Alterations of DNA damage response (DDR) genes correlate with favorable response and overall survival (OS) in anti-PD-1/PD-L1-treated advanced urothelial cancer (UC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 438-438 ◽  
Author(s):  
Monika Joshi ◽  
Petros Grivas ◽  
Amir Mortazavi ◽  
Paul Monk ◽  
Steven K. Clinton ◽  
...  
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Fisher Exact Test ◽  
Exact Test ◽  
Cox Proportional Hazard ◽  
Platinum Based Chemotherapy ◽  
Tumor Mutational Burden ◽  
Cox Proportional Hazard Regression

438 Background: DDR gene alterations may contribute to higher tumor mutational burden (TMB) via genomic instability in addition to APOBEC mutagenesis. We previously showed that ATM mutations correlated with shorter OS in UC, while Teo et al. showed patients (pts) with DDR alterations benefited from PD-1/PD-L1 blockade in advanced UC. Here, we aimed to validate those findings and further explore the prognostic role of ATM mutations in advanced UC treated with anti-PD-1/PD-L1 agents. Methods: The study included 53 pts who had FoundationOne tumor tissue genomic sequencing and anti-PD-1/PD-L1 therapy. Fisher exact test was used to test difference in objective response rate (ORR). OS was measured from time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: The cohort had a median age of 66 (range 21–81) with 34% females and 64.2% platinum-based chemotherapy. DDR alterations (including ATM) were present in 49.1% pts (26/53) and favored a higher ORR (37.5% vs. 23.1%, p = 0.26). Compared with those without DDR alterations, pts with DDR alterations (excluding ATM) seemed to have longer OS, although significance was not reached likely due to a short follow-up time (HR = 0.53, 95% CI 0.20–1.38, p = 0.19). ATM alterations seemed to favor higher response rate to PD-1/PD-L1 blockade (ORR, 40% vs. 28.9%, p = 0.6), but was associated with significantly shorter OS (HR = 5.7, 95% CI 1.65–19.74, p = 0.006) in overall pts and in subgroups with/without platinum-based chemotherapy (data not shown). Pts with ≥ 3 DDR alterations (including ATM) had substantial higher TMB (13.9–72.2 perMb, median 22.6) and benefited the most from PD-1/PD-L1 blockade with 80% ORR vs. 24.4% ORR in pts with < 3 DDR alterations. Conclusions: Our study supported that DDR alterations are associated with higher response rate and prolonged OS in advanced UC pts receiving anti-PD-1/PD-L1 agents, likely from impact on TMB. However, ATM alterations correlated with poor prognosis also in those pts. Further studies are needed to assess the clinical utility of DDR alterations in directing therapies in UC.

ATM mutation is associated with shorter overall survival in relapsed/advanced urothelial cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 370-370 ◽  
Author(s):  
Ming Yin ◽  
Petros Grivas ◽  
Amir Mortazavi ◽  
Paul Monk ◽  
Hamid Emamekhoo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Regression Analysis ◽  
Urothelial Cancer ◽  
Objective Response ◽  
Fisher Exact Test ◽  
Proportional Hazard ◽  
Exact Test ◽  
Cox Proportional Hazard ◽  
Underlying Mechanisms ◽  
Cox Proportional Hazard Regression

370 Background: Somatic mutations of ATM are frequently found in UC and have been associated with a better response to cisplatin-based neoadjuvant chemotherapy. However, we previously showed ATM mutations were associated with a short survival in UC (PMID: 29682192 ). In this study, we focused on prognostic values of mutations in ATM in tumors of patients with relapsed or advanced (TxN2-3M0-1) UC through three independent datasets. Methods: 81 UC pts who underwent FoundationOne genomic sequencing (315 cancer-related genes) were used as a discovery dataset. Results were then validated in additional 91 pts with UC who received FoundationOne test (collected separately) and 129 relapsed/advanced UC patients selected from 412 TCGA bladder cohort. Fisher Exact test was used to determine difference of ATM mutation rates. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. Results: The median ages of the 3 cohorts were 65 (44–84), 65 (21–91) and 67 (45–-90). The majority of pts were Caucasians (86.4%, 75.8% and 81.4%) and ever smokers (77.8%, 67% and 76.7%). ATM mutations were present in 14.8% (12/81), 11% (10/91) and 6.2% (8/129) of the three cohorts (Fisher Exact, p = 0.118). In all three groups of pts, ATM mutations consistently correlated with a significantly shorter OS (Discovery: HR = 2.25, 95% CI, 1.03–4.89, p = 0.041; Validation 1: HR = 3.15, 95% CI, 1.17–8.44, p = 0.023; and Validation 2: HR = 2.17, 95% CI, 0.99–4.75, p = 0.051). In 144 pts treated with cisplatin or carboplatin pooled from the three cohorts, ATM mutations correlated with a non-significantly higher objective response rate (OR = 1.54, 95% CI 0.44–5.35, p = 0.5), but were still associated with a poorer survival (HR = 1.95, 95% CI 1.00–3.83, p = 0.05). Conclusions: These results suggest that ATM mutations may be considered as a negative prognostic biomarker in relapsed/advanced UC pts. Further studies are required to determine the underlying mechanisms.

