Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: efficacy, safety, and cerebrospinal fluid biomarkers

BackgroundThe benefit of immune checkpoint inhibitors (ICIs) in patients with leptomeningeal metastases (LMM) is unknown.MethodsWe undertook a phase II trial of pembrolizumab in patients with LMM from solid tumors. Eligible patients had radiologic/cytologic LMM and Eastern Cooperative Oncology Group performance status 0–1. Pembrolizumab was administered intravenously at 200 mg q3W until disease progression/unacceptable toxicity. The primary endpoint was central nervous system (CNS) response after four cycles, defined radiologically/cytologically/clinically. Serial cerebrospinal fluid (CSF) was assessed for tumor-derived DNA (t-DNA) aneuploidy and cytokines.ResultsThirteen of a planned 16 patients were treated between April 2017 and December 2019. The study closed early for poor accrual. Median age was 57 years (range: 22–79). Sixty-two percent of patients had tumors not traditionally ICI-responsive (hormone-receptor (HR)-positive breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (non-small cell lung cancer (NSCLC)=23%, head and neck carcinoma=8%, cutaneous squamous carcinoma (CSC)=8%). CNS response was observed in 38% of patients at 12 weeks (95% CI 13.9% to 68.4%) by pre-defined criteria and LM-RANO, and 2 achieved durable complete responses (CSC=1, overall survival (OS) 3+ years; NSCLC=1, OS 9 months). Median CNS progression-free survival and OS was 2.9 months (95% CI 1.3 to NR) and 4.9 months (95% CI 3.7 to NR), respectively. Grade 3+ treatment-related adverse events occurred in 15% of patients. Sensitivity for LMM detection by t-DNA and cytopathology was 84.6% (95% CI 54.6% to 98.1%) and 53.9% (95% CI 25.1% to 80.8%), respectively. Pre-therapy and on-therapy CSF cytokine analysis demonstrated complete responders clustered together.ConclusionsPembrolizumab conferred a 38% CNS response rate in patients with LMM, a tolerable safety profile, and deep responses in selected patients with ICI-responsive tumors. CSF t-DNA may be sensitive for LMM detection, and immunologic subsets of CNS response warrant further study.Trial registration numberNCT03091478

Download Full-text

788 Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: efficacy, safety and cerebrospinal fluid biomarkers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0788 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A837-A837

Author(s):

Jarushka Naidoo ◽

Karisa Schreck ◽

Wei Fu ◽

Chen Hu ◽

Roisin Connolly ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Solid Tumors ◽

