Background

Post-operative platinum-based chemotherapy is the standard of care for resected NSCLC with nodal involvement. Expression of genes involved in DNA repair may have a prognostic role for the outcome. BRCA1 plays an important role in DNA repair pathways and could have a prognostic impact in this setting. The SCAT trial results found that for low BRCA1 levels subgroup Cis-Gem was superior to Cis-Doc and in high BRCA1 subgroup docetaxel single agent without platinum achieved similar survival to Cis-Doc. Risk of recurrence analysis according BRCA-1 levels has been performed.

Methods

From Jun/2007 to May/2013 591 patients were screened and 500 were included, 108 in the control arm treated with Cis-Docetaxel and 392 in the experimental arms treated with Cis-Gem, Cis-Doc or docetaxel alone according to terciles of BRCA1 expression level. With a cut-off September 30th 2018 and a median follow-up of 60 months, recurrence patterns were analysed for the whole group according BRCA1 levels in tumor tissue and comparison were made for risk of recurrence, single/multiple recurrence, thoracic/extrathoracic and metastatic sites (liver, bone, brain).

Results

Cumulative recurrence was evaluable in 232/456 patients (50.8%), 182/354 patients treated in the experimental arm and in 50/102 patients treated in the control arm (RR 1.04; 0.83-1.30) (p = 0.672). The majority of recurrences 159/232 (68.5%) were single site intrathoracic recurrences in 121/232 (52%) while 111/232 were extrathoracic (47.8%). Overall recurrence was 56.5% (113/200 p) for low tercile BRCA1 vs 48.8% (63/129) for intermediate tercile vs 44% (56/127) for high tercile (p = 0.025). No differences were seen between tercile groups for single site (p = 0.35), multiple site (p = 0.26), intrathoracic (p = 0.36), or extrathoracic (p = 0.38). More frequent distant metastatic sites were: bone (42 patients), brain (38 patients) and liver (11 patients). RIsk reduction was seen for brain metastases in patients with higher tercile BRCA1 (p = 0.003).

Conclusions

For NSCLC resected patients with lymph node involvement risk of recurrence remains high with a cumulative rate > 50%. Relative risk of recurrence was lower for tumors with higher BRCA1 levels. Distant metastases were seen in 47.8% of patients. Brain metastases risk was significant lower for patients with low BRCA1 expression. BRCA1 levels acts as a prognostic factor in early stages NSCLC.

Clinical trial identification

EudraCT: 2007-000067-15; NCT 00478699.

Legal entity responsible for the study

Spanish Lung Cancer Group - Grupo Español Cáncer de Pulmón.

Funding

Sanofi Aventis.

Disclosure

All authors have declared no conflicts of interest.

Background

The VNR/Cis chemotherapy doublet has been evaluated in prior positive adjuvant trials in patients with completely resected Ns-NSCLC, whereas no phase III study has so far evaluated PEM/Cis in this population. And there are few data regarding outcomes based on EGFR mutation (EGFRm) status in adjuvant chemotherapies.

Methods

Patients with completely resected Ns-NSCLC were randomized in a 1:1 ratio to receive either PEM (500 mg/m², day 1)/Cis (75 mg/m², day 1) or VNR (25 mg/m², days 1 and 8)/Cis (80 mg/m², day 1), and stratified according to sex, age, pathologic stage, EGFRm status and institution. The primary endpoint was recurrence-free survival (RFS), and, the planned sample size was 800 patients in total (Trial Identifier, UMIN000006737).

