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Browsing Over 190 Presentations
78MO - Early safety assessment of durvalumab after sCRT in patients with Stage III, unresectable NSCLC (PACIFIC-6)
- M. Garassino (Chicago, IL, United States of America)
- M. Garassino (Chicago, IL, United States of America)
- J. Mazieres (Toulouse, France)
- M. Reck (Grosshansdorf, Germany)
- A. Delmonte (Meldola, Italy)
- H. Bischoff (Heidelberg, Germany)
- R. Bernabe (Seville, Spain)
- I. Díaz Pérez (Gaithersburg, MD, United States of America)
- W. Sawyer (Cambridge, United Kingdom)
- N. Trunova (Gaithersburg, MD, United States of America)
- C. Faivre-Finn (Manchester, United Kingdom)
Abstract
Background
In the ph III PACIFIC trial, durvalumab after concurrent chemoradiotherapy (cCRT) significantly improved survival outcomes in pts with Stage III, unresectable NSCLC with manageable safety. As many pts are ineligible for cCRT, we aimed to assess durvalumab after sequential (s)CRT in pts with Stage III, unresectable NSCLC in the ph II PACIFIC-6 trial (NCT03693300).
Methods
Up to 120 pts with ECOG PS ≤2 and no progression after sCRT will receive durvalumab 1500 mg IV q4w ≤24 months or until progression, unacceptable toxicity or consent withdrawal. The primary endpoint is assessment of safety/tolerability, defined by gr 3/4 treatment-related AEs occurring within 6 months. Pre-specified early assessment was planned after ≥50 pts in a PS 0/1 cohort (∼100–120 expected) had received durvalumab ≥6 months.
Results
As of August 24, 2020, 50 pts with ECOG PS 0/1 (46%/54%) had received durvalumab for a median 24.0 weeks. Median age was 67.0 years; 64% were male; 64% had adenocarcinoma histology; 38%/52%/10% had Stage IIIA/B/C disease; and 48%/52% had PD-L1 tumor cell expression ≥/< 1%. Many pts had past/present medical conditions, including vascular (62%), metabolism (54%) and respiratory (50%) disorders. Pts had received a median 4 CT cycles, with 68% receiving a total RT dose of ≥54 to ≤60 Gy and 32% receiving >60 to ≤66 Gy. In most pts (84%), CT and RT did not overlap. Best response to prior sCRT (RECIST 1.1) included PR (74%) and SD (18%). In all, 88% had any AEs and 12% had gr 3/4 AEs; 70% had any possibly related AEs (PRAEs) and 4% had gr 3/4 PRAEs (including 2% with the gr 3/4 PRAE pneumonitis). 22% had SAEs (10% PRSAEs) and 2 pts had fatal AEs (1 pt fatal PRAE). 72% had AESIs, including pneumonitis (32%) and dermatitis/rash (28%). 9/25 pts who discontinued did so due to AEs, most commonly pneumonitis (n = 8).
Conclusions
Based on early assessment, durvalumab after sCRT appears to have a similar safety profile to that with durvalumab after cCRT in PACIFIC pts with Stage III, unresectable NSCLC. Full cohort results for safety primary analysis in the near future are awaited.
Clinical trial identification
NCT03693300.
