 1 and 2) and injection-site reactions (Part 1). Grade 3/4 TRAEs were reported in 36.5% (Part 1) and 22.5% (Part 2) of patients, the most common being hypotension (Part 1: 6.9%; Part 2: 5.0%). No Grade 5 TRAEs were observed. In Part 1, the best objective response rate (ORR; RECIST v1.1) in patients treated with pembrolizumab and CMP-001 (PS20 0.01%) was 23.5% (23/98), while CMP-001 PS20 (0.00167%) resulted in a lower ORR of 11.5% (7/61). Seven additional patients had a delayed response after initial PD (table 1). The median duration of response was >1 year. In the 37 RECIST v1.1 and post-progression responders, the mean regression in injected and noninjected target lesions was 54.7% and 52.7%, respectively. In Part 2, the best ORR with CMP-001 monotherapy was 17.5% (7/40 patients); the response duration was shorter than in Part 1. Intratumoral CMP-001 PS20 0.01% 10 mg was selected as the RP2D.Abstract 304 Table 1Best ORR With CMP-001 Plus Pembrolizumab and CMP-001 MonotherapyConclusionsIntratumoral CMP-001 was well-tolerated and provided both local and distant responses in patients with advanced melanoma with disease progression on prior PD-1 blockade. CMP-001 monotherapy induced systemic tumor regression in some patients, but duration of response was substantially increased by the addition of pembrolizumab.AcknowledgementsThis work was supported by Checkmate Pharmaceuticals. Medical writing assistance was provided by Cindy Rigby, PhD, of ApotheCom (San Francisco, CA) and was funded by Checkmate Pharmaceuticals.Trial RegistrationNCT02680184Ethics ApprovalThis study was approved by the WCG-WIRB, WIRB approval tracking number 20152597.ConsentN/AReferencesN/A

scholarly journals LGG-49. SAFETY AND EFFICACY OF TRAMETINIB (T) MONOTHERAPY AND DABRAFENIB + TRAMETINIB (D+T) COMBINATION THERAPY IN PEDIATRIC PATIENTS WITH BRAF V600-MUTANT LOW-GRADE GLIOMA (LGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii375-iii375
Author(s):  
Eric Bouffet ◽  
James A Whitlock ◽  
Christopher Moertel ◽  
Birgit Geoerger ◽  
Isabelle Aerts ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Pediatric Patients ◽  
Objective Response ◽  
Safety Data ◽  
Dose Finding ◽  
Combination Group ◽  
Clinical Activity ◽  
Low Grade ◽  
Open Label ◽  
Independent Review

Abstract BACKGROUND Children with BRAF V600-mutant LGG have suboptimal response to standard chemotherapy. Previously, D (BRAF V600 inhibitor) monotherapy has demonstrated clinical benefit in this population. We report interim analysis results of pediatric patients with recurrent/refractory BRAF V600-mutant LGG treated with either T (MEK1/2 inhibitor) monotherapy or D+T combination therapy. METHODS This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772) in pediatric patients (<18 y) with refractory/recurrent tumors. The dose-finding phase, including dose confirmation stratified by age, was followed by disease-specific cohorts at recommended dose levels. Efficacy was determined by both investigator and independent review using RANO criteria. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. RESULTS Of 49 pediatric patients with BRAF V600-mutant LGG (T, n=13; D+T, n=36) enrolled, pooled efficacy data was available for both treatments while safety data was available for 30 patients (T, n=10; D+T, n=20). Most patients (n=8/10) receiving T monotherapy withdrew/discontinued the treatment in contrast to 3/20 in the D+T group. Pyrexia occurred in 50% of patients (n=5/10) in the monotherapy group and was a frequent AE in the combination group (75%; n=15/20). Objective response rate per independent review was 15% (95% CI, 2%–45%) with T monotherapy and 25% (95% CI, 12%–42%) with D+T combination therapy. Seven patients (54%) on monotherapy and 33 patients (92%) on combination therapy had stable disease or better. CONCLUSION In pediatric patients with previously treated BRAF V600-mutant LGG, T monotherapy and D+T combination therapy demonstrated clinical activity, with pyrexia being a common AE.

Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9515-9515
Author(s):  
Omid Hamid ◽  
Ding Wang ◽  
Tae Min Kim ◽  
Sang-We Kim ◽  
Nehal J. Lakhani ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Adrenal Insufficiency ◽  
Safety Profile ◽  
Phase 1 ◽  
Objective Response ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Treatment Naïve ◽  
Grade 3

9515 Background: Fianlimab and cemiplimab are two high-affinity, fully human, hinge-stabilized IgG4 monoclonal antibodies. In a Phase 1 dose escalation study, fianlimab combined with cemiplimab showed an acceptable safety profile and some clinical activity in pts with advanced malignancies. Here, we present safety and clinical activity data from two expansion cohorts of pts with advanced melanoma (anti–programmed cell death/ligand-1 [anti–PD-(L)1] naïve or experienced) who were treated with fianlimab + cemiplimab and had an opportunity for first on-treatment tumor assessment (cut-off date: Jan 4, 2021). Methods: Pts with advanced melanoma who had no prior anti–PD-(L)1 treatment (naïve) or prior anti–PD-(L)1 treatment within 3 months of screening (experienced) received fianlimab 1600 mg + cemiplimab 350 mg by IV infusion every 3 weeks. Tumor measurements were performed every 6 weeks for the first 24 weeks and subsequently every 9 weeks per RECIST v1.1. Results: 48 pts with advanced melanoma were treated with the combination therapy: 33 were anti–PD-(L)1 naïve and 15 were anti–PD-(L)1 experienced (median age: 69 years vs 59 years; male: 66.7% vs 46.7%; Caucasian: 87.9% vs 60%). The safety profile (including immune-related adverse events [AEs]) of fianlimab + cemiplimab combination therapy was similar to that of anti–PD-1 monotherapy with one exception. The rate of adrenal insufficiency, 8.3% (4/48) of pts, is similar to the rate previously observed with anti–PD-1 + anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) combination therapy but higher than that observed with anti–PD-1 monotherapy. Grade ≥3 treatment-emergent AEs (TEAEs) occurred in 35.4% (17/48) of patients; Grade ≥3 serious TEAEs occurred in 22.9% (11/48) of patients; 8.3% (4/48) of patients discontinued treatment due to a TEAE. The most common TEAEs were fatigue (n = 15, 31.3%) and rash (n = 11, 22.9%). By investigator assessment, objective response rate (includes unconfirmed complete [CR] and partial responses [PR]) was 63.6% (3 CRs and 18 PRs) for anti–PD-(L)1 naïve pts and 13.3% (1 CR and 1 PR) for anti–PD-(L)1 experienced pts. Median progression-free survival and median duration of response for the anti–PD-(L)1 treatment naïve cohort have not been reached. Prognostic clinical markers and tumor biomarkers such as expression of LAG-3, PD-L1, and major histocompatibility complex II are being evaluated. Recruitment is ongoing. Conclusions: The safety profile of fianlimab + cemiplimab is similar to that observed with cemiplimab monotherapy and other anti–PD-1s, with the exception of higher rate of adrenal insufficiency. Fianlimab + cemiplimab combination has shown clinical activity for pts with advanced melanoma that is similar to anti–PD-1 + CTLA-4 combination therapy, but with lower demonstrated rates of TEAEs. Clinical trial information: NCT03005782.

Phase II Pilot Study of Rituximab + CHOP in Patients with Newly Diagnosed Waldenström’s Macroglobulinemia, an Eastren Cooperative Oncology Group Trial (Study E1A02).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3616-3616 ◽  
Author(s):  
Rafat Abonour ◽  
Lijun A. Zhang ◽  
Vincent Rajkumar ◽  
Gordan Srkalovic ◽  
Philip R. Greipp ◽  
...  
Keyword(s):  
Median Time ◽  
Phase Ii ◽  
Response Rate ◽  
Objective Response ◽  
Visual Disturbance ◽  
Low Grade ◽  
Minor Response ◽  
Duration Of Response ◽  
Grade 3 ◽  
A Minor