Results

Between March 2012 and August 2016, 804 patients were randomized. Of 784 for the efficacy analysis (389 in PEM/Cis and 395 in VNR/Cis), median age was 65/65 years; stage IIIA 52.2%/52.4%; adenocarcinoma, 95.9%/95.9%; and EGFR mutation, 24.1%/24.9%. With a median follow-up of 45.2 months (mo), median RFS was 38.9mo in PEM/Cis and 37.3mo in VNR/Cis with a hazard ratio (HR) of 0.98 (95% CI, 0.81--1.20; log-rank test, P = 0.948), whereas HRs in patients with or without EGFRm were 1.38 (95% CI, 0.95--1.99) and 0.87 (95% CI, 0.69--1.09), respectively (Interaction, P = 0.046). As for patients without EGFRm, median RFS was 65.2mo in PEM/Cis and 39.9mo in VNR/Cis. The overall survival rate at 3 years was 83.5% versus 87.2% with a HR of 0.98 (95% CI, 0.71 --1.35). Rates of treatment completion were 87.9% (PEM/Cis) and 72.7% (VNR/Cis), respectively (P < 0.001). Incidences of grade 3 or 4 febrile neutropenia (11.6/0.3%, P < 0.001), neutropenia (81.1/22.8%, P < 0.001), and anemia (9.3/2.8%, P < 0.001); any grade alopecia (30.1/12.8%, P < 0.001).

Conclusions

Although this phase III study did not meet the primary endpoint, PEM/CDDP had a similar efficacy to VNR/CDDP with a better tolerability as postoperative adjuvant chemotherapy for Ns-NSCLC patients. A significant interaction for RFS was found between treatment and EGFR mutation status. In patients without EGFR mutation, PEM/Cis seems to be a preferable regimen as the adjuvant chemotherapy.

Clinical trial identification

UMIN000006737.

Legal entity responsible for the study

The authors.

Funding

Health and Labor Sciences Research Grants, The Japan Agency of Medical Research and Development (AMED).

Disclosure

M. Tsuboi: Honoraria (self): AstraZeneca KK; Honoraria (self): Johnson & Johnson Japan; Honoraria (self): MSD; Honoraria (self): Chugai Pharmaceutical Co., Ltd.; Honoraria (self): Taiho Pharma; Honoraria (self): Eli Lilly Japan; Honoraria (self): Boehringer Ingelheim Japan; Honoraria (self): Ono Pharmaceutical Co., Ltd; Honoraria (self): Bristol-Myers Squibb KK; Honoraria (self): Daiichi-Sankyo; Honoraria (self): Covidien Japan; Honoraria (self): Teijin Pharma; Research grant / Funding (institution): Boehringer Ingelheim Japan. All other authors have declared no conflicts of interest.

Background

Results of the ADJUVANT trial established adjuvant gefitinib as an optimal choice for EGFR-mutated stage II-IIIA NSCLC patients. However, clinical benefit varied among patients. To investigate this heterogeneity, we performed comprehensive tumor genomic analyses on these patients. Here, we report the predictive MEDUSA model (Multiple-biomarker Evaluation to Determine the Utilization of Specific Adjuvant therapy) that can guide clinical decision of adjuvant therapy.

Methods

171 baseline specimens from ADJUVANT (n = 95, gefitinib arm; n = 76, vinorelbine plus cisplatin [VP] arm) underwent targeted sequencing (Geneseeq 422-gene panel). Predictive biomarkers were identified by Cox regression with gene-by-treatment interactions, and a multi-gene composite score was developed to compare the benefits of these treatments.

Results

EGFR mutations were confirmed in all cases. TP53, NKX2-1, CDK4, MYC and RB1 were identified as predictive biomarkers. Specifically, gefitinib-favoring biomarkers include TP53 exon4/5 mutations (interaction HR [iHR] 0.33, 95% CI 0.12-0.93, p = 0.035), and copy number gain of NKX2-1 (iHR 0.26, 95% CI 0.098-0.68, p = 0.006), CDK4 (iHR 0.14, 95% CI 0.025-0.77, p = 0.024) and MYC (iHR 0.10, 95% CI 0.011-0.98, p = 0.048). RB1 alterations strongly favored VP (iHR 4.07, 95% CI 1.56-10.53, p = 0.004). The MEDUSA model was developed based on the above, and stratified patients into 3 groups: Strong Gefitinib-favoring (SG, n = 60), Moderate Gefitinib-favoring (MG, n = 87), and VP-favoring (VP, n = 24). Notably, the SG group demonstrated significant OS benefit with adjuvant gefitinib as well: HR of OS was 0.44 (95% CI 0.2-0.98, p = 0.04).Table: 1441PD

Conclusions

Incorporating alterations in TP53, NKX2-1, CDK4, MYC and RB1, MEDUSA score could guide personalized adjuvant therapy for resected stage II-IIIA EGFR-mutant NSCLC patients.

