1079P Comparison of effectiveness and safety of nivolumab monotherapy or in combination therapy with ipilimumab in therapy-naïve and pretreated patients with advanced melanoma within the German noninterventional study NICO

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.

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Safety profile of nivolumab (NIVO) and ipilimumab (IPI) combination therapy in patients (pts) with advanced melanoma (MEL)

Annals of Oncology ◽

10.1093/annonc/mdw379.18 ◽

2016 ◽

Vol 27 ◽

pp. vi385 ◽

Cited By ~ 1

Author(s):

M. Sznol ◽

P.F. Ferrucci ◽

D. Hogg ◽

M. Atkins ◽

P. Wolter ◽

...

Keyword(s):

Combination Therapy ◽

Safety Profile ◽

Advanced Melanoma

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A noninterventional study evaluating the effectiveness of rotigotine and levodopa combination therapy in younger versus older patients with Parkinson’s disease

Expert Opinion on Pharmacotherapy ◽

10.1080/14656566.2018.1480721 ◽

2018 ◽

Vol 19 (9) ◽

pp. 937-945 ◽

Cited By ~ 3

Author(s):

Dirk Woitalla ◽

Antoine Dunac ◽

Ali Safavi ◽

Maria-Gabriella Ceravolo ◽

Juan Carlos Gomez Esteban ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Combination Therapy ◽

Older Patients ◽

Noninterventional Study

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Efficacy and safety of riociguat in combination therapy for patients with pulmonary arterial hypertension (PATENT studies)

Pulmonary Circulation ◽

10.1177/2045894020942121 ◽

2020 ◽

Vol 10 (3) ◽

pp. 204589402094212

Author(s):

Hossein-Ardeschir Ghofrani ◽

Ekkehard Grünig ◽

Pavel Jansa ◽

David Langleben ◽

Stephan Rosenkranz ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Combination Therapy ◽

Receptor Antagonist ◽

Endothelin Receptor Antagonist ◽

Walking Distance ◽

Endothelin Receptor ◽

Pretreated Patients ◽

Sequential Combination ◽

Pulmonary Arterial

Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg–maximum ( N = 131 pretreated patients) and placebo ( N = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: –8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies.

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Real‐world efficacy and safety data of nivolumab and ipilimumab combination therapy in Japanese patients with advanced melanoma

The Journal of Dermatology ◽

10.1111/1346-8138.15521 ◽

2020 ◽

Vol 47 (11) ◽

pp. 1267-1275

Author(s):

Akira Takahashi ◽

Kenjiro Namikawa ◽

Dai Ogata ◽

Eiji Nakano ◽

Shunichi Jinnai ◽

...

Keyword(s):

Combination Therapy ◽

Real World ◽

Safety Data ◽

Japanese Patients ◽

Advanced Melanoma ◽

Efficacy And Safety

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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

Journal for ImmunoTherapy of Cancer ◽

10.1136/lba2019.4 ◽

2020 ◽

Vol 8 (Suppl 1) ◽

pp. A2.2-A3 ◽

Cited By ~ 1

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.

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Pentostatin and Cyclophosphamide with or without Rituximab Has Significant Activity in Patients with Previously Treated Chronic Lymphocytic Leukemia and Other Low Grade Lymphoid Neoplasms.

Blood ◽

10.1182/blood.v104.11.3484.3484 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3484-3484 ◽

Cited By ~ 4

Author(s):

Nicole Lamanna ◽

Matt Kalaycio ◽

Peter Maslak ◽

Joseph Jurcic ◽

David A. Scheinberg ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Combination Therapy ◽

