Summary Background Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is ...characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. Methods In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov , number NCT01494688. Findings Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 64% of 25 patients), asthenia (14 56%), and pruritus (14 56%). Five serious adverse events (periorbital oedema, lupus erythematosus occurring twice, erythema, and dermohypodermitis all experienced by one 4% patient each) were reported in five patients. Three of the five serious adverse events—periorbital oedema (one 4%), lupus erythematosus (one 4%), and dermohypodermitis (one 4%)—were assessed as grade 3. Two other grade 3 events were reported: mucositis (one 4%) and fatigue (one 4%). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. Interpretation Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. Funding F Hoffmann-La Roche.
We compared the performance of six prognostic scores (Royal Marsden Hospital, MDACC: MD Anderson Clinical Center and MDACC + NLR: neutrophil‐to‐lymphocyte ratio, MD Anderson ‐ immune checkpoint ...inhibitors (MDA‐ICI), GRIm: Gustave Roussy Immune Score and LIPI: Lung Immune Prognostic Index) in predicting overall survival (OS) in phase I trial patients treated with immune checkpoint inhibitors (ICI). Medical records of patients with advanced solid tumors enrolled in ICI phase I trials between 2015 and 2018 at Institut Universitaire du Cancer de Toulouse—Oncopole were reviewed. The performance of prognostic scores on OS was compared using different criteria. A total of 259 patients were included. Median age was 63 years (range: 18‐83). Main primary cancers were melanoma (19%), head and neck (16%), lung (13%) and bladder (10%). With a median follow‐up of 15 months (95% confidence interval CI = 11.6;17.5), median OS was 12.5 months (95% CI = 10.3;16.0). All scores were associated with OS. The MDACC, LIPI and GRIm scores performed better than the others. Concordance of risk group assignment between the scoring systems was poor. According to our results, the MDACC, GRIm and LIPI scores better suited to ICI phase I settings. Adequate scoring would allow better patient selection in early ICI trials, especially during the critical period of dose escalation, and in proof‐of‐concept expansion cohorts.
What's new?
Reducing enrollment of frail patients in early clinical trials evaluating dose and anti‐tumor activity of immune checkpoint inhibitors (ICIs) should be feasible through the use of scoring systems. The relative effectiveness of scores that take account prognostic factors associated with immunotherapy, however, remains unclear. Here, the performance of six prognostic scoring systems was compared for patients enrolled in phase1 ICI trials. Three systems – the MDACC, GRIm, and LIPI – performed best in terms of discrimination and calibration when applied to overall survival. The application of these scoring systems could contribute to more efficient patient enrollment in early ICI trials.
Background
LMB‐100 is an antibody‐toxin conjugate with an antimesothelin Fab linked to a 24‐kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of ...the current first‐in‐human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin.
Methods
Cohorts of 1 to 7 patients received intravenous LMB‐100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21‐day cycle.
Results
Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose‐limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB‐100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB‐100 plasma concentrations were dose‐dependent during cycle 1. The development of antidrug antibodies decreased LMB‐100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3.
Conclusions
The MTD for single‐agent LMB‐100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first‐generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB‐100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB‐100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer.
Lay Summary
Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB‐100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A.
In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB‐100, as well as the generation of antidrug antibodies.
Ongoing phase 2 clinical trials are evaluating the combination of LMB‐100 plus pembrolizumab in patients with treatment‐refractory mesothelioma and non–small cell lung cancer.
The mesothelin‐targeting immunotoxin LMB‐100 is well tolerated with manageable adverse effects. Based on the antitumor efficacy observed in preclinical studies, the combination of LMB‐100 plus pembrolizumab currently is being evaluated in the clinic.
Bromodomain and extraterminal (BET) proteins are chromatin readers that preferentially affect the transcription of genes with super-enhancers, including oncogenes. BET proteins bind acetylated ...histone tails via their bromodomain, bringing the elongation complex to the promoter region. OTX015 (MK-8628) specifically binds to BRD2, BRD3, and BRD4, preventing BET proteins from binding to the chromatin, thus inhibiting gene transcription. OTX015 inhibits proliferation in many haematological malignancy cell lines and patient cells, in vitro and in vivo. We aimed to establish the recommended dose of OTX015 in patients with haematological malignancies. We report the results of patients with acute leukaemia (leukaemia cohort).