Clinical trial identification

NCT01405079; Release at July 29. 2011.

Legal entity responsible for the study

Chinese Thoracic Oncology Group (CTONG).

Funding

AstraZeneca Roche.

Disclosure

Y. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): MSD; Honoraria (self): BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim. H. Bao: Full / Part-time employment: Geneseeq Technology Inc. Toronto. Y. Chen: Full / Part-time employment: Geneseeq Technology Inc. Nanjing. Y.W. Shao: Full / Part-time employment: Geneseeq Technology Inc. Nanjing. All other authors have declared no conflicts of interest.

Background

NICOLAS is a single-arm phase II trial in stage III NSCLC. The safety analysis has earlier provided evidence that nivolumab administration concurrently to chemo-radiotherapy (CRT) is safe and tolerable, with respect to the occurrence of clinically relevant (grade > =3) pneumonitis. According to a hierarchical design, efficacy evaluation was planned provided the safety conclusion regarding pneumonitis was reached.

Methods

Primary efficacy endpoint is the 1-year (1y) progression-free survival (PFS) rate. Patients (pts) received 3 cycles of platinum-based chemotherapy and concurrent RT (66Gy/33fractions). Nivolumab started concurrently with CRT (360mg, Q3W) and subsequently continued as monotherapy consolidation (480mg, Q4W). The aim was a 1y PFS rate improvement of at least 15%, from 45% to 60%. A sample size of 74 evaluable pts provides power 83%, for testing this efficacy hypothesis, using an exact binomial test at 1-sided alpha 5%.

Results

PFS is evaluated in 79 pts assigned to concurrent treatment. Two pts died before starting treatment. Up to 20 March 2019, the median follow-up is 16.4 months (m) (Interquartile Range: 11-20 m). The majority of pts are male (67%), former smokers (68%), of median age 62 years. The ECOG performance status at enrolment, is PS 0/1 for 48%/52% of pts, while 64% present with stage IIIb. The Kaplan-Meier estimate of the 1y PFS rate is 54% (95% CI: 41-65%), with median PFS 12.4 m (95% CI: 9, Not estimable). Currently, 62 pts have either been followed beyond 1y or had a PFS event up to that timepoint. The 1y overall survival (OS) rate is 79% (95% CI: 68-87%) while median OS is not reached yet. The most frequent adverse events (AEs) were anaemia, fatigue and pneumonitis. No unexpected AEs or increased toxicities were observed.

Conclusions

The 1y-PFS estimate will be final when all pts have reached 1y after enrolment, in August 2019. A promising result on the PFS rate, coupled with the already reported evidence that the addition of nivolumab to CRT is safe and tolerable, would further support concurrent immunotherapy and CRT in locally advanced NSCLC.

Clinical trial identification

NCT02434081.

Legal entity responsible for the study

European Thoracic Oncology Platform (ETOP).

Funding

Bristol-Myers Squibb.