B Cell ◽

Median Number ◽

Lymphocytic Leukemia ◽

Low Grade ◽

Significant Activity ◽

Purine Analogs ◽

Heavily Pretreated ◽

Pretreated Patients

Abstract Combination therapy with purine analogs, alkylators, and/or monoclonal antibodies represents a promising new approach in the treatment of patients with chronic lymphocytic leukemia (CLL) and other low grade B cell neoplasms. Most regimens have utilized fludarabine as the purine analog, but the severe myelosuppression and immunosuppression of these combinations requires careful attention to dosing and schedule to minimize these complications. Of the purine analogs in CLL, pentostatin appears to be least myelosuppressive. We have previously reported our experience with pentostatin and cyclophosphamide (PC regimen) in a cohort of heavily pretreated patients with CLL (JCO21:1278, 2003). We have since added rituximab to this active combination (PCR regimen) and have treated a second cohort of patients with CLL and other low grade B cell neoplasms. We now report on our cumulative experience of 69 patients (23 received PC and 46 received PCR) treated with pentostatin combination therapy. The PC regimen consisted of pentostatin 4mg/m2 and cyclophosphamide 600mg/m2, given every 3 weeks for a total of 6 treatments. In the 2nd cohort of CLL patients, rituximab 375mg/m2 was added to this regimen starting with cycle 2. Supportive measures in both studies included hydration with each treatment (and monitoring of renal function) and prophylactic administration of filgrastim, sulfamethoxazole/trimethoprim, acyclovir, and antiemetics. In the first cohort of patients treated with the PC regimen, the median number of prior treatments was 3 (range 1–5) with the median age being 64 (32–77). There were responses achieved in 74% of patients with 17% complete responses seen in this heavily pretreated group. Similar (or perhaps slightly better) results were obtained with patients treated with the PCR regimen. For this cohort the median age was 62 (30–80) and the median number of prior regimens was 2 (1–7). Of the 32 patients with CLL 28 are evaluable for response: 79% responded and this includes 29% who achieved a complete response. Ten of the 14 patients with other low grade B cell diseases (SLL 8 patients, Waldenstrom’s macroglobulinemia 2 patients, follicular lymphoma 4 patients) are evaluable for response. The overall response rate for these patients was 50% (all PRs). These regimens were generally well tolerated with grade 3/4 toxicity consisting primarily of myelosuppression and its complications. We conclude that PC and PCR are highly active, well tolerated regimens even in heavily pretreated patients. We plan to conduct a multicenter study of PCR as initial therapy in patients with CLL.

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Results of a german noninterventional study (NIS) of cetuximab-based therapy in pretreated-patients (pts) with metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2010.28.15_suppl.3632 ◽

2010 ◽

Vol 28 (15_suppl) ◽

pp. 3632-3632

Author(s):

C. Jehn ◽

K. Stenzel ◽

L. Böning ◽

H. Kröning ◽

K. Possinger ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Pretreated Patients ◽

Noninterventional Study

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Initial results from a phase I, open-label, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.9028 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 9028-9028 ◽

Cited By ~ 23

Author(s):

Reinhard Dummer ◽

Caroline Robert ◽

Marta Nyakas ◽

Grant A. McArthur ◽

Ragini Reiney Kudchadkar ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Plasma Concentrations ◽

Braf Inhibitor ◽

Advanced Melanoma ◽

Clinical Activity ◽

Open Label ◽

Dose Escalation Study ◽

Pretreated Patients ◽

Initial Results

9028 Background: LGX818, a potent and selective BRAF inhibitor (BRAFi) being investigated in BRAF V600 mutant melanoma, has unique biochemical properties with a dissociation half-time > 10 times longer than other BRAF inhibitors. Methods: A phase I trial of LGX818 administered orally once (qd) or twice (bid) daily in BRAF V600 tumors was initiated to define the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and to assess pharmacokinetics and clinical activity in BRAFi–naive or pretreated patients with BRAF V600 mutant advanced melanoma. Baseline assessment of biomarkers from MAPK/PI3K pathways and pharmacodynamics were also evaluated. Results: Fifty-four patients have been enrolled in the dose-escalation phase (dose levels [DLs], 50-700 mg qd [n=42] and 75-150 mg bid [n=12]). LGX818 plasma concentrations increased proportionally by dose with a mean t1/2 of 4 hours and steady state in ≈ 15 days. The MTD/RP2D (450 mg qd) was well tolerated. Seven patients had a dose limiting toxicity (DLT): 5 at qd (1 each with hand-foot skin reaction [HFSR], foot pain, fatigue, diarrhea/rash, insomnia/asthenia) and 2 at bid (1 facial paresis/confusion, 1 musculoskeletal pain/neuralgia). All DLTs were grade 3 and reversible. The most common adverse events (≥ 20%) suspected to be treatment related were cutaneous (rash, dry skin, HFSR, pruritus, keratosis pilaris, alopecia), pain in extremity, arthralgia, and fatigue. Squamous cell carcinoma was observed in 2 patients (1 naive and 1 pretreated). As of 30 Sept 2012, the preliminary efficacy (all DLs) in patients with at least 1 postbaseline tumor assessment was 16 partial responses [PRs] (67%; 12 confirmed) out of 24 BRAFi–naive patients and 2 PRs (8.3%; 1 confirmed) among 24 BRAFi–pretreated patients. Responses were seen at all DLs from 50 to 550 mg qd. Updated safety and efficacy including time to event endpoints will be reported. Conclusions: Initial results from this study identified the MTD/RP2D as 450 mg/day and provided an early sign of promising activity in advanced melanoma. Expansion cohorts are ongoing in BRAFi–naive and BRAFi–pretreated melanoma and colorectal cancer. Clinical trial information: NCT01436656.

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