Patient case: 50-year-old male with non-small cell lung cancer; genetic feature: EGFR (T790M)

Clinical trial: U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer

Summary: This study has two parts: dose escalation and dose expansion.
  The primary objectives are:
  -  For Dose Escalation, to assess the safety and tolerability of U3-1402 in the study population and to determine the recommended dose for expansion of U3-1402 in the study population
  -  For Dose Expansion, to investigate the antitumor activity of U3-1402
  The number of treatment cycles is not fixed in this study. Participants will continue study treatment (for approximately 36 months) until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity) or other stopping reasons have been met.


Eligibility: Inclusion Criteria for both Dose Escalation and Dose Expansion:
  1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation
  2. Has at least one measurable lesion per RECIST version 1.1
  3. Has Eastern Cooperative Oncology Group performance status of 0 or 1, with no deterioration over the previous 2 weeks
  Inclusion Criteria for Dose Escalation only:
  1. Has histologically or cytologically documented adenocarcinoma NSCLC
  2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011)
  1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q)
  2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI
  3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib
  4. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening
  5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib
  6. Is willing to provide archival tumor tissue from a biopsy performed within 6 months of progression during treatment with erlotinib, gefitinib, afatinib, or osimertinib OR has at least one lesion, not previously irradiated, amenable to core biopsy and is willing to undergo screening tumor biopsy
  7. Demonstrates absence of EGFR T790M mutation if treated with erlotinib, gefitinib, or afatinib. No EGFR mutation testing is required if treated with osimertinib.
  Inclusion Criteria for both cohorts of Dose Expansion only:
  1. Has received systemic therapy for locally advanced or metastatic disease including at least 1 platinum-based chemotherapy regimen
  2. Has documented radiological disease progression during/after most recent treatment regimen for locally-advanced or metastatic disease
  3. Is willing to provide archival tumor tissue from a biopsy performed within 6 months of consent and performed after progression during/after treatment with most recent cancer therapy regimen OR has at least 1 lesion, not previously irradiated, amenable to core biopsy and is willing to undergo tumor biopsy
  Inclusion Criteria specific to Cohort 1 of Dose Expansion:
  1. Has histologically or cytologically documented adenocarcinoma NSCLC.
  2. Has documentation of radiological disease progression following one or more lines of EGFR TKI treatment. Participants with EGFR T790M mutation following treatment with erlotinib, gefitinib afatinib, or dacomitinib must have received and have documentation of radiological disease progression following treatment with osimertinib unless unable or unwilling.
  3. Has documentation of EGFR-activating mutation(s) detected from tumor tissue: G719X, exon deletion 19, L858R, or L861Q. Participants with other EGFR-activating mutations may be eligible following discussion with the Sponsor.
  Inclusion Criteria specific to Cohort 2 of Dose Expansion:
  1. Has histologically or cytologically documented squamous or non-squamous NSCLC (ie, without EGFR-mutation).
  2. Has received prior treatment with anti-PD-1 or anti-PD-L1 antibody-based regimen in the locally advanced or metastatic setting unless unable or unwilling. Participants with NSCLC known to harbor a genomic alteration(s) other than EGFR mutation(s) (eg, ALK or ROS1 fusion) for which treatment is available must have also received prior treatment with at least 1 genotype-directed therapy.
  Additional Inclusion Criteria specific to Cohort 2, Stage 2 (only if determined to be required after Stage 1):
  1. Has disease-expressing HER3 as determined by immunohistochemistry assayed by central laboratory from archival tissue or Screening tumor biopsy sample
  Exclusion Criteria for Dose Escalation and Dose Expansion:
  1. Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in Screening biopsy performed after progression
  2. Treatment with any of the following:
  1. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI), within 14 days of the first dose of study treatment
  2. Immune checkpoint inhibitor therapy within 21 days of the first dose of study treatment
  3. Prior treatment with an anti-HER3 antibody
  4. Prior treatment with a topoisomerase I inhibitor
  5. Prior treatment with an antibody-drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201a)
  6. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug treatment
  7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug treatment, or palliative radiation therapy within 2 weeks of the first dose of study drug treatment, or stereotactic radiotherapy within 1 week prior to the first dose of U3-1402
  3. Has history of other active malignancy within 3 years prior to enrollment, except:
  1. Adequately treated non-melanoma skin cancer OR
  2. Superficial bladder tumors (Ta, Tis, T1) OR
  3. Curatively treated in situ disease
  4. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy)
  5. Has history of myocardial infarction within the past 6 months
  6. Has symptomatic congestive heart failure[New York Heart Association (NYHA) Classes III-IV], unstable angina, or cardiac arrhythmia requiring antiarrhythmic treatment
  7. Has left ventricular ejection fraction (LVEF) < 45% by either echocardiogram (ECHO) or multigated acquisition scan (MUGA)
  8. Has any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG), eg, complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval > 250 milliseconds (ms)
  9. Has a mean corrected QT interval using Fridericia's Correction Formula (QTcF) prolongation to > 470 ms for females and > 450 ms for males in three successive Screening measurements
  10. Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval
  11. Has any factors that increase the risk of corrected QT (QTc) interval prolongation or risk of arrhythmic events, such as congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
  12. Has any history of interstitial lung disease (pulmonary fibrosis or severe radiation pneumonitis) or is suspected to have such disease by imaging during screening
  13. Has clinically significant corneal disease
  Additional Exclusion Criteria for Dose Expansion Cohort 2:
  1. Has documentation of one or more of the following EGFR activating mutations: G719X, exon 19 deletion, L858R, or L861Q

Relevance to patient case: definitely relevant