Intrauterine testosterone exposure and depression risk in opposite-sex and same-sex twins, a Danish register study

2021 ◽  
pp. 1-6
Author(s):  
M. Vinberg ◽  
M. K. Wium-Andersen ◽  
I. K. Wium-Andersen ◽  
M. B. Jørgensen ◽  
K. Christensen ◽  
...  
Keyword(s):  
Significant Risk ◽  
Proportional Hazard ◽  
Same Sex ◽  
Cox Proportional Hazard ◽  
Depression Risk ◽  
Prevalence Of Depression ◽  
Opposite Sex ◽  
Cox Proportional Hazard Regression

Abstract Background Males have a lower prevalence of depression than females and testosterone may be a contributing factor. A comparison of opposite-sex and same-sex twins can be used indirectly to establish the role of prenatal testosterone exposure and the risk of depression. We therefore aimed to explore differences in depression risk using opposite-sex and same-sex twins. Methods We included 126 087 opposite-sex and same-sex twins from the Danish Twin Registry followed in nationwide Danish registers. We compared sex-specific incidences of depression diagnosis and prescriptions of antidepressants between opposite-sex and same-sex twins using Cox proportional hazard regression. Results During follow-up, 2664 (2.1%) twins were diagnosed with depression and 19 514 (15.5%) twins had purchased at least one prescription of antidepressants. First, in male twins, we found that the opposite-sex male twins had the same risk of depression compared to the same-sex male twins {hazard ratio (HR) = 1.01 [95% confidence interval (CI) 0.88–1.17)]}. Revealing the risk of use of antidepressants, the opposite-sex male twins had a slightly higher risk of 4% (HR = 1.04 (95% CI 1.00–1.11)) compared with the same-sex male twins. Second, in the female opposite-sex twins, we revealed a slightly higher, however, not statistically significant risk of depression (HR = 1.08 (95% CI 0.97–1.29)) or purchase of antidepressants (HR = 1.01 (95% CI 0.96–1.05)) when compared to the same-sex female twins. Conclusions We found limited support for the hypothesis that prenatal exposure to testosterone was associated with the risk of depression later in life.

scholarly journals The association between dietary antioxidants intakes and the risk of cardiovascular disease: Tehran Lipid and Glucose Study

2020 ◽  
Author(s):  
Parvin Mirmiran ◽  
Zohreh Esfandiar ◽  
Firoozeh Hosseini-Esfahani ◽  
somayeh Hosseinpour-Niazi ◽  
Fereidoun Azizi
Keyword(s):  
Cardiovascular Disease ◽  
Vitamin E ◽  
Protective Role ◽  
Inverse Association ◽  
Dietary Intakes ◽  
Daily Consumption ◽  
Cox Proportional Hazard ◽  
Cox Proportional Hazard Regression