Abstract Waldenström’s Macroglobulinemia (WM) is a low-grade lymphoplasmacytic disorder associated with an IgM monoclonal protein that may present with anemia, lymphadenopathy, and hepatosplenomegaly. Since combination chemotherapy and Rituximab are both active in this disease, it is possible the response rate can be enhanced by using a combined modality of Rituximab and CHOP. This approach has been used in indolent lymphoma with remarkable results and limited toxicity. Objective: To determine the response rate in previously untreated patients with Waldenström’s Macroglobulinemia receiving rituximab and CHOP. Methods: This was a phase II study of standard R-CHOP in symptomatic WM patients. The study was activated on June 15, 2004 and closed on April 26, 2007 due to poor accrual. The median age of the sixteen patients enrolled was 60 (44–79 years), β2M 3 ug/ml (2.1–7.6), median hemoglobulin was 9 g/dl (7.7–10.9), Viscosity 3.4(1.6–10), and IgM 6389 (3229–13300 mg/dl). The most common symptoms were Fatigue (13/16), visual disturbance (7/16) and parasthesias or painful/numb feet (6/16). Only one patient had bulky adenopathy (6.3%). Results: Of 16 patients treated, 5 patients have no response data available (it will be presented at the meeting). Objective response was 91% (90% CI: 63.5% ∼ 99.5%) and 1 patient had a minor response with an overall response rate of 100%. Median time to response was 1.6 months from registration and median time to maximum response was 2.1 months. Median duration of response has not been reached. The median follow up time of the 16 patients was 18.3 months with a range of 3.6–24.8 months. Among the 16 treated patients, there were 8 (50%, 90% exact binomial CI: 27.9%∼72.1%) grade 4 neutropenia. 8 patients experienced grade 3 lymphopenia (50%, 90% exact binomial CI: 27.9%∼72.1%). Only 2 grade 3 febrile neutropenia were noted. As of August 4, 2007, none of the 16 patients has died. R-CHOP is a promising regimen in the treatment of patients with Waldenström’s Macroglobulinemia. To succeed in completing clinical trials in this rare disease better international collaboration and involvement in advocacy groups are required.

Salvage combination ipilimumab and nivolumab after failure of prior checkpoint inhibitor therapy in patients with advanced melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e21009-e21009 ◽  
Author(s):  
Elizabeth Mary Gaughan ◽  
Gina R. Petroni ◽  
William W. Grosh ◽  
Craig L. Slingluff
Keyword(s):  
Combination Therapy ◽  
Small Sample Size ◽  
Objective Response ◽  
Initial Therapy ◽  
Subsequent Treatment ◽  
Advanced Melanoma ◽  
Small Sample ◽  
Treatment Naïve ◽  
Clinicopathologic Factors ◽  
Clinically Significant

e21009 Background: The combination of Ipilimumab and Nivolumab is standard initial therapy in patients with advanced melanoma based on trials involving treatment-naïve patients. The benefit in those previously managed with checkpoint monotherapy is not well defined. Methods: We identified metastatic melanoma patients from our Immunotherapy database managed with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. Baseline clinical factors, treatment history, combination therapy outcome by RECIST v1.1 and toxicity data were collected. Descriptive statistics were used to summarize the data. Given the small sample size and limited numbers of deaths, it is too early to look for preliminary associations between outcomes and clinicopathologic factors. Results: We identified 19 patients treated with combination Ipilimumab/Nivolumab after progression on prior checkpoint monotherapy. The cohort included 15 men and 4 women with an average age of 63 years. Thirteen patients had M1c disease, and 7 had a BRAF mutation. Patients had received up to four lines of prior immunotherapy including 9 treated with both prior anti-PD1 and anti-CTLA4 monotherapy. Seven patients completed all four doses of combination therapy with 6 proceeding onto maintenance nivolumab. Eight patients stopped treatment due to toxicity and 4 due to progressive disease. Thirteen patients had clinically significant toxicity, with rash, colitis, hepatitis, and hypophysitis reported most frequently. There were no treatment-related deaths. Overall, 2/19 patients (10.5%, 95% CI [1.3% to 33.1%]) had an objective response (CR+PR) and 9/19 patients (47.4%, 95% CI [24.5% to 71.1%]) had disease control (CR+PR+SD). Four of the patients had stable disease for over 6 months. Six of the 19 patients went on to receive subsequent treatment. Median follow-up for patients still alive was 7 months (range 1 to 20 months) and median survival was not reached. Six-month survival was 68.5% (95% CI [39.3% to 85.8%]) Conclusions: The combination of Ipilimumab and Nivolumab can result in melanoma control in patients with progression on prior checkpoint monotherapy with an expected toxicity profile.

Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL).

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA9003-LBA9003 ◽  
Author(s):  
Mario Sznol ◽  
Harriet M. Kluger ◽  
Margaret K. Callahan ◽  
Michael Andrew Postow ◽  
Ruth Ann Gordon ◽  
...  
Keyword(s):  
Phase I Trial ◽  
Objective Response ◽  
Response Duration ◽  
Advanced Melanoma ◽  
Clinical Activity ◽  
Tumor Reduction ◽  
Duration Of Response ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Clinical Trial Information

LBA9003^ Background: We report updated survival and clinical activity in initially enrolled cohorts and activity by BRAF MT status in a phase I trial of concurrent and sequenced NIVO + IPI. Methods: MEL pts (n=53, enrolled 2009-2012, data analysis Dec 2013) with ≤3 prior therapies received IV concurrent NIVO + IPI, Q3Wk × 4 doses, followed by NIVO Q3Wk × 4. At wk 24, NIVO + IPI continued Q12Wk × 8 in pts with disease control and no DLT. Tumor responses were evaluated by WHO and immune-related criteria. Results: Pt characteristics included stage M1c: 55% and prior systemic therapy: 40%. Across doses, 1- and 2-y OS rates were 82% and 75%. Clinical activity was similar to previous reports except CRs rose to 9/53 (17%). Pts with/without tumor BRAF MT (n=36) had similar activity (Table). By wk 36, 42% demonstrated ≥80% tumor reduction. Median duration of response (DOR) was not reached (NR). Of 22 pts with objective response, 14 (64%) had DOR ≥24 wk (range: 25+, 106+). Treatment-related adverse events were as reported previously: grade 3-4, 53% of pts; most common: ↑ lipase and AST (13% ea). Data for sequenced cohorts are shown (Table). Conclusions: Concurrent NIVO + IPI therapy showed encouraging survival and a manageable safety profile in advanced MEL pts. Responses were observed regardless of BRAF MT status and were durable in the majority of pts. Forty additional pts were enrolled (last pt: Nov 2013) on a cohort of NIVO 1 mg/kg + IPI 3 mg/kg Q3Wk × 4 doses, followed by NIVO 3mg/kg Q2Wk (the selected regimen for phase II/III trials). Clinical trial information: NCT01024231. [Table: see text]

Dabrafenib + trametinib combination therapy in pediatric patients with BRAF V600-mutant low-grade glioma: Safety and efficacy results.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10506-10506
Author(s):  
Birgit Geoerger ◽  
Eric Bouffet ◽  
James A. Whitlock ◽  
Christopher L. Moertel ◽  
Darren R. Hargrave ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Pediatric Patients ◽  
Mapk Pathway ◽  
Objective Response ◽  
Safety Data ◽  
Skin Toxicity ◽  
Clinical Activity ◽  
Low Grade ◽  
Rano Criteria ◽  
Independent Review

10506 Background: Low-grade gliomas (LGGs) are the most common brain tumors among children. Pediatric LGGs are often not surgically resectable and tend to demonstrate relapsed/remitting courses with current standard chemotherapy regimens. Moreover, radiation is often avoided due to its associated neurocognitive and endocrinologic sequelae. However, in pediatric patients (pts) with BRAF V600-mutant LGG, dabrafenib monotherapy has demonstrated meaningful clinical activity and acceptable tolerability (Hargrave et al, Clin Cancer Res. 2019; NCT01677741). Here we report the efficacy and safety of dabrafenib + trametinib (D+T) combination therapy in pediatric pts with previously treated BRAF V600-mutant LGG. Methods: This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772). The limited dose-escalation (ESC) portion evaluated the D+T combination in pediatric pts ( < 18 y) with recurrent/refractory BRAF V600-mutated solid tumors that were naive to MAPK pathway–targeted therapy. This was followed by a tumor cohort expansion (EXP), and the D+T combination was evaluated in BRAF V600-mutant LGG pts at recommended dose levels. Efficacy was determined by both investigator and independent review using the RANO criteria (for gliomas). Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Results: Overall, 36 pediatric pts with LGG received D+T combination therapy (ESC, n = 16; EXP, n = 20); pooled efficacy data were available for both ESC and EXP, while LGG-specific safety data were available for EXP. At interim analysis (Aug 2019), 17 of the 20 pts in EXP remained on protocol therapy. Three pts withdrew/discontinued treatment because of AEs. Skin toxicity (95%) and pyrexia (75%) were the frequent AEs reported. No on-treatment deaths were reported. Across both ESC and EXP, the objective response rate (ORR) was 25% (95% CI, 12%–42%) per independent review (1 complete response [CR], 8 partial response [PR], 24 stable disease [SD], 2 progressive disease [PD], 1 unknown [UNK]) and 50% (95% CI, 33%–67%) per investigator review (2 CR, 16 PR, 17 SD, 1 UNK). However, ORR + SD was similar, with 92% and 97% of pts having SD or better per independent and investigator review, respectively. Conclusions: In pediatric pts with pretreated BRAF V600-mutant LGG, D+T combination therapy demonstrated clinical activity, with 92% of pts having SD or better by independent review using the RANO criteria. Pyrexia and skin toxicity were the common AEs; majority of these were low-grade and manageable. Clinical trial information: NCT02124772.

