- Pilar Garrido Lopez
- Tony S.K. Mok
LBA7 - Afatinib followed by osimertinib in patients with EGFR mutation-positive advanced NSCLC: A real-world study (GioTag)
- Maximilian J. Hochmair
- Maximilian J. Hochmair
- Alessandro Morabito
- Desiree Hao
- Chen-Ta Yang
- Ross A. Soo
- James C. Yang
- Rasim Gucalp
- Balazs Halmos
- Lara Wang
- Amanda Golembesky
- Angela Märten
- Tanja Cufer
Abstract
Background
Afatinib has demonstrated efficacy in EGFR mutation-positive (EGFRm+) NSCLC; however, resistance develops, most commonly due to the T790M mutation. Osimertinib has shown clinical activity in the treatment of T790M-positive disease following progression on a first-line tyrosine kinase inhibitor. Further information on outcomes of sequencing options is necessary to optimize treatment outcomes.
Methods
This observational study is the first to evaluate outcomes of real-world patients who sequentially received first-line afatinib followed by osimertinib. Data were retrospectively collected for patients with common EGFRm + (Del19, L858R) advanced NSCLC and who acquired T790M after first-line afatinib. Patients must have completed afatinib and started osimertinib treatment ≥10 months prior to data entry. Patients with active brain metastases were excluded. The primary outcome was time on treatment (ToT) from initiation of afatinib until discontinuation of osimertinib.
Results
A total of 204 patients were included; of these, 24.5/67.6% were Asian and non-Asian (Caucasian and African American), 15.3% had ECOG performance status ≥2, and 73.5/26.0% were Del19/L858R-positive. Overall median ToT was 27.6 months (90% CI: 25.9–31.3). Median time on afatinib and osimertinib was 11.9 months (90% CI: 10.9–12.2) and 14.3 months (90% CI: 12.8–15.9), respectively. The 2-year OS rate was 78.9%. ToT was generally consistent across patient subgroups; however, ToT was longer in Asian patients (n = 50; median 46.7 months; 90% CI: 26.8–not reached) and in those with Del19-positive disease (n = 150; median 30.3 months; 90% CI: 27.6–44.5). Patients with poor prognosis, such as those with ECOG PS ≥ 2 (n = 31, median ToT 22.2 months; 90% CI: 16.0–27.0) and stable brain metastases (n = 21, median ToT 19.4 months; 90% CI: 16.0–not reached), also appeared to derive clinical benefit. 6.6% of patients developed brain metastases on afatinib therapy.
Conclusions
In real-world clinical practice, sequential afatinib and osimertinib facilitates prolonged, chemotherapy-free treatment in patients with T790M-acquired resistance, and may be an attractive strategy, especially for Del19-positive tumors.
Editorial acknowledgement
Jane Saunders of GeoMed, an Ashfield company, part of UDG Healthcare plc.
Clinical trial identification
NCT03370770.
Legal entity responsible for the study
Boehringer Ingelheim.
Funding
Boehringer Ingelheim.
Disclosure
M.J. Hochmair: Advisory council or committee: Böhringer Ingelheim, AstraZeneca, Pfizer, MSD, Roche A. Morabito: Honoraria: Boehringer Ingelheim, Roche, AstraZeneca, Pfizer, MSD, Bristol Myers Squibb. D. Hao: Research funding and consultancy: Boehringer Ingelheim and AstraZeneca. R.A. Soo: Grants and personal fees: AstraZeneca; Personal fees: BMS, Boehringer Ingelheim, Celgene, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Ignyta. J.C-H. Yang: Personal fees: BI, Eli Lilly, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi Sankyo, AstraZeneca, Hansoh Pharmaceuticals, Takeda Pharmaceuticals. B. Halmos: Grants and personal fees: Boehringer Ingelheim, AstraZeneca, Pfizer, Novartis, Takeda, Personal fees: Genentech/Roche, Grants: Merck. L. Wang, A. Golembesky, A. Märten: Employed by Boehringer Ingelheim. T. Cufer: Consultancy and honoraria: AstraZeneca, Roche, Pfizer, MSD, Bristol Myers Squibb, Boehringer Ingelheim. All other authors have declared no conflicts of interest.