Abstract Aim: This study aimed at investigating the association between daily consumption of dietary vitamins A, E, and C, and zinc and the incidence of cardiovascular disease (CVD). Methods: Eligible adults (n=5102) were selected from the participants of the Tehran Lipid and Glucose Study with an average follow-up of 5.3 years. Dietary intakes were assessed using a valid and reliable semi-quantitative food frequency questionnaire. Anthropometrics and biochemical variables were evaluated at baseline and follow-up examinations. Multivariate Cox proportional hazard regression models were used to estimate the development of CVD associated with total intakes of vitamins A, E, and C, and zinc. Results: This study was conducted on 2,253 men and 2,849 women aged 47.0±11.6 and 45.6±10.5 years, respectively. The main sources of dietary vitamins A, E, and C and zinc were fruits, vegetables, and legumes. Risk of CVD decreased from quartile 1 to quartile 4 for vitamin E intake (HR (95% CI): 1.00, 0.91, 0.77, and 0.57; P trend =0.03). The association between risk of CVD and the quartiles of vitamins A and C and zinc intake was not significant. Conclusion : Our study suggested an inverse association between vitamin E intake and the risk of CVD. The results emphasized a potential protective role of its dietary sources in the prevention of CVD.

scholarly journals Low serum parathyroid hormone is a risk factor for peritonitis episodes in incident peritoneal dialysis patients: a retrospective study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Yuqi Yang ◽  
Jingjing Da ◽  
Yi Jiang ◽  
Jing Yuan ◽  
Yan Zha
Keyword(s):  
Risk Factor ◽  
Peritoneal Dialysis ◽  
Parathyroid Hormone ◽  
Proportional Hazard ◽  
Serum Parathyroid Hormone ◽  
Cox Proportional Hazard ◽  
Cox Proportional Hazard Regression ◽  
Gram Negative Organisms ◽  
Serum Pth

Abstract Background Serum parathyroid hormone (PTH) levels have been reported to be associated with infectious mortality in peritoneal dialysis (PD) patients. Peritonitis is the most common and fatal infectious complication, resulting in technique failure, hospital admission and mortality. Whether PTH is associated with peritonitis episodes remains unclear. Methods We examined the association of PTH levels and peritonitis incidence in a 7-year cohort of 270 incident PD patients who were maintained on dialysis between January 2012 and December 2018 using Cox proportional hazard regression analyses. Patients were categorized into three groups by serum PTH levels as follows: low-PTH group, PTH < 150 pg/mL; middle-PTH group, PTH 150-300 pg/mL; high-PTH group, PTH > 300 pg/mL. Results During a median follow-up of 29.5 (interquartile range 16–49) months, the incidence rate of peritonitis was 0.10 episodes per patient-year. Gram-positive organisms were the most common causative microorganisms (36.2%), and higher percentage of Gram-negative organisms was noted in patients with low PTH levels. Low PTH levels were associated with older age, higher eGFR, higher hemoglobin, calcium levels and lower phosphate, alkaline phosphatase levels. After multivariate adjustment, lower PTH levels were identified as an independent risk factor for peritonitis episodes [hazard ratio 1.643, 95% confidence interval 1.014–2.663, P = 0.044]. Conclusions Low PTH levels are independently associated with peritonitis in incident PD patients.

scholarly journals 363 Vactosertib and durvalumab as second or later line treatment for PD-L1 positive non-small cell lung cancer: interim result

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A388-A388
Author(s):  
Byoung Chul Cho ◽  
Ki Hyeong Lee ◽  
Ji-Youn Han ◽  
Byoung Yong Shim ◽  
Hye Ryun Kim ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Objective Response Rate ◽  
Immune Checkpoint Inhibitors ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Platinum Based Chemotherapy ◽  
Number Of Patients ◽  
Anti Tumor Activity

