Background

Dose-finding studies typically establish a maximum tolerated dose, a recent shift from this “more is better” approach towards long-term tolerability is of interest. The ongoing RP-3500 TRESR study (NCT04497116) used a comprehensive, non-randomized, dose-finding approach, focusing on longer-term tolerability to establish a patient (pt)-specific therapeutic dose level.

Methods

Bayesian Optimal Interval-based dose escalation was informed by preclinical in vivo pharmacokinetic (PK)/pharmacodynamic (PD) models (LoVo/Granta-519), clinical PK, PD biomarkers (γ-H2AX), circulating tumor DNA (ctDNA) and safety data. The optimal recommended phase 2 dose (RP2D) schedule (3 days (d) on/4d off) and efficacious dose level (>100mg) for target inhibition were chosen based on pre-clinical and clinical PK and safety data. Decrease in ctDNA mean variant allele frequency (mVAF) was a surrogate of RP-3500 activity. PK/PD modelling contributed to RP2D selection. Hematology data within Cycle 1 were used to develop a nomogram to mitigate anemia, an on-target toxicity.

Results

Pts (N=120) with recurrent tumors with selected ATR-inhibitor–sensitizing DNA damage response alterations were enrolled in the dose-escalation portion of TRESR. A subset of pts in three dose-expansion cohorts (N=25/34/26) below the highest evaluated, non-tolerated dose (200mg, 3d on/4d off) was assessed for long term safety (Table). Table: 5MO

RP-3500 safety

Conclusions

This dose optimization approach using large pt cohorts at three dosing regimens provides robust evidence to support RP-3500 RP2D in the ongoing studies (160mg, 3d on/4d off, continuous). Consistency of ctDNA mVAF decrease across cohorts supports the selected RP-3500 dose level. The hematological toxicity nomogram currently in early clinical testing will guide individualized treatment modifications to further reduce anemia rates while maintaining the therapeutic range of 120-160 mg of RP-3500.

Clinical trial identification

NCT04497116.

Editorial acknowledgement

Editorial assistance was provided by Mike Zbreski, PharmD of Onyx Medica, London, UK, supported by Repare Therapeutics Inc.

Legal entity responsible for the study

Repare Therapeutics.

Funding

Repare Therapeutics.