LBA8 - Mechanisms of acquired resistance to first-line osimertinib: Preliminary data from the phase III FLAURA study
- Byoung Chul Cho
- Byoung Chul Cho
- Ying Cheng
- Caicun Zhou
- Yuichiro Ohe
- Fumio Imamura
- Meng-Chih Lin
- Margarita Majem
- Riyaz Shah
- Yuri Rukazenkov
- Alexander Todd
- Aleksandra Markovets
- Carl Barrett
- Juliann Chmielecki
- Jhanelle E. Gray
- Suresh S. Ramalingam
Abstract
Background
In the Phase III FLAURA study (NCT02296125), osimertinib showed superior efficacy compared with standard of care (SoC) EGFR-TKIs in patients (pts) with previously untreated EGFRm advanced NSCLC. Here, we report preliminary data on mechanisms of acquired resistance to osimertinib in pts who progressed during the FLAURA study.
Methods
Pts with previously untreated EGFRm (tissue, ex19del/L858R) advanced NSCLC (N = 556) were randomised 1:1 to osimertinib 80 mg once daily (QD; n = 279) or SoC EGFR-TKI (n = 277, gefitinib 250 mg QD or erlotinib 150 mg QD). Paired plasma samples were collected at baseline and following RECIST progression and/or treatment discontinuation up to March 2018. Plasma samples were analysed using next generation sequencing (NGS, Guardant Health; Guardant360 73 gene panel or Omni 500 gene panel).
Results
In the osimertinib and SoC EGFR-TKI arms, respectively, 113/279 (41%) and 159/277 (57%) pts had experienced a progression event and/or discontinued treatment and had paired plasma samples analysed by NGS. Only pts with detectable plasma EGFRm (ex19del/L858R) at baseline were evaluable for this analysis: 91/113 (81%; osimertinib) and 129/159 (81%; SoC). In the osimertinib arm, there was no evidence of acquired EGFR T790M and the most common acquired resistance mechanism detected was MET amplification (amp; 14/91; 15%), followed by EGFR C797S mutation (6/91; 7%); other mechanisms included HER2 amp, PIK3CA and RAS mutations (2–7%). In the SoC arm, the most common resistance mechanisms were T790M mutation (60/129; 47%), MET amp (5/129; 4%) and HER2 amp (3/129; 2%).
Conclusions
In this paired sample preliminary analysis of a subpopulation of pts (with detectable baseline plasma EGFRm) who had experienced disease progression and/or discontinued treatment, heterogeneous resistance mechanisms were detected with first-line osimertinib, with MET amplification and EGFR C797S mutation being the most commonly observed. In line with previous analyses, T790M was acquired in approximately 50% of SoC-treated pts, and none of the osimertinib-treated pts; no unexpected resistance mechanisms were observed in osimertinib-treated pts. Exploration into novel acquired mutations is ongoing.
Editorial acknowledgement
Ellen Maxwell, PhD, from iMed Comms, funded by AstraZeneca in accordance with Good Publications Practice (GPP3) guidelines (ismpp.org/gpp3).
Clinical trial identification
NCT02296125.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
B.C. Cho: Honoraria/advisory boards: AstraZeneca, Roche, Boehringer Ingelheim, Novartis, MSD, Yuhan; Research grants: AstraZeneca, Novartis, Yuhan; Speakers\' bureaus: AstraZeneca, Novartis, MSD, Yuhan. C. Zhou: Honoraria: Roche, Eli Lilly, BI, Merck, Hengrui, Qiru. Y. Ohe: Grants/personal fees: AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Chugai, MSD, Novartis, Kyorin, Dainippon-Sumitomo, Daiichi-Sankyo, Boehringer Ingelheim, Bayer, Lilly, Pfizer, Ignyta, Kissei. F. Imamura: Honoraria and research grants: AstraZeneca. R. Shah: Advisory boards: AstraZeneca. Y. Rukazenkov: Employee, shareholder: AstraZeneca. A. Todd: Employee of AstraZeneca. A. Markovets, J. Chmielecki: Employee, shareholder: AstraZeneca. C. Barrett: Employee, stock holder: AstraZeneca. J.E. Gray: Advisor: AstraZeneca; Research grant: AstraZeneca and Genentech for work not directly related to this project. S.S. Ramalingam: Advisory board membership: Abbvie, Amgen, AstraZeneca, BMS, Celgene, Genentech, Lilly, Merck, Roche, Nektar, Loxo, Takeda. All other authors have declared no conflicts of interest.
