BackgroundChemotherapy remains a viable option for the management of advanced non-small-cell lung cancer (NSCLC) despite recent advances in molecular targeted therapy and immunotherapy. We evaluated the efficacy of oral 5-fluorouracil-based S-1 as second- or third-line therapy compared with standard docetaxel therapy in patients with advanced NSCLC.Patients and methodsPatients with advanced NSCLC previously treated with ≥1 platinum-based therapy were randomized 1 : 1 to docetaxel (60 mg/m2 in Japan, 75 mg/m2 at all other study sites; day 1 in a 3-week cycle) or S-1 (80–120 mg/day, depending on body surface area; days 1–28 in a 6-week cycle). The primary endpoint was overall survival. The non-inferiority margin was a hazard ratio (HR) of 1.2.ResultsA total of 1154 patients (577 in each arm) were enrolled, with balanced patient characteristics between the two arms. Median overall survival was 12.75 and 12.52 months in the S-1 and docetaxel arms, respectively [HR 0.945; 95% confidence interval (CI) 0.833–1.073; P = 0.3818]. The upper limit of 95% CI of HR fell below 1.2, confirming non-inferiority of S-1 to docetaxel. Difference in progression-free survival between treatments was not significant (HR 1.033; 95% CI 0.913–1.168; P = 0.6080). Response rate was 8.3% and 9.9% in the S-1 and docetaxel arms, respectively. Significant improvement was observed in the EORTC QLQ-C30 global health status over time points in the S-1 arm. The most common adverse drug reactions were decreased appetite (50.4%), nausea (36.4%), and diarrhea (35.9%) in the S-1 arm, and neutropenia (54.8%), leukocytopenia (43.9%), and alopecia (46.6%) in the docetaxel arm.ConclusionS-1 is equally as efficacious as docetaxel and offers a treatment option for patients with previously treated advanced NSCLC.Clinical trial numberJapan Pharmaceutical Information Center, JapicCTI-101155.

Background: Several classes of anti-cancer agents including certain immunotherapies, systemic chemotherapies, and targeted therapies including trastuzumab and T-DM1 increase the risk of interstitial lung disease (ILD) and fatal cases have been reported. For DS-8201a, interim efficacy and safety analyses of available data established a final recommended dose of 5.4 mg/kg IV q3wk in advanced HER2-positive breast cancer (BC). Based on preliminary clinical results, ILD was identified as an important risk for DS-8201a. A robust monitoring and management plan was established across all studies and an international, independent ILD adjudication committee (AC) reviews the cases reported as ILD on an ongoing basis. Methods: All subjects (sbj) who received ≥1 dose of DS-8201a across 7 ongoing studies were included in this analysis. Reported ILD (standardized MedDRA Query terms) included the terms ILD, pneumonitis, and organizing pneumonia. ILD frequencies were calculated based on investigator's assessment and after adjudication. The analysis of potential risk factors associated with ILD is ongoing. Results: As of 21 June 2018, 448 sbj received ≥1 dose of DS-8201a across multiple tumor types, including BC. Of the 321 sbj with BC, 173 (53.9%) were from Japan, 103 (32.1%) from the US, and 45 (14.0%) from 6 other countries (Spain, South Korea, Taiwan, Belgium, France, and Italy). These sbj received 1 of 7 doses of DS-8201a (0.8 mg/kg: 3 sbjs, 1.6 mg/kg: 1 sbj, 3.2 mg/kg: 3 sbjs, 5.4 mg/kg: 111 sbjs, 6.4 mg/kg: 178 sbj, 7.4 mg/kg: 20 sbj, 8.0 mg/kg: 5 sbj). Overall, 44 cases of potential ILD were reported by the investigators across all tumor types (44/448, 9.8%; Grade ≥3 10/448, 2.2%). In sbj with BC who received 5.4 mg/kg, any grade and Grade ≥3 investigator-reported ILD were 7.2% (8/111) and 0.9% (1/111), respectively. The ILD AC assessed 30 of 44 cases; 22 were considered drug-related ILD, 4 were ILD but not drug-related, and 4 were found not to be ILD. For adjudicated drug-related ILD cases, the median time to onset was 159 (range; 46-591) days from the time of first dose.   Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 All Grades All tumors, All doses (N=448)      Investigator-reported20 (4.5)14 (3.1)4 (0.9)1 (0.2)5 (1.1)44 (9.8)Cases adjudicated13840530Adjudicated as drug-related ILD9 (2.0)6 (1.3)3 (0.7)04 (0.9)22 (4.9) BC, All doses (N=321)      Investigator-reported17 (5.3)11 (3.4)3 (0.9)1 (0.3)4 (1.2)36 (11.2)Cases adjudicated11830426Adjudicated as drug-related ILD8 (2.5)6 (1.9)3 (0.9)04 (1.2)21 (6.5) BC, 5.4 mg/kg (N=111)      Investigator-reported4 (3.6)3 (2.7)001 (0.9)8 (7.2)Cases adjudicated120014Adjudicated as drug-related ILD00001 (0.9)1 (0.9)n (%), except where noted Conclusions: These analyses confirm that ILD is an important identified risk for DS-8201a. Further analyses are ongoing to better understand the potential risk factors associated with the incidence of on-treatment ILD. When ILD is suspected, early diagnosis through appropriate imaging, laboratory tests, and pulmonary consultation as well as prompt management with steroids are recommended. Citation Format: Powell CA, Camidge DR, Gemma A, Kusumoto M, Baba T, Kuwano K, Bankier A, Kiura K, Tamura K, Modi S, Tsurutani J, Doi T, Iwata H, Krop IE, Zhang L, Jasmeet S, Saito K, Shahidi J, Yver A, Takahashi S. Characterization, monitoring and management of interstitial lung disease in patients with metastatic breast cancer: Analysis of data available from multiple studies of DS-8201a, a HER2-targeted antibody drug conjugate with a topoisomerase I inhibitor payload [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-06.

Over 50% cancer bears TP53 mutation, the highly stabilized mutant p53 protein drives the tumorigenesis and progression. Mutation of p53 not only cause loss-of-function and dominant-negative effects (DNE), but also results in the abnormal stability by the regulation of the ubiquitin-proteasome system and molecular chaperones that promote tumorigenesis through gain-of-function effects. The accumulation of mutant p53 is mainly regulated by molecular chaperones, including Hsp40, Hsp70, Hsp90 and other biomolecules such as TRIM21, BAG2 and Stat3. In addition, mutant p53 forms prion-like aggregates or complexes with other protein molecules and result in the accumulation of mutant p53 in tumor cells. Depleting mutant p53 has become one of the strategies to target mutant p53. This review will focus on the mechanism of mutant p53 stabilization and discuss how the strategies to manipulate these interconnected processes for cancer therapy.

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