PDR001 Plus Imatinib for Metastatic or Unresectable GIST

Description

Immunotherapy may be the novel strategy to enhance the outcomes of TKI-refractory GIST. Although current understanding of the immune response in GIST remains limited compared to other cancer types, several data suggest that the immunotherapy may be the way to overcome the mutation-related primary and secondary TKI resistance, and the exploration is needed.

The PD-1-PD-L1 pathway is the one of key targets for immune checkpoint inhibitor, and anti-PD-1 antibodies including pembrolizumab, nivolumab has already shown a remarkable efficacy in several cancer types including melanoma, lung cancer, and gastric cancer with approval by FDA in melanoma and lung cancer. PDR001 is a novel anti-PD-1 inhibitor under investigation for the treatment of multiple tumor types, and the available safety data from on-going clinical trials indicate that PDR001 monotherapy is generally well tolerated and the safety profile appears to be similar across different tumor types.

Recent phase II study reported that pembrolizumab, an anti-PD-1 inhibitor, demonstrated only modest anti-tumor efficacy in advanced GISTs. However, the sample size was small with only 10 GIST tumors in the study, and high proportion of GIST tumors were prominently infiltrated by IDO positive M2 macrophage, which plays important role in immune suppression. Thus, further strategies are warranted to assess the combination of immune checkpoint inhibitor with an agent which can inhibit the IDO pathway in advanced GIST.

PD-L1 expression has been regarded as a promising biomarker to predict the efficacy of anti-PD-1 or PD-L1 monoclonal antibodies, although negative PD-L1 expression do not preclude the efficacy of anti-PD-1 or PD-L1 antibodies. Although the data in regards to the PD-L1 expression in metastatic GISTs are limited, a recent study showed that the PD-L1 expression is observed in the subset of localized GIST tissue samples and its expression is correlated with prognosis. Further translational research of immune milieu using GIST tissues are necessary to establish the role of immunotherapy in metastatic GISTs, and concurrent prospective studies using immune check point inhibitors may enhance the speed of this work.

The relevance of continuous KIT inhibition in tyrosine kinase inhibitor (TKI) refractory GISTs was proven in previous phase III RIGHT study which compared imatinib rechallenge and placebo after failure of at least first line imatinib and second line sunitinib. In this study, the inhibition of KIT by imatinib was significantly associated with prolonged PFS (median PFS of 1.8 months) compared to placebo (median 0.9 month; HR 0.46, 95% CI 0.27-0.78; p=0.005). Disease control rate at 12 weeks was also improved with imatinib rechallenge than placebo (32% vs 5%, p=0.003).

Immune cells such as T cells (Treg), natural killer (NK) cells, and macrophages are present in GIST tissue samples, and their presence or activation were related with prognosis or response to imatinib. Imatinib indirectly have an impact on NK cells and CD8+ T cells, and concurrent use of CTLA-4 blockade with imatinib augments the efficacy of imatinib in mouse GIST by increasing IFN-r producing CD8+ T cells. Moreover, previous study showed that imatinib potentiates antitumor T-cell responses in GISTs through the inhibition of IDO. This may suggest that concurrent use of imatinib and immune checkpoint inhibitors may enhance the efficacy of immune checkpoint inhibitors.

Based on this background, we assume that PDR001, an anti-PD-1 antibody, with imatinib might be effective in advanced GIST after failure of standard TKI therapies including imatinib, sunitinib, and regorafenib. In this phase I/II study of PDR001 plus imatinib, It is aimed to evaluate the safety and efficacy of this regimen as 4th line of treatment in advanced GIST.

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