Invited discussant
- Simon Ekman
- Simon Ekman
LBA9 - IMpower150: An exploratory analysis of efficacy outcomes in patients with EGFR mutations
- Tony S.K. Mok
- Tony S.K. Mok
- Mark A. Socinski
- Martin Reck
- Robert M. Jotte
- Darren W. Lim
- Federico Cappuzzo
- Francisco Javier Orlandi
- Daniil Stroyakovskiy
- Naoyuki Nogami
- Delvys Rodríguez-Abreu
- Denis Moro-Siblot
- Christian A. Thomas
- Fabrice Barlesi
- Gene Finley
- Anthony Lee
- Geetha Shankar
- Wei Yu
- Marcin Kowanetz
- Wei Lin
- Makoto Nishio
Abstract
Background
Atezolizumab (atezo; anti–PD-L1) inhibits PD-L1 to restore anticancer immunity; bevacizumab (bev) may enhance atezo efficacy by inhibiting VEGF immunosuppression and promoting T-cell tumour infiltration. Atezo + bev + chemotherapy (chemo) prolonged PFS and OS vs bev + CP in pts with first-line nonsquamous NSCLC in the randomised Ph III IMpower150 study, including pts with EGFR or ALK genomic alterations. Here, we further analyse the efficacy of atezo and/or bev with chemo in pts with EGFR mutations (EGFR-mt) in this study.
Methods
The 1202 enrolled pts received atezo (A) 1200 mg + bev (B) 15 mg/kg + carboplatin (C) AUC 6 + paclitaxel (P) 200 mg/m2 (ABCP) or A + C + P (ACP) or B + C + P (BCP) by IV q3w for 4 or 6 cycles per investigator (INV) decision, then q3w maintenance with atezo + bev, atezo or bev, respectively. Co-primary endpoints were OS and INV-assessed PFS in the ITT–wild-type population (excluded pts with EGFR or ALK genomic alterations). Exploratory analyses included OS and INV-assessed PFS in pts with EGFR-mt disease, pts with sensitising EGFR mutations and pts with EGFR-mt disease who had prior TKI therapy.
Results
These data represent ≥ 20-mo follow-up (data cutoff: 22 Jan 2018) in the ITT population. 124 pts were EGFR-mt, including 91 with a sensitising mutation. Baseline characteristics of EGFR-mt pts across the treatment arms were generally comparable to the ITT population. OS was improved with ABCP vs BCP in EGFR-mt pts, especially in pts with sensitising EGFR mutations (HR, 0.31 [95% CI: 0.11, 0.83]). This benefit extended to PFS (HR, 0.41 [95% CI: 0.23, 0.75]). See table for full efficacy results. Safety was similar between the EGFR-mt subgroup and the ITT population.