Checkpoint Inhibitors ◽

Squamous Carcinoma ◽

Leptomeningeal Metastasis ◽

Phase 2 ◽

Color Flow ◽

Phase 2 Trial ◽

Cytokine Analysis ◽

Dismal Prognosis

BackgroundImmune checkpoint inhibitors (ICI) have anti-cancer activity in selected patients with central nervous system (CNS) metastases. However, the benefit of ICIs in patients with leptomeningeal metastases (LMM) is unknown. We hypothesized that pembrolizumab would lead to CNS responses in patient with LMM from solid tumors, and that genomic and immunologic features of the cerebrospinal fluid (CSF) may identify biomarkers of LMM response.MethodsWe undertook a single-center investigator-initiated phase 2 trial of pembrolizumab in patients with LMM from solid tumors. Eligible patients had radiologic (>3mm on MRI) or cytologic (+CSF cells) LMM and ECOG PS 0-1. Pembrolizumab was administered IV at 200mg q3W until disease progression or unacceptable toxicity. The primary endpoint was CNS response (complete response=CR, partial response=PR or stable disease=SD) after 4 cycles, defined radiologically/cytologically/clinically. Radiologic response was assessed by RECIST v1.1 and irRC. Secondary endpoints were CNS-progression-free survival (PFS), overall survival (OS) and safety. Baseline and serial CSF samples were assessed by tumor-derived DNA aneuploidy assay (t-DNA), 16-color flow cytometry and multiplex cytokine analysis.ResultsThirteen of a planned 18 patients were treated between 04/2017-12/2019. The study closed early due to poor accrual. Median age was 57 years (range 22-79); 54% were female. The majority of patients had tumors not traditionally responsive to ICI (62%: hormone-receptor+ breast carcinoma=39%; high-grade glioma=23%), while 38% had ICI-responsive tumors (NSCLC=23%, head&neck carcinoma=8%, cutaneous squamous carcinoma=8%). CNS response was observed in 38% of patients (95% CI 13.9-68.4%). Two patients achieved durable CRs (cutaneous squamous carcinoma=1, OS 3+yrs; MET-exon14+ NSCLC=1, OS 9 mos.), 1 PR (7.7%, OS 6 mos), and 2 SDs (15.4%) in the CNS. Median CNS-PFS and OS were 2.9 mos (95% CI: 1.3-NR) and 4.9 mos (95% CI: 3.7-NR), respectively. There were no unacceptable safety signals. Sensitivity for LMM detection by t-DNA was 84.6% (95% CI: 54.6-98.1%), and 46.2% (95%CI: 19.2-74.9%) by cytopathology. Pre and on-therapy CSF cytokine analysis showed complete responders clustered together, while progressors clustered differently.ConclusionsPatients with LMM from solid tumors have a dismal prognosis and limited treatment options. In this phase 2 trial, we identified an impressive 38% CNS response rate for pembrolizumab in patients with LMM, deep and durable responses in selected patients with ICI-responsive tumors, and that pembrolizumab was well-tolerated. CSF t-DNA may be more sensitive for detection of LMM than cytopathology, and immunologic subsets of ICI-response based on cytokine profiles warrant further study. These data support investigation of pembrolizumab in larger populations with LMM.Trial RegistrationNCT03091478Ethics ApprovalThe study was approved by John’s Hopkins University’s Institututional Ethics Board, approval number J1655ConsentAll participants provided informed consent as per the study protocol

Download Full-text

Nivolumab demonstrates benefit over nomogram-predicted 12-month survival as salvage therapy for metastatic urothelial carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.6_suppl.451 ◽

2018 ◽

Vol 36 (6_suppl) ◽

pp. 451-451 ◽

Cited By ~ 1

Author(s):

Gregory Russell Pond ◽

Guru Sonpavde ◽

Matt D. Galsky ◽

Padmanee Sharma ◽

Jonathan E. Rosenberg ◽

...

Keyword(s):

Prognostic Factors ◽

Urothelial Carcinoma ◽

Salvage Therapy ◽

Group Performance ◽

Checkpoint Inhibitors ◽

Statistical Significance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Progression Free Survival ◽

Metastatic Urothelial Carcinoma

451 Background: Intermediate endpoints of benefit in metastatic urothelial carcinoma (mUC) nonrandomized trials are necessary to identify promising drugs, particularly for checkpoint inhibitors, where response and progression-free survival remain suboptimal. We previously reported a nomogram (Pond GR et al, 2017 GU Cancers Symposium) using 5 prognostic factors (hemoglobin < 10 g/dL, Eastern Cooperative Oncology Group performance status ≥1, presence of liver metastasis, time from last treatment ≤3 months, and albumin < lower limit of normal) from phase 2 trials of historical agents (eg, taxanes) to estimate 12-month overall survival (OS), against which observed survival could be compared. Nivolumab was granted approval as salvage therapy for patients with mUC, based on the CheckMate (CM) 275 trial; it is thus of interest to compare the nivolumab observed survival versus nomogram-predicted survival results. Methods: Data were obtained from CM 275, including survival and all 5 prognostic factors. Nomogram points were calculated and the expected 12-month OS was estimated. Bootstrap analyses based on 2000 replications were used to estimate 95% confidence intervals (CIs) for the median expected, observed, and difference between the expected and observed 12-month OS values. All tests were 2-sided, with statistical significance defined as P≤0.05. Results: Data were available from 270 patients from CM 275. Fifteen patients did not have albumin recorded and were excluded. Among the 255 evaluable patients, 46 (18.0%) patients had 0 adverse prognostic factors, 85 (33.3%) had 1, and 124 (48.6%) had 2 or more. The observed nivolumab 12-month OS from CM 275 (43.3% [95% CI, 37.0%-50.5%]) was 19.8% higher (95% CI, 13.6%-26.4%) when compared with the nomogram-predicted 12-month OS (23.5%; [95% CI, 22.5%-25.5%]) if patients received historical chemotherapy. Across all 2000 bootstrap samples, the observed nivolumab 12-month OS exceeded the nomogram-predicted 12-month OS. Conclusions: Nivolumab was associated with a significantly improved 12-month OS compared with historical chemotherapy based on the value predicted by the validated nomogram incorporating baseline prognostic factors. Clinical trial information: NCT02387996.