BackgroundTargeting transforming growth factor-β (TGF-β) is reported to augment the efficacy of immune checkpoint inhibitors (ICIs) through either enhanced anti-tumor immunity or the correction of tumor microenvironment (TME). Therefore, the combination of vactosertib, a highly selective TGF-β RI kinase inhibitor, and durvalumab is anticipated to improve anti-tumor activity of the ICI. A phase 1b/2a study was conducted to evaluate the combination of vactosertib and durvalumab in patients with advanced NSCLC who progressed after platinum-based chemotherapy.MethodsPatients were treated with vactosertib at a dose of 200 mg twice daily (five days on and two days off) and durvalumab at a dose of 1500 mg every four weeks. Eligible patients were ≥19 years old with good performance status (ECOG 0–1) and have no prior exposure to immune checkpoint inhibitors or other TGF- β R1 kinase inhibitors. The objectives of this analysis were to evaluate the safety, antitumor activity including objective response rate (ORR), duration of response (DOR), and time to response (TTR) as well as circulating pharmacodynamic biomarkers related to TGF-β signaling. Response was assessed per RECIST (v1.1).ResultsBy August 4 2020, twenty-six PD-L1 positive (SP263 assay) patients were analyzed. Median age was 61.5 years (range 48–83), 69.2% were male, median number of previous lines of chemotherapy was 1 (range 1–4), and all patients were PD-L1 positive (15 patients with PD-L1≥25% and 11 patients with PD-L1 1–24%). The most frequently reported treatment-related adverse events (TRAE) were itching (38.5%) and skin rash (34.6%), but no Gr≥3 itching and rash were observed. Each case of the following was reported as Grade 3 TRAEs: adrenal insufficiency, anemia, and pneumonitis; Grade 4 TRAE, CPK increase, was observed in one patient. Objective response rate was 30.8% and 40.0% in patients with PD-L1≥1% and ≥25% respectively. Circulating PAI-1 and CTGF evaluated in 15 patients decreased significantly on Cycle 1 day 5. Ongoing biomarker results will be presented.ConclusionsThe combination of vactosertib and durvalumab has demonstrated a manageable safety profile and encouraging anti-tumor activity as a potential therapeutic strategy in patients with advanced NSCLC. The efficacy outcomes of this combination in a larger number of patients with advanced NSCLC will be followed.Trial RegistrationNCT03732274Ethics ApprovalThe study was approved by Ethics Board of Severance Hospital (4-2018-0892), National Cancer Center (NCC2019-0057), St. Vincent’s Hospital (VC19MDDF0205), and Chungbuk National University Hospital (2019-08-015).

scholarly journals Association of cervical carcinogenesis risk with HPV16 E6 and E7 variants in the Taizhou area, China

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mei-Zhen Dai ◽  
Yi Qiu ◽  
Xing-Hong Di ◽  
Wei-Wu Shi ◽  
Hui-Hui Xu
Keyword(s):  
Cervical Cancer ◽  
Cervical Carcinogenesis ◽  
Chi Square ◽  
Major Health Problem ◽  
Hpv16 E6 ◽  
Exact Test ◽  
Chi Square Test ◽  
E6 And E7

Abstract Background Human papillomavirus (HPV) type 16 accounts for a larger share of cervical cancer and has been a major health problem worldwide for decades. The progression of initial infection to cervical cancer has been linked to viral sequence properties; however, the role of HPV16 variants in the risk of cervical carcinogenesis, especially with longitudinal follow-up, is not fully understood in China. Methods We aimed to investigate the genetic variability of HPV16 E6 and E7 oncogenes in isolates from cervical exfoliated cells. Between December 2012 and December 2014, a total of 310 single HPV16-positive samples were selected from women living in the Taizhou area, China. Sequences of all E6 and E7 oncogenes were analysed by PCR-sequencing assay. Detailed sequence comparison, genetic heterogeneity analyses and maximum-likelihood phylogenetic tree construction were performed with BioEdit Sequence Alignment Editor and MEGA X software. Data for cytology tests and histological diagnoses were obtained from our Taizhou Area Study with longitudinal follow-up for at least 5 years. The relationship between HPV16 variants and cervical carcinogenesis risk was analysed by the chi-square test or Fisher’s exact test. Results In this study, we obtained 64 distinct variation patterns with the accession GenBank numbers MT681266-MT681329. Phylogenetic analysis revealed that 98.3% of HPV16 variants belong to lineage A, in which the A4 (Asian) sublineage was dominant (64.8%), followed by A2 (12.1%), A1 (11.4%), and A3 (10.0%). The A4 (Asian) sublineage had a higher risk of CIN2+ than the A1–3 (European) sublineages (OR = 2.69, 95% CI = 1.04–6.97, P < 0.05). Furthermore, nucleotide variation in HPV16 E6 T178G is associated with the development of cervical cancer. Conclusion These data could provide novel insights into the role of HPV16 variants in cervical carcinogenesis risk in China.