Disclosure

S. Peters: Honoraria (self): AbbVie; Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Biocartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Clovis; Honoraria (self): Daiichi Sankyo; Honoraria (self): Debiopharm; Honoraria (self): Eli Lilly; Honoraria (self): Roche; Honoraria (self): Foundation Medicine; Honoraria (self): Illumina; Honoraria (self): Janssen; Honoraria (self): Merck Sharp & Dohme; Honoraria (self): Merck Serono; Honoraria (self): Merrimack; Honoraria (self): Novartis; Honoraria (self): Pharma Mar; Honoraria (self): Pfizer; Honoraria (self): Regeneron; Honoraria (self): Sanofi; Honoraria (self): Seattle Genetics; Honoraria (self): Takeda. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: AbbVie; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck KGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy: Blue print medicines; Advisory / Consultancy: Celgene; Advisory / Consultancy: Quadrant health; Advisory / Consultancy: Janssen ; Advisory / Consultancy: Medscape; Advisory / Consultancy: Touchtime. A. Tufman: Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Celgene. M. Guckenberger: Advisory / Consultancy: AstraZeneca; Research grant / Funding (self): Varian. E. Nadal: Advisory / Consultancy: BMS. M. Pless: Advisory / Consultancy: AbbVie; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy: Eisei; Advisory / Consultancy: Janssen; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Takeda. A. Martinez-Marti: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy: MSD Oncology. M. Lambrecht: Advisory / Consultancy: AstraZeneca. N. Andratschke: Honoraria (self): AstraZeneca; Research grant / Funding (self): Brainlab. R.A. Stahel: Honoraria (self): AbbVie; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self): MSD; Honoraria (self), Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self): Takeda; Research grant / Funding (self): BMS; Research grant / Funding (self): Genentech. J.F. Vansteenkiste: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Apotex. D. De Ruysscher: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Research grant / Funding (institution): Philips; Research grant / Funding (institution): Varian. All other authors have declared no conflicts of interest.

Background

Third-generation regimens with chemoradiotherapy (CRT) has been established as one of a standard treatment for patients with unresectable stage III non-small cell lung cancer (NSCLC) after first results of the phase III WJTOG0105 trial. However, the long-term survival and cumulative incidences of toxicity associated with CRT remains unclear. We report survival and late toxicities with a follow-up period of 10 years.

Methods

Eligible patients were randomly assigned to A (control), four cycles of mitomycin (8 mg/m2 on day 1)/vindesine (3 mg/m2 on days 1, 8)/cisplatin (80 mg/m2 on day 1) plus thoracic radiotherapy (TRT) 60 Gy; B, weekly irinotecan (20 mg/m2)/carboplatin (area under the plasma concentration-time curve [AUC] 2) for 6 weeks plus TRT 60 Gy, followed by two courses of irinotecan (50 mg/m2 on days1, 8)/carboplatin (AUC 5 on day1); C, weekly paclitaxel (40mg/m2)/carboplatin (AUC 2) for 6 weeks plus TRT 60 Gy, followed by two courses of paclitaxel (200mg/m2 on day1)/carboplatin (AUC 5 on day 1). Kaplan-Meier survival curves and 5- and 10-year survival probabilities were calculated. Late toxicities were defined as occurring later than 90 days after CRT initiation.

Results

From September 2001 to September 2005, 440 patients (arm A, n = 146; arm B arm, n = 147; arm C, n = 147) were enrolled. In the arm A, B and arm C, median overall survival (OS) time was 20.5, 19.8 and 22.0 months, 5-year survival probability was 20.9%, 16.0% and 18.2%, and 10-year survival probability was 13.6%, 7.5% and 15.2%, respectively. There were no significant differences in OS among the treatment arms. The 10-year progression-free survival (PFS) probability was 8.5%, 6.5%, and 11.1% in arm A, B and C. %Grade 3/4 late toxicities were 3.4% (heart 0.7%, lung 2.7%) in arm A and only lung 3.4% in arm B and lung 4.1% in arm C. No additional cases of late toxicity (Grade 3/4) were seen since the initial report.

Conclusions

Arm C shows similar efficacy and toxicity profiles compared with arm A, even 10 years after starting treatment. However, 10-year PFS probability was only 11%, and thus new treatment strategies incorporating immunotherapy are required.

Clinical trial identification

UMIN000030811.

Legal entity responsible for the study

West Japan Oncology Group.

Funding

Has not received any funding.

