Salvage chemotherapy after immune checkpoint inhibitor (ICI) treatment has been reported to increase the antitumor effect. There are also some reports that activation of vascular endothelial growth ...factor (VEGF) / its receptor (VEGFR) signal is one of the ICI resistant mechanism, and that combination therapy of VEGF / VEGFR inhibitor and ICI had synergistic effect. In ICI pretreated patients, docetaxel and ramucirumab combination therapy (DOC+RAM) may be more effective. In order to verify this hypothesis, the retrospective observation study was conducted.
From June 2013 to July 2018, in 39 patients with advanced / recurrent non-small cell lung cancer who underwent DOC+RAM therapy at our hospital the efficacy and safety were analysed based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history.
Of the 39 patients treated with DOC+RAM, 18 (pre-ICI+: 46%) patients had been pretreated with ICI. The characteristics (pre-ICI+/ pre-ICI-) were as follows; median age was 67/65 years, median treatment line was 3/3, ECOG PS:0,1 was 94%/86%, 83%/48% were male, 72%/95% had adenocarcinoma, and 89%/67% were smokers, PD-L1status ≧50% was 6%/5%, 11%/38% had EGFR mutation. The ORRs for DOC+RAM in pre-ICI+ and pre-ICI- were 38.9% vs. 19.0%, respectively (p=0.29). Median progression free survival was 5.7 vs. 2.3 months (hazard ratio (HR), 0.36; 95% confidential interval CI, 0.16-0.80). Median overall survival was 13.8 vs. 10.5 months (HR, 0.41; 95% CI, 0.16-1.04). Because of adverse events, nine patients (50%) in pre-ICI+ group and two patients (9.5%) in pre-ICI- group discontinued DOC+RAM therapy. Adverse events such as fever (50%/38%), myalgia (39%/9.5%), arthritis (33%/4.8%), pleural effusion (22%/4.8%) and pneumonitis (17%/4.8%) tended to be more frequent in pre-ICI+ group. There were no grade 5 AEs.
In this study, statistically significant prolongation of PFS, the tendency of tumor regression improvement and OS prolongation achieved by DOC + RAM, and the concern of increased toxicity were shown in pre-ICI+ patients.
Daijiro Harada.
Has not received any funding.
D. Harada: Honoraria (self), Research grant / Funding (institution): AstraZeneca K.K.; Research grant / Funding (institution): Novartis International AG; Research grant / Funding (institution): Kissei Pharmaceutical Co., Ltd; Research grant / Funding (institution): Takeda Pharmaceutical Company Limited.; Honoraria (self): Ono Pharmaceutical Co., Ltd.; Honoraria (self): Bristol-Myers Squibb Company; Honoraria (self): Kyowa Hakko Kirin Co., Ltd.; Honoraria (self): Eli Lilly and Company Nyse: LLY; Honoraria (self): MSD K.K. ; Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self): Nippon Boehringer Ingelheim Co ., Ltd. T. Kozuki: Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Research grant / Funding (institution): AstraZeneca K.K; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan K.K.; Honoraria (self): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Research grant / Funding (institution): Bristol-Myers K.K; Honoraria (self): Ono Pharmaceutical Co., Ltd.; Honoraria (self): MSD K.K; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): Kyowa Hakko Kirin Co., Ltd; Honoraria (self): Nippon Beohringer Ingelheim Co., Ltd.; Honoraria (self): Nippon-Kayaku Co.; Research grant / Funding (institution): Merck Serono. N. Nogami: Honoraria (self): Astellas Pharma; Honoraria (self): AstraZeneca; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Eli Lilly; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Pfizer. All other authors have declared no conflicts of interest.
The objective of this study was to select, for a phase III trial, the more promising of weekly-dose intensive chemotherapy or amrubicin plus cisplatin as subsequent therapy after induction ...chemoradiotherapy for previously untreated limited-disease small cell lung cancer (LD-SCLC).
