Background

Most patients (pts) with locally advanced, unresectable non-small cell lung cancer (NSCLC) progress despite concurrent chemoradiation therapy (cCRT). Here we report interim results from a global, Phase 3 study (NCT02125461) of the anti-PD-L1 durvalumab as consolidation therapy in Stage III pts without progression following platinum-based cCRT.

Methods

Pts with a WHO performance status 0/1 (any PD-L1 status) who received ≥2 cycles of platinum-based cCRT without progression were randomized (2:1) 1–42 days post-cCRT to receive durvalumab 10 mg/kg IV Q2W or placebo for up to 12 months, stratified by age, sex, and smoking history. Co-primary endpoints were progression-free survival (PFS; blinded independent central review, RECIST v1.1) and overall survival (OS). Secondary endpoints included 12- and 18-month PFS rates, objective response rate (ORR), duration of response (DoR), time to death or distant metastasis (TTDM) and safety.

Results

Between May 2014 and April 2016, 713 pts were randomized of whom 709 received consolidated treatment (durvalumab, n = 473; placebo, n = 236). Baseline characteristics were well balanced. As of Feb 13, 2017 (data cutoff), median follow-up was 14.5 months. Median PFS from randomization was significantly longer with durvalumab (16.8 months, 95% CI, 13.0–18.1) versus placebo (5.6 months, 95% CI, 4.6–7.8; stratified HR 0.52, 95% CI, 0.42–0.65; P < 0.0001). 12- and 18-month PFS rates were 55.9% versus 35.3% and 44.2% versus 27.0%, respectively. ORR was higher (28.4% vs 16.0%; P < 0.001) and median DoR was longer (not reached vs 13.8 months) with durvalumab consolidation therapy. Median TTDM was longer with durvalumab (23.2 vs 14.6 months; stratified HR 0.52, 95% CI, 0.39–0.69; P < 0.0001). OS data were immature at the time of interim PFS analysis. Comparing durvalumab with placebo, grade 3/4 adverse events (AEs) occurred in 29.9% and 26.1%; most common was pneumonia (4.4% vs 3.8%). 15.4% and 9.8% discontinued due to AEs.

Conclusions

Durvalumab demonstrated significant and clinically meaningful improvement in PFS, which was supported by secondary endpoints, and was well tolerated. Durvalumab is a promising therapeutic option in this setting.

(Dr. Scott J. Antonia of H. Lee Moffitt Cancer Center and Research Institute is the lead author for this study. Dr. Luis Paz-Ares is presenting on his behalf).

Clinical trial identification

NCT02125461 (April 25, 2014)

Legal entity responsible for the study

AstraZeneca

Funding

AstraZeneca

Disclosure

L. Paz-Ares: Consultancy fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, Roche, Lilly, Boehringer Ingelheim, Novartis, and Ariad. A. Villegas: Speaker honoraria from Celgene, Alexion, and Bristol-Myers Squibb. R. Hui: Advisory board fees from AstraZeneca, Merck Sharp and Dohme, and Novartis, and a speaker honorarium from Merck Sharp and Dohme. A. Chiappori: Speaker honoraria from Genentech, Merck, Takeda, Novartis, Pfizer, Boehringer Ingelheim, and Celgene, and research support from Novartis and Bristol-Myers Squibb. M. de Wit: A speaker honorarium from AstraZeneca. T. Mekhail: A speaker honorarium and research support from AstraZeneca. D. Planchard: Advisory board fees from AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, Novartis, Roche, Lilly, and Boehringer Ingelheim. H. Jiang, Y. Huang, P.A. Dennis: Full-time employee of AstraZeneca with stock ownership. All other authors have declared no conflicts of interest.

Background

Several guidelines recommend a follow-up based on clinic visits and chest CT-scans for completely resected NSCLC. However, evidence to support these recommendations is poor, in the absence of randomized data. The IFCT-0302 trial is a randomized multicenter trial which compared 2 follow-up programs for completely resected stage pI, II, IIIA and T4 (pulmonary nodules in the same lobe) N0-2 NSCLC (TNM 6^th edition).

Methods

In the control arm (arm 1), follow-up consisted of clinical examination and Chest X-ray (CXR). In the experimental arm (arm 2), patients underwent clinical examination, CXR, thoraco-abdominal CT-scan (CT) plus bronchoscopy (optional for adenocarcinomas). In both arms, procedures were repeated every 6 months after randomization during the first 2 years, and yearly until 5 years. Supplementary procedures were allowed in case of symptoms. The primary endpoint was overall survival (OS).

