Displaying One Session

Alicante Auditorium (Hall 3) Poster Discussion session
Date
28.09.2019
Time
16:30 - 18:00
Location
Alicante Auditorium (Hall 3)
Chairs
  • Christian Dittrich (Vienna, Austria)
  • Hendrik-Tobias Arkenau (London, United Kingdom)
  • Udai Banerji (Sutton, Surrey, United Kingdom)
  • Ulrik N. Lassen (Copenhagen, Denmark)
Poster Discussion – Developmental therapeutics Poster Discussion session

443PD - Genomic characteristics and predicted ancestry of NTRK1/2/3 and ROS1 fusion-positive tumours from >165,000 pan-solid tumours (ID 5576)

Presentation Number
443PD
Lecture Time
16:30 - 16:30
Speakers
  • Timothy R Wilson (South San Francisco, CA, United States of America)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

Fusions involving ROS1 or NTRK1/2/3 are oncogenic drivers that occur in < 1% of solid tumors. Small molecule inhibitors of NTRK (e.g. entrectinib and larotrectinib) and ROS1 (e.g. entrectinib and crizotinib) have shown clinically meaningful responses in NTRK fusion + solid tumors and in ROS1 fusion + NSCLC. We assessed the genomic landscape in these rare tumors to test for co-occurrence of clinically relevant biomarkers that may impact response to these inhibitors.

Methods

Comprehensive genomic profiling of > 300 cancer-related genes, including tumor mutational burden (TMB) and predicted ancestry, was done at Foundation Medicine on 166,067 tumors from 75 solid tumor types, most from the US. Odds ratios for mutational co-occurrence were generated using Fisher’s exact test.

Results

Across all solid tumors, NTRK and ROS1 fusions were statistically significantly mutually exclusive with driver alterations in KRAS, APC and PIK3CA. ROS1 fusions were also mutually exclusive with BRAF, PTEN and FBXW7. There was significant co-occurrence of NTRK fusions with alterations in 15 genes, including IGF1R, CDKN2B and CDK4. ROS1 fusions co-occurred with alterations in SMARCD1, CDKN2A/B and SETD2. No enrichment or exclusivity was seen with clinically actionable biomarkers such as EGFR, ERBB2, RET, ALK or MET. TMB was similar in NTRK and ROS1 fusion + vs – tumors. There was a higher NTRK prevalence in patients with primarily East Asian ancestry (0.46%, p = 0.015) compared to South Asian (0.37%), American (0.34%), European (0.29%) or African (0.32%) ancestry, while there was a higher prevalence of ROS1 across all tumor types in East (0.74%, p < 0.001) and South (0.78%, p = 0.001) Asian ancestry groups compared to American (0.40%), European (0.31%) or African (0.31%) ancestry.

Conclusions

Across tumor types, NTRK and ROS1 fusions generally did not co-occur with clinically actionable alterations (e.g. EGFR, ERBB2) or alterations that are clear oncogenes (e.g. KRAS, BRAF). ROS1 and NTRK fusions occur at a slightly higher frequency in patients of primarily Asian ancestry compared to other ancestries. Future studies will evaluate these implications on response to NTRK and ROS1 inhibitors.

Legal entity responsible for the study

F. Hoffmann-La Roche.

Funding

F. Hoffmann-La Roche.

Disclosure

T.R. Wilson: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech. E.S. Sokol: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Foundation Medicine. S.E. Trabucco: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Foundation Medicine. J.Y. Newberg: Full / Part-time employment: Foundation Medicine. B. Simmons: Full / Part-time employment: Roche; Full / Part-time employment: Genentech. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche; Full / Part-time employment: Genentech. S.L. Maund: Full / Part-time employment: Genentech.

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Poster Discussion – Developmental therapeutics Poster Discussion session

LBA28 - Genomic landscape of entrectinib resistance from ctDNA analysis in STARTRK-2 (ID 5510)

Presentation Number
LBA28
Lecture Time
16:30 - 16:30
Speakers
  • Robert Charles Doebele (Aurora, CO, United States of America)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

Entrectinib is a small molecule inhibitor of ROS1 and TRKA,B,C, with deep and durable responses observed in ROS1 fusion-positive NSCLC (ROS1+) and NTRK1,2,3 fusion-positive solid tumours (NTRK+). Despite clinically meaningful activity, progression on entrectinib eventually occurs. Understanding the mechanisms of resistance could inform subsequent new personalised therapeutic options in these patients.

Methods

Blood samples were collected at baseline and at the time of progression from most patients in the NTRK+ and ROS1+ patient populations enrolled on STARTRK-2 (NCT02568267). These were tested using the Foundation Medicine FoundationOne Liquid NGS-based test that assesses base substitutions, indels and rearrangements from 324 genes (including ROS1 and NTRK1,2,3), as well as copy number alterations from select genes using circulating tumour DNA (ctDNA) extracted from the plasma of patients from pre-treatment and following progression on entrectinib.

Results

Of the 54 patients with NTRK+ tumours, 29 had paired samples at baseline and at progression at the time of data cut-off. Ten patients (34%) had a detectable NTRK solvent front mutation at disease progression (NTRK1: n = 5; NTRK3: n = 5), which were not detected in the pre-treatment sample. BRAF V600E and KRAS G12D mutations were detected at progression from a pancreatic cancer patient who had a partial response. Of the 53 patients with ROS1+ NSCLC, 18 had paired samples at baseline and at progression at the time of data cut-off. Four CD74-ROS1 and one SLC34A2-ROS1 patients showed the emergence of an acquired ROS1 resistance mutation (G2032R and F2004C/I) at disease progression (28%), which were not present before treatment. One NRAS Q61K mutation was detected at the end of treatment collection sample from a patient who had a partial response.

Conclusions

From blood analysis, acquired resistance mutations were detected in 34% of NTRK+ solid tumour and 28% of the ROS1+ NSCLC cohorts, all of which were mutations in the kinase domain of the oncogenic driver. One additional patient from each cohort showed the emergence of a mutation in an oncogene within the MAPK pathway. Resistance to entrectinib can occur by multiple mechanisms, which should be studied in larger cohorts.

Clinical trial identification

NCT02568267.

Legal entity responsible for the study

F. Hoffman-La Roche.

Funding

F. Hoffman-La Roche.

Disclosure

R.C. Doebele: Shareholder / Stockholder / Stock options: Rain Therapeutics; Advisory / Consultancy: Chair of Scientific Advisory Board for Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer, Trovagene, Ariad, Takeda, AstraZeneca, Genentech/Roche, Ignyta, Loxo, Rain.; Research grant / Funding (self), Research grant / Funding (institution): Ignyta, Loxo, Mirati.; Licensing / Royalties: Abbott Molecular, Rain Therapeutics, GVKbio, Chugai, Loxo, Ignyta, Genentech, Ariad, Foundation Medicine, Black Diamond.. R. Dziadziuszko: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis; Research grant / Funding (institution): Roche, Bristol-Myers Squibb, Merck, AstraZeneca, Pfizer, Novartis, Boehringer Ingelheim, Clovis; Travel / Accommodation / Expenses: Travels: Roche, AstraZeneca. A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health; Research grant / Funding (institution): Pfizer, Exelixis, GlaxoSmithKlein, Teva, Taiho, PharmaMar; Research grant / Funding (self): Foundation Medicine; Travel / Accommodation / Expenses: Merck - Food/Beverage, Puma - Food/Beverage; Honoraria (self): Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice. A. Shaw : Honoraria (self), Advisory / Consultancy: ARIAD, Bayer, Blueprint Medicines, Chugai, Daiichi Sankyo, EMD Serono, Foundation Medicine, Genentech/Roche, Guardant, Ignyta, KSQ Therapeutics, Natera, Novartis, Pfizer, Taiho Pharmaceutical, Takeda, and TP Therapeutics; Research grant / Funding (institution): Daiichi Sankyo, Ignyta, Novartis, Pfizer, Roche/Genentech, and TP Therapeutics. J. Wolf: Advisory / Consultancy, Officer / Board of Directors: AbbVie, AstraZeneca, Blueprint, BMS, Boehringer Ingelheim, Chugai, Ignyta, Janssen, Lilly, Loxo, MSD, Novartis, Pfizer, Roche, Takeda; Research grant / Funding (institution): BMS, Jannsen, MSD, Novartis, Pfizer. A.F. Farago: Research grant / Funding (institution): AstraZeneca, AbbVie, Genentech, BMS, Merck, PharmaMar, Amgen, Bayer, Loxo, Ignyta; Advisory / Consultancy: Genentech, Bayer, AbbVie, AstraZeneca, Boehringer Ingelheim, Loxo, PharmaMar. L. Dennis: Research grant / Funding (institution), Full / Part-time employment: Foundation Medicine. T. Riehl: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. B. Simmons: Full / Part-time employment: Roche. C. Wu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. C. Chang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. V. Choeurng: Full / Part-time employment: Genentech, Inc. T.R. Wilson: Shareholder / Stockholder / Stock options: Roche; Full / Part-time employment: Genentech.

