Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours

abstracts

Annals of Oncology

Table: 446PD Best Tumor Response in 29* Patients

NSCLC (n ¼ 10) Partial Response Stable Disease Progressive Disease CRC/Other (n ¼ 19) Stable Disease Progressive Disease

Frequency

Duration of Response or Stable Disease**

5 (2 confirmed) 4 1***

7.3 - 27.4 weeks 8.4 - 25.1 weeks n/a

14 5***

7.3 - 24.0 weeks 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.

446PD

Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours

R. Govindan1, M.G. Fakih2, T.J. Price3, G.S. Falchook4, J. Desai5, J.C. Kuo6, J.H. Strickler7, J.C. Krauss8, B.T. Li9, C.S. Denlinger10, G. Durm11, J. Ngang12, H. Henary12, G. Ngarmchamnanrith12, E. Rasmussen13, P.K. Morrow12, D.S. Hong14 1 Department of Medical Oncology, Alvin J Siteman Cancer Center at Washington University School of Medicine, St Louis, MO, USA, 2 Department of GI Medical Oncology, City of Hope National Medical Center, Duarte, CA, USA, 3Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville South, Australia, 4Sarah Cannon Research Institute, HealthONE, Denver, CO, USA, 5Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, 6Department of Medical Oncology, Scientia Clinical Research Ltd, Randwick, Australia, 7Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, NC, USA, 8 Division of Hematology/Oncology, Internal Medicine, University of Michigan, Ann Arbor, MI, USA, 9Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 10Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA, 11Department of Hematology/Oncology, Indiana University, Simon Cancer Center, Indianapolis, IN, USA, 12Global Development, Amgen Inc., Thousand Oaks, CA, USA, 13Global Biostatistics, Amgen Inc., Thousand Oaks, CA, USA, 14 Dept of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA Background: The KRASG12C mutation occurs in 13% of lung cancers (11% of nonsmall 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

Volume 30 | Supplement 5 | October 2019

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 LaRoche; 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: BristolMyers 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

doi:10.1093/annonc/mdz244 | v163

Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz244.008/5578102 by University of New England user on 23 October 2019

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.

abstracts

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

R.B. Corcoran1, K.T. Do2, J.M. Cleary3, A.R. Parikh4, O.O. Yeku1, C.D. Weekes1, J. Veneris2, L.G. Ahronian1, G. Mauri5, E.E. Van Seventer1, I.J. Fetter1, J.M. Gurski1, U.A. Matulonis6, D. Juric4, K.T. Flaherty1, R.J. Sullivan1, J.W. Clark1, R.S. Heist1, G.I. Shapiro6 1 Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 2Cancer Institute, Dana Farber Cancer Institute, Boston, MA, USA, 3Medicine, Dana-Faber Cancer Institute, Boston, AL, USA, 4Cancer Center, Massachusetts General Hospital, Boston, MA, USA, 5Oncology, Niguarda Cancer Center, Milan, Italy, 6Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA, 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 d114 only of a 28d cycle in schedule C. Pre-treatment and d15 on-treatment biopsies and serial cell-free (cf)DNA were obtained.

v164 | Developmental Therapeutics

Results: To date, 43 patients (pts) (median age 60) initiated treatment (A [n ¼ 9]; B [n ¼ 11]; C [n ¼ 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 þ 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 þ SD) 46.2%. Early potential disease-specific differences in efficacy were noted. In GYN pts at all doses, overall DCR ¼ 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 NþT 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.

448PD

Genomic profiling of three pathways through molecular profilingbased assignment of cancer therapy (NCI- MPACT)

A. Chen1, S. Kummar2, S.S. Khan3, N. Moore3, L. Rubinstein3, G. O’Sullivan Coyne4, Y. Zhao3, A. Palmisano3, P. Williams5, V. Datta5, D. Sims5, C. Karlovich5, C.-J. Lih5, K.P.S. Raghav6, F. Meric-Bernstam7, S. Leong8, S. Waqar9, N. Takebe3, E. Sharon1, J. Doroshow3 1 Early Clinical Trials Development Program, National Cancer Institute, Bethesda, MD, USA, 2Oncology, Stanford University, Stanford, CA, USA, 3Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA, 4Division Of Cancer Treatment and Diagnosis, Developmental Therapeutics Clinic, National Cancer Institute, Bethesda, MD, USA, 5Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA, 6Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 7Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 8Division of Medical Oncology, University of Colorado Denver School of Medicine, Aurora, AL, USA, 9Division of Oncology, Washington University School of Medicine, St Louis, MO, USA 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) PI3Keverolimus (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.

Volume 30 | Supplement 5 | October 2019

Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz244.008/5578102 by University of New England user on 23 October 2019

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.

Annals of Oncology