In this dose-escalation, phase 1 study we recruited patients from seven university hospital centres (in France five, UK one, and Canada one). Adults with acute leukaemia who had failed or had a contraindication to standard therapies were eligible to participate. OTX015 was given orally at increasing doses from 10 mg/day to 160 mg/day (14 of 21 days), using a conventional 3 + 3 design. In this open-label trial, OTX015 was initially administered once a day, with allowance for exploration of other schedules. The primary endpoint was dose-limiting toxicity (DLT), assessed during the first treatment cycle (21 days). The study is ongoing and is registered with ClinicalTrials.gov, NCT01713582.
Between Jan 18, 2013, and Sept 9, 2014, 41 patients, 36 with acute myeloid leukaemia, a median age of 70 years (IQR 60-75) and two lines of previous therapy, were recruited and treated across six dose levels of OTX015. No DLT was recorded until 160 mg/day, when one patient had grade 3 diarrhoea and another had grade 3 fatigue. However, concomitant grade 1-2 non-DLT toxic effects (ie, gastrointestinal, fatigue, or cutaneous) from 120 mg doses hampered patient compliance and 80 mg once a day was judged the recommended dose with a 14 days on, 7 days off schedule. Common toxic effects for all OTX015 doses were fatigue (including grade 3 in three patients) and bilirubin concentration increases (including grade 3-4 in two patients). OTX015 plasma exposure increased proportionally up to 120 mg/day with trough concentrations in the in-vitro active range from 80 mg/day (274 nmol/L). Three patients (receiving 40 mg/day, 80 mg/day, and 160 mg/day) achieved complete remission or complete remission with incomplete recovery of platelets lasting 2-5 months, and two additional patients had partial blast clearance. No predictive biomarkers for response have been identified so far.
The once-daily recommended dose for oral, single agent oral OTX015 use in patients with acute leukaemia for further phase 2 studies is 80 mg on a 14 days on, 7 days off schedule.
Oncoethix GmbH, a wholly owned subsidiary of Merck Sharp & Dohme Corp.
Purpose The KEYNOTE-028 trial ( ClinicalTrials.gov identifier: NCT02054806) was designed to assess the safety and efficacy of pembrolizumab in 20 programmed death ligand 1-positive, advanced solid ...tumor cohorts. Here, we present the results from the cohort of patients with advanced cervical cancer. Methods Patients were treated with pembrolizumab 10 mg/kg every 2 weeks for up to 24 months. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was overall response rate per Response Evaluation Criteria in Solid Tumors, version 1.1, by investigator review. Safety was a secondary end point. Results Twenty-four patients were enrolled in the cervical cancer cohort. The median age was 42 years (range, 26 to 62 years), 22 patients (92%) had received prior radiation therapy, and 15 patients (63%) had received two or more lines of therapy, including bevacizumab (10 of 24 patients), for advanced disease. At the data cutoff, median follow-up duration was 11.0 months (range, 1.3 to 32.2 months). Overall response rate was 17% (95% CI, 5% to 37%); four patients (17%) achieved a confirmed partial response, and three patients (13%) had stable disease. Median duration of response for the four patients who achieved a partial response was 5.4 months (4.1 to 7.5 months). Treatment related adverse events (AEs) were experienced by 18 patients (75%); only rash (n = 5; 21%) and pyrexia (n = 4; 17%) and occurred in ≥ 10% of patients. Five patients experienced grade 3 treatment-related AEs. No grade 4 treatment-related AEs or deaths were observed. Conclusion In patients with programmed death ligand 1-positive advanced cervical cancer, pembrolizumab demonstrated antitumor activity and exhibited a safety profile consistent with that seen in other tumor types.
Colorectal cancers (CRCs) expressing programmed death ligand 1 (PD-L1) have poor prognosis. In the multicohort KEYNOTE-028 trial, the anti-PD-1 antibody pembrolizumab was evaluated in 20 ...PD-L1-positive advanced solid tumors. Herein, we report results for the advanced CRC cohort.
Patients with advanced, treatment-resistant PD-L1-positive carcinoma of the colon or rectum were enrolled, regardless of microsatellite instability (MSI) status. Pembrolizumab 10 mg/kg was administered every 2 weeks for up to 2 years or until disease progression/unacceptable toxicity. Response was assessed every 8 weeks for the first 6 months and every 12 weeks thereafter. Primary end points were safety and overall response rate by investigator review per Response Evaluation Criteria in Solid Tumors version 1.1. Data cutoff was June 20, 2016.