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Poster Discussion – Developmental therapeutics Poster Discussion session

444PD - Safety and preliminary clinical activity of repotrectinib in patients with advanced ROS1/TRK fusion-positive solid tumors (TRIDENT-1 study) (ID 4536)

Presentation Number
444PD
Lecture Time
16:30 - 16:30
Speakers
  • Alexander Drilon (New York, NY, United States of America)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

Repotrectinib is a next-generation ROS1/TRK/ALK TKI with >90-fold potency versus crizotinib against ROS1 and >100-fold potency versus larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. Preclinical studies demonstrate robust activity against all known ROS1/TRK resistance mutations, including the most common solvent-front mutations (SFM) ROS1 G2032R, TRKA G595R, and TRKC G623R/E.

Methods

In the ongoing phase 1 study (NCT03093116), TKI-naïve and TKI-pretreated (≥1 TKI) pts with advanced ROS1, TRK, or ALK fusion+ solid tumors received repotrectinib. Endpoints include safety, PK, and confirmed overall response (cORR).

Results

As of 4-March-2019, 83 pts were treated with repotrectinib (dose levels from 40 mg QD to 200 mg BID under fasted/fed conditions). Most AEs were manageable and grade (gr) 1-2. The most common treatment-emergent AEs (found in > 30% of pts) were dizziness (57%), dysgeusia (51%), dyspnea (30%), and fatigue (30%). Four DLTs occurred and were manageable with dose modifications: gr3 dyspnea/hypoxia (n = 1); gr2 (n = 1) and gr3 (n = 1) dizziness at 160 mg BID, and gr3 dizziness (n = 1) at 240 mg QD. In ROS1+ NSCLC, the median number of prior TKIs was 1 (0-3); all TKI-naïve and 77% of TKI-pretreated pts received prior chemotherapy. In 11 evaluable TKI-naïve ROS1+ NSCLC pts, cORR by Blinded Central Review (BCR) was 82% (95% CI 48 - 98); median duration of response was not reached ((range 5.6 - 17.7+ months (mos)). In 18 ROS1+ NSCLC pts pretreated with 1 prior TKI, cORR by BCR was 39% (95% CI 17 – 64), and in 11 pts with 1 prior TKI at doses of 160 mg QD or above cORR was 55% (95% CI 23 - 83). All pts with ROS1 G2032R had tumor regression [cORR of 40% (n = 2/5)]. In 1 TKI-pretreated pt with ETV6-NTRK3+ and an acquired TRKC G623E-mutant salivary gland tumor, a cPR of 9.8 mos was achieved; the patient was treated for 17.9 mos. Enrollment continues. Updated data in ∼10 additional ROS1+ NSCLC and TRK+ solid tumor pts will be presented.

Conclusions

Repotrectinib was well tolerated and demonstrated encouraging overall clinical activity in pts with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors.

Clinical trial identification

NCT03093116.

Legal entity responsible for the study

Turning Point Therapeutics Inc, San Diego, CA, USA.

Funding

Turning Point Therapeutics Inc, San Diego, CA, USA.

Disclosure

A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche; Honoraria (self), Advisory / Consultancy: Loxo Oncology/Bayer/Lilly; Honoraria (self), Advisory / Consultancy: TP Therapeutics Inc; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (institution), Advisory / Consultancy: Takeda/Ariad/Milenium; Honoraria (self), Advisory / Consultancy: Helsinn; Honoraria (institution), Advisory / Consultancy: Beigene; Honoraria (self), Advisory / Consultancy: BergenBio; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy: Tyra Biosciences; Research grant / Funding (institution): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: MORE Health; Honoraria (self), Advisory / Consultancy: Verastem; Travel / Accommodation / Expenses: Puma; Research grant / Funding (institution): Teva; Research grant / Funding (institution): GlaxoSmithKlein. B.C. Cho: Shareholder / Stockholder / Stock options: heraCanVac Inc; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Research grant / Funding (institution): AtraZeneca; Honoraria (self), Research grant / Funding (institution): MOGAM Institute; Honoraria (self): Dong-A ST; Licensing / Royalties: Champions Oncology. J.J. Lin: Speaker Bureau / Expert testimony: TP Therapeutics Inc; Honoraria (institution): Chugai; Honoraria (institution): Boehringer-Ingelheim. V. Zhu: Shareholder / Stockholder / Stock options: TP Therapeutics Inc; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astra Zeneka; Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Honoraria (self): Biocept; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche/Genentech. R.D. Camidge: Research grant / Funding (self): Takeda. S. Stopatschinskaja: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: TP Therapeutics Inc. J..J. Cui: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: TP Therapeutics Inc. D.M. Hyman: Advisory / Consultancy, Travel / Accommodation / Expenses: Chugai; Advisory / Consultancy: CytomX Therapeutics; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Research grant / Funding (self): Puma Biotechnology; Research grant / Funding (self): Loxo. S. Ou: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: TP Therapeutics Inc; Shareholder / Stockholder / Stock options: Ignyta; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ariad; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech/Roche; Honoraria (self), Research grant / Funding (institution): Ignyta; Honoraria (self): Novartis; Research grant / Funding (institution): Blueprint Medicine. A.T. Shaw: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Ariad; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Blueprint Medicine; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: EDM Serono; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: KSQ Therapeutics; Advisory / Consultancy: Natera; Advisory / Consultancy: Loxo; Advisory / Consultancy: Takeda; Advisory / Consultancy: Bayer; Advisory / Consultancy: Chugai Pharm; Research grant / Funding (institution): TP Therapeutics. R.C. Doebele: Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Licensing / Royalties: Ignyta; Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Genentech; Shareholder / Stockholder / Stock options: Roche; Research grant / Funding (institution), Licensing / Royalties: Rain Therapeutics; Licensing / Royalties: Abbott Molecular. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

445PD - Durability of response with larotrectinib in adult and pediatric patients with TRK fusion cancer (ID 5684)

Presentation Number
445PD
Lecture Time
16:30 - 16:30
Speakers
  • David M. Hyman (New York, United States of America)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

Genomic rearrangements involving NTRK1/2/3 result in constitutively active TRK fusion proteins that are oncogenic drivers in multiple pediatric and adult cancers. Larotrectinib is a selective TRK inhibitor approved by the FDA in 2018 for the treatment of any TRK fusion cancer based on a primary analysis in 55 patients from 3 clinical trials [Drilon et al. NEJM 2018]. For the first time, we now report median duration of response (DOR) data in this primary cohort, as well as updated data in an expanded cohort of 159 total TRK fusion patients treated with larotrectinib, with 153 (55 primary + 98 supplemental) evaluable for efficacy.

Methods

Patients with TRK fusion cancer detected by local molecular profiling were treated with larotrectinib across 3 studies (NCT02122913, NCT02637687, and NCT02576431). Disease status was assessed by investigators using RECIST 1.1. Data cut-off was 19 February 2019.

Results

In the primary cohort of 55 patients with a median follow-up of 26 months, the median DOR in 44 patients with complete or partial responses was 35.2 months (95% CI 21.2–NE), with 17 progression events and 27 responses ongoing (range 1.6–44 months). The median PFS in the primary cohort was 25.8 months (95% CI 9.9–NE), with 27 patients having progressed. In the expanded combined dataset, the most common tumor types included soft tissue sarcoma (n = 36), infantile fibrosarcoma (n = 29), thyroid carcinoma (n = 26), salivary gland carcinoma (n = 21), and lung cancer (n = 12). The median age was 43 years, ranging from <1 month to 84 years; 33% <18 yr. The overall ORR was 79% (95% CI 72–85), with complete responses in 16%. Adverse events were primarily grade 1-2, with 13% of patients having had a grade 3-4 event related to larotrectinib. Only one patient discontinued due to an AE related to larotrectinib.

Conclusions

These data confirm the marked tissue-agnostic efficacy and long durability of response in patients with TRK fusion cancer treated with larotrectinib. Larotrectinib continued to demonstrate a favorable long-term safety profile. Screening patients for NTRK gene fusions should be actively considered.

Clinical trial identification

NCT02122913, NCT02637687, NCT02576431.

Editorial acknowledgement

Editorial assistance was provided by Michael Sheldon, PhD, of Scion, London, UK, funded by Bayer.

Legal entity responsible for the study

Bayer.

Funding

Bayer.

