Patients with radioiodine-refractory differentiated thyroid cancer (DTC) previously treated with vascular endothelial growth factor receptor (VEGFR)-targeted therapy have aggressive disease and no ...available standard of care. The aim of this study was to evaluate the tyrosine kinase inhibitor cabozantinib in this patient population.
In this global, randomised, double-blind, placebo-controlled, phase 3 trial, patients aged 16 years and older with radioiodine-refractory DTC (papillary or follicular and their variants) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to oral cabozantinib (60 mg once daily) or matching placebo, stratified by previous lenvatinib treatment and age. The randomisation scheme used stratified permuted blocks of block size six and an interactive voice–web response system; both patients and investigators were masked to study treatment. Patients must have received previous lenvatinib or sorafenib and progressed during or after treatment with up to two VEGFR tyrosine kinase inhibitors. Patients receiving placebo could cross over to open-label cabozantinib on disease progression confirmed by blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (confirmed response per Response Evaluation Criteria in Solid Tumours RECIST version 1.1) in the first 100 randomly assigned patients (objective response rate intention-to-treat OITT population) and progression-free survival (time to earlier of disease progression per RECIST version 1.1 or death) in all patients (intention-to-treat ITT population), both assessed by BIRC. This report presents the primary objective response rate analysis and a concurrent preplanned interim progression-free survival analysis. The study is registered with ClinicalTrials.gov, NCT03690388, and is no longer enrolling patients.
Between Feb 27, 2019, and Aug 18, 2020, 227 patients were assessed for eligibility, of whom 187 were enrolled from 164 clinics in 25 countries and randomly assigned to cabozantinib (n=125) or placebo (n=62). At data cutoff (Aug 19, 2020) for the primary objective response rate and interim progression-free survival analyses, median follow-up was 6·2 months (IQR 3·4–9·2) for the ITT population and 8·9 months (7·1–10·5) for the OITT population. An objective response in the OITT population was achieved in ten (15%; 99% CI 5·8–29·3) of 67 patients in the cabozantinib group versus 0 (0%; 0–14·8) of 33 in the placebo (p=0·028) but did not meet the prespecified significance level (α=0·01). At interim analysis, the primary endpoint of progression-free survival was met in the ITT population; cabozantinib showed significant improvement in progression-free survival over placebo: median not reached (96% CI 5·7–not estimable NE) versus 1·9 months (1·8–3·6); hazard ratio 0·22 (96% CI 0·13–0·36; p<0·0001). Grade 3 or 4 adverse events occurred in 71 (57%) of 125 patients receiving cabozantinib and 16 (26%) of 62 receiving placebo, the most frequent of which were palmar–plantar erythrodysaesthesia (13 10% vs 0), hypertension (11 9% vs 2 3%), and fatigue (ten 8% vs 0). Serious treatment-related adverse events occurred in 20 (16%) of 125 patients in the cabozantinib group and one (2%) of 62 in the placebo group. There were no treatment-related deaths.
Our results show that cabozantinib significantly prolongs progression-free survival and might provide a new treatment option for patients with radioiodine-refractory DTC who have no available standard of care.
Exelixis.
Cabozantinib is an oral tyrosine kinase inhibitor that targets VEGFR, MET and the TAM (TYRO3, AXL, MER) family of kinase receptors. In addition to their role in tumor growth and angiogenesis, ...cabozantinib targets promote an immune-suppressive microenvironment. Cabozantinib is approved as single-agent therapy for patients with advanced hepatocellular carcinoma who received prior sorafenib. Owing to its antitumor and immunomodulatory properties, cabozantinib is being developed in combination with immune checkpoint inhibitors. Early studies of these combinations have shown promising antitumor activity and tolerability in patients with solid tumors. Here, we describe the rationale and design of COSMIC-312, a Phase III study evaluating the safety and efficacy of cabozantinib in combination with atezolizumab (anti–PD-L1 monoclonal antibody) versus sorafenib for treatment-naive patients with advanced hepatocellular carcinoma.
