Patritumab Deruxtecan in Patients With Solid Tumor Harboring an NRG1 Fusion

Summary

The NRG1 gene is located on chromosome 8 (8p12 region) and encode NRG1. NRG1 gene is translated to generate six different proteins (I-VI) and at least 31 isoforms. NRG1 proteins are structurally related to EGF and contain an EGF-like motif that binds and activates ErbB3 and ErbB4. Upon ligand binding, these receptors form homodimers or heterodimers, which results in phosphorylation of the intrinsic kinase domain, and activation of the PI3K-AKT, MAPK, and other pathways. The overall incidence of NRG1 fusions is very rare. In many tumor types, only limited numbers of NRG1 fusion variant have been identified. By percentage, there is no organ dominance of the presence of NRG1 fusions. In an analysis of 21, 858 tumor specimens that underwent anchored multiplex PCR for targeted RNA sequencing, the prevalence of NRG1 fusions was 0.2%. Of these, CD74 was the most common partner (29%), followed by ATP1B1 (10%), SDC4 (7%), and RBPMS (5%), and most CD74-NRG1 fusions have been reported in patients with lung IMA. NRG1 fusions result in aberrant expression of the epidermal growth factor (EGF)-like domain of neuregulin-1 (NRG1) on the cell surface binds primarily to ErbB3 and ErbB4, leading to heterodimerization or oligomerization with other ERBB family members. NRG1-mediated activation of ErbB3 promotes dimerization with EGFR, ErbB2, and ErbB4. These partners phosphorylate ErbB3, forming docking sites for SH2-domain proteins, leading to pathologic activation of multiple signal transduction pathways, including the phosphoinositide 3-kinase (PI3K) pathway. Subsequently, ErbB3 expression was noted at high levels, and the proteins were phosphorylated, in fusion-positive cases. Targeting ErbB3 signaling therefore represents a promising therapeutic approach for patients with NRG1 fusion-positive malignancies.

Eligibility

Inclusion Criteria:

* Sign and date the tissue informed consent form (ICF) and the main ICF, prior to the start of any study-specific qualification procedures.
* Male or female participants aged ≥18 years (follow local regulatory requirements if the legal age of consent for study participation is \>18 years old).
* Histologically or cytologically documented locally advanced or metastatic solid tumor not amenable to curative surgery or radiation.
* Documentation of NRG1 fusion detected from tumor tissue or blood sample, including but not limited to TruSightOncology-500, Guardant-360 or FoundationOne®CDx (F1CDx).
* At least 1 measurable lesion confirmed by investigator as per RECIST v1.1
* At least 1 measurable lesion confirmed per RECIST v1.1
* Consented and willing to provide required tumor tissue of sufficient quantity (as defined in the Laboratory Manual) and of adequate tumor tissue content (as confirmed by hematoxylin and eosin \[H\&E\] staining). Required tumor tissue can be provided as either:

  1. Pretreatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR
  2. Archival tumor tissue collected from a biopsy performed within 3 months prior to signing of the tissue consent and since progression while on or after treatment with the most recent cancer therapy regimen.
* Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening.
* Has adequate bone marrow reserve and organ function based on local laboratory data within 14 days prior to Cycle 1 Day

  1. Platelet count: ≥100,000/mm\^3 or ≥100 × 10\^9/L (platelet transfusions are not allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility)
  2. Hemoglobin: ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
  3. Absolute neutrophil count: ≥1500/mm\^3 or ≥1.5 × 10\^9/L
  4. Serum creatinine (SCr) or creatinine clearance (CrCl): SCr ≤1.5 × upper limit of normal (ULN), OR CrCl ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl
  5. Aspartate aminotransferase/alanine aminotransferase: ≤3 × ULN (if liver metastases are present, ≤5 × ULN)
  6. Total bilirubin: ≤1.5 × ULN if no liver metastases (\<3 × ULN in the presence of documented Gilbert's syndrome \[unconjugated hyperbilirubinemia\] or liver metastases)
  7. Serum albumin: ≥2.5 g/dL
  8. Prothrombin time (PT) or PT-International normalized ratio (INR) and activated partial thromboplastin time (aPTT)/PTT: ≤1.5 × ULN, except for subjects on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator

Exclusion Criteria:

* Any history of interstitial lung disease (including pulmonary fibrosis or radiation pneumonitis) has current interstitial lung disease (ILD) or is suspected to have such disease by imaging during screening.
* Clinically severe respiratory compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:

  1. Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months prior to the study enrollment, severe asthma, severe chronic obstructive pulmonary disease \[COPD\]), restrictive lung disease, pleural effusion);
  2. Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); OR prior complete pneumonectomy.
* Is receiving chronic systemic corticosteroids dosed at \>10 mg prednisone or equivalent anti-inflammatory or any form of immunosuppressive therapy prior to enrollment. Participants who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study.
* Evidence of any leptomeningeal disease.
* Evidence of clinically active spinal cord compression or brain metastases.
* Inadequate washout period prior to Cycle 1 Day 1, defined as:

  1. Whole brain radiation therapy \<14 days or stereotactic brain radiation therapy \<7 days;
  2. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), \<14 days or 5 half-lives, whichever is longer;
  3. Monoclonal antibodies, other than immune checkpoint inhibitors, such as bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) \<28 days;
  4. Immune checkpoint inhibitor therapy \<21 days;
  5. Major surgery (excluding placement of vascular access) \<28 days;
  6. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation \<28 days or palliative radiation therapy \<14 days; or
  7. Chloroquine or hydroxychloroquine \<14 days.
* Prior treatment with an anti-human epidermal growth factor receptor 3 (HER3) antibody or single-agent topoisomerase I inhibitor.
* Prior treatment with an antibody drug conjugate (ADC) that consists of any topoisomerase I inhibitor
* Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, Grade ≤1 or baseline. Participants with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator.
* Has history of other active malignancy within 3 years prior to enrollment, except:

  1. Adequately treated non-melanoma skin cancer;
  2. Superficial bladder tumors (Ta, Tis, T1);
  3. Well-differentiated thyroid cancer
  4. Adequately treated intraepithelial carcinoma of the cervix uteri;
  5. Low risk non-metastatic prostate cancer (with Gleason score \<7, and following local treatment or ongoing active surveillance);
  6. Any other curatively treated in situ disease.
* Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1
* Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1.

Conditions2

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