Disclosure

D.M. Hyman: Advisory / Consultancy: Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer Pharmaceuticals, Genentech / F. Hoffmann-La Roche; Research grant / Funding (self): Loxo Oncology, Bayer Pharmaceuticals, PUMA Biotechnology, AstraZeneca. C.M. van Tilburg: Advisory / Consultancy: Novartis, Bayer. D.S.W. Tan: Advisory / Consultancy: Novartis, Merck Loxo AstraZeneca Roche Pfizer; Travel / Accommodation / Expenses: Pfizer Boehringer Ingelheim Roche; Honoraria (self): BMS, Takeda, Novartis, Roche, Pfizer; Research grant / Funding (self): Novartis, GSK, AstraZeneca. A.F. Farago: Research grant / Funding (self): Bayer, Loxo Oncology; Advisory / Consultancy: Bayer, Loxo Oncology. T.W. Laetsch: Advisory / Consultancy: Novartis, Bayer, Loxo, Lill; Research grant / Funding (self): Pfizer Novartis Bayer Loxo Abbvie Amgen Atara Biotherapeutics BMS Lilly Epizyme GSK Janssen Jubilant Pharmaceuticals Novella Clinical, Servier. S. Kummar: Honoraria (self): Bayer; Advisory / Consultancy: Bayer; Travel / Accommodation / Expenses: Bayer. F. Doz: Research grant / Funding (institution): BMS, Celgene; Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Bayer, BMS, Celgene, Loxo Oncology, Servier. U.N. Lassen: Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer. S.G. DuBois: Advisory / Consultancy: Loxo; Travel / Accommodation / Expenses: Loxo, Roche; Honoraria (self): Loxo; Research grant / Funding (self): Millennium, Merck, Novartis Roche Lilly Lilly Loxo BMS. R. McDermott: Travel / Accommodation / Expenses: Janssen-Cilag, Pfizer; Honoraria (self): Bayer, Sanofi, Janssen, Astellas, BMS, MSD, Pfizer, Novartis, Clovis; Research grant / Funding (self): Sanofi, Janssen, Bayer, Astellas. L. Mascarenhas: Research grant / Funding (institution): AstraZeneca, Eli Lilly. J.D. Berlin: Research grant / Funding (institution): PsiOxus, Bayer, EMD Serono, Symphogen, Roche/Genentech, Immunomedics, Novartis, Taiho, AbbVie (pharamcyclics), Boston Biomedical, FivePrime, Loxo, Incyte, Macrogenics; Honoraria (self): Nestle; Advisory / Consultancy: Rafeal, Seattle Genetics, EMD Serono, Bayer, eisai, Taiho, Armo,Gritstone, AstraZeneca, Celgene, Erytech. E.R. Rudzinski: Advisory / Consultancy: Bayer. M.C. Cox: Full / Part-time employment: Loxo Oncology. S. Nanda: Full / Part-time employment: Loxo Oncology. B.H. Childs: Full / Part-time employment: Bayer. A. Drilon: Advisory / Consultancy: Loxo Oncology/Bayer, Ignyta, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, Takeda/Ariad/Millenium, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Bayer, Tyra; Research grant / Funding (self): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Honoraria (institution): Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho; Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: MORE Health. D.S. Hong: Research grant / Funding (self): AbbVie, Adaptimmune, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, MiRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seatt; Travel / Accommodation / Expenses: Loxo, MiRNA, ASCO, AACR, SITC, Genmab; Advisory / Consultancy: Alpha Insights, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint Global, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics; Shareholder / Stockholder / Stock options: Molecular Match, OncoResponse, Presagia Inc. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

Invited Discussant 443PD, LBA28, 444PD and 445PD (ID 6708)

Lecture Time
16:30 - 16:45
Speakers
  • Christian Dittrich (Vienna, Austria)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00
Poster Discussion – Developmental therapeutics Poster Discussion session

Q&A led by Discussant (ID 6726)

Lecture Time
16:45 - 16:52
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00
Poster Discussion – Developmental therapeutics Poster Discussion session

446PD - Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours (ID 2937)

Presentation Number
446PD
Lecture Time
16:52 - 16:52
Speakers
  • Ramaswamy Govindan (St Louis, MO, United States of America)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

The KRASG12C mutation occurs in ∼13% of lung cancers (11% of non-small cell lung cancer [NSCLC]), 3% of colorectal cancer (CRC) and appendix cancers, and 1–3% of other solid tumors. KRASG12C is a driver of tumorigenesis, but there are no approved therapies targeting this mutation. AMG 510, a novel, orally administered small molecule, specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state. A phase 1, first-in-human, open-label, multicenter study is underway to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510 in adult patients (pts) with locally-advanced/metastatic KRASG12C solid tumors (NCT03600883).

Methods

Key eligibility: measurable/evaluable disease with identified KRASG12C mutation, refractory to standard therapy; ECOG PS ≤ 2; life expectancy >3 months; no active brain metastases; no myocardial infarction <6 months of enrollment. In dose exploration, 4 pt cohorts enroll sequentially to identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). After MTD or RP2D identification, ∼60 pts will enroll into dose-expansion cohorts. Primary endpoints are incidence of dose-limiting toxicities (DLTs) and adverse events (AEs); secondary endpoints include response (eg, best response, objective response rate, progression-free survival; assessed every 6 weeks) and PK.

Results

As of 4 April 2019, 35 (19 CRC, 14 NSCLC, 2 other [appendix]; 21 women; median age 55 [range: 33-77] years) pts have been enrolled; all had ≥2 prior lines of therapy. No DLTs have been reported. 16 pts reported AMG 510-related AEs, 2 with grade 3 related AEs (anemia, diarrhea). Best tumor responses are tabulated. 26 pts remain on study.

446PD

Best Tumor Response in 29* Patients
FrequencyDuration of Response or Stable Disease**
NSCLC (n = 10)
Partial Response5 (2 confirmed)7.3 - 27.4 weeks
Stable Disease48.4 - 25.1 weeks
Progressive Disease1***n/a
CRC/Other (n = 19)
Stable Disease147.3 - 24.0 weeks
Progressive Disease5***n/a

Six pts (4 NSCLC; 2 CRC/Other) did not have a post-baseline radiographic scan as of the data cutoff date (4 April 2019).

Duration of response as of the data cutoff date. All 5 pts with partial response are still on treatment as of the data cutoff date.

Two of these pts (1 NSCLC; 1 CRC) had early (prior to week 6) clinical progressive disease.

Conclusions

AMG 510 is well tolerated with no DLTs at studied doses. Early results suggest antitumor activity of single-agent AMG 510 in pts with KRASG12C mutant solid tumors. Updated results will be presented.

Clinical trial identification

NCT03600883 (ClinicalTrials.gov).

Editorial acknowledgement

Dianne Tomita, MPH, a consultant to Amgen Inc.

Legal entity responsible for the study

Amgen Inc.

Funding

Amgen Inc.

Disclosure

R. Govindan: Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self): Millennium; Honoraria (self): F Hoffman La-Roche; Honoraria (self): Janssen; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: EMD Sereno; Advisory / Consultancy: BMS; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Nektar; Advisory / Consultancy: Merck; Advisory / Consultancy: Celgene; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Phillips Gilmore; Advisory / Consultancy: GSK; Advisory / Consultancy: Jounce; Advisory / Consultancy: Inivata. M.G. Fakih: Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Array; Research grant / Funding (self): Novartis; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen. T.J. Price: Research grant / Funding (self): Amgen. G.S. Falchook: Licensing / Royalties: Wolters Kluwer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Fujifilm; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: Millennium; Speaker Bureau / Expert testimony: Total Health Conferencing; Research grant / Funding (institution): 3-V Biosciences; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ARMO; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bioatla; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ciclomed; Research grant / Funding (institution): Curegenix; Research grant / Funding (institution): Curis; Research grant / Funding (institution): DelMar; Research grant / Funding (institution): eFFECTOR; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Hutchison MediPharma; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): Jounce; Research grant / Funding (institution): Kolltan; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): miRNA Therapeutics; Research grant / Funding (institution): National Institutes of Health; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Oncothyreon; Research grant / Funding (institution): Precision Oncology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Regenix; Research grant / Funding (institution): Strategia; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): University of Texas MD Anderson Cancer Center; Research grant / Funding (institution): Vegenics; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): American Society of Clinical Oncology. J. Desai: Advisory / Consultancy, Research grant / Funding (self): Roche; Research grant / Funding (self): GSK; Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Beigene; Research grant / Funding (self): Bristol-Myers Squibbb; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly.J.C. Kuo: Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Zucero Therapeutics; Travel / Accommodation / Expenses: MSD. J.H. Strickler: Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): Amgen; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (self): Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self): Seattle Genetics; Advisory / Consultancy: Chengdu Kanghong Biotechnology; Advisory / Consultancy: Chugai; Advisory / Consultancy, Research grant / Funding (self): OncoMed; Research grant / Funding (self): Exelixis; Research grant / Funding (self): Gilead Sciences; Research grant / Funding (self): Macrogenics; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Nektar Therapeutics. J.C. Krauss: Research grant / Funding (self): Amgen; Research grant / Funding (self): NSABP Foundation; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Boehringer Ingelheim; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Oncomed Pharmaceuticals; Research grant / Funding (self): Ignyta/Roche; Research grant / Funding (self): Baxalta; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Isofol. B.T. Li: Research grant / Funding (self): Amgen; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Hengrui Therapeutics. C.S. Denlinger: Research grant / Funding (self): Amgen; Advisory / Consultancy, Research grant / Funding (self): Bristol Myer Squibb; Research grant / Funding (self): Sanofi; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Array BioPharma; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): BeiGene; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Macrogenics; Research grant / Funding (self): Agios Pharmaceuticals; Research grant / Funding (self): Lycera; Research grant / Funding (self): Merrimack Pharmaceuticals; Advisory / Consultancy: Merck. G. Durm: Research grant / Funding (self): Merck; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): AstraZeneca. J. Ngang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. H. Henary: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. G. Ngarmchamnanrith: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. E. Rasmussen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. P.K. Morrow: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. D.S. Hong: Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Amgen; Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Research grant / Funding (self): BMS; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Eisai; Research grant / Funding (self): Fate Therapeutics; Advisory / Consultancy, Research grant / Funding (self): Genentech; Research grant / Funding (self), Travel / Accommodation / Expenses: Genmab; Research grant / Funding (self): Ignyta; Advisory / Consultancy, Research grant / Funding (self): Infinity; Research grant / Funding (self): Kite; Research grant / Funding (self): Kyowa; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self), Travel / Accommodation / Expenses: LOXO; Research grant / Funding (self): Merck; Research grant / Funding (self): Medimmune; Research grant / Funding (self): Mirati; Research grant / Funding (self), Travel / Accommodation / Expenses: miRNA; Research grant / Funding (self): Molecular Template; Research grant / Funding (self): Mologen; Research grant / Funding (self): NCI-CTEP; Research grant / Funding (self): Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy, Research grant / Funding (self): Seattle Genetics; Advisory / Consultancy, Research grant / Funding (self): Takeda; Travel / Accommodation / Expenses: AACR; Travel / Accommodation / Expenses: ASCO; Travel / Accommodation / Expenses: SITC; Advisory / Consultancy: Alpha Insights; Advisory / Consultancy: Axiom; Advisory / Consultancy: Baxter; Advisory / Consultancy: GLG; Advisory / Consultancy: Group H; Advisory / Consultancy: Guidepoint Global; Advisory / Consultancy: Janssen; Advisory / Consultancy: Merrimack; Advisory / Consultancy: Medscape; Advisory / Consultancy: Numab; Advisory / Consultancy: Tieza Therapeutics; Advisory / Consultancy: Web MD; Advisory / Consultancy: Molecular Match; Officer / Board of Directors: OncoResponse; Advisory / Consultancy: Presagia Inc.

