Patient case: 62-year-old male with cholangiocarcinoma; genetic feature: PIK3CA (1047H)

Clinical trial: Study of Pembrolizumab in Subjects With Advanced Gastric or Gastroesophageal Junction Adenocarcinoma Who Progressed After First-Line Therapy With Platinum and Fluoropyrimidine: Integration of Molecular Subtypes Through Integrative Genomic Analysis

Summary: Gastric cancer (GC) is the second most common cause of cancer related mortality and the fourth most common cancer worldwide. The molecular classification of GC and the relevance of pre-clinical models are not well established, creating challenges in discovering novel molecularly targeted therapies. In order to address these issues, we conducted an integrated molecular data analysis of three hundred Asian Gastric tumors through the Asian Cancer Research Group (ACRG). We performed an integrated genomic analyses based on target sequencing, gene expression profiling, copy number variations, Lauren's histological classification, Epstein Barr Virus (EBV) status, TP53 status in three hundred GC specimens.
  We first divided GC into four subgroups based on gene expression profiling and TP53 status:
  1. epithelial MSS-TP53 inactive;
  2. epithelial MSS-TP53 active;
  3. MSI; and
  4. mesenchymal.
  With an integrative analysis with target sequencing and copy number variations, epithelial MSS-TP53 inactive GCs are characterized by predominantly hypermutated intestinal tumors (including majority of mutations in KRAS) with MLH1 loss through promoter methylation and MSS-TP53 active GCs are characterized by intact TP53 pathway with high frequency of EBV infection or frequently mutated oncogenes (e.g. PIK3CA). MSI subtype with TP53 pathway inactive characterized by TP53 loss through deleterious mutations in TP53 or MDM2 amplification and further characterized by both focal amplifications in oncogenes such as HER2, EGFR, cMET, CCNE1 as well as large scale chromosomal gains and losses. The above subtypes exhibited differential prognosis with the mesenchymal subtype displaying the worst survival (2.2 years) and the MSI subtype the most favorable survival (5.6 years). The GC subtypes and their association with prognosis were independently validated in three GC cohorts. We additionally showed significant association of global gene expression immune patterns, like adaptive immune system and inflammation, as well as expression of PD-L1, with the genomic defined subtypes.
  In the phase Ib KEYNOTE-012 study which evaluated pembrolizumab monotherapy at 10 mg/kg ever 2 weeks in patients with gastric cancer were recently reported. Most patients had two or more prior lines of therapy. In the study, 41% of evaluable patients showed tumor shrinkage. The overall response rate in 39 patients were 31%.
  The preliminary data showed a Not significant correlation between PD-L-1 expression and ORR (P=0.071).
  Given the mutual association of tumor genetic markers, gene expression and potential markers of response to immune therapy identified through the collaborative work between SMC and MERCK MSD and Lilly, we plan to perform a phase II study with integrative genomic analysis (whole exome and RNA sequencing) in pre and post biopsy specimens to better define those GCs who may benefit from pembro.


Eligibility: Inclusion Criteria:
  1. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent for Biomedical Research. However, the subject may participate in the main trial without participating in Biomedical Research.
  2. Be 19 years of age on day of signing informed consent
  3. Have histologically or cytologically-confirmed diagnosis of gastric or Gastroesophageal Junction Adenocarcinoma
  4. Have metastatic disease or locally advanced, unresectable disease.
  5. Has experienced documented objective radiographic or clinical disease progression during or after first-line therapy containing any platinum,fluoropyrimidine doublet.
  6. Have measurable disease based on RECIST as determined by investigator. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  7. Be willing to provide fresh tissue for biomarker analysis, and, based on the adequacy of the tissue sample quality for assessment of biomarker status. Repeat samples may be required if adequate tissue is not provided. Newly obtained endoscopic biopsy specimens are preferred to archived samples and formalin-fixed, paraffin-embedded block specimens are preferred to slides.
  8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
  9. Demonstrate adequate organ function, all screening labs should be performed within 10 days of treatment initiation.
  10. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  11. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
  12. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
  Exclusion Criteria:
  1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
  2. Has squamous cell or undifferentiated gastric cancer.
  3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  4. Has a known history of active Bacillus Tuberculosis
  5. Hypersensitivity to pembrolizumab or any of its excipients.
  6. Has had a prior anti-cancer monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered from adverse events due to agents administered more than 4 weeks earlier.
  7. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered from adverse events due to a previously administered agent.
  8. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  9. Has known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  10. Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is not considered a form of systemic treatment.
  11. Has known history of, or any evidence of active, non-infectious pneumonitis.
  12. Has an active infection requiring systemic therapy.
  13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  14. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  15. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  17. Has a known history of Human Immunodeficiency Virus
  18. Has known active Hepatitis B or Hepatitis C
  19. Has received a live vaccine within 30 days of planned start of study therapy.
  20. Is or has an immediate family member who is investigational site or staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject.

Relevance to patient case: not relevant