Background

We present efficacy and safety data of Asian vs non-Asian patients (pts) in the global phase III ALEX study of ALC (600 mg BID) vs CRZ (250 mg BID) in treatment-naïve advanced ALK+ NSCLC.

Methods

Pts aged ≥18 years were randomised 1:1 to receive ALC or CRZ until progression, toxicity, withdrawal or death. Race was a randomisation stratification factor. The primary endpoint was investigator (INV)-assessed progression-free survival (PFS). Secondary endpoints were: Independent Review Committee (IRC)-assessed PFS, time to central nervous system (CNS) progression, objective response rate (ORR) by INV, overall survival (OS) and safety.

Results

In total, 303 pts were randomised (ALC N = 152 [N = 69 Asian, N = 83 non-Asian]; CRZ N = 151 [N = 69 Asian, N = 82 non-Asian]). Baseline characteristics were consistent between Asian and non-Asian subgroups, except median weight. Efficacy and safety data were similar between subgroups (table). PFS by INV was longer with ALC in Asian (HR 0.46) and non-Asian (HR 0.49) pts. Median OS has not yet been reached in either subgroup but data are immature: Asian HR 0.68, non-Asian HR 0.82. Rate of treatment discontinuation due to adverse events (AE): Asian 13.0% ALC, 11.6% CRZ; non-Asian 9.6% ALC, 13.4% CRZ. AE profiles of Asian and non-Asian subgroups were consistent with the ITT population. Diarrhoea was more common with CRZ in both subgroups vs ALC (Asian 15.0% ALC, 39.1% CRZ; non-Asian 10.0% ALC, 50.0% CRZ). Nausea was more common with CRZ in both subgroups vs ALC (Asian 10.1% ALC, 42.0% CRZ; non-Asian 17.0% ALC, 52.4% CRZ) and was more common in non-Asian vs Asian pts. Pharmacokinetics data of the subgroups will be presented.

Conclusions

Efficacy and safety data were similar between Asian and non-Asian pts for ALC or CRZ. The results confirm ALC 600 mg BID dosage is more effective than CRZ in Asian and non-Asian pts, and has an acceptable safety profile in Asian pts.

Clinical trial identification

NCT02075840

Legal entity responsible for the study

F. Hoffmann-La Roche

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

T.S.K. Mok: Consultant (Participated in Advisory Boards for the last two years): AstraZeneca, BI, Pfizer, Novartis, SFJ, Roche, MSD, Clovis Oncology, BMS, Eisai and Taiho. S. Peters: Education grants, provided consultation, attended advisory boards and/or provided lectures for the following organizations: Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Clovis, Eli Lilly, F. Hoffmann-La Roche, Janssen, Merck Sharp and Dohme and Merck Serono, Pfizer, Regeneron and Takeda. D.R. Camidge: Roche Genetech, Genoptix, G1 Therapeutics, Orion, Clovis, Ariad, Novartis, Celgene, Array, Abbvie, Eli Lilly. S-H.I. Ou: Corporate-sponsored research to institutions: Pfizer, Roche, Astra Zeneca, ARIAD, Ignyta and other substantive relationships including: Pfizer, Roche, Astra Zeneca, ARIAD, Ignyta and Foundation Medicine. J.S. Ahn: Personal fees from BMS, Eisai, Janssen, Roche, Menarini and Boehringer Ingelheim, B.C. Cho: Research funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST; Consulting role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Yuhan, Pfizer, Eli Lilly. S.L. Geater: Funding to institute for clinical research: Astra Zaneca, Boehringer Ingelheim, Novartis, Samsung, Roche, J. Ho: Speaker’s honorarium and research funding from Roche. A. Zeaiter: Employment at F. Hoffmann-La Roche. B. Balas: Employee and stockholder at F. Hoffmann-La Roche Ltd. E. Nueesch, E. Mitry: Employee at F. Hoffmann-La Roche, P.N. Morcos: Employment and stock ownership at F. Hoffmann-La Roche. All other authors have declared no conflicts of interest.

Table: 410O_PR

Efficacy and safety data by subgroups

Background

Humanized recombinant endostatin (rh-endostatin, Sulijia®) is an inhibitor of tumor angiogenesis. We aimed to assess efficacy and safety of rh-endostatin or placebo with vinorelbine/cisplatin (NP) as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC).

Methods

In this multi-centre, double-blind, placebo-controlled, randomized phase 3 trial, we enrolled treatment-naïve patients with stage IV NSCLC. Patients were randomly allocated (2:1) to receive 4-cycle NP and either rh-endostatin 7.5mg/m² or matching placebo on day 1-14 of a 21-day cycle, non-progressive patients then received rh-endostatin or placebo until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). This study was registered with NCT03117335 and ChiCTR-TRC-11001539.

