In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus ...gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data.
LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases.
Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.
In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.
NCT01466660.
RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC). Pralsetinib, a highly potent, oral, central nervous system-penetrant, selective RET inhibitor, previously demonstrated clinical ...activity in patients with RET fusion–positive NSCLC in the phase I/II ARROW study, including among treatment-naive patients. We report an updated analysis from the ARROW study.
ARROW is a multi-cohort, open-label, phase I/II study. Eligible patients were ≥18 years of age with locally advanced or metastatic solid tumours and an Eastern Cooperative Oncology Group performance status of 0-2 (later 0-1). Patients initiated pralsetinib at the recommended phase II dose of 400 mg once daily until disease progression, intolerance, consent withdrawal, or investigator’s decision. The co-primary endpoints (phase II) were overall response rate (ORR) by blinded independent central review and safety.
Between 17 March 2017 and 6 November 2020 (data cut-off), 281 patients with RET fusion–positive NSCLC were enrolled. The ORR was 72% 54/75; 95% confidence interval (CI) 60% to 82% for treatment-naive patients and 59% (80/136; 95% CI 50% to 67%) for patients with prior platinum-based chemotherapy (enrolment cut-off for efficacy analysis: 22 May 2020); median duration of response was not reached for treatment-naive patients and 22.3 months for prior platinum-based chemotherapy patients. Tumour shrinkage was observed in all treatment-naive patients and in 97% of patients with prior platinum-based chemotherapy; median progression-free survival was 13.0 and 16.5 months, respectively. In patients with measurable intracranial metastases, the intracranial response rate was 70% (7/10; 95% CI 35% to 93%); all had received prior systemic treatment. In treatment-naive patients with RET fusion–positive NSCLC who initiated pralsetinib by the data cut-off (n = 116), the most common grade 3-4 treatment-related adverse events (TRAEs) were neutropenia (18%), hypertension (10%), increased blood creatine phosphokinase (9%), and lymphopenia (9%). Overall, 7% (20/281) discontinued due to TRAEs.
Pralsetinib treatment produced robust efficacy and was generally well tolerated in treatment-naive patients with advanced RET fusion–positive NSCLC. Results from the confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting are pending.
•Pralsetinib produced an ORR of 72% in treatment-naive patients with RET fusion–positive NSCLC.•Pralsetinib was generally well tolerated and there were no new safety signals.•The confirmatory phase III AcceleRET Lung study (NCT04222972) of pralsetinib versus standard of care in the first-line setting is ongoing
Genexol-PM is a novel Cremophor EL (CrEL)-free polymeric micelle formulation of paclitaxel (Taxol). This multicenter phase II study was designed to evaluate the efficacy and safety of the combination ...of Genexol-PM and cisplatin for the treatment of advanced non-small-cell lung cancer (NSCLC).
Patients with advanced NSCLC received Genexol-PM 230 mg/m2 and cisplatin 60 mg/m2 on day 1 of a 3-week cycle as first-line therapy. Intrapatient dose escalation of Genexol-PM to 300 mg/m2 was carried out from the second cycle if the prespecified toxic effects were not observed after the first cycle.
Sixty-nine patients were enrolled in this study. Overall response rate was 37.7%. The median time to progression was 5.8 months and the median survival period was 21.7 months. The major non-hematologic toxic effects included grade 3 peripheral sensory neuropathy (13.0%) and grade 3/4 arthralgia (7.3%). Four patients (5.8%) experienced grade 3/4 hypersensitivity reactions. The major hematological toxic effects were grade 3/4 neutropenia (29.0% and 17.4%, respectively).
Genexol-PM plus cisplatin combination chemotherapy showed significant antitumor activity. The use of CrEL-free, polymeric micelle formulation of paclitaxel allowed administration of higher doses of paclitaxel compared with the CrEL-based formulation without significant increased toxicity.
Chromosomal rearrangements involving RET, which are found in about 1% of non-small cell lung cancer (NSCLC), define a unique molecular subset. We performed this study to examine the efficacy and ...safety of vandetanib 300 mg daily in this patient population.