Download Full-text

Effectiveness and Safety of Immune Checkpoint Inhibitors for Patients with Advanced Non Small-Cell Lung Cancer in Real-World: Review and Meta-Analysis

Cancers ◽

10.3390/cancers13061388 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1388

Author(s):

Manlio Mencoboni ◽

Marcello Ceppi ◽

Marco Bruzzone ◽

Paola Taveggia ◽

Alessia Cavo ◽

...

Keyword(s):

Clinical Trials ◽

Real World ◽

Group Performance ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Small Cell ◽

Small Cell Lung ◽

Eligibility Criteria

Immunotherapy based on anti PD-1/PD-L1 inhibitors is the new standard of advanced non-small cell lung cancers. Pembrolizumab, nivolumab and atezolizumab are used in clinical practice. The strict eligibility criteria of clinical trials do not allow researchers to fully represent treatment effects in the patients that will ultimately use these drugs. We performed a systematic review and a meta-analysis to evaluate the effectiveness and safety of these drugs, and more generally of ICIs, as second-line therapy in NSCLC patients in real world practice. MEDLINE, PubMed, Scopus and Web of Science were searched to include original studies published between January 2015 and April 2020. A total of 32 studies was included in the meta-analysis. The overall radiological response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and overall survival (OS) were 21%, 52%, 3.35 months and 9.98 months, respectively. The results did not change when analysis was adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) and age. A unitary increase in the percent of patients with liver and CNS metastases reduced the occurrence of DCR by 7% (p < 0.001) and the median PFS by 2% (p = 0.010), respectively. The meta-analysis showed that the efficacy and safety of immunotherapy in everyday practice is comparable to that in clinical trials.

Download Full-text

Phase II Trial of the Combination of Bevacizumab and Erlotinib in Patients Who Have Advanced Hepatocellular Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.3301 ◽

2009 ◽

Vol 27 (6) ◽

pp. 843-850 ◽

Cited By ~ 231

Author(s):

Melanie B. Thomas ◽

Jeffrey S. Morris ◽

Romil Chadha ◽

Michiko Iwasaki ◽

Harmeet Kaur ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Response Rate ◽

Group Performance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Evaluation Criteria ◽

