In patients with GIST, imatinib C(min) at steady state was significantly associated with albumin concentration, creatinine clearance, and previous major gastrectomy. Although its clinical impact is unclear at present time, monitoring of imatinib C(min) might be particularly important for optimal treatment with imatinib in patients who have undergone major gastrectomy.

Cancers with an advanced stage at diagnosis were associated with an increased risk of suicide within 1 year of diagnosis.

I n the era of cancer immunotherapy, the number of clinical trials for immunotherapeutic agents has been growing. Immune checkpoint inhibitors (ICIs) that target cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand (PD-L1) have been studied in clinical trials and applied in clinical practice (1).A subset of patients treated with ICI manifest an atypical pattern of tumor response either after an increase of tumor burden or appearance of new lesions, a phenomenon termed pseudoprogression, which is classified as progressive disease by conventional response criteria (2,3). This triggered efforts to develop criteria including immune-related response criteria (irRC) in 2009, immune-related Response Evaluation Criteria in Solid Tumors (RECIST; irRECIST) in 2013, and iRECIST in 2017 (2,(4)(5)(6).Along with increasing recognition of pseudoprogression and its importance, several studies evaluated its incidence and patterns (7-9). But a unifying definition of pseudoprogression is lacking. Although studies have raised the need for robust data on pseudoprogression (10,11), to our knowledge, there is no evidence-based systematic summary of definitions and incidence of pseudoprogression.We performed a systematic review and meta-analysis of published clinical trial reports to determine the incidence of pseudoprogression during treatment with ICI and Purpose: To evaluate by systematic review and meta-analysis the incidence of pseudoprogression in cancer treatment with ICIs, and compare the incidence according to response criteria, tumor types, and immunotherapeutic agents. Materials and Methods:Medline and Embase were searched to identify relevant studies published before December 31, 2018. Clinical trials, post hoc analysis of clinical trials, and prospective studies on ICI treatment in patients with malignant solid tumors were included. Pooled incidence of pseudoprogression for all included studies, per definition of pseudoprogression, cancer type, and drug type, was obtained by random-effects models with inverse variance weighting model. Results:Seventeen studies with 3402 patients were analyzed. The pooled incidence of pseudoprogression was 6.0% (95% confidence interval: 5.0%, 7.0%). The definition of pseudoprogression were divided into four categories: progressive disease followed by partial response (PR) or complete response (CR) but not stable disease (SD) with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (six studies); progressive disease followed by SD or PR or CR with RECIST 1.1 (five studies); progressive disease followed by SD or PR or CR with RECIST 1.0 (three studies); and progressive disease followed by SD or PR or CR with immunerelated response criteria (irRC) (three studies). Incidence of pseudoprogression varied from 4.5% to 8.0% per definition, ranged from 5.0% to 7.0% per cancer type, and was 5.6% with the monotherapy of programmed cell death-1 inhibitor. Conclusion:The overall incidence of pseudoprogression was 6.0% and was less than 10% in...

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Despite wide recognition of iRECIST, evidence regarding the impact of iRECIST over RECIST 1.1 is lacking. We aimed to evaluate the impact of iRECIST on assessing treatment efficacy of immune checkpoint inhibitors (ICIs) over RECIST 1.1. Articles that evaluated the treatment response and outcome based on both RECIST 1.1 and iRECIST were eligible. Data regarding overall response rates (ORR) and disease control rate (DCR) based on RECIST 1.1 and iRECIST, and data required to estimate individual patient data of progression-free survival (PFS) were extracted. Estimates were compared using meta-regression and pooled incidence rate ratios. The pooled difference of restricted mean survival time (RMST) of PFS between two criteria were calculated. Eleven studies with 6210 patients were analyzed. The application of iRECIST had no impact on the response-related endpoint by showing no significantly different ORR and DCR from RECIST 1.1 (pooled ORR, 23.6% and 24.7% [p = 0.72]; pooled DCR, 45.3% and 48.7% [p = 0.56] for iRECIST and RECIST 1.1, respectively) and had a minor impact on a survival endpoint by showing longer RMST of PFS than RECIST 1.1 (pooled difference, 0.46 months; 95% CI, 0.10–0.82 months; p = 0.01). Such a modest benefit of iRECIST should be considered when we design a clinical trial for immune checkpoint inhibitors.

Key Points Question What are the definition, incidence, and challenges associated with the current assessment of hyperprogressive disease among patients receiving immune checkpoint inhibitor therapy for cancer? Findings In this systematic review and meta-analysis of 24 studies including 3109 patients, the definition of hyperprogressive disease varied across studies and was divided into 4 categories: tumor growth rate ratio, tumor growth kinetics ratio, early tumor burden increase, and combinations of these categories. The incidence of hyperprogressive disease varied from 6% to 43%. Meaning Varying definitions and incidences of hyperprogressive disease indicate the need for establishing uniform and clinically relevant criteria based on currently available evidence.

Oncogenic EGFR is essential for the development and growth of non-small cell lung cancer (NSCLC), but the precise roles of EGFR in lung cancer metabolism remain unclear. Here, we show that EGFR mutation-mediated enhancement of glycolysis is critical for EGFR stability. EGFR knockdown significantly decreased levels of glycolytic pathway intermediates via transcriptional regulation of glycolytic genes. EGFR mutation-enhanced glycolysis was required for fueling the tricarboxylic acid cycle, a critical component of EGFR stability. Nonsustained ATP production enhanced reactive oxygen species accumulation and subsequent JNK-mediated activation of autophagy, which in turn induced EGFR degradation. Our data show that EGFR-mutant NSCLCs require EGFR mutation-enhanced glycolysis to maintain EGFR stability. This pathway may serve as an attractive therapeutic target for EGFR-mutant NSCLCs. Enhanced glycolysis by EGFR mutation is required for maintaining EGFR levels via inhibition of JNK-induced autophagy. This provides a promising rationale for use of JNK activators in patients with EGFR-mutated NSCLC. .

The efficacy and safety of osimertinib were demonstrated in clinical trials; however, real-world clinical data, particularly the resistance profile, are limited. Here, we investigated the efficacy, safety, and resistance profile of osimertinib in real-world practice. We reviewed medical records of T790M mutation-positive lung cancer patients who started osimertinib between February 2016 and June 2017. Molecular pathologic data of biopsy samples obtained after acquisition of resistance to osimertinib were also analyzed. The study included 23 patients with a median age of 59 years. The median follow-up duration was 11.9 months (IQR, 4.7–15.8). Objective response was achieved in 17 (73.9%) patients, and the disease was controlled in 22 (95.7%) patients. Median progression-free survival (PFS) was 7.4 months (95% CI, 3.6–11.0). Adverse events were minimal except for one case of pneumonitis. Of 14 patients experiencing disease progression, 10 underwent re-biopsy. The T790M mutation disappeared in seven patients (70%), and one showed wild-type conversion. PFS was shorter in the T790M-loss group than in the T790M-persistent group (4.4 vs. 7.7 months). Two patients with small cell transformation responded well to subsequent chemotherapy. One patient developed a C797S mutation that became undetectable after two cycles of gemcitabine and cisplatin followed by six cycles of pembrolizumab, after which the patient responded well to osimertinib. In conclusion, osimertinib showed favorable efficacy and safety in real-world practice comparable to those observed in clinical trials. Repeat biopsy after the acquisition of resistance to osimertinib is helpful to direct further treatment strategies.