Disclosure

E. Fontana: Financial Interests, Personal, Full or part-time Employment: Hospital Corporation of America (HCA) International. D. Spigel: Financial Interests, Personal, Research Grant: Aeglea BioTherapeutics; Financial Interests, Personal, Research Grant: Agios; Financial Interests, Personal, Research Grant: Apollomics; Financial Interests, Personal, Research Grant: Arcus; Financial Interests, Personal, Research Grant: Arrys Therapeutics; Financial Interests, Personal, Research Grant: Astellas; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Research Grant: BeiGene; Financial Interests, Personal, Research Grant: BIND Therapeutics; Financial Interests, Personal, Research Grant: BioNTech RNA Pharmaceuticals; Financial Interests, Personal, Research Grant: Blueprint Medicine; Financial Interests, Personal, Research Grant: Boehringer Ingelheim; Financial Interests, Personal, Research Grant: Bristol-Myers Squibb; Financial Interests, Personal, Research Grant: Calithera; Financial Interests, Personal, Research Grant: Celgene; Financial Interests, Personal, Research Grant: Celldex; Financial Interests, Personal, Research Grant: Clovis; Financial Interests, Personal, Research Grant: Cyteir Therapeutics; Financial Interests, Personal, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Research Grant: Denovo Biopharma; Financial Interests, Personal, Research Grant: Eisai; Financial Interests, Personal, Research Grant: Elevation Oncology; Financial Interests, Personal, Research Grant: EMD Serono; Financial Interests, Personal, Research Grant: Evelo Biosciences; Financial Interests, Personal, Research Grant: G1 Therapeutics; Financial Interests, Personal, Research Grant: Roche/Genentech; Financial Interests, Personal, Research Grant: GlaxoSmithKline; Financial Interests, Personal, Research Grant: GRAIL; Financial Interests, Personal, Research Grant: Hutchison MediPharma; Financial Interests, Personal, Research Grant: ImClone Systems; Financial Interests, Personal, Research Grant: Incyte; Financial Interests, Personal, Research Grant: ImmunoGen; Financial Interests, Personal, Research Grant: Ipsen; Financial Interests, Personal, Research Grant: Janssen; Financial Interests, Personal, Research Grant: Kronos Bio; Financial Interests, Personal, Research Grant: Lilly; Financial Interests, Personal, Research Grant: Loxo Oncology; Financial Interests, Personal, Research Grant: MacroGenics; Financial Interests, Personal, Research Grant: MedImmune; Financial Interests, Personal, Research Grant: Merck; Financial Interests, Personal, Research Grant: Molecular Partners; Financial Interests, Personal, Research Grant: Molecular Template; Financial Interests, Personal, Research Grant: Nektar; Financial Interests, Personal, Research Grant: Neon Therapeutics; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Novocure; Financial Interests, Personal, Research Grant: Oncologie; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: PTC Therapeutics; Financial Interests, Personal, Research Grant: PureTech Health; Financial Interests, Personal, Research Grant: Razor Genomics; Financial Interests, Personal, Research Grant: Repare Therapeutics; Financial Interests, Personal, Research Grant: Rgenix; Financial Interests, Personal, Research Grant: Takeda; Financial Interests, Personal, Research Grant: Tesaro; Financial Interests, Personal, Research Grant: Tizona Therapeutics; Financial Interests, Personal, Research Grant: Transgene; Financial Interests, Personal, Research Grant: UT Southwestern; Financial Interests, Personal, Research Grant: Verastem; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Curio Science; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: Evidera; Financial Interests, Personal, Advisory Role: Exelixis; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Intellisphere; Financial Interests, Personal, Advisory Role: Ipsen Biopharmaceuticals; Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal, Advisory Role: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Mirati Therapeutics; Financial Interests, Personal, Advisory Role: Molecular Templates; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Novocure; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Puma Biotechnology; Financial Interests, Personal, Advisory Role: Regeneron Pharmaceuticals; Financial Interests, Personal, Advisory Role: Roche/Genentech; Financial Interests, Personal, Advisory Role: Sanofi-Aventis. M. Højgaard: Other, Personal, Advisory Board: LingoMedical; Financial Interests, Personal, Stocks/Shares: Bavarian Nordic; Financial Interests, Personal, Stocks/Shares: Pacific Biosciences; Financial Interests, Personal, Stocks/Shares: Illumina Inc.; Non-Financial Interests, Institutional, Principal Investigator: Amgen; Non-Financial Interests, Institutional, Principal Investigator: Incyte Cooperation; Other, Personal, Member of the Board of Directors: Danish Medicines Council. S. Lheureux: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics; Non-Financial Interests, Personal, Advisory Board: AstraZeneca; Non-Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Non-Financial Interests, Personal, Advisory