Progression Free Survival ◽

Advanced Hepatocellular Carcinoma ◽

Study Objective ◽

Advanced Hcc

Purpose The study objective was to determine the proportion of patients with hepatocellular carcinoma (HCC) treated with the combination of bevacizumab (B) and erlotinib (E) who were alive and progression free at 16 weeks (16-week progression-free survival [PFS16]) of continuous therapy. Secondary objectives included response rate, median PFS, survival, and toxicity. Patients and Methods Patients who had advanced HCC that was not amenable to surgical or regional therapies, up to one prior systemic treatment; Childs-Pugh score A or B liver function; Eastern Cooperative Oncology Group performance status 0, 1, or 2 received B 10 mg/kg every 14 days and E 150 mg orally daily, continuously, for 28-day cycles. Tumor response was evaluated every 2 cycles by using Response Evaluation Criteria in Solid Tumors Group criteria. A total of 40 patients were treated. Results The primary end point of PFS16 was 62.5%. Ten patients achieved a partial response for a confirmed overall response rate (intent-to-treat) of 25%. The median PFSevent was 39 weeks (95% CI, 26 to 45 weeks; 9.0 months), and the median overall survival was 68 weeks (95% CI, 48 to 78 weeks; 15.65 months). Grades 3 to 4 drug-related toxicity included fatigue (n = 8; 20%), hypertension (n = 6; 15%), diarrhea (n = 4; 10%) elevated transaminases (n = 4; 10%), gastrointestinal hemorrhage (n = 5; 12.5%), wound infection (n = 2; 5%) thrombocytopenia (n = 1; 2.5%), and proteinuria, hyperbilirubinemia, back pain, hyperkalemia, and anorexia (n = 1 each). Conclusion The combination of B + E in patients who had advanced HCC showed significant, clinically meaningful antitumor activity. B + E warrant additional evaluation in randomized controlled trials.

Download Full-text

Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer

ESMO Open ◽

10.1136/esmoopen-2018-000375 ◽

2018 ◽

Vol 3 (4) ◽

pp. e000375 ◽

Cited By ~ 21

Author(s):

Jean-David Fumet ◽

Nicolas Isambert ◽

Alice Hervieu ◽

Sylvie Zanetta ◽

Jean-Florian Guion ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Checkpoint Inhibitors ◽

Target Therapy ◽

Performance Status ◽

Human Monoclonal Antibody ◽

Eastern Cooperative Oncology Group ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Mutational Status

Background5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy.MethodsThis phase II study (ClinicalTrials.gov NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400 mg/m²)/5-fluorouracil (400 mg/m² as bolus followed by 2400 mg/m2 as a 46-hour infusion)/oxaliplatin (85 mg/m2) every 14 days with D (750 mg) D1 every 14 days and T (75 mg) D1 every 28 days. After six cycles of FOLFOX only D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with α=10%, β=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.

Download Full-text

Activity of Eribulin in Patients With Advanced Liposarcoma Demonstrated in a Subgroup Analysis From a Randomized Phase III Study of Eribulin Versus Dacarbazine

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.6605 ◽

2017 ◽

Vol 35 (30) ◽

pp. 3433-3439 ◽

Cited By ~ 44

Author(s):

George D. Demetri ◽

Patrick Schöffski ◽

Giovanni Grignani ◽

Jean-Yves Blay ◽

Robert G. Maki ◽

...

Keyword(s):

Subgroup Analysis ◽

Group Performance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Progression Free Survival ◽

Hazard Ratio ◽

Phase Iii ◽

Eribulin Mesylate ◽

Systemic Treatments ◽

Phase Iii Study

Purpose A phase III study comparing eribulin with dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma showed a significant improvement in overall survival (OS) for the eribulin arm, with a manageable toxicity profile. We now report the histology-specific subgroup analysis of the efficacy and safety of eribulin compared with dacarbazine in patients with LPS, an independently randomized stratified subgroup of this phase III trial. Methods Patients ≥ 18 years with advanced or metastatic dedifferentiated, myxoid/round cell, or pleomorphic LPS incurable by surgery or radiotherapy were included. Patients with Eastern Cooperative Oncology Group performance status ≤ 2 and two or more prior systemic treatment regimens, including one with anthracycline, were randomly assigned 1:1 to receive eribulin mesylate (1.4 mg/m2 intravenously on days 1 and 8) or dacarbazine (850, 1,000, or 1,200 mg/m2 intravenously on day 1) every 21 days. OS, progression-free survival (PFS), and safety were analyzed. Results In the LPS subgroup, OS was significantly improved: 15.6 versus 8.4 months (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P < .001) with eribulin versus dacarbazine, respectively. Longer OS with eribulin was observed in all LPS histologic subtypes and in all geographic regions evaluated. PFS was also improved with eribulin versus dacarbazine (2.9 v 1.7 months, respectively; hazard ratio, 0.52; 95% CI, 0.35 to 0.78; P = .0015). Adverse events were similar between arms. Conclusion In patients with previously treated LPS, eribulin was associated with significantly superior OS and PFS compared with dacarbazine. Eribulin represents an important treatment option for patients with LPS, a sarcoma subtype for which limited effective systemic treatments are available. Further studies are justified to explore the role of eribulin in earlier lines of therapy as well as in combination with other agents.