Results

Between January 2005 and November 2012, 1775 patients were randomized (arm 1: 888; arm 2: 887). Patient characteristics were well-balanced between the two arms: males 76.3%, median age 63 years (range: 34-88), squamous and large cell carcinomas 39.5%, stage I 68.1%, stage II 13.7%, stage III 18.3%, lobectomy or bilobectomy 86.6%, pre- and/or post-operative radiotherapy 8.7%, and pre- and/or post-operative chemotherapy 45%. Median follow-up was 8.7 yrs (95% CI: 8.5-9). OS was not significantly different between arms (HR = 0.92, 95% CI: 0.8-1.07; p = 0.27). Median OS was 8.2 yrs (95% CI: 7.4-9.6) and 10.3 yrs (95% CI: 8.5-not reached) in arms 1 and 2, respectively. Three-year disease-free survival rates were 63.3% (95%CI: 60.2%-66.5%), and 60.2% (95% CI: 57.0%-63.4%), respectively. Eight-year OS rates were 51.1% (95% CI: 47.2%-55.1%) and 55.6% (95% CI: 51.7%-59.4%) respectively.

Conclusions

The IFCT-0302 trial is the first randomized study of follow-up in resected NSCLC. The primary endpoint was not met. A longer follow-up is necessary not to miss a potential long-term OS benefit of CT-scan-based surveillance.

Clinical trial identification

NCT00198341

Legal entity responsible for the study

Intergroupe Francophone de Cancérologie Thoracique (IFCT)

Funding

Ministère de la Santé (PHRC), Fondation de France, Laboratoire Lilly

Disclosure

E. Quoix: Non-financial support from AMGEN, Pfizer, BMS. Personal fees from Abbvie, Clovis and Lilly. Personal fees and non-financial support from Boehringer Ingelheim. All other authors have declared no conflicts of interest.

Background

Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both EGFRm and EGFR T790M resistance mutations. Pre- and early clinical data suggest osimertinib may also be effective as initial therapy for EGFRm advanced NSCLC. FLAURA (NCT02296125) is a PhIII, double-blind, randomised study assessing efficacy and safety of osimertinib vs SoC EGFR-TKI in first-line pts with EGFRm advanced NSCLC.

Methods

Eligible pts: ≥18 years, no prior EGFR-TKI/systemic anti-cancer therapy for advanced disease, with Ex19del/L858R EGFRm advanced NSCLC. Neurologically stable pts with CNS mets were allowed, provided definitive treatment/steroids were completed for ≥2 weeks. Pts were randomised 1:1 to osimertinib 80 mg once daily (qd) orally (po) or SoC EGFR-TKI (gefitinib 250 mg or erlotinib 150 mg qd po), stratified by mutation status (Ex19del/L858R) and race (Asian/non-Asian). Primary endpoint: progression-free survival (PFS) by RECIST v1.1, by investigator. Data cut-off: 12 June 2017.

Results

Globally, 556 pts were randomised to treatment. Baseline characteristics were balanced across arms (osimertinib/SoC): female 64/62%; Asian 62/62%, Ex19del 57/56%, L858R 35/32%, CNS mets 19/23%.Table:

LBA2_PR

PFS benefit was consistent across all subgroups, including pts with/without CNS mets at study entry. Median total treatment duration (range): 16.2 (0.1–27.4) months with osimertinib; 11.5 (0–26.2) with SoC. All causality adverse events (AEs), by investigator: osimertinib, 98% (Gr ≥ 3, 34%); SoC, 98% (Gr ≥ 3, 45%). AEs leading to discontinuation: osimertinib, 13%; SoC, 18%. Most common all causality AEs with osimertinib: diarrhoea (58% [Gr ≥ 3, 2%]), dry skin (32% [<1%]); SoC: diarrhoea (57% [3%]), dermatitis acneiform (48% [5%]).

Conclusions

Osimertinib demonstrated a superior risk/benefit over SoC as first-line therapy in pts with advanced EGFRm NSCLC.

Clinical trial identification

NCT02296125

Legal entity responsible for the study

AstraZeneca

Funding

AstraZeneca

Disclosure

S. Ramalingam: Advisory Board Meeting for: Astra Zeneca, Bristol-Myers Squibb, Genentech, Boehringer-Ingelheim. F. Imamura: Research fund and honoraria from AstraZeneca. N. Nogami: Funding from AstraZeneca. Y. Ohe: Honorarium/Consultant/Expert Testimony/Research Funding (Institution); AstraZeneca, Chugai, Lilly, ONO, BMS, Daiichi-Sankyo, Nippon Kayaku, Boehringer, Bayer, Pfizer, MSD, Taiho, Clovis, Sanofi, Novartis, Kyorin, Dainippon-Sumitomo, Merck. J.F. Vansteenkiste: Grants/research support: AstraZeneca Honoraria/consultation fees: AstraZeneca, Novartis, MSD, Boehringer-Ingelheim, Eli-Lilly, Roche. C. Zhou: Lecture honorarium: Eli Lily, AstraZeneca, Roche, Pfizer, Sanofi, Boehringer-Ingelheim, Henrui Advisory Board: Roche, Boehringer-Ingelheim, AstraZeneca. J. Gray: Consultant/Advisory Boards: AstraZeneca, Celgene, Eli Lilly, Janssen, Boehringer-Ingelheim, Clovis. Research Funding: Array, AstraZeneca, Merck, Trovagene. R. Hodge, Y. Rukazenkov: Employee of, and shareholder in, AstraZeneca. J-C. Soria: Consultancy fees for AstraZeneca, Roche. All other authors have declared no conflicts of interest.