Board: Shattuck lab; Non-Financial Interests, Personal, Advisory Board: Merck. N.B. Mettu: Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Mereo BioPharma; Financial Interests, Institutional, Research Grant: OncoMed Pharmaceuticals; Financial Interests, Institutional, Research Grant: Amphivena Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Biomed Valley Discoveries; Financial Interests, Institutional, Research Grant: Erytech Pharma; Financial Interests, Institutional, Research Grant: Incyte Corporation; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant: Revolution Medicines, Inc; Financial Interests, Institutional, Research Grant: Syros Pharmaceuticals; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: Marc Lustgarten Pancreatic Cancer Foundation; Financial Interests, Institutional, Research Grant: Armo BioSciences/Eli Lilly; Financial Interests, Institutional, Research Grant: NIH; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb. R. Plummer: Financial Interests, Personal, Advisory Board: Astex Therapeutics; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Biosceptre; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: CV6 Therapeutics; Financial Interests, Personal, Advisory Board: Cybrexa; Financial Interests, Personal, Advisory Board: Ellipses; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Faber; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Institutional, Royalties: Clovis Oncology; Financial Interests, Personal, Other, Homoraria: Beigene; Financial Interests, Personal, Other, Honorarium as member of IDMC: SOTIO. P. Manley: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics. D. Ulanet: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. V. Rimkunas: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. I.M. Silverman: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. J. O'Connell: Financial Interests, Personal, Advisory Role: Repare Therapeutics. R. McDougall: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics. M. Wainszelbaum: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics. Y. Xu: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics. M. Koehler: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics; Financial Interests, Personal, Stocks/Shares: Repare Therapeutics. A.J. Fretland: Financial Interests, Personal, Full or part-time Employment: Repare Therapeutics. T.A. Yap: Financial Interests, Institutional, Research Grant: Repare Therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Artios; Financial Interests, Institutional, Research Grant: Bayer; Financial Interests, Institutional, Research Grant: Beigene; Financial Interests, Institutional, Research Grant: BioNTech; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Clovis; Financial Interests, Institutional, Research Grant: Constellatior; Financial Interests, Institutional, Research Grant: Cyteir; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Research Grant: Forbius; Financial Interests, Institutional, Research Grant: F-Star; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Haihe; Financial Interests, Institutional, Research Grant: ImmuneSensor; Financial Interests, Institutional, Research Grant: Ionis; Financial Interests, Institutional, Research Grant: Ipsen; Financial Interests, Institutional, Research Grant: Jounce; Financial Interests, Institutional, Research Grant: Karyopharm; Financial Interests, Institutional, Research Grant: KSQ; Financial Interests, Institutional, Research Grant: Kyowa; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Rubius; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Scholar Rock; Financial Interests, Institutional, Research Grant: Seattle Genetics; Financial Interests, Institutional, Research Grant: Tesaro; Financial Interests, Institutional, Research Grant: Vivace; Financial Interests, Institutional, Advisory Role: Ribon Therapeutics; Financial Interests, Personal, Advisory Role: Repare Therapeutics; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Almac; Financial Interests, Personal, Advisory Role: Aduro; Financial Interests, Personal, Advisory Role: Artios; Financial Interests, Personal, Advisory Role: Athena; Financial Interests, Personal, Advisory Role: Atrin; Financial Interests, Personal, Advisory Role: Axiom; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Calithera; Financial Interests, Personal, Advisory Role: Clovis; Financial Interests, Personal, Advisory Role: Cybrexa; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Advisory Role: F-Star; Financial Interests, Personal, Advisory Role: GLG; Financial Interests, Personal, Advisory Role: Guidepoint; Financial Interests, Personal, Advisory Role: Ignyta; Financial Interests, Personal, Advisory Role: I-Mab; Financial Interests, Personal, Advisory Role: ImmuneSensor; Financial Interests, Personal, Advisory Role: Jansen; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Schrodinger; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Varian; Financial Interests, Personal, Advisory Role: Zai Labs; Financial Interests, Personal, Advisory Role: Zielbio. All other authors have declared no conflicts of interest.