Editorial acknowledgement
Medical writing support, which was in accordance with Good Publication Practice (GPP3) guidelines, was provided by Andrew Gannon of Cirrus Communications (New York, NY), an Ashfield company, and was funded by AstraZeneca.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
M.C. Garassino: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), PI, MISP in Thimic malignancies; Speaker, advisory board: Eli Lilly; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), Local PI, Enrollment in clinical Trials in NSCLC; Speaker;advisory board: Otsuka Pharma; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), PI, Enrollment and Steering Committee in clinical Trials in NSCLC; Consulting, advisory boards, lectures; steering committee: AstraZeneca; Advisory/Consultancy, Research grant/Funding (self), PI, Enrollment in clinical Trials in NSCLC; advisory board: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), PI, Enrollment in clinical Trials in NSCLC; Speaker, advisory board: BMS; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), PI, Enrollment in clinical Trials in NSCLC; Speaker, advisory board: Roche; Advisory/Consultancy, Research grant/Funding (self), PI, MISP MISP Sunitinib in thymic malignancies; advisory board: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), PI, Enrollment in clinical Trials in NSCLC; Speaker, advisory board: Celgene; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Incyte; Advisory/Consultancy: Inivata; Advisory/Consultancy, Speaker Bureau/Expert testimony: Takeda; Research grant/Funding (self), PI, Enrollment in clinical Trials Thimic malignancies: Tiziana Sciences; Research grant/Funding (self), PI, Enrollment in clinical Trials in NSCLC: Clovis; Research grant/Funding (self), PI, Enrollment in clinical Trials in NSCLC: Merck Serono; Advisory/Consultancy, Research grant/Funding (self), PI, Enrollment in clinical Trials in Mesothelioma; advisory board: Bayer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (self), PI, Enrollment in clinical Trials in NSCLC; consulting, advisory boards, lectures; steering committee: MSD; Advisory/Consultancy, Research grant/Funding (self), Local PI, Enrollment and Steering committee in clinical Trials in NSCLC; advisory board: GlaxoSmithKline S.p.A.; Advisory/Consultancy, Research grant/Funding (self), Advisory board; PI, Enrollment in clinical Trials: Sanofi-Aventis; Advisory/Consultancy, Research grant/Funding (self), PI, Enrollment in clinical Trials; Advisory board; steering committee: Spectrum Pharmaceutcials; Advisory/Consultancy, Research grant/Funding (self), PI, Enrollment in clinical Trials; Advisory board; steering committee: Blueprint Medicine; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Daiichi Sankyo; Research grant/Funding (institution): Merck KGaA; Advisory/Consultancy, Research grant/Funding (self): Janssen; Non-remunerated activity/ies, Principal Investigator Keynote 189;MISP pembrolizumab in low expressors PD-L1(J. Mazieres: Advisory/Consultancy: Merck; Advisory/Consultancy, Research grant/Funding (self): Roche; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Hengrui; Advisory/Consultancy: Daiichi; Advisory/Consultancy: Boehringer; Advisory/Consultancy, Research grant/Funding (self): Pierre Fabre. M. Reck: Honoraria (self), Honoraria for lectures and consultancy: Amgen; Honoraria (self), Honoraria for lectures and consultancy: AstraZeneca; Honoraria (self), Honoraria for lectures and consultancy: BMS; Honoraria (self), Honoraria for lectures and consultancy: Boehringer Ingelheim; Honoraria (self), Honoraria for lectures and consultancy: Lilly; Honoraria (self), Honoraria for lectures and consultancy: Merck; Honoraria (self), Honoraria for lectures and consultancy: MSD; Honoraria (self), Honoraria for lectures and consultancy: Novartis; Honoraria (self), Honoraria for lectures and consultancy: Pfizer; Honoraria (self), Honoraria for lectures and consultancy: Roche; Honoraria (self), Honoraria for lectures and consultancy: Samsung. R. Bernabe: Research grant/Funding (institution): Roche. I. Diaz Perez: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. W. Sawyer: Full/Part-time employment, Contractor: AstraZeneca. N. Trunova: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. C. Faivre-Finn: Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: AstraZeneca; Research grant/Funding (self), Travel/Accommodation/Expenses: Elekta. All other authors have declared no conflicts of interest.
Is there a role for I-O in the peri-operative setting for NSCLC?
- H. Wakelee (Stanford, CA, United States of America)
- H. Wakelee (Stanford, CA, United States of America)
Q&A and live discussion
- A. Speakers (, Switzerland)
- A. Speakers (, Switzerland)
Welcome and Introduction
- M. Perol (Lyon, France)
- M. Perol (Lyon, France)
Your perspective and personal story
- F. Blackhall (Manchester, United Kingdom)
- F. Blackhall (Manchester, United Kingdom)
Radiotherapy: Revisiting indication and techniques
- D. Gomez (New York, NY, United States of America)
- D. Gomez (New York, NY, United States of America)
Systemic treatment for non-oncogene addicted NSCLC
- L. Hendriks (Maastricht, Netherlands)
- L. Hendriks (Maastricht, Netherlands)
How is pandemic affecting women careers?