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Poster Discussion – Developmental therapeutics Poster Discussion session

447PD - Phase I/II study of combined BCL-XL and MEK inhibition with navitoclax (N) and trametinib (T) in KRAS or NRAS mutant advanced solid tumours (ID 4748)

Presentation Number
447PD
Lecture Time
16:52 - 16:52
Speakers
  • Ryan B. Corcoran (Boston, MA, United States of America)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

MEK inhibitors (MEKi) lack single agent clinical efficacy in RAS mutant cancers, likely because MEKi produce only a cytostatic response in preclinical RAS mutant cancer models. BCL-XL is an anti-apoptotic BCL2 family protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. BCL-XL was found to bind and inhibit BIM, the key pro-apoptotic protein induced by MEKi. Combined BCL-XL/MEK inhibition led to tumor regressions in mouse models of RAS mutant cancers.

Methods

In dose escalation, N (150, 200, 250, 300mg daily) was given d1-28 (after a 7d lead at 150mg daily). T (1, 1.5, 2mg daily) was given d1-28 in schedules A and B, or d1-14 only of a 28d cycle in schedule C. Pre-treatment and d15 on-treatment biopsies and serial cell-free (cf)DNA were obtained.

Results

To date, 43 patients (pts) (median age 60) initiated treatment (A [n = 9]; B [n = 11]; C [n = 23]), 38 in dose escalation; 66.7% had ≥4 prior therapies. 9/43 (20.9%) had colorectal cancer (CRC), 8/43 (18.6%) pancreatic, 9/43 (20.9%) NSCLC and 11/43 (25.6%) gynecologic (GYN) cancers. 14/43 (32.6%) were KRAS G12D, 7/43 (16.3%) G12C, 7/43 (16.3%) G12V.Recommended phase 2 dose (RP2D) was established as T 2mg d1-14 + N 250mg d1-28.Gr 3-4 treatment related AEs occurred in 40% pts, with AST increase, diarrhea, decreased platelets most common. At RP2D, 2/13 evaluable pts had confirmed PR (15.4%) with disease control rate (DCR; PR + SD) 46.2%. Early potential disease-specific differences in efficacy were noted. In GYN pts at all doses, overall DCR = 63.6%, with 2/11 (18.1%) with ongoing confirmed PR (-60% and -51% by RECIST), including one >20 mos. By contrast no PRs were seen in 9 CRC pts, with overall DCR only 22%. Evidence of MAPK pathway inhibition was observed in on-treatment tumor biopsies. Pts with PR/SD had a median decrease in mutant KRAS levels in cfDNA of 64% by 4 wks.

Conclusions

Combination of N+T was tolerable, and R2PD was established. Initial signs of efficacy were noted, with favorable DCR and durable PRs in RAS mutant GYN pts. Expansion cohorts are currently enrolling in GYN, NSCLC, pancreatic pts, and NRAS mutant cancers. Updated efficacy and correlative data will be presented.

Clinical trial identification

NCT02079740.

Legal entity responsible for the study

NCI/CTEP.

Funding

NCI/CTEP.

Disclosure

R.B. Corcoran: Honoraria (self): Array Biopharma; Honoraria (self): Astex Pharmaceuticals; Honoraria (self): BMS; Honoraria (self): FOG Pharma; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Fount Therapeutics; Honoraria (self): N-of-one; Honoraria (self): Revolution Medicines; Advisory / Consultancy, Shareholder / Stockholder / Stock options: nRichDx; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Avidity Biosciences; Honoraria (self): Novartis; Honoraria (self): Taiho. L.G. Ahronian: Full / Part-time employment: Tango Therapeutics. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

448PD - Genomic profiling of three pathways through molecular profiling-based assignment of cancer therapy (NCI- MPACT) (ID 4556)

Presentation Number
448PD
Lecture Time
16:52 - 16:52
Speakers
  • Alice Chen (Bethesda, United States of America)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

Emerging clinical data show prediction of response to therapies targeting specific genetic aberrations have unexpectedly variable outcomes. This multicenter, double-blind, randomized trial opened in 2013 to compare response rates (RR) between 2 groups of patients (pts) identified to have an actionable mutation of interest (aMOI) in one of 3 genetic pathways (DNA repair, PI3K, or RAS/RAF/MEK): group A) Pts treated with agent(s) targeting one selected pathway (experimental arm-A) and B) Pts treated with agent(s) not targeting that pathway (control arm-B). Based on the data available at the time, the aMOI selection criteria encompassed alterations throughout the entire selected pathway instead of specific genetic changes.

Methods

Primary objective is to compare the RR (CR and PR) and 4 months PFS between treatments arms A and B. A CLIA-certified genetic analysis of a fresh tumor biopsy was performed at entry. Pts with an aMOI were randomized 2:1 to arm A vs. B. Study drugs were: 1) DNA repair-a) veliparib & temozolomide (VT); b) AZD1775 & carboplatin (AC); pts with p53 mutations were preferentially selected for AC; 2) PI3K- everolimus (E); 3) RAS- trametinib(T). At disease progression, Arm B pts could cross over to their target arm (A).

Results

193 pts underwent biopsies; >90% of samples completed DNA sequencing. 96 pts (50%) had an aMOI and were randomized to treatment. Cohort VT had insufficient accrual on the experimental arm to be evaluable. AC, E and T cohorts were closed due to futility. Enrollment rate after treatment assignment was 77% for Arm A and 53%, for arm B. Attrition analysis between arms A and B are ongoing.

Conclusions

The increasing availability of genetic sequencing and bias toward expected benefit of highly specific treatment agents may account for the large number pt withdrawal from Arm A. This imbalance made comparison of arms A and B uninterpretable. The trial has been amended to employ a non-randomized design to complete the assessment of VT’s activity. Analysis of the aMOIs are ongoing to develop a more stringent selection criteria for future precision medicine trials.

Clinical trial identification

NCT01827384.

Editorial acknowledgement

Christina Rosenberger, PhD.

Legal entity responsible for the study

NCI.

Funding

NCI.

Disclosure

S. Kummar: Advisory / Consultancy: Corvus Pharmaceuticals; Advisory / Consultancy: MedTree; Advisory / Consultancy: Nodus Therapeutics; Advisory / Consultancy: Genentech; Advisory / Consultancy: ShangPharma Innovation; Advisory / Consultancy: Seattle Genetics; Travel / Accommodation / Expenses: Bayer; Shareholder / Stockholder / Stock options: Dhrishti Inc.; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Jounce Therapeutics; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): Advenchen Laboratories; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Taiho Pharmaceutical. N. Moore: Licensing / Royalties: Nestle Nutrition. P. Williams: Licensing / Royalties, I was a co-inventor of the DLBCL cell of origin patent recently filed by the NIH: NIH; Research grant / Funding (institution): Illumina. K.P.S. Raghav: Advisory / Consultancy: Bayer; Travel / Accommodation / Expenses: TRACON Pharma; Honoraria (self): Bayer; Honoraria (self): Eisai. F. Meric-Bernstam: Advisory / Consultancy: Genentech; Advisory / Consultancy: Inflection Biosciences; Advisory / Consultancy: Pieris Pharmaceuticals; Advisory / Consultancy: Clearlight Diagnostics; Advisory / Consultancy: Darwin Health; Advisory / Consultancy: Samsung Bioepis; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Aduro Biotech; Advisory / Consultancy: Origimed; Advisory / Consultancy: Xencor; Advisory / Consultancy: Debiopharm Group; Advisory / Consultancy: Mersana; Honoraria (self): Sumitomo Group; Honoraria (self): Dialectica; Research grant / Funding (self): Novartis; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Taiho Pharmaceutical; Research grant / Funding (self): Genentech; Research grant / Funding (self): Calithera Biosciences; Research grant / Funding (self): Debiopharm Group. S. Leong: Shareholder / Stockholder / Stock options: Antares Pharmaceuticals; Shareholder / Stockholder / Stock options: Spectrum Pharmaceuticals; Honoraria (self): Lilly; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Lilly. S. Waqar: Research grant / Funding (institution): Spectrum Pharmaceuticals; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Newlink Genetics; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Synermore biologics; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Vertex; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Stem CentRx; Research grant / Funding (institution): Hengrui Therapeutics; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): ARIAD. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

449PD - Precision medicine: Preliminary results from the initiative for molecular profiling and advanced cancer therapy 2 (IMPACT 2) study (ID 4548)

Presentation Number
449PD
Lecture Time
16:52 - 16:52
Speakers
  • Apostolia Maria Tsimberidou (Houston, United States of America)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

Precision medicine is associated with favorable outcomes in selected patients. We initiated IMPACT 2, a randomized study to compare PFS in patients with metastatic cancer treated on the basis of tumor genomic profiling results vs. those whose treatment was not selected based on genomic analysis. Herein, we assessed the association between patient characteristics and overall survival (OS).