Background

PARP inhibitors (PARPi) have shown significant benefits in cancer patients with deficient homologous recombination repair (HRD; induced by BRCA mutations for example). However, they show no or very limited efficacy in tumors with active or proficient homologous recombination repair (HRP). In the current study, we propose a novel therapeutic strategy, based on drug combination to achieve synthetic lethality independently of the tumor genetics.

Methods

AsiDNA^TM is a double-strand DNA molecule that mimics endogenous DNA breaks to interfere with the DNA damage (DD) response. This decoy agonist molecule induces a false DD signaling through DNA-PK over-activation, and thus hijacks several DNA repair proteins from sites of real DD. We analyzed the effects of AsiDNA treatment on double strand break repair activities through homologous recombination and assessed the efficacy of the combination with PARPi (Olaparib and Talazoparib) in HRP tumor models.

Results

The AsiDNA-induced false damage signaling abrogated the HR repair through a “bluring” effect which limited the efficient recruitment of HR proteins (BRCA1, RAD51) to sites of PARPi-induced double-strand DNA breaks. The combined treatment induced a drug-driven synthetic lethality which was specific to tumor cells and is not observed in non-tumor cells predicting a good safety of the association. The AsiDNA-induced functional HRD was confirmed in different tumor models (breast, ovarian and prostate cancer cells) and is driven for at least one to two weeks after AsiDNA treatment, paving the way for a more appropriate patient-friendly treatment schedule. This concept was also validated in patient biopsies from DRIIV-1a clinical trial, where AsiDNA-treated tumors for three weeks showed clear tendency to switch from HRP to HRD. In addition to primary HRP tumors intrinsically resistant to PARPi, AsiDNA also sensitized de novo HRP tumors, that evolved from HRD to HRP under PARPi treatment pressure, through the restoration of the HR pathway.

Conclusions

These results point to the therapeutic opportunity of combining AsiDNA and PARPi in HRP tumors to overcome intrinsic or acquired resistance in clinical situation.

Legal entity responsible for the study

The authors.

Funding

Onxeo.

Disclosure

W. Jdey, V. Trochon-Joseph, C. Doizelet, V. Hayes, A. Cohendet, M. Lienafa, C. Zandanel, O. De Beaumont: Financial Interests, Institutional, Full or part-time Employment: Onxeo. J. Miara: Financial Interests, Institutional, Member of the Board of Directors: Onxeo.

Background

Small cell lung cancer (SCLC) is a poorly immunogenic, high-grade neuroendocrine carcinoma arising in the lung. Immune checkpoint blockade (ICB) added to chemotherapy is now the standard upfront therapy for SCLC but leads to a modest increase in overall survival and progression-free survival. These modest benefits underscore the critical need to identify pathways and targets that can durably enhance the antitumor responses of ICB in SCLC. SCLC is characterized by a ubiquitous loss of TP53 which disrupts the G1-S cell cycle checkpoint and as a result, most SCLC is dependent on G2-M cell cycle checkpoint regulators including WEE1. We and others have shown that DNA damage response (DDR) components are overexpressed in SCLC and targeting DDR could be an effective therapeutic strategy in SCLC.

Methods

In this study, we have performed WEE1 inhibition either alone or in combination with PD-L1 blockade in a panel of SCLC models.

Results

We demonstrate that inhibition of WEE1 induces G2/M cell cycle arrest, DNA damage, and cytosolic DNA accumulation in SCLC models. We further show that WEE1 targeting activates the STING-TBK1-IRF3 pathway which increases type I interferons (IFN-α and IFN-β) and pro-inflammatory chemokines (CXCL10 and CCL5), facilitating an immune response via CD8⁺ cytotoxic T-cell infiltration. We further show that WEE1 inhibition concomitantly activates the STAT1 pathway, increasing IFN-γ and PD-L1 expression. Consistent with these findings, combined WEE1 inhibition (AZD1775) and PD-L1 blockade caused remarkable tumor regression, activation of type I and II interferon pathways, and infiltration of cytotoxic T-cells in multiple immunocompetent SCLC genetically engineered mouse models, including an aggressive model with stabilized MYC.

Conclusions

Our study demonstrates the cell-autonomous and immune-stimulating activity of WEE1 inhibition in SCLC. Given the increasing importance of immunotherapy for the management of SCLC and that WEE1 inhibitors are already in clinical trials, combining a WEE1 inhibitor with PD-L1 blockade may offer a particularly attractive strategy for the treatment of SCLC and contribute to the rapid translation of this combination into the clinic.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

Patients (pts) with advanced NSCLC harboring HER2 ex20ins mutations have a poor prognosis with no approved targeted therapy. Poziotinib is a potent tyrosine kinase inhibitor (TKI) able to target the inaccessible binding pocket of ex20ins. Cohort 4 of the ZENITH20 phase 2 study aims to evaluate the clinical efficacy of poziotinib in treatment-naïve pts with advanced HER2 ex20ins NSCLC. Preliminary efficacy and safety of QD dosing in this cohort were presented previously. Here, we present the primary efficacy analysis of the full cohort of 70 patients.