ClinicalTrial.gov Registration: NCT03755791
Background
At an interim analysis (median follow‐up, 6.2 months; n = 187), the phase 3 COSMIC‐311 trial met the primary end point of progression‐free survival (PFS): cabozantinib improved PFS versus ...a placebo (median, not reached vs. 1.9 months; p < .0001) in patients with previously treated radioiodine‐refractory differentiated thyroid cancer (RAIR‐DTC). The results from an exploratory analysis using an extended datacut are presented.
Methods
Patients 16 years old or older with RAIR‐DTC who progressed on prior lenvatinib and/or sorafenib were randomized 2:1 to oral cabozantinib tablets (60 mg/day) or a placebo. Placebo patients could cross over to open‐label cabozantinib upon radiographic disease progression. The objective response rate (ORR) in the first 100 randomized patients and the PFS in the intent‐to‐treat population, both according to Response Evaluation Criteria in Solid Tumors version 1.1 by blinded, independent review, were the primary end points.
Results
At the data cutoff (February 8, 2021), 258 patients had been randomized (cabozantinib, n = 170; placebo, n = 88); the median follow‐up was 10.1 months. The median PFS was 11.0 months (96% confidence interval CI, 7.4–13.8 months) for cabozantinib and 1.9 months (96% CI, 1.9–3.7 months) for the placebo (hazard ratio, 0.22; 96% CI, 0.15–0.32; p < .0001). The ORR was 11.0% (95% CI, 6.9%–16.9%) versus 0% (95% CI, 0.0%–4.1%) (p = .0003) with one complete response with cabozantinib. Forty placebo patients crossed over to open‐label cabozantinib. Grade 3/4 treatment‐emergent adverse events occurred in 62% and 28% of the cabozantinib‐ and placebo‐treated patients, respectively; the most common were hypertension (12% vs. 2%), palmar–plantar erythrodysesthesia (10% vs. 0%), and fatigue (9% vs. 0%). There were no grade 5 treatment‐related events.
Conclusions
At extended follow‐up, cabozantinib maintained superior efficacy over a placebo in patients with previously treated RAIR‐DTC with no new safety signals.
In the randomized, double‐blind, placebo‐controlled, phase 3 COSMIC‐311 study, cabozantinib significantly improved progression‐free survival versus a placebo at the initial data cutoff in patients with radioiodine‐refractory differentiated thyroid cancer who had been treated previously with a vascular endothelial growth factor receptor–targeted therapy. After extended follow‐up in a larger intent‐to‐treat population, cabozantinib maintained its superiority versus a placebo with no new safety signals.
This phase II study evaluated the safety and efficacy of single-agent amrubicin versus topotecan in patients with small-cell lung cancer (SCLC) sensitive to first-line platinum-based chemotherapy.
...Patients were randomly assigned 2:1 to amrubicin (40 mg/m(2)/d in a 5-minute intravenous IV infusion, days 1 through 3, every 21 days) or topotecan (1.5 mg/m(2)/d in a 30-minute IV infusion, days 1 through 5, every 21 days). The primary efficacy end point was overall response rate (ORR) for amrubicin. Secondary end points included time to progression, median progression-free survival (PFS), and median overall survival (OS).
Of 76 patients enrolled, 50 patients were randomly assigned to amrubicin, and 26 patients were randomly assigned to topotecan. Amrubicin treatment resulted in a significantly higher ORR than topotecan (44% v 15%; P = .021). Median PFS and median OS were 4.5 months and 9.2 months with amrubicin and 3.3 months and 7.6 months with topotecan, respectively. Tolerability was similar with both agents. However, grade 3 or worse neutropenia and thrombocytopenia seemed to be more frequent in the topotecan group as compared with the amrubicin group (78% and 61% v 61% and 39%, respectively).