- P. Garrido Lopez (Madrid, Spain)
- P. Garrido Lopez (Madrid, Spain)
Innovation in limited disease
- C. Faivre-Finn (Manchester, United Kingdom)
- C. Faivre-Finn (Manchester, United Kingdom)
Welcome and introduction
- M. Reck (Grosshansdorf, Germany)
- M. Reck (Grosshansdorf, Germany)
Invited Discussant 203MO and 61MO
- Y. Lievens (Gent, Belgium)
- Y. Lievens (Gent, Belgium)
99O_PR - KRYSTAL-1: Activity and Preliminary Pharmacodynamic (PD) Analysis of Adagrasib (MRTX849) in Patients (Pts) With Advanced Non-Small- Cell Lung Cancer (NSCLC) Harboring KRASG12C Mutation
- G. Riely (New York, NY, United States of America)
- G. Riely (New York, NY, United States of America)
- S. Ou (Orange, CA, United States of America)
- I. Rybkin (Detroit, United States of America)
- A. Spira (Fairfax, United States of America)
- K. Papadopoulos (San Antonio, TX, United States of America)
- J. Sabari (New York, NY, United States of America)
- M. Johnson (Nashville, TN, United States of America)
- R. Heist (Boston, MA, United States of America)
- L. Bazhenova (La Jolla, CA, United States of America)
- M. Barve (Dallas, TX, United States of America)
- J. Pacheco (Aurora, United States of America)
- K. Velastegui (San Diego, CA, United States of America)
- C. Cilliers (San Diego, CA, United States of America)
- P. Olson (San Diego, CA, United States of America)
- J. Christensen (San Diego, CA, United States of America)
- T. Kheoh (San Diego, CA, United States of America)
- R. Chao (San Diego, CA, United States of America)
- P. Janne (Boston, MA, United States of America)
Abstract
Background
KRAS, the most frequently mutated oncogene in cancer, is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRASG12C mutations occur in approximately 14% of NSCLC (adenocarcinoma). Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRASG12C that irreversibly and selectively binds to KRASG12C, locking it in its inactive state and was optimized for favorable PK properties, including oral bioavailability, long half-life (∼24 h), and extensive tissue distribution.
Methods
KRYSTAL-1 (NCT03785249) is a multi-cohort phase I/II study evaluating adagrasib in pts with advanced or metastatic solid tumors, including NSCLC, harboring a KRASG12C mutation previously treated with chemotherapy and an anti-PD-(L)1. Exploratory endpoints include correlative analysis of co-occurring genetic alterations in tumor tissue at baseline and evaluation of the modulation of PD markers, including transcriptomics, in pretreatment and on-study biopsies.
Results
As of 30 August 2020, 79 pts with pretreated NSCLC were treated with adagrasib 600 mg BID (phase I/Ib and phase II). Most commonly reported (>20%) TRAEs included: nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased ALT (23%). Among the 51 pts evaluable for clinical activity, 45% (23/51) had a partial response (PR) and 26 pts had stable disease (SD). In a subpopulation of pts with STK11-comutations, ORR was 64% (9/14). Preliminary PD and mechanistic biomarker analyses on pre- and post-treatment tumor NSCLC biopsies (n = 3) demonstrate downregulation of KRAS/MAPK pathway genes including DUSP6 and SPRY4. In pts with tumors harboring STK11-comutations, there was minimal expression of immune transcripts (eg, CD4 and CD8) at baseline and these transcripts were increased after treatment with adagrasib suggesting a potential immune response to therapy.