Methods

ZENITH20-4 enrolled pts with locally advanced or metastatic treatment-naïve advanced HER2 ex20ins NSCLC. Poziotinib was administered orally 16 mg QD or 8 mg BID, with optional dose interruptions/reductions for toxicity. The primary endpoint was objective response rate (ORR) by independent review (RECIST 1.1). Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and safety.

Results

In total, 70 pts (QD, n = 48; BID, n = 22) were treated; 14 remain on study (n = 3 and n = 11, respectively). Demographics were representative of this population. Among those treated with QD and BID dosing, 90% and 68% had dose interruptions, and 79% and 64% required dose reductions, respectively. Treatment-related AEs of any grade occurred in all pts treated with QD and 86% (n = 19) of pts treated with BID dosing. Among grade 3 AEs, the most common were rash (n = 17 [35%]; n = 4 [18%]), stomatitis/mucosal inflammation (n = 10 [21%]; n = 3 [14%]), and diarrhea (n = 7 [15%]; n = 3 [14%]). Combined ORR was 41% (95% CI: 30%, 54%), and 4 pts had unconfirmed responses (uORR = 47%). DCR was 73%, median DoR was 5.7 months (range: 1.2, >19.1), with 34% of pts having a DOR of >6 months, and median PFS was 5.6 months (range: 0, >20.2).

Conclusions

For both QD and BID dosing regimens, poziotinib therapy demonstrated statistically significant clinically meaningful efficacy in pts receiving front-line treatment for HER2 ex20ins NSCLC. Tolerability was improved with BID dosing, and overall AEs were manageable with dose modifications.

Clinical trial identification

NCT03318939.

Editorial acknowledgement

Medical writing support was provided by Meghan Sullivan, PhD (MedVal Scientific Information Services, LLC), and was funded by Spectrum Pharmaceuticals, Inc.

Legal entity responsible for the study

Spectrum Pharmaceuticals, Inc.

Funding

Spectrum Pharmaceuticals, Inc.

