Virtual Library

Background:
The study aimed to (i) develop a recurrence risk-scoring model in stage I lung adenocarcinoma (LAD) after complete lobectormy; (ii) explore the high-risk population that would benefit from adjuvant chemotherapy (ACT).

Methods:
A retrospective study was performed on 4606 patients with pathologically confirmed stage I LAD who underwent complete lobectomy at Shanghai Chest Hospital from 2008 to 2014. Patients were categorized into the non-ACT group (n = 3514) and ACT group (n = 1092). The nomogram was developed in the non-ACT group using Cox proportional hazards regression to predict 5-year recurrence-free survival (RFS). The predictive value was compared between the nomogram and the 8[th] edition of TNM system. The population that benefited from ACT was determined by comparing RFS between the non-ACT and the ACT group as stratified by the TNM stage, risk score quartiles and 5-year recurrence probability, respectively. The optimal cut-off scores were determined using X-tile software.

Results:
Six independent predictors including age, gender, tumor size, pathological subtype, visceral pleural invasion (VPI), and lymphovascular invasion (LVI) were associated with recurrence. The nomogram showed a better accuracy in predicting RFS than the TNM staging [C-index: 0.784 (95% CI: 0.756–0.812) vs 0.719 (95% CI: 0.689–0.749), P = 0.0017]. A trend in ACT benefit was observed along with the increasing risk scores. An improved RFS was exhibited after ACT for patients having a 50% recurrence probability (P = 0.0286). The optimal cut-off of the risk score was set at 203 and 244. ACT was detrimental in patients with risk scores below 203 (P < 0.0001) and beneficial in those with risk scores above 245 (P = 0.0416). Patients with score ≥ 245 accounted for 0.4% of stage IA patients and 7.5% of stage IB patients, respectively. In stage IB, patients with predominant solid/micropapillary subtype (62.8%) was the subgroup with the most percentage of score ≥ 245.

Conclusions:
The nomogram provided a more accurate RFS prediction for lobectomized stage I LAD. High-risk population, determined as recurrence risk score ≥ 245, may benefit from postoperative ACT.

Clinical trial identification:


Legal entity responsible for the study:
Shanghai Chest Hospital, Shanghai Jiao Tong University, China

Funding:
Has not received any funding

Disclosure:
All authors have declared no conflicts of interest.

Background:
The NVALT-11/DLCRG-02 randomized phase III study compared PCI to observation after chemo-radiotherapy for stage III NSCLC and showed a significant decrease in time to develop symptomatic brain metastases in the PCI arm at the expense of more low-grade mostly neurological toxicity (HR 0.25 95% CI 0.11–0.58). We here report on the QoL.

Methods:
EORTC QLQ-C30 and EuroQol 5D (EQ-5D) data measured before PCI and 3, 12, and 24 months thereafter were compared for both arms. Specifically, functional scales and global health status scores (QLQ-C30) as well as VAS and utility scores (EQ-5D) were analysed using non-parametric tests.

Results:
In total, 86 and 88 patients were included in the PCI and observational arm respectively, accumulating to 853 observations (five observations completely missing). Baseline QoL was similar between both arms, except for emotional (p = 0.025) and cognitive functioning (p = 0.039) which showed a significantly better score in the PCI arm. At three months, the observational arm scored significantly better on the EQ-VAS (median 70 vs 60, p = 0.017), while EQ-5D utility scores (Dutch tariff) were similar. At three months, QLQ-C30 showed that physical functioning, cognitive functioning, and global disease specific QoL were significantly better in the observational arm (median 83 vs 73, p = 0.003, median 100 vs 83, p = 0.006 and median 67 vs 67, p = 0.017). At later time-points, except for significantly better cognitive functioning at 24 months in the observational arm (median 83 vs 67, p = 0.017), no significantly different QoL (either QLQ-C30 or EQ-5D) was observed between the two arms.Table:Median scores of functional scales and global health status scores of QLQ-C30 and VAS and utility scores of EQ-5D