Methods

Patients with advanced, metastatic cancer underwent tumor biopsy and genomic profiling (Foundation One). Variants were filtered to eliminate germline mutations (annotation, ANNOVAR) and artifacts. Patients were presented at tumor board and were randomized if they met criteria for clinical trials. OS was measured from enrollment on study until last follow-up or death from any cause.

Results

From 5/2014 to 4/2017, 320 of 391 enrolled patients completed tumor profiling. Baseline characteristics (n = 320) were as follows: men, 47%; median age, 63 yrs (range, 25-83); performance status 1, 88%; median no. of prior therapies, 3 (range, 0-14); liver metastases, 40%; albumin < 3.5 g/L, 12%; LDH > 618 IU/L, 29%; platelet count > or < the normal limits, 15%. Most common tumor types were head and neck, 19%; gastrointestinal, 16%; and lung, 11%. Most frequently mutated genes: TP53, 42%; KRAS,16%; PIK3CA,12%; and CDKN2A, 11%. Of 320 patients, 69 (22%) were randomized; of the remaining 251 patients, 153 (61%) received other treatment (investigational or standard). Results of multivariate analyses for OS are displayed below.

449PD

Multivariate analysis, OS
Risk FactorHR95% CIP
Age ≥ 60 yrs1.021.00-1.03.009
Liver metastases1.431.07-1.91.02
LDH > 618 IU/L2.191.61-2.97< .0001
Albumin < 3.5 g/dL1.901.26-2.87.002
KRAS mutated2.271.57-3.28< .0001
TP53 mutated1.381.04-1.84.03

Conclusions

In patients with metastatic cancer, age < 60 yrs, absence of liver metastases, normal albumin and LDH levels, and absence of KRAS or TP53 mutations were independent factors predicting longer OS. We demonstrated the feasibility of molecular profiling using newly obtained tumor biopsies and treating patients prospectively. The study is ongoing. Outcomes for randomized patients are awaited upon completion of the study.

Clinical trial identification

www.clinicaltrials.gov NCT02152254, First posted June 2, 2014.

Legal entity responsible for the study

The authors.

Funding

Foundation Medicine.

Disclosure

A.M. Tsimberidou: Research grant / Funding (institution): IMMATICS; Research grant / Funding (institution): Tempus; Research grant / Funding (institution): Parker Institute for Cancer Immunotherapy; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Baxalta; Research grant / Funding (institution): Foundation Medicine; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Placon Therapeutics; Research grant / Funding (institution): Karus Therapeutics; Research grant / Funding (institution): Tvardi; Research grant / Funding (institution): OBI Pharma; Advisory / Consultancy: Roche, Europe; Advisory / Consultancy: Covance; Advisory / Consultancy: Genentech. D.S. Hong: Research grant / Funding (self): Adaptimmune; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Bayer; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Daichi-Sanko; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Infinity; Research grant / Funding (institution): Kite; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): LOXO; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Molecular Template; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

Invited Discussant 446PD, 447PD, 448PD and 449PD (ID 6712)

Lecture Time
16:52 - 17:07
Speakers
  • Hendrik-Tobias Arkenau (London, United Kingdom)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00
Poster Discussion – Developmental therapeutics Poster Discussion session

Q&A led by Discussant (ID 6725)

Lecture Time
17:07 - 17:14
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00
Poster Discussion – Developmental therapeutics Poster Discussion session

450PD - A phase I study of ATR inhibitor, AZD6738, as monotherapy in advanced solid tumours (PATRIOT part A, B) (ID 1915)

Presentation Number
450PD
Lecture Time
17:14 - 17:14
Speakers
  • Magnus Dillon (London, United Kingdom)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

ATR inhibition (ATRi) exploits high levels of replication stress and G1/S cell cycle checkpoint dysfunction frequently seen in cancers, increasing DNA damage and inducing mitotic crisis. ATRi may also potentiate DNA-damaging anticancer therapies to improve clinical activity.

Methods

We present results from the monotherapy phase of a study of AZD6738, an oral ATRi in patients with advanced solid tumours (NCT02223923). Endpoints were MTD, safety, tolerability, pharmacokinetics (PK) and preliminary efficacy. MTD and PK were previously presented.

Results

Forty-six patients enrolled and received at least 1 dose AZD6738 to February 2019, 24 completed ≥1 cycle (28 days) of treatment in the dose-escalation phase, 20 commenced treatment in expansion phase, testing 2 different schedules at MTD (160 mg BD). The median number of cycles was 3 (range 2-12) in dose-escalation phase and 4 (1-12) in the dose-expansion cohort. 17/26 (65%) patients in dose escalation and 7/20 (35%) in dose-expansion had G ≥ 3 treatment-related adverse events (TRAEs). An intermittent schedule (2-week-on, 2-week-off) was better tolerated than continuous dosing, with G ≥ 3 TRAEs in 4/6 (67%) receiving continuous and 3/15 (20%) with intermittent dosing. The most common TRAEs were fatigue, anaemia, nausea and thrombocytopenia; 20 (77%) of patients in dose escalation and 16 (80%) in expansion discontinued AZD6738 due to progressive disease (PD). 5 (19%) patients in dose-escalation and 1 (5%) in dose-expansion discontinued due to toxicity. Best overall response was confirmed partial response (PR) in 3 (7%) participants, unconfirmed PR in 1 (2%), stable disease (SD) in 22 (48%) and PD in 12 (26%). Early clinical PD or toxicity prevented radiological assessment in 8 (17%). 5/24 (21%) participants in dose-escalation and 5/20 (25%) in dose-expansion had SD of ≥ 4 cycles (16 weeks) duration.

Conclusions

AZD6738 is well tolerated at 160 mg BD on a 2-week-on, 2-week-off schedule. ATRi monotherapy resulted in confirmed PR and a high proportion of prolonged SD. Future cohorts will enrich for DNA damage response-deficient tumours. A parallel dose-escalation study of AZD6738 combined with palliative radiotherapy is underway. Funding: CRUKD/14/007.

Clinical trial identification

NCT02223923; EudraCT: 2013-003994-84.

Legal entity responsible for the study

Royal Marsden NHS Foundation Trust and The Institute of Cancer Research: Royal Cancer Hospital.

Funding

Cancer Research UK, ECMC Combinations Alliance, AstraZeneca.

Disclosure

S.A. Smith: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. E. Dean: Full / Part-time employment: AstraZeneca. J. Spicer: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self): Lilly; Honoraria (self): Lytix Biopharma; Honoraria (self): Pierre Fabre; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Shionogi; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Quintiles; Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: AstraZeneca. M.D. Forster: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharpe & Dohme; Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly. K.J. Harrington: Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca-Medimmune; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Lytix Biopharma; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dohme; Advisory / Consultancy: Merck; Advisory / Consultancy: Oncos Therapeutics; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Viralytics; Research grant / Funding (self): Oncolytics Biotech. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

451PD - Updated results of the PARP1/2 inhibitor pamiparib in combination with low-dose (ld) temozolomide (TMZ) in patients (pts) with locally advanced or metastatic solid tumours (ID 4517)

Presentation Number
451PD
Lecture Time
17:14 - 17:14
Speakers
  • Agostina Stradella (Hospitalet de Llobregat, Spain)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

DNA damage caused by TMZ can sensitize tumors to PARP inhibitors. Pamiparib is an investigational PARP1/2 inhibitor that has shown PARP trapping activity, brain penetration, and synergistic cytotoxicity with ld TMZ in nonclinical studies.

Methods

This ongoing study consists of a dose-escalation phase (3 + 3 design) and a dose-expansion phase enrolling pts with gastric or small cell lung cancer (GC and SCLC). During dose escalation, pamiparib was administered at 60 mg PO BID on days 1–28 and ld TMZ was given at escalating doses PO QD on days 1–7, 1–14, or 1–28 of 28-day cycles. During dose expansion, pts are being treated at the recommended phase 2 dose (RP2D); eligibility criteria include metastatic GC and extensive stage SCLC pts treated with ≤2 prior lines of chemotherapy. Tumor assessments are performed every 8 weeks. Primary and secondary endpoints include safety/tolerability and antitumor activity (RECIST v1.1)/PK, respectively; biomarker assessment (eg, BRCA) is exploratory. We present updated results that include the RP2D and data from expansion cohort pts.