This study was a multi-center, open-label, phase II clinical trial. Patients were enrolled if they had metastatic or recurrent NSCLC with a RET rearrangement, which was confirmed by fluorescence in situ hybridization, had progressive disease against platinum-based doublet chemotherapy, and had a performance status of 0–2. The primary endpoint was the objective response rate.
A total of 18 patients were enrolled in this study between July 2013 and October 2015. Patients were aged 35–71 years; three had a performance status of 2, and the majority were a heavily pretreated population (≥ two different previous chemotherapy regimens in 72% of the patients). Among the 17 evaluable patients, three had a partial response (objective response rate = 18%) and eight had a stable disease (disease control rate = 65%). Among these patients, the partial response or disease stabilization was durable for more than 6 months in eight patients. Vandetanib also showed a progression-free survival of 4.5 months, and an overall survival of 11.6 months during a median follow-up duration of 14 months. The safety profile was comparable with previous studies of vandetanib. Most vandetanib-related adverse events were mild with prevalent hypertension and rash (in >70% of patients). Grade 3 toxicity included hypertension (n = 3), QT prolongation (2), and elevation of aminotransferases (1), and as a consequence the dose was reduced in four patients. There were no adverse events associated with grade 4 or 5 toxicity.
Vandetanib is moderately active in pretreated patients with advanced NSCLC-harboring RET rearrangements.
Superelastic conducting fibers with improved properties and functionalities are needed for diverse applications. Here we report the fabrication of highly stretchable (up to 1320%) sheath-core ...conducting fibers created by wrapping carbon nanotube sheets oriented in the fiber direction on stretched rubber fiber cores. The resulting structure exhibited distinct short- and long-period sheath buckling that occurred reversibly out of phase in the axial and belt directions, enabling a resistance change of less than 5% for a 1000% stretch. By including other rubber and carbon nanotube sheath layers, we demonstrated strain sensors generating an 860% capacitance change and electrically powered torsional muscles operating reversibly by a coupled tension-to-torsion actuation mechanism. Using theory, we quantitatively explain the complementary effects of an increase in muscle length and a large positive Poisson's ratio on torsional actuation and electronic properties.
The mechanism of primary resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC) has not been clearly understood.
...Eleven patients exhibiting primary resistance (disease progression <3 months) were identified among 197 consecutive NSCLC patients with TKI-sensitive EGFR mutations who received EGFR TKIs at Seoul National University Hospital. Treatment-naïve tumors were examined for concurrent genetic alterations using fluorescence in situ hybridization and targeted deep sequencing of cancer-related genes. Deletion polymorphism of Bcl-2-interacting mediator of cell death (BIM) gene was examined to validate its predictive role for TKI outcome.
The median progression-free survival (PFS) for patients receiving EGFR TKIs was 11.9 months, and the response rate 78.8%. Among the 11 patients exhibiting primary resistance, a de novo T790M mutation was identified in one patient, and two exhibited mesenchymal-epithelial transition amplification and anaplastic lymphoma kinase fusion. Targeted deep sequencing identified no recurrent, coexistent drivers of NSCLC. Survival analysis revealed that patients with recurrent disease after surgery had a longer PFS than those with initial stage IV disease. However, BIM deletion polymorphism, line of treatment, EGFR genotype, and smoking were not predictive of PFS for EGFR TKIs.
We identified coexistent genetic alterations of cancer-related genes that could explain primary resistance in a small proportion of patients. Our result suggests that the mechanism of primary resistance might be heterogeneous.