	Median (PCI)				Median (Observation)
	T0	T3	T12	T24	T0	T3	T12	T24
QLQ-C30
Physical	77	73	87	80	80	83	80	77
Role	67	67	67	67	67	67	67	67
Emotional	83	83	83	92	75	88	83	88
Cognitive	100	83	83	67	83	100	83	83
Social	83	83	100	83	83	83	83	92
Global QoL	67	67	67	67	67	67	67	67
EQ-5D
Utility score	0.843	0.775	0.805	0.843	0.811	0.811	0.775	0.843
VAS score	65	60	70	75	70	70	69	70

Conclusions:
In conclusion, despite substantially reducing the incidence of brain metastases in NSCLC patients, PCI impairs short term generic QoL as well as disease specific QoL. The impact on long term QoL is limited to problems concerning cognitive functioning only.

Clinical trial identification:


Legal entity responsible for the study:
Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose (NVALT)

Funding:
Has not received any funding

Disclosure:
All authors have declared no conflicts of interest.

Background:
Along with improving efficacy outcomes such as progression-free survival (PFS) after concurrent chemoradiotherapy (cCRT) in locally advanced, unresectable NSCLC, it is critical that new therapies are well tolerated in the curative intent setting. We studied the impact of 12 mo of durvalumab on disease symptoms in this setting using patient-reported outcomes (PROs). In a post-hoc analysis of time to deterioration, we adjusted for transient symptom changes by requiring two consecutive deterioration recordings.

Methods:
Patients whose disease did not progress after ≥2 cycles of platinum-based cCRT were randomised 2:1 1–42 days post-cCRT to durvalumab 10 mg/kg i.v. or placebo every 2 weeks for up to 12 mo/progression. Co-primary endpoints were PFS and overall survival. PROs were assessed using EORTC QLQ-C30 v3 and QLQ-LC13. Time to deterioration was defined as time from randomisation until the first clinically relevant deterioration (≥10 point change); in the post-hoc analysis, deterioration confirmation was required at the next time point. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using a stratified Cox proportional-hazards model.

Results:
In the pre-specified analysis, there was no difference between treatment arms in time to deterioration besides other pain, which favoured durvalumab vs placebo (HR 0.72; 95% CI 0.58–0.89). Our post-hoc analysis indicated notable delays in deterioration of overall pain (HR 0.75; 95% CI 0.60–0.93), chest pain (HR 0.74; 95% CI 0.57–0.97), arm/shoulder pain (HR 0.74; 95% CI 0.58–0.95), nausea/vomiting (HR 0.72; 95% CI 0.54–0.97), insomnia (HR 0.75; 95% CI 0.58–0.97) and haemoptysis (HR 0.70; 95% CI 0.50–0.99) in favour of durvalumab, with no between-group differences for other items.

Conclusions:
PACIFIC primary analysis showed that durvalumab significantly improved PFS vs placebo (16.8 mo vs 5.6 mo, respectively) in the post-cCRT setting, and was well tolerated, largely without PRO deterioration. Our post-hoc analysis indicates a delay in several PROs with durvalumab not observed in the pre-specified analysis. Confirmation of worsening may provide a more precise picture of deterioration than one time point alone.

Clinical trial identification:
NCT02125461 (April 25, 2014)

Legal entity responsible for the study:
AstraZeneca PLC

Funding:
AstraZeneca

Disclosure:
R. Hui: Personal fees from the following: AstraZeneca, Merck Sharp and Dohme: Advisory Board Member and Speaker Honorarium; Novartis, Pfizer: Advisory Board Member; BMS, Boehringer Ingelheim: Speaker Honorarium. A. Villegas: Celgene, Alexion, BMS: Speaker's Bureau. A. Ryden, Y. Zhang, P. Dennis: AstraZeneca: full-time employment and stock ownership. S. Antonia: Moffitt Cancer Center: Full-time employment, Grants/research support; Novartis: Grants/research support, Advisory board, Honorarium recipient; BMS, Merck, Boehringer Ingelheim, AstraZeneca, Memgen: Advisory board, Honorarium recipient; CBMG: Advisory board, Stock/shareholder, Honorarium recipient. All other authors have declared no conflicts of interest.