Results

As of 1 March 2019, 66 pts were enrolled in 8 dose escalation cohorts and 24 pts were enrolled at the RP2D pamiparib 60 mg PO BID days 1–28 and TMZ 60 mg PO QD days 1–7 (N = 90). Median age was 65 years (range, 30–85) and median prior lines of therapy was 3 (range, 1–10). The most common adverse events (AEs) related to study drugs across all doses were nausea (46%; 0% grade (G)3/4), anemia (43%; 24% G3/4), fatigue (41%; 1% G3/4), neutropenia (26%; 21% G3/4), and thrombocytopenia (27%; 14% G3/4). There were no fatal AEs. Pamiparib + TMZ plasma exposure was similar to that of each single agent. Among 63 dose escalation pts with measurable disease evaluated for efficacy, 9 achieved partial response (PR; 14%; 95% CI, 7–25) across ld TMZ doses and indications (6 confirmed PR). Responses were seen in pts regardless of known BRCA status. Disease control rate was 53% and median duration of response was 5.5 months (range, 1.9–7.3).

Conclusions

Pamiparib combined with ld TMZ continues to demonstrate promising antitumor activity and remains generally well tolerated in pts with advanced solid tumors.

Clinical trial identification

NCT03150810.

Editorial acknowledgement

Ira Mills, PhD, and Shannon Davis at Ashfield Healthcare Communications, Middletown, CT.

Legal entity responsible for the study

BeiGene USA, Inc.

Funding

BeiGene USA, Inc.

Disclosure

A. Stradella: Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Pfizer. M.L. Johnson: Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Stemcentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Neovia; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Hengrui Therapeutics, INC; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Daiichi - Sankyo; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): GI Therapeutics; Research grant / Funding (institution): Dynavax; Advisory / Consultancy: Celgene; Advisory / Consultancy: LOXO. S. Goel: Research grant / Funding (self), Support for clinical trial: BeiGene. S.R. Chandana: Research grant / Funding (institution): START MIDWEST; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Eisai; Advisory / Consultancy: Astrazaneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Advisory / Consultancy: AMGEN. M.D. Galsky: Advisory / Consultancy: Merck; Advisory / Consultancy: Genentech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: BMS; Advisory / Consultancy: Dracen; Advisory / Consultancy: Dragonfly Therapeutics; Advisory / Consultancy: AstraZeneca. E. Calvo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Nanobiotix; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: GLG; Honoraria (self), Advisory / Consultancy: PsiOxus Therapeutics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy: Medscape; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Cerulean Pharma; Honoraria (self), Advisory / Consultancy: EUSA; Honoraria (self), Advisory / Consultancy: Gehrmann Consulting; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Guidepoint; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Honoraria (self), Advisory / Consultancy: Amcure; Honoraria (self), Advisory / Consultancy: OncoDNA; Honoraria (self), Advisory / Consultancy: Alkermes; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: START Madrid; Leadership role, Full / Part-time employment, Officer / Board of Directors: HM Hospitals Group; Shareholder / Stockholder / Stock options: Oncoart Associated; Shareholder / Stockholder / Stock options: International Cancer Consultants; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): ACEO; Research grant / Funding (institution): Amcure; Research grant / Funding (institution): AMGEN; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): H3; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Kura; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Menarini; Research grant / Funding (institution): Merus; Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Principia; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Transgene; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Innovio; Research grant / Funding (institution): MSD; Research grant / Funding (institution), Officer / Board of Directors: PsiOxus; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Daiichi; Research grant / Funding (institution): ORCA; Research grant / Funding (institution): Boston Therapeutics; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): DebioPharm; Research grant / Funding (institution): Boehringen Ingelheim; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Millenium; Research grant / Funding (institution): Synthon; Research grant / Funding (institution): Spectrum; Research grant / Funding (institution): Rigontec; Leadership role, Founder and president: non-for-profit Foundation INTHEOS; Officer / Board of Directors: Zeist. V. Moreno: Advisory / Consultancy: BMS. H. Park: Research grant / Funding (institution), And non-financial support: BeiGene; Research grant / Funding (institution): Ambrx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daiichi Pharmaceutical; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Hoffman-LaRoche; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): MERCK; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis Pharmaceuticals; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron Pharmaceuticals; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Vertex Pharmaceuticals; Research grant / Funding (institution): Xencor Inc. A. Cervantes: Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Merck Serono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Officer / Board of Directors: Biomedical Research Institute INCLIVA; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Servier; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Astelas; Advisory / Consultancy: Amgen; Advisory / Consultancy: Foundation Medicine; Research grant / Funding (institution): Fibrogen; Research grant / Funding (institution): Amcure; Research grant / Funding (institution): Sierra Oncology; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Genentech.L. Fariñas Madrid: Research grant / Funding (institution), Support for clinical trial: BeiGene. L. Mileshkin: Travel / Accommodation / Expenses: BeiGene. R. Plummer: Honoraria (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Astex Pharmaceuticals; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Modulatex; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Octimet; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Vertex; Research grant / Funding (institution): AstraZeneca/MedImmune; Licensing / Royalties, Named on patent of use of PARP inhibitor rucaparib (Inst): PARP inhibitor rucaparib (Inst). J. Evans: Research grant / Funding (institution), Support for clinical trials: BeiGene; Advisory / Consultancy: Karus Therapeutics; Advisory / Consultancy: Baxalta. A. Prawira: Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Akesobio; Research grant / Funding (institution): CStone; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Arcusbio; Research grant / Funding (institution): Apollomics; Research grant / Funding (institution): Henlius; Research grant / Funding (institution): Five Prime; Research grant / Funding (institution): Viamet. R.J. Pelham: Full / Part-time employment: BeiGene. S. Mu: Full / Part-time employment: BeiGene. C. Andreu-Vieyra: Full / Part-time employment: BeiGene. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

452PD - Safety, antitumor activity, and pharmacokinetics (PK) of pamiparib (BGB-290), a PARP1/2 inhibitor, in patients (pts) with advanced solid tumours: Updated phase I dose-escalation/expansion results (ID 2588)

Presentation Number
452PD
Lecture Time
17:14 - 17:14
Speakers
  • Mark Voskoboynik (Melbourne, VIC, Australia)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

Pamiparib is an investigational PARP1/2 inhibitor that has demonstrated brain penetration and PARP–DNA complex trapping in preclinical studies. In the phase 1 dose-escalation/expansion study of pts with advanced solid tumors, pamiparib was generally well tolerated and showed preliminary antitumor activity. Here we report updated antitumor activity focused on the ovarian cancer cohort and safety data.

Methods

This is a two-stage dose-escalation/expansion study (NCT02361723). The dose-escalation study component established the pamiparib PK profile, and the recommended phase 2 dose (RP2D) of pamiparib administered orally 60 mg BID in pts with solid tumors. The dose-expansion component was conducted in pts with ovarian, breast, prostate, gastric, and small cell lung cancer.

Results

As of 1 January 2019, 97 pts (median age, 60 years; Eastern Cooperative Oncology Group performance status of 0, 1, or 2 [37%, 62%, and 1%, respectively]) were enrolled in the dose-escalation (n = 60) and dose-expansion (n = 37) components. Among the 97 enrolled pts, 48 pts (n = 30, ovarian pts) received 60 mg BID, the RP2D. Of 57 ovarian pts in the efficacy evaluable population (≥1 postbaseline tumor assessment), 22 (39%) achieved a confirmed objective response (complete response, n = 4; partial response, n = 18) per RECIST v1.1 criteria. Median duration of response was 12.3 months (range, 1.3–40.8). Biomarker data will be included in future analyses. In the safety population (n = 97), drug-related adverse events (AEs) in ≥ 10% of pts were nausea, fatigue, anemia, diarrhea, vomiting, and decreased appetite. The most common drug-related G3 (no G4 or G5) AEs were anemia (18.6%) and neutropenia (6.2%). AEs led to treatment discontinuation in 6.2% of pts. Four pts died due to disease progression with non-drug–related AEs. Pamiparib plasma exposure generally increased with increased dose, with a median t1/2 of ∼13 hours.

Conclusions

Pamiparib continues to be generally well tolerated and demonstrates antitumor activity in this update of an ongoing, phase 1 dose-escalation/expansion study in pts with advanced solid tumors.

Clinical trial identification

NCT02361723.

Editorial acknowledgement

Editorial/writing support was provided by Ira Mills, PhD, and Shannon Davis at Ashfield Healthcare Communications, Middletown, CT.

Legal entity responsible for the study

BeiGene.

Funding

BeiGene.