Conclusions
IMpower150 is the first randomised Ph III trial of a checkpoint inhibitor to show a benefit in pretreated EGFR-mt pts. Adding atezo to standard-of-care bev and chemo provided survival benefit in EGFR-mt pts who have failed TKIs, for whom this regimen may represent a new treatment option. Sensitising EGFR mutations are defined as exon 19 deletions or L858R mutations. NE, not estimable.mOS, mo HR (95% CI) ABCP ACP BCP ABCP vs BCP ACP vs BCP EGFR-mt NE n = 34 21.4 n = 45 18.7 n = 45 0.61 (0.29, 1.28) 0.93 (0.51, 1.68) Sensitising EGFR mutationa NE n = 26 21.2 n = 33 17.5 n = 32 0.31 (0.11, 0.83) 0.90 (0.47, 1.74) Received prior TKI therapy NE n = 22 18.4 n = 27 17.5 n = 28 0.39 (0.14, 1.07) 0.99 (0.49, 1.98) mPFS, mo HR (95% CI) EGFR-mt 10.2 n = 34 6.9 n = 45 6.9 n = 45 0.61 (0.36, 1.03) 1.14 (0.73, 1.78) Sensitising EGFR mutationa 10.3 n = 26 6.0 n = 33 6.1 n = 32 0.41 (0.23, 0.75) 1.01 (0.61, 1.70) Received prior TKI therapy 9.7 n = 22 5.7 n = 27 6.1 n = 28 0.42 (0.22, 0.80) 1.20 (0.69, 2.09)
Editorial acknowledgement
Jessica Bessler of Health Interactions, funded by F. Hoffmann-La Roche.
Clinical trial identification
NCT02366143.
Legal entity responsible for the study
F. Hoffmann-La Roche.
Funding
F. Hoffmann-La Roche.
Disclosure
T.S.K. Mok: Honor/Speaker B: AZ, BI, Roche, Pfizer, Lilly, Merck, MSD, Novartis, SFJ, ACEA, Vertex, BMS, geneDecode, OncoGenex, Celgene, Ignyta, Cirina, Fishawack, Sanomics*, Janssen, Takeda, Chi-Med*, OrigiMed, Hengrui, Sanofi, Yuhan(*Stock) Employee: CUHK. M.A. Socinski: Honoraria, Speakers\' bureau, Research Funding Genentech. M. Reck: Advisor/Board member: Lilly, Roche, BI, BMS, MSD, AstraZeneca, Merck, Novartis, Pfizer, Celgene; Speakers’ bureau: Roche, Lilly, Pfizer, BI, AstraZeneca, MSD, BMS, Merck, Novartis, Pfizer, Celgene. R.M. Jotte: Speakers\' bureau, Travel and accommodation expenses, Honoraria: Bristol-Myers Squibb. F. Cappuzzo: Speakers or advisory board: Roche, AZ, BMS, Pfizer, MSD, Takeda. F.J. Orlandi: Consulting/advisory role: AZ, Roche, BMS, MSD, Lilly, Pfizer Travel and accommodation expenses: Pfizer, MSD, AZ, Roche, BMS; Research Funding AZ, Amgen, Roche, BI, Astellas Medivation, MSD, BMS, Celltrion; Speakers: AstraZEneca. N. Nogami: Honoraria: AstraZeneca, Pfizer Inc., Ono Pharmaceutical CO., Ltd., Kyowa Hakko Kirin, Taiho Phamaceutical Co.,Ltd., Chugai Pharmaceutical Co., Ltd, Eli Lilly Japan, Boehringer Ingelheim, MSD KK. D. Rodríguez-Abreu: Speakers\' bureau: MSD, Roche, BMS, AstraZeneca, Pfizer. D. Moro-Siblot: Honoraria, consulting/advisory role: Roche, MSD, Pfizer, Novartis, BMS, AstraZeneca, Lilly; Travel and accommodation expenses: Roche, MSD, Pfizer, BMS, AstraZeneca. F. Barlesi: Personal fees: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer. G. Finley: Promotional speaking: Bristol Meyers, Boehringer Ingleheim, Astellas Medivation, Merck. A. Lee: Employee, owner of stock: Genentech. G. Shankar, W. Yu: Employee: Genentech. M. Kowanetz: Genentech Employee with Roche Stock. Patent biomarkers and methods of treating PD-1 and PD-l1 related conditions pending. W. Lin: Employee: Genentech; Stock owner: Roche. M. Nishio: Speakers/advisory: Ono Pharma, BMS, Pfizer, Chugai Pharma, Lilly, Taiho Pharma, AZ, BI, MSD, Novartis, Daiichi Sankyo, Merck Serono; Research Funding MSD, Novartis, Ono Pharma, Chugai Pharma, BMS, Taiho Pharma, Lilly, AZ, Pfizer, Astellas. All other authors have declared no conflicts of interest.