Of 137 patients with CRC and samples evaluable for PD-L1 expression, 33 (24%) had PD-L1-positive tumors, of which 23 were enrolled. Median follow-up was 5.3 months, and 8 patients (35%) reported treatment-related adverse events (AEs), most commonly fatigue (n = 3, 13%), stomatitis (n = 2, 9%), and asthenia (n = 2, 9%). One patient (4%) experienced grade 4 treatment-related increased blood bilirubin. No grade 3 AEs, discontinuations, or deaths were attributed to treatment. Most patients (n = 15, 65%) experienced progressive disease. One partial response occurred in a patient (4%) with MSI-high CRC.
Pembrolizumab demonstrated a favorable safety profile in advanced PD-L1-positive CRC. Antitumor activity was observed in a single patient with MSI-high CRC, warranting further evaluation in this patient population. (Clinicaltrials.gov registration: NCT02054806).
Gender disparities in scientific publications have been identified in oncological research. Oral research presentations at major conferences enhance visibility of presenters. The share of women ...presenting at such podia is unknown. We aim to identify gender‐based differences in contributions to presentations at two major oncological conferences. s presented at plenary sessions of the American Society of Clinical Oncology (ASCO) Annual Meetings and European Society for Medical Oncology (ESMO) Congresses were collected. Trend analyses were used to analyze female contribution over time. The association between presenter's sex, study outcome (positive/negative) and journals' impact factors (IFs) of subsequently published papers was assessed using Chi‐square and Mann–Whitney U tests. Of 166 consecutive s presented at ASCO in 2011–2018 (n = 34) and ESMO in 2008–2018 (n = 132), 21% had female presenters, all originating from Northern America (n = 17) or Europe (n = 18). The distribution of presenter's sex was similar over time (p = 0.70). Of 2,425 contributing authors to these presented s, 28% were women. The proportion of female authors increased over time (p < 0.05) and was higher in s with female (34%) compared to male presenters (26%; p < 0.01). Presenter's sex was not associated with study outcome (p = 0.82). Median journals' IFs were lower in papers with a female first author (p < 0.05). In conclusion, there is a clear gender disparity in research presentations at two major oncological conferences, with 28% of authors and 21% of presenters of these studies being female. Lack of visibility of female presenters could impair acknowledgement for their research, opportunities in their academic career and even hamper heterogeneity in research.
What's new?
Presenting one's research at a conference is a great way to get your name and ideas heard within the professional community. In this study, the authors investigated how often women served as presenters at plenary sessions of ASCO Annual Meetings and ESMO Congresses. Looking through 166 s over a period of 8 years, they found that 21% had female presenters, while 28% of study authors were female. Lack of visibility for female researchers at conferences can slow their career progress, and greater representation should be encouraged.
Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with ...BRAFi treatment-naïve and pretreated
-mutant melanoma.
The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50-700 mg) or twice-daily (75-150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic
-mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib.
Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of
V600E-mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar-plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months 95% confidence interval (CI), 7.4-not reached (NR). In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9-3.7).
Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma.
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Response Evaluation Criteria in Solid Tumors (RECIST) evaluation does not take into account the pretreatment tumor kinetics and may provide incomplete information about experimental drug activity. ...Tumor growth rate (TGR) allows for a dynamic and quantitative assessment of the tumor kinetics. How TGR varies along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown.
Medical records from all patients (N = 253) prospectively treated in 20 phase I trials were analyzed. TGR was computed during the pretreatment period (reference) and the experimental period. Associations between TGR, standard prognostic scores Royal Marsden Hospital (RMH) score, and outcome progression-free survival (PFS) and overall survival (OS) were computed (multivariate analysis).
We observed a reduction of TGR between the reference versus experimental periods (38% vs. 4.4%; P < 0.00001). Although most patients were classified as stable disease (65%) or progressive disease (25%) by RECIST at the first evaluation, 82% and 65% of them exhibited a decrease in TGR, respectively. In a multivariate analysis, only the decrease of TGR was associated with PFS (P = 0.004), whereas the RMH score was the only variable associated with OS (P = 0.0008). Only the investigated regimens delivered were associated with a decrease of TGR (P < 0.00001, multivariate analysis). Computing TGR profiles across different clinical trials reveals specific patterns of antitumor activity.
Exploring TGR in phase I patients is simple and provides clinically relevant information: (i) an early and subtle assessment of signs of antitumor activity; (ii) independent association with PFS; and (iii) it reveals drug-specific profiles, suggesting potential utility for guiding the further development of the investigational drugs.
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