Disclosure

Y. Zenke: Honoraria (self): Boheniger Ingelheim; Honoraria (self): Chugai Pharma; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): MSD Oncology; Research grant / Funding (institution): MSD. M. Tsuboi: Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Daiichi Sankyo; Honoraria (self): Chugai Pharma; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Teijin Pharma; Honoraria (self): Johnson and Johnson; Honoraria (self): Coviden; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): Boehringer Ingelheim. M. Satouchi: Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Chugai Pharma; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Pfizer; Honoraria (self): Boheriner Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Novartis; Honoraria (self): Lilly; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Ignyta. H. Daga: Honoraria (self): MSD; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Chugai; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Chugai. D. Fujimoto: Honoraria (self): AstraZeneca; Honoraria (self): Ono Pharmaceutical; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Chugai Pharama; Honoraria (self): MSD; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Lilly; Research grant / Funding (institution): AstraZeneca. M. Mori: Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharma; Honoraria (self): MSD; Honoraria (self): Ono Pheramceutical; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Lilly; Research grant / Funding (institution): Chugai Pharma. T. Hirashima: Honoraria (self): Ono pharmaceutical; Honoraria (self): MSD; Honoraria (self): AstraZeneca; Honoraria (self): Lilly; Honoraria (self): Chugai Pharma; Honoraria (self): Brisotol-Myers Squibb; Honoraria (self): Pfizer; Honoraria (self): Kyowa-Hakko-Kirin; Honoraria (self): Boehringer Ingelheim; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Brisotol-Myers Squibb; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Taiho Pharmaceutical. N. Yamamoto: Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (institution): Bristol-Myers Squibb. K. Nakagawa: Honoraria (self), Research Funding(instistution): Astellas Pharma Inc.; Honoraria (self), Research Funding(instistution): AstraZeneca K.K.; Honoraria (self), Research Funding(instistution): MSD K.K.; Honoraria (self), Research Funding(instistution): Ono Pharmaceutical Co.,Ltd.; Honoraria (self), Research Funding(instistution): Daiichi Sankyo Co., Ltd.; Honoraria (self), Research Funding(instistution): Taiho Pharmaceutical Co.,Ltd.; Honoraria (self), Research Funding(instistution): Bristol-Myers Squibb Company; Honoraria (self): KYORIN Pharmaceutical Co.,Ltd.; Honoraria (self): Nichi-Iko Pharmaceutical Co., Ltd.; Honoraria (self): Hisamitsu Pharmaceutical Co.,Inc.; Honoraria (self), Research Funding(instistution): Takeda Pharmaceutical Co.,Ltd.; Honoraria (self), Research Funding(instistution): Chugai Pharmaceutical Co.,Ltd.; Honoraria (self), Research Funding(instistution): Eli Lilly Japan K.K.; Honoraria (self): Nippon Boehringer Ingelheim Co.,Ltd.; Honoraria (self), Research Funding(instistution): Novartis Pharma K.K.; Honoraria (self), Research Funding(instistution): Pfizer Japan Inc.; Honoraria (self): Thermo Fisher Scientific K.K.; Advisory / Consultancy, Research Funding(instistution): Astellas Pharma Inc.; Advisory / Consultancy: Takeda Pharmaceutical Co.,Ltd.; Research grant / Funding (institution): Merck Serono Co., Ltd. All other authors have declared no conflicts of interest.

Background

In the Phase III PACIFIC trial of patients with unresectable, Stage III non-small cell lung cancer (NSCLC) without progression after chemoradiotherapy (CRT), durvalumab significantly improved the primary endpoints progression-free survival (PFS) and overall survival (OS) versus placebo and was well-tolerated. Any-grade pneumonitis or radiation pneumonitis (‘pneumonitis’) occurred in 161 (33.9%) and 58 (24.8%) patients treated with durvalumab and placebo, respectively, with similar grade 3/4 rates (3.6% and 3.0%). Exploratory analyses were performed to investigate the efficacy of durvalumab in patients who developed pneumonitis.