Results

Between November 11^th, 2011, and September 2^nd, 2015, 560 patients were enrolled in this study. The median PFS was 5·4 months (95%CI 4·9-5·8) for patients in rh-endostatin plus NP group and 4·7 months (95%CI 4·4-5·9) for those in placebo plus NP group (Hazard Ratio [HR] 0·692; 95% CI 0·523-0·915; p = 0.0098). Subgroup analysis showed that patients with squamous NSCLC (5·0 [4·3-5·4] vs 3·9 [2·8-4·4] months, HR 0·440 [0·261-0·741], p = 0·0021) and smokers (5·0 [4·5-5·4] vs 4·4 [3·2-4·7] months, HR 0·629 [0·437-0·905], p = 0·0124) had significantly longer PFS in the rh-endostatin plus NP group than those in the placebo plus NP group. Adverse events were 99·7% (364/365) in the rh-endostatin plus NP group and 99·4% (180/181) in the placebo plus NP group. The most common grade 3 or worse adverse events were leukopenia (rh-endostatin vs placebo: 69·6% [254/365] vs 53% [96/181], p = 0·0002), neutropenia (77% [281/365] vs 65·2% [118/181], p = 0·0041), and decreased hemoglobin (19·7% [72/365] vs 12·2% [22/181], p = 0·0301).

Conclusions

Rh-endostatin plus NP improves PFS and is well tolerated as first-line treatment for patients with stage IV NSCLC, especially those with squamous NSCLC and smokers.

Clinical trial identification

ClinicalTrials.gov ID: NCT03117335 Protocol No.:TG1107RHE.

Legal entity responsible for the study

Jiangsu Wuzhong Pharmaceutical Group Operation

Funding

Jiangsu Wuzhong Pharmaceutical Group Operation

Disclosure

All authors have declared no conflicts of interest.

Background

Olmutinib (HM61713) is an oral EGFR mutant specific tyrosine kinase inhibitor (TKI) which has shown modest clinical activity and tolerability in patients with EGFR TKI pretreated NSCLC harboring a T790M mutation in a phase I study. The global Phase II trial was designed to evaluate the efficacy and safety of olmutinib 800mg monotherapy in patients with T790M-positive NSCLC.

Methods

Patients received olmutinib 800 mg/day in 21-day cycles. Primary endpoint was centrally confirmed objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), and safety. This study was conducted at 68 sites in 10 countries (Korea, Malaysia, Taiwan, the Philippines, Australia, Italy, Spain, Germany, US and Canada).

Results

162 patients (median age: 63) were enrolled in the study. After median 5.9 months of follow up, median treatment duration was 5.3 months (range: 0.03-13.01). Among 115 patients evaluable for independent reviewer response assessment, 59 (51.3%) patients achieved objective response, including 51 (44.4%) patients with confirmed response. Median PFS was 6.9 months (95% CI 5.8–not reached) and DCR was 87.8% (101/115). In post-hoc subgroup analysis, ORR was 43.3% (95% CI 30.6-56.8) in patients with brain metastases and 45.5% (95% CI 32.0-59.5) without brain metastases at baseline. Median PFS in patients with brain metastases (6.8 months; 95% CI 5.4-not reached) was similar to that in patients without brain metastases (9.5 months; 95% CI 5.8-not reached). In this study, the most common treatment-related AEs were diarrhea (37.7%), hyperkeratosis, nausea, and rash (25.3% of each). The proportion of patients with treatment-related AEs (Grade3) was 45.1% and 9 (5.6%) patients discontinued treatment. Dose reductions to 600mg and to 400mg were reported in 54 (33.3%) patients and in 7 (4.3%) patients, respectively. One case of toxic epidermal necrolysis (TEN) with fatal outcome was reported.

Conclusions

Olmutinib showed modest activity with tolerable safety profile in patients with T790M+ NSCLC who had previously received an EGFR TKI. Optimal dose of olmutinib is being determined by additional translational studies, to produce more improved therapeutic outcome in phase III clinical trials.

Clinical trial identification

NCT02485652.

Legal entity responsible for the study

Hanmi Pharmaceutical Co., Ltd.

Funding

Hanmi Pharmaceutical Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

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 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.

Clinical trial identification

NCT02125461 (April 25, 2014).