Amrubicin shows promising activity, with an ORR of 44% compared with an ORR of 15% for topotecan as second-line treatment in patients with SCLC sensitive to first-line platinum-based chemotherapy. In addition, the safety profiles were comparable; however, a trend was noted for more frequent grade 3 or worse neutropenia and thrombocytopenia in the topotecan group as compared with the amrubicin group. Additional studies are ongoing.
Bendamustine hydrochloride is an alkylating agent with novel mechanisms of action. This phase II multicenter study evaluated the efficacy and toxicity of bendamustine in patients with B-cell ...non-Hodgkin's lymphoma (NHL) refractory to rituximab.
Patients received bendamustine 120 mg/m(2) intravenously on days 1 and 2 of each 21-day cycle. Outcomes included response, duration of response, progression-free survival, and safety.
Seventy-six patients, ages 38 to 84 years, with predominantly stage III/IV indolent (80%) or transformed (20%) disease were treated; 74 were assessable for response. Twenty-four (32%) were refractory to chemotherapy. Patients received a median of two prior unique regimens. An overall response rate of 77% (15% complete response, 19% unconfirmed complete response, and 43% partial) was observed. The median duration of response was 6.7 months (95% CI, 5.1 to 9.9 months), 9.0 months (95% CI, 5.8 to 16.7) for patients with indolent disease, and 2.3 months (95% CI, 1.7 to 5.1) for those with transformed disease. Thirty-six percent of these responses exceeded 1 year. The most frequent nonhematologic adverse events included nausea and vomiting, fatigue, constipation, anorexia, fever, cough, and diarrhea. Grade 3 or 4 reversible hematologic toxicities included neutropenia (54%), thrombocytopenia (25%), and anemia (12%).
Single-agent bendamustine produced durable objective responses with acceptable toxicity in heavily pretreated patients with rituximab-refractory, indolent NHL. These findings are promising and will serve as a benchmark for future clinical trials in this novel patient population.
While multikinase inhibitors with RET activity are active in
-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of ...novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by
alterations.
The RET-inhibitory activity of RXDX-105 was assessed by biochemical and cellular assays, followed by
tumor growth inhibition studies in cell line- and patient-derived xenograft models. Antitumor activity in patients was assessed by imaging and Response Evaluation Criteria in Solid Tumors (RECIST).
Biochemically, RXDX-105 inhibited wild-type RET, CCDC6-RET, NCOA4-RET, PRKAR1A-RET, and RET M918T with low to subnanomolar activity while sparing VEGFR2/KDR and VEGFR1/FLT. RXDX-105 treatment resulted in dose-dependent inhibition of proliferation of
-rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in
, and
containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLCγ. Additionally, a patient with advanced
-rearranged lung cancer had a rapid and sustained response to RXDX-105 in both intracranial and extracranial disease.
These data support the inclusion of patients bearing
alterations in ongoing and future molecularly enriched clinical trials to explore RXDX-105 efficacy across a variety of tumor types.
.
Amrubicin is a synthetic anthracycline with potent topoisomerase II inhibition. This phase II study was conducted to confirm safety and activity of amrubicin in the treatment of refractory small-cell ...lung cancer (SCLC).
Patients with refractory SCLC (either with progressive disease as best response or progression within 90 days of first-line therapy) received amrubicin (40 mg/m(2)/d for 3 every 21 days). The primary end point was overall response rate (ORR); secondary end points included progression-free survival (PFS), overall survival (OS), and change in left ventricular ejection fraction (LVEF).