Disclosure

M. Voskoboynik: Honoraria (self): AstraZeneca; Honoraria (self): MSD Oncology; Travel / Accommodation / Expenses: Bristol-Myers Squibb. L. Mileshkin: Travel / Accommodation / Expenses, Beigene paid for flights and accommodation for me to attend and present at the ASCO STIC meeting Jan 2018: Beigene. M. Millward: Research grant / Funding (self), Per patient payments for clinical trials: Beigene; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Bristol-Myers Squibb; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Merck Sharp & Dohme; Advisory / Consultancy, Advisory Board for Immuno-Oncology: Roche; Advisory / Consultancy, Advisory Board for Immuno-Oncology: AstraZeneca. K. Zhang: Full / Part-time employment: Beigene. M. Zhang: Full / Part-time employment: Beigene. S. Mu: Full / Part-time employment: Beigene. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

Invited Discussant 450PD, 451PD and 452PD (ID 6714)

Lecture Time
17:14 - 17:29
Speakers
  • Udai Banerji (Sutton, Surrey, United Kingdom)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00
Poster Discussion – Developmental therapeutics Poster Discussion session

Q&A led by Discussant (ID 6724)

Lecture Time
17:29 - 17:36
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00
Poster Discussion – Developmental therapeutics Poster Discussion session

LBA29 - Immune activation with a novel immune switch anti-macrophage antibody (anti-Clever-1 mAb; FP-1305) in phase I/II first-in-human MATINS trial in patients with advanced solid tumours (ID 6587)

Presentation Number
LBA29
Lecture Time
17:36 - 17:36
Speakers
  • Petri Bono (Helsinki, Finland)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

CLEVER-1 is a scavenger receptor that is highly expressed on tumor associated macrophages (TAMs) and mediates the clearance of “unwanted” self-components. Pre-clinical studies demonstrate that CLEVER-1 inhibition switches TAMs to a pro-inflammatory phenotype and reactivates CD8+ T-cell responses with a robust anti-tumour activity (Viitala et al. Clin Cancer Res 2019). Targeting CLEVER-1 could overcome the immunosuppressive tumour microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody.

Methods

MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients (pts) with advanced, IO-refractory melanoma, cholangiocarcinoma, hepatocellular, colorectal, and pancreatic ductal adenocarcinoma (PDAC)

Results

11 pts (median age 57) were enrolled in four cohorts (0.3, 1.0, 3.0 or 10 mg/kg) and received 1-8 cycles (median 3) of FP-1305 every three weeks. FP-1305 has been well tolerated without dose-limiting toxicities. Most frequent treatment-emergent adverse events (AEs; ≥20%) were fatigue and raised ALT and AST levels. Initial FP-1305 dosing led to an increase in blood NK cells (median 154 %), CD8+/CD4+ T cell ratio (median 121 %), B cells (median 143 %) and a decrease in regulatory T cells (median 65 % from baseline). Clinical benefits have been observed in two colorectal cancer pts. One with an ongoing partial response (-52%) and another with disease stabilization along with a decline in Carcinoembryonic antigen (CEA). The updated safety and efficacy results will be reported.

Conclusions

FP-1305 is the first macrophage checkpoint candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. Analysis of circulating immune cells after administration of FP-1305 demonstrates Th1 activation as well as mobilization of NK cells and B cells.

Clinical trial identification

EudraCT: 2018-002732-24 (obtained 09 Jul 2018).

Legal entity responsible for the study

Faron Pharmaceuticals Ltd.

Funding

Faron Pharmaceuticals Ltd.

Disclosure

P. Bono: Full / Part-time employment, Employment: Terveystalo; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Stock owenership and Scientific Board member: TILT Biotherapeutics; Spouse / Financial dependant, Family member’s stock ownereship: Faron pharmaceuticals; Advisory / Consultancy: Faron pharmaceuticals; Advisory / Consultancy, Scientific Board member: Oncorena; Advisory / Consultancy: Pfizer; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Orion Pharma; Advisory / Consultancy: Ipsen ; Honoraria (self), Data safety monitoring Board member: Herantis Pharma. M. Hollmen: Advisory / Consultancy, Shareholder / Stockholder / Stock options, patent holder: faron pharmaceuticals. P. Jaakkola: Advisory / Consultancy: Faron Pharmaceuticals. S. Shetty: Advisory / Consultancy: Faron Pharmaceuticals. A. Thibault: Full / Part-time employment: Simbec-Orion. M.J.A. de Jonge: Advisory / Consultancy: Faron Pharmaceuticals. A.R. Minchom: Advisory / Consultancy: Faron Pharmaceuticals. Y.T. Ma: Advisory / Consultancy: Faron Pharmaceuticals. C. Yap: Advisory / Consultancy: Faron Pharmaceuticals. D. Robbrecht: Advisory / Consultancy: Faron Pharmaceuticals. S. Jalkanen: Shareholder / Stockholder / Stock options: Faron Pharmaceuticals. M.K. Karvonen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Mandelin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Koivunen: Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AstraZeneza; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: KaikuHealth; Research grant / Funding (self): Roche. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

453PD - Safety, anti-tumour activity, and biomarker results of the HER2-targeted bispecific antibody ZW25 in HER2-expressing solid tumours (ID 3575)

Presentation Number
453PD
Lecture Time
17:36 - 17:36
Speakers
  • Funda Meric-Bernstam (Houston, TX, United States of America)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

ZW25, a novel IgG1 bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including improved receptor internalization and downregulation relative to trastuzumab. Safety, anti-tumor activity, and biomarker data from an ongoing phase 1 trial of ZW25 monotherapy in solid tumors other than breast cancer, are presented here.

Methods

Eligible patients with HER2 IHC 3+, IHC 2+/FISH+, or IHC 2+/FISH- tumors confirmed by central review of fresh or archival biopsies, who had progressed on all standard therapies, were enrolled. Assessments included tumor evaluations (RECIST 1.1 Q8W), circulating tumor DNA (ctDNA; pre-dose C1 D1, C2 D15, treatment end), and standard safety evaluations.

Results

A total of 43 patients, including 17, 6, 10, and 10 with gastroesophageal adenocarcinoma (GEA), biliary tract cancers, colorectal cancer, and other cancers, respectively, received single agent ZW25 at 10 mg/kg QW or 20 mg/kg Q2W. The median number of prior therapies was 3 (range 1-6) for all patients. For GEA and non-GEA patients, 88% and 35% respectively received at least one unique prior HER2 therapy. The most common treatment-related adverse events (all Grade 1 or 2) were diarrhea (49%) and infusion related reaction (34%). The objective response rate (all partial response (PR)) for response evaluable patients was 41% (14/34), stable disease (SD) in 38% (13/34), and progressive disease in 21% (7/34). The majority of patients (74%; 25/34) experienced a decrease in the sum of diameters for their target lesions. Compared to FISH, the positive predictive value of HER2 amplification in pre-dose C1D1 ctDNA was 90% (95% CI 79-96%), negative predictive value 45% (25-67%), and diagnostic accuracy 79% (63-90%). Disease control (PR or SD) > 5 months was associated with lower level of copy number adjusted mutational variant allele frequency in pre-treatment ctDNA (Mann Whitney p = 0.0085).

Conclusions

ZW25 has been well tolerated with promising single agent activity in heavily pre-treated patients. These data support further clinical development of this bispecific antibody in HER2-expressing solid tumors.

Clinical trial identification

NCT03929666.

Legal entity responsible for the study

Zymeworks, Inc.

Funding

Zymeworks, Inc.

Disclosure

F. Meric-Bernstam: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Calithera; Research grant / Funding (institution): Debio; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): CytomX; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): eFFECTOR; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Guardant Health; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self): Sumitomo Dainippon Pharma; Dialectica; Advisory / Consultancy: Genentech; Inflection; Pieris; Darwin Health; Samsung Bioepis; Aduro; Spectrum; OrigiMed; Debio; Xencor; Jackson Laboratory; Mersana; Seattle Genetics; Zymeworks; Kolon; Parexel International. M. Beeram: Speaker Bureau / Expert testimony, Speaker’s bureau: Genentech. K. Lee: Honoraria (self): BMS; Honoraria (self): Eli Lilly; Research grant / Funding (institution): ALX Oncology; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Green Cross Corp; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharmacyclics; Travel / Accommodation / Expenses: BMS. Y. Kang: Advisory / Consultancy: Ono; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSKBiopharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Merck; Advisory / Consultancy: Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis. J. Chaves: Shareholder / Stockholder / Stock options: Northwest Medical Specialties, PLLC. C. Vaklavas: Advisory / Consultancy, no compensaton: Genentech; Advisory / Consultancy: Daiichi-Sankyo; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pharmacyclics; Research grant / Funding (institution): Tracon; Research grant / Funding (institution): Innocrin; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): H3 Biomedicine. D. Oh: Advisory / Consultancy: Genentech; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Zymeworks; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Array; Research grant / Funding (institution): Eli Lilly. E. Elimova: Full / Part-time employment, spouse is employee in vaccine global division: Meric; Advisory / Consultancy: BMS; Honoraria (self): Zymeworks. C. Ferrario: Honoraria (self): Pfizer; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Merck; Honoraria (self): Astellas Pharma; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony, Speaker’s bureau: Novartis; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Cascadian Therapeutics; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Merck; Novartis; Roche/Genentech; Sanofi; Pfizer; Janssen; Zymeworks; Travel / Accommodation / Expenses: Novartis; Roche. A. Fortenberry: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. G. Rowse: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. T. Gray: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. R. Lai: Full / Part-time employment: Zymeworks, Inc.; Shareholder / Stockholder / Stock options: Zymeworks, Inc. E. Hamilton: Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Lilly; Advisory / Consultancy, No personal compensation: Lilly; Research grant / Funding (institution): Pfizer; Advisory / Consultancy, No personal compensation: Pfizer; Research grant / Funding (institution): Genentech/Roche; Speaker Bureau / Expert testimony, No personal compensation: Genentech/Roche; Advisory / Consultancy: Flatiron Health; Research grant / Funding (institution): Cascadian Therapeutics; Research grant / Funding (institution): Hutchinson MediPharma; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): StemCentrx; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Curis; Research grant / Funding (institution): Verastem; Research grant / Funding (institution): Zymeworks; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Rgenix; Novartis; Mersana; TapImmune; BerGenBio; Tesaro; Medivation; Kadmon, Boehringer Ingelheim; Eisai; H3 Biomedicine; Radius Health; Acerta; Takeda; Macrogenics; Immunomedics; FujiFilm; Effector. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