Manual occupations with high all-cause mortality: The contribution of socioeconomic and occupational characteristics

2020 ◽  
pp. 140349482096065
Author(s):  
Hanna Rinne ◽  
Mikko Laaksonen
Keyword(s):  
High Mortality ◽  
Excess Mortality ◽  
Proportional Hazard ◽  
Individual Level ◽  
Cox Proportional Hazard ◽  
Occupational Characteristics ◽  
Study Population ◽  
Cox Proportional Hazard Regression ◽  
Year 2000

Aims: Most high mortality-risk occupations are manual occupations. We examined to what extent high mortality of such occupations could be explained by education, income, unemployment or industry and whether there were differences in these effects among different manual occupations. Methods: We used longitudinal individual-level register-based data, the study population consisting of employees aged 30–64 at the end of the year 2000 with the follow-up period 2001–2015. We used Cox proportional hazard regression models in 31 male and 11 female occupations with high mortality. Results: There were considerable differences between manual occupations in how much adjusting for education, income, unemployment and industry explained the excess mortality. The variation was especially large among men: controlling for these variables explained over 50% of the excess mortality in 23 occupations. However, in some occupations the excess mortality even increased in relation to unadjusted mortality. Among women, these variables explained a varying proportion of the excess mortality in every occupation. After adjustment of all variables, mortality was no more statistically significantly higher than average in 14 occupations among men and 2 occupations among women. Conclusions: The high mortality in manual occupations was mainly explained by education, income, unemployment and industry. However, the degree of explanation varied widely between occupations, and considerable variation in mortality existed between manual occupations after controlling for these variables. More research is needed on other determinants of mortality in specific high-risk occupations.

Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma (TITAN-TCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 446-446
Author(s):  
Marc-Oliver Grimm ◽  
Bernd Schmitz-Dräger ◽  
Uwe Zimmermann ◽  
Barbara Grün ◽  
Gustavo Bruno Baretton ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Transitional Cell ◽  
Added Value ◽  
Phase Iii ◽  
First Line ◽  
Third Line

446 Background: Several PD-1 immune-checkpoint inhibitors including Nivolumab (Nivo) are approved in urothelial cancer. Recently, in the front line setting, improved activity of combined PD-L1 and CTLA4 immune-checkpoint inhibition has been reported and a phase III trial with Nivolumab + Ipilimumab (Nivo+Ipi) is ongoing. Here we report a response-based tailored approach starting treatment with Nivo monotherapy using Nivo+Ipi as immunotherapeutic “boost”. Methods: Between July 2017 and April 2019 86 patients were enrolled and treated according to protocol version 3 (cohort 1). Patients started with Nivo 240 mg Q2W induction. After 4 dosings and tumor assessment at week 8 (i) responders (PR/CR) to Nivo monotherapy continued with maintenance while (ii) patients with stable (SD) or progressive disease (PD) received 2 cycles Nivo3+Ipi1 followed by another 2 cycles Nivo1+Ipi3 if not responding. Median follow-up is 8.7 months. The primary endpoint is confirmed investigator-assessed objective response rate (ORR) per RECIST1.1. Secondary endpoints include activity of Nivo monotherapy at week 8, remission rate with Nivo+Ipi “boosts”, safety, overall survival and quality of life. Results: Of the patients 42, 39 and 5 were first, second and third line, respectively. Median age was 67 years (range 45-84), 61 patients (71 %) were male and 25 female. ORR with Nivo monotherapy at first assessment (week 8) was 29 % and 23 % in first and second/third line, respectively. Of the patients 41 received Nivo+Ipi “boosts” after week 8 while 12 received later “boosts”. Best overall response (BOR) rate with Nivo induction ± Nivo+Ipi “boosts” was 48 % and 27 % in first and second/third line, respectively. In first line 7/17 (41 %) patients receiving Nivo+Ipi after week 8 had an improved response compared to 2/24 (8.3 %) in second/third line. Of the patients who continued with Nivo maintenance after week 8 and received later “boosts” 2/12 (17 %) had a PR and 2/12 (17 %) improved to SD. Treatment-related AEs will be presented. Conclusions: TITAN–TCC explores a response-driven use of Nivo+Ipi as an immunotherapeutic “boost”. In first line, this significantly improved ORR compared to the expected response rate of Nivo monotherapy, providing further evidence to the added value of Ipi in combination with Nivo. Further follow-up is ongoing to characterize duration and depth of response. Clinical trial information: NCT03219775 . Research Sponsor: Bristol-Myers Squibb[Table: see text]

scholarly journals Rapid Point-Of-Care Serology and Clinical History Assessment Increase Protection Provided by RT-PCR Screening: A Pilot Study Involving Three Nursing Homes in Brescia, a Hotspot of Lombardy