Seventy-five patients with a median progression-free interval after first-line therapy of 38 days were enrolled; 69 patients received a median of four amrubicin cycles (range, one to 12 cycles). The ORR was 21.3% (95% CI, 12.7% to 32.3%), with one complete response (1.3%) and 15 partial responses (20%). Median PFS and OS were 3.2 months (95% CI, 2.4 to 4.0 months) and 6.0 months (95% CI, 4.8 to 7.1 months), respectively. The ORR in 43 patients who never responded to first-line therapy was 16.3% (95% CI, 6.8% to 30.7%). Most commonly reported grade 3 or 4 adverse events included neutropenia (67%), thrombocytopenia (41%), and anemia (30%), with febrile neutropenia in 12%. There was no decrease in mean LVEF with cumulative amrubicin doses exceeding 750 mg/m(2).
Single-agent amrubicin showed promising activity with a 21.3% ORR and an acceptable safety profile when used as second-line therapy patients with platinum-refractory SCLC. Amrubicin did not induce early cardiotoxicity, but its long-term effects are unknown.
Improved sensitivity and efficiency of detection and quantification of carriage of Neisseria meningitidis (Nm) in young people is important for evaluation of the impact of vaccines upon transmission ...and associated population-wide effects. Saliva collection is quick, non-invasive and facilitates frequent sampling, but has been reported to yield low sensitivity by culture. We re-evaluated this approach in a follow-up cross sectional study using direct and culture-amplified PCR.
In April 2016 we collected paired oropharyngeal swabs (OPS) and saliva samples from 1005 healthy students in Portugal into STGG broth and stored them at -80°C until DNA extraction and batched qPCR analysis. Samples were also cultured on GC agar plates for 72h and PCR done on DNA extracts from overall growth. Nm isolates were also sought from a selection of 50 samples. qPCR amplification targets were superoxide dismutase sodC and capsular locus/genogroup-specific genes (B, C, W, X and Y) and, for cultured isolates only, porA. Cycle threshold values of ≤36 were considered positive.
556 tests (460 samples, 363 subjects, 36.1%) were positive for Nm (sodC) and 65 (45, 36, 3.6%) for MenB. More salivas were positive by direct sodC qPCR (211, 21.0%) than OPS (126, 12.5%) but fewer were positive by culture-amplified qPCR (94 vs. 125). For both sample types, many that were negative on direct qPCR came positive on culture-amplification and Nm was consistently isolated from salivas in which culture amplified the PCR signal. Using both methods on both samples yielded 36.1% Nm and 5.5% encapsulated Nm carriage rates while direct qPCR on OPS alone detected 12.5% and 2.2%.
Detectable MenB carriage rates (2.9%) were lower than 4 years earlier (6.8%) in this population (p = 0.0003). Viable meningococci were often present in saliva. Although evidence of encapsulated Nm was less frequent in saliva than OPS, collection is more acceptable to subjects allowing more frequent sampling. Use of culture-amplification increases detection sensitivity in both sample types, especially when combined with direct PCR. Combining these samples and/or methodologies could greatly enhance the power of carriage studies to detect the impact of vaccines upon carriage and transmission.
IntroductionWhile still a ubiquitous disease of childhood, chickenpox has been effectively controlled in many countries through the use of vaccination. Previous health economic assessment of the use ...of these vaccines in the UK were based on limited quality of life data and only routinely collected epidemiological outcomes.Methods and analysisThis two armed study will carry prospective surveillance of hospital admissions and recruit from community settings to measure the acute quality of life loss caused by paediatric chickenpox both in the UK and in Portugal. The quality of life effects on children and their primary and secondary caregivers will be assessed using the EuroQol EQ-5D with the Child Health Utility instrument (CHU-9) in addition for children. Results will be used to derive quality-adjusted life year loss estimates for cases of simple varicella and the secondary complications.Ethics and disseminationWe have received National Health Service ethical approval (REC ref: 18/ES/0040) for the inpatient arm, university ethical approval (University of Bristol ref: 60721) for the community arm and 10 sites currently are recruiting in the UK and 14 in Portugal. Informed consent is obtained from the parent(s). Results will be disseminated in peer-reviewed publications.Trial registration numberISRCTN15017985.
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