454PD - First in human, a phase I study of ISU104, a novel ErbB3 monoclonal antibody, in patients with advanced solid tumours (ID 1831)

Presentation Number
454PD
Lecture Time
17:36 - 17:36
Speakers
  • Sung-Bae Kim (Seoul, Korea, Republic of)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

ErbB3, a heterodimeric partner of EGFR or ErbB2, is activated by heregulin binding in various cancers. ISU104, blocking ErbB3 activation and dimerization, showed anti-tumor effects in various preclinical models as mono- or combination-therapy.

Methods

In the part 1, we enrolled the patients with advanced solid tumor who were refractory to standard treatments. Study was conducted with a standard 3 + 3 dose escalation scheme at 5 different doses (1, 3, 5, 10, 20 mg/kg/day). Dose-limiting toxicities (DLTs) were evaluated during the 1st Cycle of 28 days. Thereafter, ISU104 was given weekly, and tumor response was assessed every 8 weeks. Blood samples for pharmacokinetics (PK) and immunogenicity studies were performed.

Results

In the part 1, 15 patients (13 males, 2 females) were enrolled. Median age was 54 (range 36–96). No DLT was observed even at the maximum dose (20mg/kg/day). The most common drug-related adverse events (AEs) were oral mucositis (n = 3), pruritus (n = 2), diarrhea (n = 2), and fatigue (n = 2), but of which were grade 1. Only two grade 3 AEs were noted; asthenia (n = 1) and anemia (n = 1). Thirteen subjects were assessable; 7 stable diseases and 1 partial response (table). One responder lasted up to 40 weeks. Drug clearances tend to decrease (0.77±0.41 ml/h/kg at 1 mg/kg; 0.20±0.03 ml/h/kg at 20 mg/kg) and half-lives to increase (44.50±5.74 h at 1 mg/kg; 269.86±19.08 h at 20 mg/kg) as dose is increased. PK analysis and modeling suggested target-mediated clearance of ISU104 and saturation of target binding at 3 mg/kg, and the dosing regimen for the part 2 of the current study, which would be 20 mg/kg tri-weekly.

454PD

Cancer typeHypopharynxHypopharynx*RectalBreastPalateRectalSubmandibularParotidColonNSCLCEsophagusTonsilEsophagus
Best responsePRSDSDSDSDSDSDSDPDPDPDPDPD
Maximum change in tumor size (target lesion) (%)-60.5-21.9-21.4-8.10.52.83.66.913.213.517.428.173.7

Double primary with esophagus

Conclusions

Intravenous administrations of ISU104 were well tolerated up to 20 mg/kg/day without DLT, and showed disease control rate of 60.0%. Safety and efficacy of ISU104 as mono- or combination-therapy and potential biomarkers will be further explored in head and neck, colorectal and breast cancers.

Clinical trial identification

NCT03552406.

Legal entity responsible for the study

ISU Abxis.

Funding

KDDF: Korea Drug Development Fund.

Disclosure

B. Keam: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy: Genexin; Research grant / Funding (self): ONO; Research grant / Funding (self): MSD; Research grant / Funding (institution): AstraZeneca. T.M. Kim: Research grant / Funding (institution): AstraZeneca. K. Park: Advisory / Consultancy: Astellas Pharma; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Lilly; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Kyowa Hakko Kirin; Advisory / Consultancy: Norvatis; Advisory / Consultancy: Ono Pharmaceutical; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: AZD. J.S. Ahn: Advisory / Consultancy: Samsung Bioepis; Honoraria (institution): Menarini; Honoraria (institution): Amgen; Honoraria (institution): Pfizer; Honoraria (institution): AstraZeneca; Honoraria (institution): Roche; Honoraria (institution): Janssen; Honoraria (institution): MSD; Honoraria (institution): Bristol-Myers Squibb-Ono Pharmaceutical; Honoraria (institution): Eisai; Honoraria (institution): Boehringer Ingelheim. J. Juhn: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: ISU Abxis. S. Kim: Full / Part-time employment: ISU Abxis. S. Hong: Shareholder / Stockholder / Stock options, Full / Part-time employment: ISU ABXIS. M. Ahn: Honoraria (institution), Advisory / Consultancy: AstraZeneca; Honoraria (institution), Advisory / Consultancy: BMS; Honoraria (institution), Advisory / Consultancy: MSD; Honoraria (institution): ONO; Honoraria (institution), Advisory / Consultancy: Roche; Advisory / Consultancy: TAKEDA; Advisory / Consultancy: Novartis; Advisory / Consultancy: Alpha pharmaceutical. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

455PD - First-in-human, first-in-class phase I study of MTL-CEBPA, a RNA oligonucleotide targeting the myeloid cell master regulator C/EBP-α, in patients with advanced hepatocellular cancer (HCC) (ID 2878)

Presentation Number
455PD
Lecture Time
17:36 - 17:36
Speakers
  • Debashis Sarker (London, United Kingdom)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00

Abstract

Background

MTL-CEBPA is a first-in-class small activating RNA (saRNA) oligonucleotide which specifically up-regulates the myeloid cell master regulator, C/EBP-α (CCAAT/enhancer-binding protein alpha).

Methods

We conducted a phase I, 3 + 3 dose escalation and dose expansion trial of MTL-CEBPA in adults with HCC or secondary liver cancer. Patients received intravenous MTL-CEBPA at 28-160 mg/m2 for 3 weeks either QW, BIW at d1 and d2, BIW at d1 and d3, or TIW at d1, d2, and d3 followed by a rest period of 1 week. Adverse events (AEs), serum PK, WBC biomarkers and anti-tumour activity were assessed.

Results

38 participants (31 HCC, 4 colorectal, 2 fibrolamellar, 1 ampullary) have been treated across 6 dose levels (28-160 mg/m2) and 3 dosing schedules: 29M/9F, median age 66 years (range 27 - 80), ECOG PS 0/1: 16/22. In 28 HCC patients evaluable for efficacy, PR was achieved in 1 pt, SD > 1 year in 1 patient and SD < 1 year in 11 pts. After discontinuation of MTL-CEBPA, four sorafenib- naïve HCC patients were treated with sorafenib; 3/4 had durable CR (14, 12 and 9 months) and 1/4 had PR [6 months] by RECIST 1.1. Treatment-related adverse events (all grades) that occurred in more than 10% of patients were fatigue (23.7%), thrombocytopaenia (13.2%), anaemia (13.2%), elevated AST (13.2%), elevated ALP (10.5%), hypoalbuminaemia (10.5%), increased ALT (10.5%) and increased bilirubin (10.5%); no maximum dose was reached in any dosing cohorts. Target engagement was evidenced in evaluable patients by a significant 1.5 fold increase in CEBPA mRNA in WBC and a significant increase in WBC count consistent with C/EBP-α dependent granulopoiesis. Altered immunological markers were observed in WBC of one patient including decreased levels of ADA, PD-L1 and CXCR4 mRNA.

Conclusions

MTL-CEBPA is a first-in-class therapy targeting the myeloid cell master regulator C/EBP-α. In HCC patients MTL-CEBPA demonstrated a good safety profile, induced altered gene expression in WBC and as well as anti-tumour activity. These encouraging phase I data validate targeting of CEBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

Clinical trial identification

NCT02716012.

Legal entity responsible for the study

MiNA Therapeutics.

Funding

MiNA Therapeutics.

Disclosure

D. Sarker: Travel / Accommodation / Expenses: MiNA Therapeutics; Honoraria (self): MSD; Honoraria (self): EISAI; Honoraria (self): BAYER; Honoraria (self), Travel / Accommodation / Expenses: IPSEN. K. HUANG: Research grant / Funding (self): MiNA Therapeutics. N. Habib: Shareholder / Stockholder / Stock options: MiNA Therapeutics. All other authors have declared no conflicts of interest.

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Poster Discussion – Developmental therapeutics Poster Discussion session

Invited Discussant LBA29, 453PD, 454PD and 455PD (ID 6718)

Lecture Time
17:36 - 17:51
Speakers
  • Ulrik N. Lassen (Copenhagen, Denmark)
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00
Poster Discussion – Developmental therapeutics Poster Discussion session

Q&A led by Discussant (ID 6723)

Lecture Time
17:51 - 17:58
Location
Alicante Auditorium (Hall 3), Fira Gran Via, Barcelona, Spain
Date
28.09.2019
Time
16:30 - 18:00