Disclosure

S. Sun: Other, Personal, Other, Consultancy fees: AstraZeneca; Other, Personal, Other, Consultancy fees: Bristol Myers Squibb; Other, Personal, Other, Consultancy fees: Novartis; Other, Personal, Other, Consultancy fees: Pfizer; Other, Personal, Other, Consultancy fees: Takeda. A. Prelaj: Financial Interests, Personal, Other, Personal fees: Roche; Financial Interests, Personal and Institutional, Other, Personal fees: AstraZeneca; Financial Interests, Personal, Other, Personal fees: Bristol Myers Squibb. C. Baik: Financial Interests, Personal and Institutional, Other, Research funding and Consultancy fees: AstraZeneca; Financial Interests, Personal and Institutional, Other, Research funding and Consultancy fees: Blueprint Medicines; Financial Interests, Personal and Institutional, Other, Research funding and Consultancy fees: Daiichi Sankyo; Financial Interests, Personal and Institutional, Other, Research funding and Consultancy fees: Turning Point Therapeutics; Financial Interests, Personal, Other, Consultancy fees: Guardant; Financial Interests, Personal, Other, Consultancy fees: Regeneron; Financial Interests, Personal, Other, Consultancy fees: Silverback; Financial Interests, Personal, Other, Consultancy fees: Takeda; Financial Interests, Institutional, Funding: AbbVie; Financial Interests, Institutional, Funding: Genentech; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Eli Lilly; Financial Interests, Institutional, Funding: Loxo Oncology; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Rain Therapeutics; Financial Interests, Institutional, Funding: Spectrum. X. Le: Financial Interests, Personal and Institutional, Other, Research funding and Consulting/advisory fees: EMD Serono; Financial Interests, Personal, Other, Consulting/advisory fees: AstraZeneca; Financial Interests, Personal, Other, Consulting/advisory fees: Spectrum; Financial Interests, Personal, Other, Consulting/advisory fees: Novartis; Financial Interests, Personal and Institutional, Other, Research funding and Consulting/advisory fees: Eli Lilly; Financial Interests, Personal and Institutional, Other, Research funding and Consulting/advisory fees: Boehringer Ingelheim; Financial Interests, Personal, Other, Consulting/advisory fees: Hengrui; Financial Interests, Personal, Other, Consulting/advisory fees: Janssen; Financial Interests, Personal, Other, Consulting/advisory fees: AbbVie; Financial Interests, Institutional, Funding: Regeneron. M. Garassino: Financial Interests, Personal and Institutional, Other: AstraZeneca; Financial Interests, Personal and Institutional, Other: MSD International; Financial Interests, Institutional, Other: MSD; Financial Interests, Personal and Institutional, Other: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Other: Boehringer Ingelheim Italia; Financial Interests, Personal and Institutional, Other: Celgene; Financial Interests, Personal and Institutional, Other: Eli Lilly; Financial Interests, Personal and Institutional, Other: Ignyta; Financial Interests, Personal and Institutional, Other: Incyte; Financial Interests, Personal, Other: Inivata; Financial Interests, Personal and Institutional, Other: MedImmune; Financial Interests, Personal and Institutional, Other: Novartis; Financial Interests, Personal and Institutional, Other: Pfizer; Financial Interests, Institutional, Other: Pfizer (MISP); Financial Interests, Personal and Institutional, Other: Roche; Financial Interests, Personal and Institutional, Other: Takeda; Financial Interests, Personal, Other: Seattle Genetics; Financial Interests, Personal, Other: Mirati; Financial Interests, Personal, Other: Daiichi Sankyo; Financial Interests, Personal, Other: Regeneron; Financial Interests, Personal, Other: Merck; Financial Interests, Institutional, Other: Tiziana; Financial Interests, Institutional, Other: Foundation Medicine; Financial Interests, Institutional, Other: GlaxoSmithKline; Financial Interests, Institutional, Other: Spectrum; Other, Personal and Institutional, Funding: AIRC; Other, Personal and Institutional, Funding: AIFA; Other, Personal and Institutional, Funding: Ministry of Health of Italy; Other, Personal and Institutional, Funding: TRANSCAN. M. Wollner: Financial Interests, Personal, Other, Honoraria: MSD; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Institutional, Advisory Role: Roche Israel; Financial Interests, Personal, Advisory Role: Takeda; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Roche Israel; Financial Interests, Personal, Speaker’s Bureau: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Institutional, Funding: MSD; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bristol Myers Squibb. E. Haura: Financial Interests, Personal and Institutional, Other, Principal investigator and Consultant: Revolution Medicines; Non-Financial Interests, Personal and Institutional, Other, Principal investigator and Consultant: Revolution Medicines; Non-Financial Interests, Personal, Other, Consultant: Janssen; Non-Financial Interests, Personal, Other, Consultant: Ellipses Pharma. Z. Piotrowska: Financial Interests, Personal, Advisory Board: Blueprint Medicines; Financial Interests, Personal, Other, Consulting: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: Cullinan; Financial Interests, Personal, Advisory Board: C4 Therapeutics; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Institutional, Funding: Blueprint Medicines; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: AbbVie; Financial Interests, Institutional, Funding: Daiichi Sankyo; Financial Interests, Institutional, Funding: Cullinan; Financial Interests, Institutional, Funding: Tesaro/GlaxoSmithKline; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Spectrum; Financial Interests, Institutional, Funding: Takeda; Financial Interests, Institutional, Funding: Novartis. M. Socinski: Financial Interests, Personal, Other, Honoraria: Genentech; Financial Interests, Personal, Other, Honoraria: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: Celgene; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Guardant Health; Financial Interests, Personal, Other, Honoraria: Bayer; Financial Interests, Personal, Other, Honoraria: Merck; Financial Interests, Personal, Other, Honoraria: Roche/Genentech; Financial Interests, Personal, Other, Honoraria: Eli Lilly; Financial Interests, Personal, Other, Honoraria: AstraZeneca/MedImmune; Financial Interests, Personal, Other, Honoraria: Janssen; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Speaker’s Bureau: Genentech; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: Bayer; Financial Interests, Personal, Speaker’s Bureau: Merck; Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Speaker’s Bureau: Blueprint Medicines; Financial Interests, Personal, Speaker’s Bureau: G1 Therapeutics; Financial Interests, Personal, Speaker’s Bureau: Guardant Health; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Regeneron/Sanofi; Financial Interests, Personal, Speaker’s Bureau: Jazz Pharmaceuticals; Financial Interests, Personal, Speaker’s Bureau: Janssen Oncology; Financial Interests, Institutional, Funding: Genentech; Financial Interests, Institutional, Funding: Spectrum; Financial Interests, Institutional, Funding: AstraZeneca/MedImmune. L. Dreiling: Financial Interests, Personal, Full or part-time Employment: Spectrum; Financial Interests, Personal, Stocks/Shares: Spectrum. G. Bhat: Financial Interests, Personal, Full or part-time Employment: Spectrum; Financial Interests, Personal, Stocks/Shares: Spectrum. F. Lebel: Financial Interests, Personal, Full or part-time Employment: Spectrum; Financial Interests, Personal, Stocks/Shares: Spectrum; Financial Interests, Personal, Leadership Role: Spectrum. All other authors have declared no conflicts of interest.