Abstract not provided

Background:
In the FLAURA phase 3 study, the third-generation EGFR-TKI osimertinib significantly improved progression-free survival (PFS) vs SoC EGFR-TKIs (gefitinib or erlotinib) in pts with previously untreated Ex19del/L858R (EGFRm) advanced NSCLC (hazard ratio [HR] 0.46 [95% CI 0.37, 0.57]; p < 0.001). Interim overall survival (OS) data was encouraging but not formally statistically significant (HR 0.63 [95% CI 0.45, 0.88]; p = 0.007). Here we report exploratory post-progression outcomes.

Methods:
Pts were randomised 1:1 to receive osimertinib (80 mg orally [PO], once daily [QD]) or SoC (gefitinib 250 mg PO QD or erlotinib 150 mg PO QD). Treatment beyond disease progression was allowed if the investigator judged continued clinical benefit; investigators determined subsequent therapy. Pts receiving SoC could cross over to osimertinib after objective disease progression with documented post-progression T790M-positive mutation status.

Results:
At data cutoff, 12 June 2017, 138/279 (49%) and 213/277 (77%) pts discontinued osimertinib and SoC, respectively; 82 (29%) and 129 (47%) received a subsequent treatment: EGFR-TKI-containing, 29 (10%) and 97 (35%; 55 [20%] osimertinib); platinum chemotherapy-containing, 46 (16%) and 27 (10%). Median time (mths) to discontinuation of study treatment or death: osimertinib 20.8 (95% CI 17.2, 24.1) vs SoC 11.5 (10.3, 12.8). Median time (mths) to discontinuation of any EGFR-TKI (study treatment and subsequent EGFR-TKI, not interrupted by non-EGFR-TKI therapy) or death: osimertinib 23.0 (19.5, not calculable [NC]) vs SoC 16.0 (14.8, 18.6). Time-to-event post-progression endpoints all favoured osimertinib (Table).

	Osimertinib(n = 279)	SoC (n = 277)
Disease progression or death, n (%)	136 (49)	206 (74)
Remained on study treatment for at least 7 days post investigator assessed progression, n/N (%)	91/136 (67)	145/206 (70)
Median duration on study treatment post-progression (95% CI), wks[a]	8.1 (6.3, 12.3)	7.0 (5.9, 8.1)
TFST
Pts who started FST or died, n (%)	115 (41)	175 (63)
Started FST, n (%)	82 (29)	129 (47)
Died, n (%)	33 (12)	46 (17)
Median TFST or death (95% CI), mths[a]	23.5 (22.0, NC)	13.8 (12.3, 15.7)
HR (95% CI)[b]	0.51 (0.40, 0.64), p < 0.0001
PFS2 (investigator assessed)
Second progression or death, n (%)	73 (26)	106 (38)
Median PFS2 (95% CI), mths[a]	NC (23.7, NC)	20.0 (18.2, NC)
HR (95% CI)[b]	0.58 (0.44, 0.78), p = 0.0004
TSST
Pts who started SST or died, n (%)	74 (27)	110 (40)
Started SST, n (%)	24 (9)	39 (14)
Died, n (%)	50 (18)	71 (26)
Median TSST or death (95% CI), mths[a]	NC (NC, NC)	25.9 (20.0, NC)
HR (95% CI)[b]	0.60 (0.45, 0.80), p = 0.0005

aCalculated using the Kaplan-Meier method.bHR and CI were obtained directly from the U and V statistics. The analysis was performed using a log rank test stratified by race (Asian versus non-Asian) and mutation type (Ex19del vs L858R). 2-sided p-value. CI, confidence interval; FST, first subsequent therapy (second-line treatment); HR, hazard ratio; NC, not calculable; PFS2, second progression-free survival (or death) post initiation of second-line treatment (i.e. time from randomisation to second progression on subsequent treatment); TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death; SST, second subsequent therapy; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1.

Conclusions:
PFS benefit with osimertinib was preserved throughout time-to-event post-progression endpoints. Step-wise increase of the statistically significant HRs (PFS 0.46, TFST 0.51, PFS2 0.58, TSST 0.60) provides confidence in the interim OS data.