Conclusions
Adagrasib is tolerable and has demonstrated clinical activity in pts with previously treated KRASG12C-mutant NSCLC. Additional PD and mechanistic data will be presented.
Clinical trial identification
NCT03785249.
Editorial acknowledgement
Editorial support was provided by Robin Serody of Axiom Healthcare Strategies.
Legal entity responsible for the study
Mirati Therapeutics, Inc.
Funding
Mirati Therapeutics, Inc.
Disclosure
G.J. Riely: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda; Advisory/Consultancy: Mirati Therapeutics. S-H.I. Ou: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: TP Therapeutics; Speaker Bureau/Expert testimony: Genentech; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Takeda; Shareholder/Stockholder/Stock options: Turning Point Therapeutics. I. Rybkin: Advisory/Consultancy: AstraZeneca. A. Spira: Shareholder/Stockholder/Stock options: Lilly; Advisory/Consultancy: Incyte; Advisory/Consultancy: Amgen; Advisory/Consultancy: Novartis; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Gritstone; Advisory/Consultancy: Jazz Pharmaceuticals; Honoraria (self): CytomX Therapeutics; Honoraria (self): AstraZeneca/MedImmune; Honoraria (self): Merck; Honoraria (self): Takeda; Honoraria (self): Amgen; Honoraria (self): Janssen Oncology; Honoraria (self): Novartis; Honoraria (self): Bristol Myers Squibb; Honoraria (self): Bayer. K. Papadopoulos: Advisory/Consultancy: Bayer; Advisory/Consultancy: ArQule; Advisory/Consultancy: Basilea. M. Johnson: Spouse/Financial dependant: Otsuka; Travel/Accommodation/Expenses: AbbVie; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Genentech; Travel/Accommodation/Expenses: Incyte; Travel/Accommodation/Expenses: Merck; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Sanofi. R.S. Heist: Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Tarveda; Advisory/Consultancy: Apollonia; Honoraria (self): Chugai/Roche. L. Bazhenova: Shareholder/Stockholder/Stock options: Epic Sciences; Advisory/Consultancy, Research grant/Funding (self): Beyond Spring Pharmaceuticals; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: Roche; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: G1; Advisory/Consultancy: Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Merck; Advisory/Consultancy: Johnson & Johnson; Advisory/Consultancy: BMSi; Advisory/Consultancy: Daichi Sankyo; Advisory/Consultancy: Neuvogen. J.M. Pacheco: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Hengrui; Advisory/Consultancy: Gerson Lehrman; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Takeda. K. Velastegui: Full/Part-time employment: Mirati Therapeutics, Inc. C. Cilliers: Full/Part-time employment: Mirati Therapeutics, Inc. P. Olson: Full/Part-time employment: Mirati Therapeutics, Inc. J.G. Christensen: Leadership role, Shareholder/Stockholder/Stock options, Officer/Board of Directors: Mirati Therapeutics, Inc; Advisory/Consultancy: BridgeBio; Leadership role, Shareholder/Stockholder/Stock options: BCTG Acquisition; Shareholder/Stockholder/Stock options: Bluebird Bio. T. Kheoh: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc; Shareholder/Stockholder/Stock options: Tocagen. R.C. Chao: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc. P.A. Jänne: Shareholder/Stockholder/Stock options: Gatekeeper Pharmaceuticals; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Loxo; Research grant/Funding (self): Revolution Medicines; Advisory/Consultancy, Research grant/Funding (self): Takeda; Research grant/Funding (self): Puma Biotechnology; Advisory/Consultancy, Research grant/Funding (self): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (self): Lilly; Advisory/Consultancy, Research grant/Funding (self): Daichi Sankyo; Research grant/Funding (self): Astellas; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Chugai; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Araxes; Advisory/Consultancy: Ignyta; Advisory/Consultancy: Novartis; Advisory/Consultancy: Biocartis; Advisory/Consultancy: Voronoi; Advisory/Consultancy: SFJ Pharmaceuticals; Advisory/Consultancy: Silicon Therapeutics. All other authors have declared no conflicts of interest.