Legal entity responsible for the study

AstraZeneca

Funding

AstraZeneca

Disclosure

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: Seaker honorarium from AstraZeneca. T. Mekhail: 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. S.J. Antonia: Advisory board fees from AstraZeneca.

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%. 

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 LLP

Funding

AstraZeneca LLP

Disclosure

Y. Ohe: Honoraria: AstraZeneca, Chugai, Lilly, ONO, BMS, Daiichi-Sankyo, Nipponkayaku, Boehringer Ingelheim, Bayer, Pfizer, MSD, Taiho. Research Funding : AstraZeneca, Chugai, Lilly, ONO, BMS, Kyorin, Dainippon- Sumitomo, Pfizer, Taiho, Novartis, Merck Serono, Consulting or Advisory Role: AstraZeneca, Chugai, Lilly, ONO, Novartis. S. Ramalingam: Advisory Board Meeting for: AstraZeneca, Bristol-Myers Squibb, Genentech, Boehringer Ingelheim. F. Imamura: Research funding and honoraria from AstraZeneca. N. Nogami: Research funding: AstraZeneca. J. Vansteenkiste: Research funding: AstraZeneca; honoraria/consulting: 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: Employee of AstraZeneca and own AstraZeneca shares. Y. Rukazenkov: Full time employee of AstraZeneca and hold shares in AstraZeneca. J.-C. Soria: Consultancy fees for AstraZeneca, Roche. All other authors have declared no conflicts of interest.

Background

CNS metastases (mets) are common in pts with EGFRm advanced NSCLC. Osimertinib is a third-generation, CNS-active EGFR-TKI that potently and selectively inhibits both EGFRm and EGFR T790M resistance mutations. Preclinical studies have shown CNS penetration of osimertinib, and clinical data from Ph II and III trials showed CNS activity in pts with T790M-positive advanced NSCLC.

Methods

The Ph III FLAURA study (NCT02296125) compared osimertinib vs SoC EGFR-TKI in previously untreated pts with EGFRm advanced NSCLC. 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). Neurologically stable pts with CNS mets were allowed, provided definitive treatment/steroids were completed for ≥2 weeks. A prespecified subgroup analysis investigated CNS activity in pts with CNS mets present on baseline brain scan, as assessed by blinded independent central neuroradiology review (BICR). Endpoints included CNS progression-free survival by RECIST v1.1, CNS objective response rate and duration of CNS response. The CNS full analysis set (cFAS) included pts with ≥1 measurable and/or non-measurable CNS lesion present on baseline brain scan by BICR; the CNS evaluable for response set (cEFR) included only pts with ≥1 measurable CNS lesion.

Results

As of 12 June 2017, 128/556 pts (23%) were included in the cFAS (osimertinib: 61, SoC, 67). Baseline characteristics were balanced across treatment arms (osimertinib/SoC): female 62/61%; Asian, 66/55%, prior brain radiotherapy, 25/24%. Efficacy in the cFAS and cEFR are shown in the table:Table: LBA5

Conclusions

In patients with documented CNS mets by neuroradiology BICR, osimertinib had superior CNS PFS compared to SoC, with a benefit similar to that reported in the overall group of patients. CNS response rate was higher and more durable with osimertinib.

Clinical trial identification

NCT02296125

Legal entity responsible for the study

AstraZeneca

Funding

AstraZeneca

Disclosure

J. Vansteenkiste: Personal fees (lectures and consulting) for AstraZeneca. B.C. Cho: Research funding: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST; Consulting role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Yuhan, Pfizer, Eli Lilly. S. Bohnet: advisory board membership. N. Nogami: Dr. Nogami reports other from AstraZeneca, other from Chugai Pharmaceutical Co., Ltd., other from Pfizer Japan Inc., other from Eli Lilly Japan K.K., other from Ono Pharmaceutical Co., LTD., other from Taiho Pharmaceutical Co., Ltd, outside the submitted work. I. Okamoto: Grants and personal fees from AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Taiho Pharmaceutical, Boehringer Ingelheim, and Pfizer Japan, R. Hodge: Employee and shareholder of AstraZeneca, conducts analysis of osimertinib data at AstraZeneca in addition to the submitted work. A. McKeown: Employee and shareholder: AstraZeneca. A.P. Brown: Employee and stock owner of AstraZeneca. Y. Rukazaencov: Full salaried employee of AstraZeneca and holds shares in AstraZeneca. S. Ramalingam: Advisory boards for Amgen, Astra Zeneca, Abbvie, BMS, Lilly, Celgene, Genentech, and Novartis, outside the submitted work. All other authors have declared no conflicts of interest.