Invited discussant
- Shun Lu
- Shun Lu
547O - Stereotactic Ablative Radiotherapy for oligometastatic cancers: Efficacy and Toxicity Results from the randomized SABR-COMET Trial
- Suresh Senan
- Suresh Senan
- Robert Olson
- Stephen Harrow
- Stewart Gaede
- Alexander Louie
- Cornelius Haasbeek
- Liam Mulroy
- Michael Lock
- George Rodrigues
- Brian Yaremko
- Devin Schellenberg
- Belal Ahmad
- Gwendolyn Griffioen
- Sashendra Senthi
- Mitchell Liu
- Karen Moore
- Suzanne Currie
- Glenn Bauman
- Andrew Warner
- David Palma
Abstract
Background
Patients with a limited number of metastases may have a survival benefit if all disease sites are eradicated. We performed a randomized trial to study the impact of stereotactic ablative radiotherapy (SABR) in patients presenting with metachronous oligometastases.
Methods
Eligible patients had a controlled primary malignancy with 1-5 metastatic lesions, all of which were suitable for SABR, had an ECOG performance status 0-1, and life expectancy >6 months. Stratification was by number of metastases (1-3 vs. 4-5). Randomization was in a 1:2 ratio between palliative standard of care (SOC) [Arm 1] vs. SOC plus SABR to all metastatic lesions [Arm 2]. The primary endpoint was overall survival (OS). A randomized phase II screening design was employed with a two-sided alpha of 0.20 (wherein a p-value <0.20 designates a positive trial) to provide an initial comparison of the two treatment strategies. Secondary endpoints included progression-free survival (PFS), toxicity, and QOL (assessed using the FACT-G).
Results
Between 2012-2016, 99 patients were randomized (33 in Arm 1, 66 in Arm 2) at centres in Canada, Europe and Australia. Median age was 68 (range 43-89) and the commonest primary tumor types were breast (n = 18), lung (n = 18), colorectal (n = 18) and prostate (n = 16). Most patients (n = 92) had 1-3 metastases. Median follow-up was 26 months. Median OS was 28 months in Arm 1 (95% CI 19-33 months) vs. 41 months in Arm 2 (95% CI: 26 months to ‘not reached’; stratified log-rank p = 0.09). Median PFS was 6.0 months in Arm 1 (95% CI: 3.4-7.1 months) vs. 12 months in Arm 2 (95% CI: 6.9-30 months; stratified log-rank p = 0.001). Grade ≥2 treatment related adverse events occurred in 9% in Arm 1, and 29% in Arm 2 (p = 0.026). No differences in overall FACT-G scores were seen at 6 months (mean 82.5 vs. 82.6 respectively; p = 0.992). Rates of related grade ≥ 2 toxicity after SABR were 25% for lung lesions, 31% for bony lesions, 33% for liver and 57% for adrenals (p = 0.45). Lesional control rates after SABR ranged from 100% (in adrenals), 76% (bone), 75% (liver) and 70% (lung), p = 0.56.
Conclusions
SABR for oligometastases was associated with an improvement in OS, and a doubling in PFS. Future studies should evaluate techniques to improve lesional control rates.
Clinical trial identification
NCT01446744.
Legal entity responsible for the study
Ontario Institute for Cancer Research.
Funding
Ontario Institute for Cancer Research, and a London Regional Cancer Program Catalyst Grant.
Disclosure
S. Senan: Departmental research Funding ViewRay Inc, Varian Medical Systems; Advisory boards: AstraZeneca, Celgene, MSD. R. Olson, D. Schellenberg: Research Funding Varian Medical Systems. All other authors have declared no conflicts of interest.
Invited discussant
- Melvin Lee Kiang Chua
- Melvin Lee Kiang Chua