scholarly journals KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma

2020 ◽  
Vol 8 (2) ◽  
pp. e001806
Author(s):  
Pier Francesco Ferrucci ◽  
Anna Maria Di Giacomo ◽  
Michele Del Vecchio ◽  
Victoria Atkinson ◽  
Henrik Schmidt ◽  
...  
Keyword(s):  
Statistical Significance ◽  
Objective Response ◽  
Study Drug ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Phase 2 ◽  
Double Blind ◽  
Intention To Treat ◽  
Duration Of Response ◽  
Grade 3

BackgroundIn the KEYNOTE-022 study, pembrolizumab with dabrafenib and trametinib (triplet) improved progression-free survival (PFS) versus placebo with dabrafenib and trametinib (doublet) without reaching statistical significance. Mature results on PFS, duration of response (DOR), and overall survival (OS) are reported.MethodsThe double-blind, phase 2 part of KEYNOTE-022 enrolled patients with previously untreated BRAFV600E/K-mutated advanced melanoma from 22 sites in seven countries. Patients were randomly assigned 1:1 to intravenous pembrolizumab (200 mg every 3 weeks) or placebo plus dabrafenib (150 mg orally two times per day) and trametinib (2 mg orally one time a day). Primary endpoint was PFS. Secondary endpoints were objective response rate, DOR, and OS. Efficacy was assessed in the intention-to-treat population, and safety was assessed in all patients who received at least one dose of study drug. This analysis was not specified in the protocol.ResultsBetween November 30, 2015 and April 24, 2017, 120 patients were randomly assigned to triplet (n=60) or doublet (n=60) therapy. With 36.6 months of follow-up, median PFS was 16.9 months (95% CI 11.3 to 27.9) with triplet and 10.7 months (95% CI 7.2 to 16.8) with doublet (HR 0.53; 95% CI 0.34 to 0.83). With triplet and doublet, respectively, PFS at 24 months was 41.0% (95% CI 27.4% to 54.2%) and 16.3% (95% CI 8.1% to 27.1%); median DOR was 25.1 months (95% CI 14.1 to not reached) and 12.1 months (95% CI 6.0 to 15.7), respectively. Median OS was not reached with triplet and was 26.3 months with doublet (HR 0.64; 95% CI 0.38 to 1.06). With triplet and doublet, respectively, OS at 24 months was 63.0% (95% CI 49.4% to 73.9%) and 51.7% (95% CI 38.4% to 63.4%). Grade 3–5 treatment-related adverse events (TRAEs) occurred in 35 patients (58%, including one death) receiving triplet and 15 patients (25%) receiving doublet.ConclusionIn BRAFV600E/K-mutant advanced melanoma, pembrolizumab plus dabrafenib and trametinib substantially improved PFS, DOR, and OS with a higher incidence of TRAEs. Interpretation of these results is limited by the post hoc nature of the analysis.

scholarly journals 383 Durable responses with intratumoral electroporation of plasmid interleukin 12 plus pembrolizumab in patients with advanced melanoma progressing on an anti-PD-1 antibody: updated data from keynote 695

