Milind Javle, MD, of the MD Anderson Cancer Center, led off the roundtable dialogue on emerging therapies in biliary tract cancers (BTCs) with a discussion around methylthioadenosine phosphorylase (MTAP) loss in cholangiocarcinoma (CCA). MTAP is located on the 9p21 chromosome, where CDKN2A/B is also located. CDKN2A/B loss occurs in 19% to 27% of BTCs and is almost always associated with subsequent MTAP loss. Although CDKN2A is not a druggable target, it has been hypothesized that MTAP can be targeted using protein arginine methyltransferase 5 (PRMT5) inhibitors. MTAP enzyme loss is associated with an accumulation of methylthioadenosine substrate, which in turn inhibits PRMT5, a key methylation enzyme in the S-adenosyl methionine (SAM) cycle; therefore, PRMT5 inhibitors may be a future therapeutic approach in BTC. The folate cycle also plays an important role in the regeneration of the SAM pathway; it has been hypothesized that MTAP loss can be targeted using antifolate agents such as pemetrexed. Resistance to immune checkpoint inhibitors (ICIs) may also be of concern in MTAP loss tumors because 9p21 loss results in a “cold” immune microenvironment, which may not be responsive to immunotherapy. Intrahepatic cholangiocarcinoma (iCCA) with MTAP loss also results in reduced CD3+, CD4+, CD8+, and inducible co-stimulator T-cells, and MTAP loss and SMAD4 mutations have been associated with low PD-L1 positivity. Although CDKN2A/B is not targetable, MTAP loss is a potential therapeutic target with several therapies currently under investigation.
Rachna Shroff, MD, MS, of the University of Arizona Cancer Center, discussed MDM2 as a potential molecular target. MDM2 works hand in hand with p53, and overexpression of MDM2 leads to p53 degradation and tumor proliferation. Although MDM2 amplifications in BTC are rare, an incidence in iCCA of approximately 6% has been seen and suggests MDM2 is a negative prognostic marker in BTC1; one study demonstrated significantly shorter overall survival in patients with MDM2 amplifications compared with those without this amplification.2 BI 907828 is in development as a potent MDM2/p53 antagonist and has been shown to have a dual mode of action with direct tumor targeting plus immunomodulation in preclinical models.3 NCT03449381 is a phase 1 study evaluating BI 907828 monotherapy in patients with advanced solid tumors; cohort 2 included patients with BTC with p53 wild-type and MDM2-amplified tumors. Early data showed that 84% of patients across all dose levels achieved at least stable disease and 2 of 4 patients with BTC achieved a confirmed partial response.4 A phase 2 multi-cohort basket trial is planned for patients with MDM2-amplified and p53 wild-type tumors, which will also include a BTC cohort.
Jennifer Knox, MSc, MD, FRCPC, of the Princess Margaret Cancer Centre in Toronto, discussed targeting KRAS, which she deemed “the holy grail of undruggable genomic drivers.” The first drugs to target KRAS were mutant-specific and targeted G12C; however, there has been increasing excitement around targets for other alleles as well as pan-(K)RAS inhibitors in clinical and preclinical development.5 Dr. Knox detailed the pros and cons of pan versus mutant- or allele-selective KRAS targeting. Allele-specific KRAS drugs are better tolerated, are able to combine with other agents, have a more sustained target inhibition, and can be used in early treatment.5 However, these therapies are restricted to patients with specific mutant variants, are prone to on-target resistance, and the feasibility of developing allele-selective drugs beyond G12C/D and G13C is a concern. Pan-KRAS drugs can be used in a broader population, in cancers driven by KRAS wild type, and in heterogeneous cancers driven by multiple KRAS aberrations and can overcome on-target KRAS resistance; however, the toxic effects on normal tissues when inhibiting wild-type KRAS in humans have yet to be determined.5 The frequency of KRAS in BTC has been previously reported as anywhere from 12% to 42%, with very few reports describing specific KRAS variants. There is a need for continued research into relevant targets, and both allele-specific and pan-KRAS targeting techniques have been a focus of ongoing research and development.
Mark Yarchoan, MD, from Johns Hopkins Medicine, discussed novel immunotherapies in BTC. CCA is an immunosuppressed tumor type characterized by low tumor-mutation burden and PD-L1 expression.6 With results from TOPAZ-1, there is now evidence that iCCA can benefit from immunotherapy.7 In this regard, there are a number of novel ICIs currently being investigated in CCA, including antagonists of T-cell immunoglobulin and mucin domain 3 (TIM3), lymphocyte activation gene-3 (LAG-3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT). Data from other tumor types may help develop a rationale for using other ICIs in CCA. For example, nivolumab plus a LAG-3 inhibitor (relatlimab) showed a small benefit over nivolumab alone in metastatic melanoma.8 However, there may be a declining benefit of consecutive ICI use; a subgroup of patients with melanoma who received nivolumab plus relatlimab eventually progressed and then received nivolumab plus ipilimumab, but demonstrated almost no response, although first-line treatment with nivolumab plus ipilimumab has been shown to result in a 50% objective response ratio (ORR) in these patients.8
To convert CCA into an immune-sensitive tumor, a variety of components need to be considered: there needs to be induction of a T-cell response, reversal of immune deficits, and modulation of the tumor microenvironment (TME). Adoptive cell therapies have been used in other tumor types to initiate the immune cascade, which suggests a possible approach in CCA. Finally, it has been shown that there are 4 distinct, molecularly defined subsets of CCA, categorized into 4 clusters, in which the TME differs, suggesting the need for an individualized approach to immunotherapy in CCA.
Finally, Richard Kim, MD, from the Moffitt Cancer Center, discussed a novel approach with dual blockade of vascular endothelial growth factor (VEGF) and delta-like protein-4 (DLL4). DLL4 plays an important role in angiogenesis, and animal studies have shown that DLL4 is controlled by VEGF and that DLL4/Notch signal transduction supports VEGF function. It has been hypothesized that joint inhibition of the 2 pathways may be synergistic. Currently, 3 bispecific antibodies are under development that utilize this strategy, with CTX-009 being the most advanced. Interim phase 2 data of CTX-009 in combination with paclitaxel in BTC demonstrated an ORR of 42%.9 Based on this single-arm study, there is a phase 2/3 trial of CTX-009 plus paclitaxel versus paclitaxel alone in patients with unresectable advanced metastatic BTC to confirm the efficacy of this combination.
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