2021 ◽  
Vol 9 ◽  
Author(s):  
Antonella Savio ◽  
Stefano Calza ◽  
Gianbattista Guerrini ◽  
Valentina Romano ◽  
Eleonora Marchina
Keyword(s):  
Nursing Homes ◽  
Close Contact ◽  
Fisher Exact Test ◽  
Rt Pcr ◽  
Positive Serology ◽  
Serological Screening ◽  
Pcr Screening ◽  
Exact Test ◽  
Viral Spread

Background: COVID-19 outbursts have been registered worldwide within care homes with asymptomatic transmission combined with shortage/inaccuracy of diagnostic tests undermining the efforts at containment of the disease. Nursing facilities in Lombardy (Italy) were left with no, or limited, access to testing for 8 weeks after the outbreak of COVID-19.Methods: This study includes 246 residents and 286 workers of three different nursing homes in Brescia-Lombardy. Clinical questionnaires and rapid serology tests were devised to integrate the data of the first available RT-PCR screening. Follow-up serology after 60-days was performed on 67 of 86 workers with positive serology or clinically suspicious.Findings: Thirty-seven residents and 18 workers had previous positive RT-PCR. Thorough screening disclosed two additional RT-PCR-positive workers. Serology screening revealed antibodies in 59 residents and 48 workers, including 32/37 residents and all workers previously positive at RT-PCR. Follow up serology disclosed antibodies in two additional workers with recent symptoms at the time of screening. The professionals in close contact with residents had more infections (47/226–20.79% vs. 1/60–1.66%; p = 0.00013 Fisher exact-test). A suspicious clinical score was present in 44/64 residents and in 41/50 workers who tested positive with either method with totally asymptomatic disease more frequent among residents 28.1 vs. 10.0% (p = 0.019 Fisher exact-test).Interpretation: Based on the available RT-PCR ± results at the time of symptoms/contacts, our integrated clinical and serological screening demonstrated sensitivity 89% and specificity 87%. This multimodal assessment proved extremely useful in understanding the viral spread in nursing homes, in defining its stage and in implementing protective measures. Rapid serology tests demonstrated efficient and particularly suited for older people less able to move/cooperate.

scholarly journals Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study

2020 ◽  
Vol 38 (24) ◽  
pp. 2753-2761 ◽  
Author(s):  
Caicun Zhou ◽  
Xingya Li ◽  
Qiming Wang ◽  
Guanghui Gao ◽  
Yiping Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Unmet Need ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Grade 3

PURPOSE Targeted therapies against non–small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-mutant advanced NSCLC in a prospective, multicenter, open-label, single-arm, phase II study. PATIENTS AND METHODS Patients with stage IIIB or IV HER2-mutant lung adenocarcinoma who were previously treated with platinum-based chemotherapy were enrolled to receive pyrotinib at a dose of 400 mg/d for 21-day cycles. The primary end point was objective response rate per independent review committee (IRC). RESULTS Between October 20, 2016, and December 10, 2018, 60 patients received pyrotinib monotherapy. At baseline, 58 (96.7%) were stage IV, and 25 (41.7%) received at least 2 lines of prior chemotherapy. As of data cutoff on June 20, 2019, IRC-assessed objective response rate was 30.0% (95% CI, 18.8% to 43.2%). All subgroups of patients with different HER2 mutation types showed a favorable objective response rate. The objective response rates were similar between patients with and without brain metastases (25.0% v 31.3%). The median duration of response was 6.9 months (95% CI, 4.9 to 11.1 months). The median progression-free survival was 6.9 months (95% CI, 5.5 to 8.3 months) per IRC. The median overall survival was 14.4 months (95% CI, 12.3 to 21.3 months). Treatment-related adverse events of grade 3 or 4 occurred in 28.3% of patients, with the most common being diarrhea (20.0%; all grade 3). No treatment-related deaths were reported. CONCLUSION Pyrotinib showed promising antitumor activity and an acceptable safety profile in chemotherapy-treated patients with HER2-mutant NSCLC.

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