Methods

Patients with WHO PS 0/1 (irrespective of tumor PD-L1 status) with ≥2 cycles of platinum-based CRT were randomized (2:1), 1–42 days following CRT, to durvalumab 10 mg/kg intravenously every 2 weeks or placebo for up to 12 months, stratified by age, sex, and smoking history. PFS and time to death or distant metastasis (TTDM) were assessed by blinded independent central review using RECIST v1.1. The impact of pneumonitis on efficacy was assessed via Cox proportional hazards models. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented.

Results

As of 22 March 2018, 713 patients were randomized of whom 709 received treatment. Using a step-wise approach, pneumonitis was assessed via univariate analyses and, when adjusted for the occurrence of (time-dependent) pneumonitis in the models, OS, PFS, and TTDM were consistent with results for the ITT population (Table). The pneumonitis time-dependent covariate was not significant (P > 0.1) in all models.Table:

1459PD OS, PFS, and TTDM, adjusted for the time-dependent occurrence of pneumonitis* and for the ITT population

Conclusions

Treatment benefit with durvalumab versus placebo was maintained regardless of the occurrence of pneumonitis, which predominantly occurred with low-grade severity as previously reported. These findings suggest that low-grade pneumonitis should not deter use of durvalumab.

Clinical trial identification

NCT02125461 (release date: 29 April 2014).

Editorial acknowledgement

Andrew Gannon, MS, MA, of Cirrus Communications (New York, NY), an Ashfield company, in accordance with Good Publication Practice (GPP3) guidelines and funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

J.F. Vansteenkiste: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Advisory / Consultancy: Apotex; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: BMS. J. Naidoo: Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche/Genentech. C. Faivre-Finn: Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Elekta; Travel / Accommodation / Expenses: Pfizer. M. Özgüroğlu: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Jannsen; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Sanofi; Honoraria (self), Honoraria (institution), Advisory / Consultancy: Astellas; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Roche; Travel / Accommodation / Expenses: BMS. A. Villegas: Speaker Bureau / Expert testimony: AstraZeneca. D. Daniel: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Guardant Health; Research grant / Funding (institution): Janssen Research and Development; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): Merck & Co., Inc.; Research grant / Funding (institution): Novartis Pharmaceuticals Corporation; Research grant / Funding (institution): Abb Vie, Inc.; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): ARMO BioSciences; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merus NV; Research grant / Funding (institution): Daiichi Sankyo. S. Murakami: Research grant / Funding (institution): Takeda Pharmaceutical; Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharmaceutical; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Ono Pharmaceutical. R. Hui: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Merck Sharp and Dohme; Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb. K.H. Lee: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca. B.C. Cho: Advisory / Consultancy, Research grant / Funding (self): Novartis; Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): MOGAM Institute; Research grant / Funding (self): Dong-A ST; Research grant / Funding (self): Champions Oncology; Advisory / Consultancy, Research grant / Funding (self): Janssen; Advisory / Consultancy, Research grant / Funding (self): Yuhan; Advisory / Consultancy, Research grant / Funding (self): Ono; Research grant / Funding (self): Dizal Pharma; Research grant / Funding (self): MSD; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy: MSD; Shareholder / Stockholder / Stock options: TheraCanVac Inc. K. Kubota: Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Eli Lilly; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Novaltis; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Kyowa Hakko KIRIN. M. Taboada: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Wadsworth: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P.A. Dennis: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. S.J. Antonia: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self): CBMG; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy: Memgen; Advisory / Consultancy, Travel / Accommodation / Expenses: FLX Bio; Shareholder / Stockholder / Stock options: Cellular Biomedicine Group.

Background

The aim of this study was to describe the expression profiles of newly discovered B7 family (B7-H4, VISTA, B7-H6, HHLA2), IDO-1, PD-L1 and CD8 in resected lung adenocarcinoma tumor tissues and try to find potential immune target for lung cancer with EGFR mutation.