Patients (pts) aged 20-70 years with untreated clinical stage II/III LD-SCLC were eligible. After one cycle of accelerated hyperfractionation thoracic radiotherapy with etoposide plus cisplatin, pts without progression were randomized to either 3 cycles of cisplatin 25mg/m2 (days 1, 8), doxorubicin 40mg/m2 (day 1), etoposide 80mg/m2 (days 1-3), and vincristine 1mg/m2 (day 8) every 2 weeks (CODE) or amrubicin 40mg/m2 (days 1-3) and cisplatin 60mg/m2 (day 1) every 3 weeks (AP). The primary endpoint was the 1-year progression-free survival (PFS) after randomization. The sample size was 72 to select the arm yielding a better 1-year PFS (55% vs. 65%) with a correct selection probability of 80%.
From March 2011 to February 2014, 85 pts were registered. After the induction chemoradiotherapy, 75 pts were randomized to CODE (n=39) or AP (n=36). The one-year PFS (95% CI) was 41.0% (25.7-55.8) in the CODE arm and 54.3% (36.6-69.0) in the AP arm. Grade 4 neutropenia and grade 3 febrile neutropenia occurred in 47% and 16% in the CODE arm and 78% and 42% in the AP arm, respectively. In patients aged 61 years or older, they were noted in 48% and 19% in the CODE arm and 88% and 48% in the AP arm, respectively. In women, they were noted in 20% and none in the CODE arm and 86% and 71% in the AP arm, respectively. Grade 3 pneumonitis was noted in one patient each in both arms. Secondary malignancies developed in 4 pts in the CODE arm and 2 pts in the AP arm. The 5-year survival (95% CI) in all 85 pts was 43.2% (32.5-53.4). The 5-year survival in all pts after randomization for CODE and AP arms were 35.3% (20.6-50.2) and 45.2% (28.3-60.7), respectively. The HR (95% CI) of AP arms to CODE arm was 0.70 (0.39-1.25).
An overall survival profile of AP was relatively good when compared to that of the historical control, but hematological toxicity was severe in AP, especially in older and female patients.
JCOG.
JCOG.
All authors have declared no conflicts of interest.
Human epidermal growth factor 2 (HER2) is a potential driver oncogene. Although HER2-targeted precision therapy has been tested in non-small cell lung cancer (NSCLC), the demographic characteristics ...of HER2-positive NSCLC have not been systematically defined.
Patients with pathologically confirmed stage IIIB/IV or recurrent NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, were prospectively registered. HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays were performed to screen patients. HER2 mutations were identified by using direct gene sequencing. The aim of this study was to clarify the frequency, characteristics, and outcome of HER2-positive NSCLC. HER2 was defined as positive if the tumor harbored IHC3+, IHC2+/FISH+, or exon 20 insertion mutations.
Of the 1,126 tumors screened, 34 (3.0%) were IHC3+, and 34 (3.0%) were IHC2+/FISH+. Among the 724 epidermal growth factor receptor wild-type tumors, 21 (2.9%) were HER2-mutant tumors, including A775-G776insYVMA (n = 15). Interestingly, the IHC3+ tumors and mutant tumors were entirely exclusive. Female patients had HER2-mutant tumors more frequently, whereas both IHC3+ and IHC2+/FISH+ tumors were detected more often in male subjects and smokers. Patients with an HER2-aberrant tumor had a significantly worse prognosis than those with epidermal growth factor receptor-positive and anaplastic lymphoma kinase-positive tumors, possibly due to the low proportion that received HER2-targeted therapies (n = 15 26%) and low response rates of 0% and 14% in patients with HER2-overexpressing and HER2-mutant tumors, respectively.
This prospective large-scale cohort study is the first to show comprehensively the frequency and clinical demographic characteristics of those with HER2-positive advanced lung tumors in detail, providing critical historical data for future drug development against HER2-positive NSCLC. Future treatment strategies would be developed stratified according to the types of HER2 aberrations.
UMIN Registration No. 000017003; URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000019691
PDF