Download Full-text

Attenuated regimen of biweekly gemcitabine/nab-paclitaxel in patients aged 65 years or older with advanced pancreatic cancer

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284820974912 ◽

2020 ◽

Vol 13 ◽

pp. 175628482097491

Author(s):

Hasan Rehman ◽

Jeffrey Chi ◽

Nausheen Hakim ◽

Shreya Prasad Goyal ◽

Coral Olazagasti ◽

...

Keyword(s):

Pancreatic Cancer ◽

Group Performance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Advanced Pancreatic Cancer ◽

Progression Free Survival ◽

Poor Performance ◽

Poor Performance Status ◽

Weekly Schedule ◽

Dose Reductions

Background: Treatment with gemcitabine/nab-paclitaxel confers a survival benefit over gemcitabine monotherapy in patients with advanced pancreatic cancer (APC). However, such treatment can be associated with significant toxicities especially in older patients and carries practical disadvantages related to a weekly schedule along with financial cost. We retrospectively analyzed patients >65 years of age with APC who received a modified biweekly regimen of gemcitabine/nab-paclitaxel to evaluate efficacy and toxicity. Methods: Patients aged >65 years with chemo-naïve APC with Eastern Cooperative Oncology Group performance status ⩽2 were studied. Patients were treated with a modified regimen of gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 every 2 weeks on days 1 and 15 of a 28-day cycle. Patients were evaluated for progression-free survival (PFS) and overall survival (OS) with analyses performed using the Kaplan–Meier method. Adverse events were recorded on the day of chemotherapy. Cancer antigen 19.9 was measured in every cycle and restaging scans were performed every two cycles. Results: A total of 73 patients (median age: 73 years; range: 66–93) were treated with biweekly gemcitabine/nab-paclitaxel as first-line treatment. The median OS and PFS were 9.1 months and 4.8 months, respectively. Around 66% of patients received growth-factor support based on American Society of Clinical Oncology guidelines and no patient developed neutropenic fever. The incidences of grade ⩾3 toxicity for neutropenia, anemia, thrombocytopenia, and neurotoxicity were 2%, 7%, 3%, and 5%, respectively. Dose reductions of gemcitabine/nab-paclitaxel were required in 10% and 4% patients, respectively. Conclusion: In patients older than >65 years of age with APC, a modified regimen of biweekly gemcitabine/nab-paclitaxel was found to be effective when compared with the historical control from the MPACT study. This regimen allowed for fewer dose reductions, reduced healthcare costs from additional appointments, travel-related cost, as well as a favorable side-effect profile while maintaining efficacy. Though retrospective in nature, this study underlines the need for further investigation, particularly in elderly patients with poor performance status, such as those with pancreatic cancer, and in order to combine with a third agent, such as a targeted treatment or immunotherapy.

Download Full-text

Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001146 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001146

Author(s):

Gil Awada ◽

Laila Ben Salama ◽

Jennifer De Cremer ◽

Julia Katharina Schwarze ◽

Lydia Fischbuch ◽

...