Methods

A total of 372 adenocarcinoma lung cancer patients who underwent lung cancer resection were selected in the discovery cohort. The validation cohort contains another 231 adenocarcinoma lung cancer patients. Expression of B7-H4, VISTA, B7-H6, HHLA2, IDO-1, PD-L1 and CD8 was determined by immunohistochemical staining.

Results

In the discovery cohort, 44.9% (167/372) of B7H4, 75.8% (282/372) of VISTA, 84.7% (315/372) of B7H6, 61.0% (227/372) of IDO-1 was positively stained in lung adenocarcinoma tissues. In the validation cohort, majority of cases was positive for B7H4 (41.6%, 96/231), VISTA (74.5%, 172/231), B7H6 (86.4%, 200/231) and IDO-1 (57.1%, 132/231), which was similar to the initial cohort. The positive expression rate of B7H4 in EGFR mutation group was significantly higher than that in wild type group in both cohort (P < 0.05). However, expressions of IDO-1, PD-L1 and CD8 in wild type group were significantly higher than that in mutation group in discovery cohort, which was confirmed in the validation cohort. In the discovery cohort, the median IHC scores of B7H4 and HHLA2 for the EGFR mutation group were significantly higher than those in wild type group (P = 0.045 for B7H4; P = 0.003 for HHLA2). Whereas the median IHC scores of IDO-1 and PD-L1 in wild type group were significantly higher than those in mutation group (P = 0.000 for IDO-1; P = 0.000 for PD-L1). Results in the validation cohort confirmed observation above. In both discovery and validation set, the co-expressions of B7-H6, IDO-1, PD-L1 and CD8 were significantly higher in EGFR wild type group than those in EGFR mutation group.

Conclusions

Aberrant expressions of B7-H4 and HHLA2 were more obvious in EGFR mutation lung cancer. High co-expression of CD8 and IDO-1 in EGFR wild type patients reveals a potential good clinical efficacy of anti-IDO-1 therapy in patients with EGFR wild type.

Legal entity responsible for the study

Jifeng Feng.

Funding

The National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.

Background

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).

Methods

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 25 mg/m² (days 1, 8), doxorubicin 40 mg/m² (day 1), etoposide 80 mg/m² (days 1-3), and vincristine 1 mg/m² (day 8) every 2 weeks (CODE) or amrubicin 40 mg/m² (days 1-3) and cisplatin 60 mg/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%.

Results

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).

Conclusions

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.

Legal entity responsible for the study

JCOG.

Funding

JCOG.

Disclosure

All authors have declared no conflicts of interest.

Background

Chemotherapy (chemo)-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Current supportive therapies are lineage specific and administered after damage has occurred. T, a highly selective, reversible CDK4/6 inhibitor and first-in-class myelopreservation agent, preserves HSPCs during chemotherapy, improving its safety and tolerability. This trial (NCT03041311) studied the benefits of T in ES-SCLC patients receiving 1L chemo + atezolizumab (A).

Methods

This placebo (P)-controlled, double-blind, Ph2 study randomized (1:1) chemo-naïve ES-SCLC pts with adequate organ function, ECOG 0-2, and no symptomatic brain mets, to T or P with etoposide/carboplatin/A (ECA) for four induction cycles followed by maintenance (A). Prophylactic growth factors were prohibited in cycle 1; otherwise standard supportive care was allowed. Prespecified lineage-specific endpoints assessed the effect of T on myelosuppression. Tumor response was assessed using RECIST v1.1. FACT-L and FACT-An were evaluated.

Results

T + ECA was well tolerated with fewer ≥ G3 AEs in T (62% overall; 50% any drug related) vs P (87%; 74%), primarily due to less heme toxicity. T improved ANC, RBC measures and SOC interventions (Table). T also delayed time to deterioration in some PRO functioning domains and anemia symptoms. T did not affect chemo efficacy as measured by ORR and PFS; OS will be presented.Table: 1742PD

Conclusions

Addition of T improves safety/tolerability of chemo as shown by statistically significant and clinically meaningful improvement in myelosuppression endpoints, reduction of chemo side effects, and SOC interventions and no detriment to anti-tumor efficacy. These data confirm the myelopreservation benefits of T seen in another 1L ES-SCLC trial (NCT02499770).