Clinical trial identification:
ClinicalTrials.gov NCT02296125

Legal entity responsible for the study:
AstraZeneca

Funding:
AstraZeneca

Disclosure:
D. Planchard: Advisory boards: Astrazeneca, Boehringer, BMS, Pfizer, Novartis, MSD, Roche M. Boyer: Research funding and/or honoraria for advisory board work or talks, paid to my institution, from: AstraZeneca, Roche, Merck Sharpe and Dohme, Pfizer, Amgen, Bristol-Myers Squibb. P. Cheema: Advisory board/Honorarium: AstraZeneca Research grant: AstraZeneca T. Takahashi: Honoraria: AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Ono Pharmaceutical, Grants: AstraZeneca KK, Pfizer Japan Inc., Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K. A. Todd: Employee of AstraZeneca but own no stocks or shares, and am not a member of any board. I am not aware of any other conflicts of interest or opportunities for financial gain. A. McKeown: Employee of, and shareholder in, AstraZeneca. Y. Rukazenkov: Employee of and shareholder in AstraZeneca. Y. Ohe: Grants and personal fees from AstraZeneca, during the conduct of the study; grants and personal fees from AstraZeneca, grants and personal fees from Ono, grants and personal fees from BMS, grants and personal fees from Chougai, grants and personal fees from Pfizer, grants and personal fees from MSD, grants and personal fees from Novartis, grants from Kyorin, grants from Dainippon- Sumitomo, personal fees from Daiichi-Sankyo, personal fees from Nipponkayaku, personal fees from Boehringer Ingelheim, personal fees from Bayer, grants and personal fees from Lilly, outside the submitted work. All personal fees were honoraria for consulting or lectures. All other authors have declared no conflicts of interest.

Background:
Our previous study demonstrated that liver metastases (LM) were the negative predictive and prognostic factor in EGFR-mutant NSCLC patients (Pts) treated with EGFR-TKIs, suggesting that additional treatment is warranted. Recently, several studies reported that local therapy could significantly improve progression-free survival (PFS) in NSCLC Pts with oligometastatic or oligoprogressive disease. This study aimed to investigate whether addition of local therapy to EGFR-TKIs could provide survival benefit in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM.

Methods:
Pts with EGFR-mutant NSCLC and LM were included. Oligometastatic LM was defined as <5 sites in liver without extrahepatic metastases at initial diagnosis. Oligoprogressive LM was defined as <5 sites in liver without extrahepatic metastases during TKIs therapy. For oligoprogressive cohort, PFS1 was calculated from time of initiation of TKI therapy to first RECIST 1.1 defined progress disease (PD) or death. PFS2 was calculated from time of initiation of TKI therapy to off-TKI PD.

Results:
289 Pts with LM were enrolled (55 with oligometastatic LM and 63 with oligoprogressive LM). In oligometastatic cohort, 18 Pts received EGFR-TKIs (E) and 21 Pts received TKIs plus local therapy (E + LT) as first-line treatment. Median PFS was significantly longer in E + LT group than in E group (12.2 vs. 7.9 m, P = 0.030). Median OS was numerically longer in E + LT group than in E group (31.7 vs. 21.3 m, P = 0.102). In oligoprogressive cohort, 19 Pts received continuation of TKIs plus local therapy (cE + LT) and 22 Pts received switch therapy (ST). Median PFS1 was comparable. Median PFS2 was dramatically longer in cE + LT group than in ST group (13.9 vs. 8.8 m, P = 0.050). Median OS was marginally significantly longer in cE + LT group than in ST group (24.7 vs. 15.7 m, P = 0.085). Multivariate analysis revealed that addition of local therapy was independently associated with prolonged PFS and OS in Pts with oligometastatic LM.

Conclusions:
The current study indicated that EGFR-TKIs plus local therapy demonstrated the prolonged survival benefit than TKIs alone in EGFR-mutant NSCLC Pts with oligometastatic or oligoprogressive LM.

Clinical trial identification:


Legal entity responsible for the study:
Shanghai Pulmonary Hospital

Funding:
Has not received any funding

Disclosure:
All authors have declared no conflicts of interest.

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