Keyword(s):

Adverse Events ◽

Group Performance ◽

Performance Status ◽

Objective Response ◽

Eastern Cooperative Oncology Group ◽

Progression Free Survival ◽

Recurrent Glioblastoma ◽

Synergistic Activity ◽

Open Label ◽

Corticosteroid Dose

BackgroundNo treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death ligand 1 blocking monoclonal antibody avelumab may result in synergistic activity against rGB.MethodsAdult patients with rGB following prior surgery, radiation therapy and temozolomide chemotherapy were stratified according to their baseline use of corticosteroids. Patients with a daily dose of ≤8 mg of methylprednisolone (or equivalent) initiated treatment with axitinib (5 mg oral two times per day) plus avelumab (10 mg/kg intravenous every 2 weeks) (Cohort-1). Patients with a higher baseline corticosteroid dose initiated axitinib monotherapy; avelumab was added after 6 weeks of therapy if the corticosteroid dose could be tapered to ≤8 mg of methylprednisolone (Cohort-2). Progression-free survival at 6 months (6-m-PFS%), per immunotherapy response assessment for neuro-oncology criteria, served as the primary endpoint.ResultsBetween June 2017 and August 2018, 54 patients (27 per cohort) were enrolled and initiated study treatment (median age: 55 years; 63% male; 91% Eastern Cooperative Oncology Group Performance Status 0–1). Seventeen (63%) patients treated in Cohort-2 received at least one dose of avelumab. The 6-m-PFS% was 22.2% (95% CI 6.5% to 37.9%) and 18.5% (95% CI 3.8% to 33.2%) in Cohort-1 and Cohort-2, respectively; median overall survival was 26.6 weeks (95% CI 20.8 to 32.4) in Cohort-1 and 18.0 weeks (95% CI 12.5 to 23.5) in Cohort-2. The best objective response rate was 33.3% and 22.2% in Cohort-1 and Cohort-2, respectively, with a median duration of response of 17.9 and 19.0 weeks. The most frequent treatment-related adverse events were dysphonia (67%), lymphopenia (50%), arterial hypertension and diarrhea (both 48%). There were no grade 5 adverse events.ConclusionThe combination of avelumab plus axitinib has an acceptable toxicity profile but did not meet the prespecified threshold for activity justifying further investigation of this treatment in an unselected population of patients with rGB.

Download Full-text

Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation

Journal of Clinical Oncology ◽

10.1200/jco.19.02931 ◽

2020 ◽

Vol 38 (13) ◽

pp. 1378-1388 ◽

Cited By ~ 33

Author(s):

Eileen M. O’Reilly ◽

Jonathan W. Lee ◽

Mark Zalupski ◽

Marinela Capanu ◽

Jennifer Park ◽

...

Keyword(s):

Phase Ii ◽

Group Performance ◽

Phase Ii Trial ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Progression Free Survival ◽