Clinical trial identification

GIT28-05: NCT03041311, EudraCT2017-000358-20.

Legal entity responsible for the study

G1 Therapeutics, Inc.

Funding

G1 Therapeutics, Inc.

Disclosure

D. Daniel: Research grant / Funding (institution): G1 Therapeutics; Research grant / Funding (institution): ER Squibb & sons; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingleheim; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Roche. D. Spigel: Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): G1 Therapeutics. J. Jaal: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim. L. Hart: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: G1 Therapeutics. K.D. Koynov: Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Roche; Honoraria (institution): Boehringer Ingelheim; Honoraria (institution): servier; Honoraria (institution): Novartis; Honoraria (institution): Merck; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: MSD; Honoraria (institution): Bayer; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Astelas; Honoraria (self), Honoraria (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (institution): Intellect Pharma; Travel / Accommodation / Expenses: AstraZeneca. Z.(. Yang: Full / Part-time employment: G1 Therapeutics. S.G. Wolfe: Full / Part-time employment: G1 Therapeutics. R. Malik: Full / Part-time employment: G1 Therapeutics. S.R. Morris: Full / Part-time employment: G1 Therapeutics. J.M. Antal: Full / Part-time employment: G1 Therapeutics. All other authors have declared no conflicts of interest.

Background

All malignant mesothelioma (MM) patients progress after first-line therapy. We examined whether switch maintenance gemcitabine in patients, who did not show progression after first-line platinum-pemetrexed, could prolong time to disease progression.

Methods

NVALT19 was an open label, randomized phase II trial, conducted in The Netherlands. Main eligibility criteria were pathologically proven MM, ECOG-PS 0-2 and completion of 4-6 cycles of first-line platinum-pemetrexed without progression. Patients were randomized 1:1 between gemcitabine (1250 mg/m2 day 1 and 8 of 3 weekly schedule) or best supportive care (BSC). Gemcitabine was given until disease progression, severe toxicity or patient request for discontinuation. Primary endpoint was progression free survival (PFS) determined by local physician according to modified RECIST (mRECIST) or death in the intention-to-treat population. It was computed that 118 events would yield 90% power to detect an increase in PFS from median 3.5 months to median 6 months at 90% confidence level.

Results

Between March 2014 and February 2019, 130 patients were randomized, 65 in each arm. PFS was significantly longer with gemcitabine (median 6.2 months [range 4.6-8.7m]) than in the BSC arm (3.2 [2.8-4.2m]; hazard ratio 0.42; 95% confidence interval [CI], 0.28-0.63; p < 0.0001). The PFS probability at 12 months was 25% for Maintenance Gemcitabine (95% CI: 16.3 - 38.5%) and 3.3% for BSC (95% CI: 0.8 - 13%). Central revision of PFS, by a blinded radiologist, also showed significant benefit for gemcitabine (median 5.3 months [4.2-7.1m]) above BSC (2.8 [2.5-3.3m]; hazard ratio 0.42; 95% CI 0.28 to 0.62; p < 0.0001). Grade 3-4 adverse events (AE) occurred more in the gemcitabine arm (57% of patients) vs 13% in the BSC-arm. Neutropenia (22%), nausea (6%) and lung infection (5%) were most common treatment related grade III AE’s. Three patients (5%) experienced grade IV neutropenia. One patient died in the gemcitabine arm due to treatment related sepsis. Data on dose intensity will follow at ESMO 2019.

Conclusions

Switch maintenance gemcitabine after first-line chemotherapy significantly improves the PFS in malignant mesothelioma, with a manageable toxicity profile.

Clinical trial identification

NTR4132.

Legal entity responsible for the study

Stichting NVALT studies.

Funding

Dutch Cancer Society and Stichting NVALT studies.

Disclosure

All authors have declared no conflicts of interest.