Background

EGFR is a potent oncogene commonly altered in cancers including NSCLC and GBM. NSCLC driven by canonical EGFR mutations can be treated by inhibitors including osimertinib. However, there is an unmet need to treat NSCLC tumors with acquired drug resistance mutations including C797S, or tumors expressing non-canonical EGFR mutations that are intrinsically resistant to these agents. We have revealed how EGFR oncogenic mutations in GBM drive a conformational structure that promotes formation of a covalently linked homodimer. Reversible inhibitors can promote this oncogenic dimer and result in paradoxical stimulation. Effective targeting of the full spectrum of EGFR mutants in NSCLC and GBM requires a CNS-penetrant agent that is not only potent and selective, but also irreversible to circumvent paradoxical activation.

Methods

The in vitro activity and irreversible binding of BDTX-1535 was studied. CNS exposure was assessed in rats and dogs. Antitumor activity was assessed across a broad range of mouse PDX, including intracranial, models.

Results

BDTX-1535 is an orally available, CNS penetrant, potent and selective irreversible inhibitor of EGFR mutations and amplification. As well as canonical EGFR mutations, it potently inhibits intrinsic resistance mutations that are inadequately controlled by approved EGFR inhibitors (e.g., G719X). It retains irreversible activity against acquired resistance mutations to 3rd generation EGFR TKIs (e.g., L858R/C797S). BDTX-1535 potently suppresses phosphorylation of EGFR mutants for greater than 24h following a single oral dose. Broad antitumor efficacy is achieved across NSCLC/GBM PDX tumors expressing a family of EGFR oncogenic mutations. BDTX-1535 exhibits a CNS Kpuu of 0.58 and 0.48 in rat and dog, respectively, and achieves survival benefit in a PDX intracranial murine model of GBM.

Conclusions

The preclinical characterization of BDTX-1535 supports potential for effectively treating NSCLC and GBM patients expressing mutations that are inadequately addressed by current EGFR inhibitors. BDTX-1535 is currently under phase I clinical investigation in NSCLC and GBM patients expressing targeted oncogenic EGFR mutations.

Legal entity responsible for the study

Black Diamond Therapeutics.

Funding

Black Diamond Therapeutics.

Disclosure

M.C. Lucas, A. Trombino, S. Eathiraj: Financial Interests, Personal, Stocks/Shares: Black Diamond Therapeutics; Financial Interests, Personal, Full or part-time Employment: Black Diamond Therapeutics. M. Merchant, M. O'Connor, S. Smith, W. Zhang, J. Simon, N. Waters, E. Buck: Financial Interests, Personal, Full or part-time Employment: Black Diamond Therapeutics; Financial Interests, Personal, Stocks/Shares: Black Diamond Therapeutics.