High Response Rate ◽

Open Label ◽

Free Survival ◽

Palb2 Mutation

PURPOSE Five percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline BRCA1/2 or PALB2 (g BRCA/PALB2+) mutation. Phase IB data from a trial that used cisplatin, gemcitabine, and veliparib treatment demonstrated a high response rate (RR), disease control rate (DCR), and overall survival (OS) in this population. We designed an open-label, randomized, multicenter, two-arm phase II trial to investigate cisplatin and gemcitabine with or without veliparib in g BRCA/PALB2+ PDAC. PATIENTS AND METHODS Eligible patients had untreated g BRCA/PALB2+ PDAC with measurable stage III to IV disease and Eastern Cooperative Oncology Group performance status of 0 to 1. Treatment for patients in arm A consisted of cisplatin 25 mg/m2 and gemcitabine 600 mg/m2 intravenously on days 3 and 10; treatment for patients in arm B was the same as that for patients in arm A, and arm A also received veliparib 80 mg orally twice per day on days 1 to 12 cycled every 3 weeks. The primary end point was RRs of arm A and arm B evaluated separately using a Simon two-stage design. Secondary end points were progression-free survival, DCR, OS, safety, and correlative analyses. RESULTS Fifty patients were evaluated by modified intention-to-treat analysis. The RR for arm A was 74.1% and 65.2% for arm B ( P = .55); both arms exceeded the prespecified activity threshold. DCR was 100% for arm A and 78.3% for arm B ( P = .02). Median progression-free survival was 10.1 months for arm A (95% CI, 6.7 to 11.5 months) and 9.7 months for arm B (95% CI, 4.2 to 13.6 months; P = .73). Median OS for arm A was 15.5 months (95% CI, 12.2 to 24.3 months) and 16.4 months for arm B (95% CI, 11.7 to 23.4 months; P = .6). Two-year OS rate for the entire cohort was 30.6% (95% CI, 17.8% to 44.4%), and 3-year OS rate was 17.8% (95% CI, 8.1% to 30.7%). Grade 3 to 4 hematologic toxicities for arm A versus arm B were 13 (48%) versus seven (30%) for neutropenia, 15 (55%) versus two (9%) for thrombocytopenia, and 14 (52%) versus eight (35%) for anemia. CONCLUSION Cisplatin and gemcitabine is an effective regimen in advanced g BRCA/PALB2+ PDAC. Concurrent veliparib did not improve RR. These data establish cisplatin and gemcitabine as a standard approach in g BRCA/ PALB2+ PDAC.

Download Full-text

Population Pharmacokinetics/Pharmacodynamics of Dabrafenib Plus Trametinib in Patients with BRAF-Mutated Metastatic Melanoma

Cancers ◽

10.3390/cancers12040931 ◽

2020 ◽

Vol 12 (4) ◽

pp. 931 ◽

Cited By ~ 1

Author(s):

David Balakirouchenane ◽

Sarah Guégan ◽

Chantal Csajka ◽

Anne Jouinot ◽

Valentine Heidelberger ◽

...

Keyword(s):

Metastatic Melanoma ◽

Group Performance ◽

Performance Status ◽

Eastern Cooperative Oncology Group ◽

Systemic Exposure ◽

Progression Free Survival ◽

The Elderly ◽

Cox Models ◽

Plasma Ratio ◽

Metastatic Sites

Patients treated with dabrafenib/trametinib (DAB/TRA) exhibit a large interindividual variability in clinical outcomes. The aims of this study were to characterize the pharmacokinetics of DAB, hydroxy-dabrafenib (OHD), and TRA in BRAF-mutated patients and to investigate the exposure–response relationship for toxicity and efficacy in metastatic melanoma (MM) patients. Univariate Fisher and Wilcoxon models including drug systemic exposure (area under the plasma concentration curve, AUC) were used to identify prognostic factors for the onset of dose-limiting toxicities (DLT), and Cox models for overall (OS) and progression-free survival (PFS). Seventy-three BRAF-mutated patients were included in pharmacokinetic (n = 424, NONMEM) and 52 in pharmacokinetic/pharmacodynamic analyses. Age and sex were identified as determinants of DAB and OHD clearances (p < 0.01). MM patients experiencing DLT were overexposed to DAB compared to patients without DLT (AUC: 9624 vs. 7485 ng∙h/mL, respectively, p < 0.01). Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2 and plasma ratio AUCOHD/AUCDAB ≥ 1 were independently associated with shorter OS (HR: 6.58 (1.29–33.56); p = 0.023 and 10.61 (2.34–48.15), p = 0.022, respectively). A number of metastatic sites ≥3 and cerebral metastases were associated with shorter PFS (HR = 3.25 (1.11–9.50); p = 0.032 and HR = 1.23 (1.35–10.39), p = 0.011; respectively). TRA plasma exposure was neither associated with toxicity nor efficacy. Our results suggest that early drug monitoring could be helpful to prevent the onset of DLT in MM patients, especially in fragile patients such as the elderly. Regarding efficacy, the clinical benefit to monitor plasma ratio AUCOHD/AUCDAB deserves more investigation in a larger cohort of MM patients.

Download Full-text