We conducted a systemic evaluation to describe the effect of minimal residual disease (MRD) kinetics on long-term allogeneic transplantation outcome by analyzing 95 adult transplants with ...Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who received first-line two courses of imatinib-based chemotherapy (median follow-up 5 years). MRD monitoring was centrally evaluated by real-time quantitative PCR (4.5 log sensitivity). After the first course of imatinib-based chemotherapy, 33 patients (34.7%) achieved at least major molecular response. On the basis of MRD kinetics by the end of two courses of imatinib-based chemotherapy, we stratified entire patients into four subgroups: early-stable molecular responders (EMRs, n=33), late molecular responders (LMRs, n=35), intermediate molecular responders (IMRs, n=9) and poor molecular responders (PMRs, n=18). Multivariate analysis showed that the most powerful factor affecting long-term transplantation outcome was MRD kinetics. Compared with EMRs, IMRs or PMRs had significantly higher risk of treatment failure in terms of relapse and disease-free survival (DFS). LMRs had a tendency toward a lower DFS. Quantitative monitoring of MRD kinetics during the first-line imatinib-based chemotherapy course is useful in identifying subgroups of Ph-positive ALL transplants at a high risk of relapse.
Summary
To review the effect of teriparatide as an adjunctive modality for bisphosphonate-related osteonecrosis of the jaws (BRONJ), we describe a series of cases of teriparatide therapy for the ...treatment of BRONJ and serial changes of serum osteoclacin (s-OC) and serum C-terminal telopeptide cross-link of type I collagen (s-CTX).
Introduction
Management of BRONJ is quite challenging and the currently recommended modalities for BRONJ are still suboptimal. For the improvement of bony remodeling, some clinicians advocated bisphosphonate holiday although validity of this drug holiday has been debated so far. Recently, the use of teriparatide was introduced in several cases, but the number of the publication is limited and mostly anecdotal so far.
Method
Bisphosphonate was suspended and teriparatide was given to six patients diagnosed with BRONJ by single bone specialist. Medical record review and interviews were carried out. S-CTX and s-OC were measured at the baseline, 2 months and 3 months later teriparatide therapy. The outcome of the treatment and the change of biochemical markers were compared.
Result
In all six patients, s-OC values were significantly elevated within 2 months after teriparatide treatment and the BRONJ lesions were healed. S-CTX values were also elevated in four patients, whereas those of the rest two patients stayed within minimal change. The change was marginally significant at 3 months.
Conclusion
In terms of the multifactorial etiology of BRONJ, bone formation suppression was noticed in the patients. Based upon this finding, the short-term use of teriparatide might be beneficial to the resolution of BRONJ lesions by improving suppressed bone remodeling.
In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy ...or in combination with pembrolizumab.
Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.
Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs–the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs–the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.
Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.
•First-in-human phase 1 study in patients with advanced solid tumors who received vibostolimab alone or with pembrolizumab.•Vibostolimab plus pembrolizumab was well tolerated in advanced solid tumors.•Vibostolimab plus pembrolizumab demonstrated antitumor activity in patients with advanced solid tumors.
P53 inactivation by p53 mutation and E6 oncoprotein has a crucial role in human carcinogenesis. DDX3 has been shown to be a target of p53. In this study, we hypothesized that DDX3 loss by p53 ...inactivation may promote tumor malignancy and poor patients' outcome. Mechanically, DDX3 loss by p53 knockdown and E6 overexpression was observed in A549 lung cancer cells. Conversely, DDX3 expression was markedly elevated by wild-type (WT) p53 ectopic expression in p53-null H1299 cells, E6-knockdown TL-1 lung cancer and SiHa cervical cancer cells. Interestingly, DDX3 loss promotes soft-agar growth and invasive capability; however, both capabilities were suppressed by DDX3 overexpression. We next expected that DDX3 loss might result in Slug-suppressed E-cadherin expression via decreased MDM2-mediated Slug degradation. As expected, MDM2 transcription is suppressed by DDX3 loss via decreased SP1 binding activity to the MDM2 promoter. Consequently, Slug expression was elevated by the reduction of MDM2 because of DDX3 loss, and E-cadherin expression was suppressed by Slug. Consistent observations in the correlation of DDX3 loss with MDM2, Slug and E-cadherin were seen in lung tumors from lung cancer patients. In addition, patients with low-DDX3 tumors had poorer survival and relapse than patients with high-DDX3 tumors. In conclusion, we suggest that DDX3 loss by p53 inactivation via MDM2/Slug/E-cadherin pathway promotes tumor malignancy and poor patient outcome.
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