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A417-A417
Author(s):  
Pablo Fernandez-Penas ◽  
Matteo Carlino ◽  
Katy Tsai ◽  
Victoria Atkinson ◽  
Monaster Shaheen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Objective Response ◽  
Safety Data ◽  
Response Duration ◽  
Advanced Melanoma ◽  
Interleukin 12 ◽  
Open Label ◽  
Kaplan Meier ◽  
Duration Of Response ◽  
Grade 3

BackgroundElectroporated plasmid interleukin-12 (pIL-12-EP; tavokinogene telseplasmid; TAVO) induces sustained intratumoral expression of IL-12, a cytokine that is integral for response to anti-PD-1 antibodies. Here, we present updated safety and response duration data from KEYNOTE 695, a Phase 2, multicenter, open-label trial of pIL-12-EP in combination with pembrolizumab in patients with stage III/IV melanoma immediately following confirmed progression on an anti-PD-1 antibody.MethodsPatients with confirmed disease progression after ≥12 weeks‘ treatment with an anti-PD-1 antibody alone or in combination were eligible. Patients received intratumoral pIL-12-EP on days 1, 5 and 8 every 6 weeks and pembrolizumab 200 mg every 3 weeks. Responses were assessed by the investigator at 12-week intervals using RECIST v1.1; overall survival (OS) and duration of response (DoR) assessments were conducted using the Kaplan-Meier method.ResultsOf the first 56 patients treated, 50% had visceral disease (M1b-d), 80% had received 1–2 and 20% ≥3 prior lines of therapy, 27% had prior ipilimumab and 21% prior BRAF/MEK inhibitors. 61% of patients were primary refractory to anti-PD-1. 54 patients were efficacy evaluable, defined as patients who had at least one post-treatment scan. The investigator-assessed objective response rate (ORR) per RECIST was 27.8% (4 CR, 11 PR); ORR per iRECIST was 29.6%. In patients with M1b-d staging, ORR was 33.3% (n=9/27), and in those receiving prior ipilimumab, ORR was 33.3% (n=5/15). Seven patients had 100% reduction in target lesions, and regression was observed in non-injected lesions. The median DoR had not been reached. With a median follow up of 19.3 months, the median OS (95% CI) was 24.5 (14.4, NR) months (figure 1). The study is now fully enrolled. In 105 patients with safety data, there were no Grade 4/5 treatment-related adverse events (TRAEs) reported. Grade 3 TRAEs occurred in 5.7% and comprised cellulitis in two patients and arthralgia, pneumonitis, enteritis, keratoacanthoma, lichen planus and musculoskeletal chest pain in one patient each. The Grade 1/2 TRAEs in ≥10% patients were fatigue (27.6%), procedural pain (20.0%), diarrhea (17.1%), nausea (10.5%) and pruritus (10.5%). ORR by blinded independent central review has commenced and a global phase 3 trial is planned.Abstract 383 Figure 1Overall survival in patients treated with pIL-12-EP in combination with pembrolizumab. Dark grey bars: time on study treatment, light grey bars: end of treatment to death or censoringConclusionsPatients with anti-PD-1 therapy refractory advanced melanoma can achieve deep, durable responses in both injected and non-injected lesions with pIL-12-EP plus pembrolizumab. Intratumoral pIL-12-EP in combination with pembrolizumab was generally well tolerated, with minimal Grade 3 and no Grade 4/5 TRAEs.Trial RegistrationNCT03132675Ethics ApprovalThe study was approved by a central IRB and/or local institutional IRB/Ethics Committee as required for each participating institution.ConsentWritten informed consent was obtained from the patients participating in the trial; the current abstract does not include information requiring additional consent

Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma

2017 ◽  
Vol 35 (7) ◽  
pp. 785-792 ◽  
Author(s):  
Jeffrey S. Weber ◽  
F. Stephen Hodi ◽  
Jedd D. Wolchok ◽  
Suzanne L. Topalian ◽  
Dirk Schadendorf ◽  
...  
Keyword(s):  
Safety Profile ◽  
Objective Response ◽  
Safety Data ◽  
Advanced Melanoma ◽  
Phase Iii ◽  
Low Grade ◽  
Two Phase ◽  
Grade 3 ◽  
Time To Onset ◽  
Safety Guidelines

Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy. Results Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs. Conclusion Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit.

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