Gastric cancer (GC), is a leading cause of cancer-related death, is a heterogeneous disease where survival depends on factors such as biological differences, MSI status, EBV status, region, ethnicity and patterns of care. The biological context for immune responsiveness and resistance in the clinical are only now starting emerge. Although GC has similar levels of PDL1 IC and TC expression to lung cancer, the approvals and success of immunotherapy in GC to date has been mixed.
We explored 2 randomized MetMAb trials (Ph3 Study 1 YO28322 and Ph2 Study 2 YO28252) in combination with mFOLFOX6 in metastatic HER2-negative and MET-positive GC. We used Study 1 (n = 146) to uncover novel GC biology using Nanostring based gene expression analyses and Study 2 (n = 70) to confirm the findings. Late Stage GC (Stage IV biopsies) GC from the Study 1 and 2 were compared against early stage GC (Stage I, II and III) in resections from the ACRG GC dataset.
Retrospective analysis revealed key biological differences between early and late stage GC. In 1L mGC with stage IV tissue, unbiased prognostic analyses uncovered genes that grouped into: Immune/Effector T cell genes (Teff), Stromal genes and Differentiation/Proliferation genes as significantly associated with OS. Patients with high Teff genes had poor prognosis (Low/High HR: 0.43, p- value 0.01) and the worst prognosis was seen when both Teff and stromal genes were high. Furthermore, we confirmed these findings in Study 2. We found that EMT, Notch and TGFb pathways interacted with the Teff genes and were all associated with the poor Teff prognosis. Importantly immune/Teff genes have good prognosis in early stage GC and this is largely driven by MSI-H patients. Finally, when assessing what genes changed going from early to late stage, EMT, Notch, Wnt genes played a role in the transition to a more aggressive and metastatic disease.
Although GC has been challenging to treat, it may be possible to increase the success of immunotherapy with carefully tailored combination therapies in the Stage IV setting with molecules that inhibit pathways such as Notch, Wnt and TGFb. Furthermore, it may make a lot of sense to take immunotherapies into Stage I, II and III GC where the immune and Teff gene prognosis is good and the disease is less convoluted.
Clinical trial identification
YO28322: NCT01662869 YO28252: NCT01590719.
Legal entity responsible for the study
Hoffmann-La Roche, Genentech.
M. Das Thakur, K. Okrah, D. Shames, P. Hegde, C. Bais: Employee: Hoffmann-La Roche.