Many of our Medical Oncologists and Clinical Investigators have just returned from presenting their latest data at the European Society for Medical Oncology’s (ESMO) World Congress on Gastrointestinal Cancer (WCGIC 2022), 29 June – 02 July, Barcelona, chaired by VHIO’s Director, Josep Tabernero, alongside Founding Congress Chair, Eric Van Cutsem, University Hospital Gasthuisberg (Leuven, Belgium), and Vice Chair, Michel Ducreux, Institut Gustave Roussy (Paris, France).
We take this opportunity to highlight a pick of three VHIO (co) led studies that were selected for presentation at this annual gathering of leading experts in gastrointestinal cancer from across the globe:
Exploring the tumor immune microenvironment of colorectal cancer patients with coexistent MSI-high status and BRAF V600E mutation
In a study (1) co-authored by VHIO’s Director Josep Tabernero, research led by Mohamed Salem, Levine Cancer Institute in Charlotte, North Carolina (USA), has shed light on the impact of the critical BRAF V600E mutation on the tumor immune microenvironment and associated genomic alterations in a subset of colorectal cancer (CRC) patients exhibiting microsatellite instability-high (MSI-H) or mismatch-repair-deficient (dMMR) colorectal cancer.
Colorectal cancer, the third most common cancer and second highest cause of cancer death worldwide, is a heterogeneous and complex disease characterized by multiple genetic alterations, each with a different prognosis and response to therapy. In CRC patients, a common mutation in the BRAF gene known as V600E (a substitution of glutamic acid for valine in position 600 of the protein), accounts for 95% of all BRAF mutations. This mutation represents a poor prognostic factor, with a median overall survival of just 10-20 months in such patients diagnosed with advanced disease.
This V600E mutation is related to the CpG island methylator phenotype (CIMP), a distinct epigenetic subtype of CRC that is found in up to 20% of CRCs, and is associated with MSI-high status, leading to a sporadic MSI phenotype. Despite this biological connection, the precise impact of BRAF V600E mutations on the tumor microenvironment and immunometabolic characteristics of MSI-H/dMMR CRC has not been well characterized.
“Almost 30% of BRAF V600E metastatic CRC tumors have microsatellite instability. Considering the immunogenic nature of these tumors, patients with BRAF V600E and MSI tumors have been included in studies evaluating the efficacy of immune checkpoint inhibitors. However, while immunotherapy and combined strategies with checkpoint inhibitors plus BRAF inhibitors show promise, some responses are relatively short,” says Josep Tabernero, co-author of this study.
“The disparity in response not only highlights the heterogeneous nature of BRAF-V600E tumors, but also the need to achieve a deeper understanding of BRAF-V600-mutant biology and identify those patients who would be most likely to respond to these novel therapies,” adds Josep Tabernero.
Aimed at potentiating treatment strategies for this subset of patients, including immune checkpoint inhibitors (ICIs) and second-line BRAF targeted therapy plus EGFR inhibitors, the present study sought to establish the impact of the V600E mutation on the immune microenvironment among patients with MSI-high status.
The investigators analyzed a total of 459 MSI-H/dMMR CRC tumors, of which 123 harbored V600E mutations (the remaining 339 were normal at that position). Using next-generation sequencing, they assessed several markers of tumor immunogenicity in wild-type versus V600E-mutated tumors, including tumor mutational burden (TMB), neoantigen tumor burden (NTB), PD-L1 expression, immune filtration, and immune-metabolomic pathways.
Compared to the BRAF wildtype, the data showed significantly higher TMB in V600E tumors, but no significant differences in other indicators, including NTB, immune score, or T cell infiltration. Natural killer (NK) cell infiltration was higher in the BRAF V600E cohort, and the BRAF mutated tumors also harbored a higher frequency of genomic alterations compared to wildtype. The results revealed a number of significantly altered signaling pathways, most of which are connected to immune cell signaling and metabolism.
“Achieving a deeper understanding of the immunometabolic interplay in the tumor microenvironment could provide important insights into cancer drug resistance as well as treatment response in this subset of patients,” observes Tabernero.
Considering the significant metabolic reprogramming of MSI-H/dMMR BRAF V600E-mutated mCRC, these tumors may be associated with immunologic characteristics. Noting that BRAF mutant and wild-type CRCs exhibit similar NTB and T-cell infiltration, the authors suggest that both are likely to equally benefit from treatment with immune checkpoint inhibitors (ICIs).
“Our findings confirm the results of subgroup analysis from the KEYNOTE-177 study, where both groups benefited equally from an ICI. Future studies will inform on the efficacy of combinatorial approaches pairing ICIs with BRAF inhibitors plus anti-EGFR blockade for the treatment of BRAF-mutant MSI-high colorectal cancer,” concludes Josep Tabernero.
Larotrectinib continues to step up in the treatment of metastatic tropomyosin receptor kinase fusion gastrointestinal cancer
Results of updated analysis from an expanded dataset of patients with TRK fusion gastrointestinal (GI) cancer treated with a first-in-class tropomyosin receptor kinase (TRK) inhibitor, larotrectinib, in the phase II multi-center non-randomized basket NAVIGATE clinical trial (NCT02576431) were presented by lead author Elena Garralda, Director of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM) – CaixaResearch (2).
Larotrectinib is approved for treating adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion – a rare genetic abnormality than can occur in various tumor types- without a known acquired resistance mutation, that are either metastatic or not amenable to surgery, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment. Approval was based on data from the NAVIGATE study and two other multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), and SCOUT (NCT02637687).
This first-in-class TRK inhibitor has previously demonstrated an objective response rate (ORR) of 41% across 18 patients with GI cancer, data of which were presented at ESMO’s virtual WCGI last year, 2021 (2). Now, the investigators have reported longer follow up data on the efficacy of larotrectinib. 34 patients with metastatic TRK fusion GI across several tumor types in the NAVIGATE trial were included in this present analysis.
“Building on previously reported findings, and thanks to the basket design of this innovative study, we have been able to confirm the proven efficacy of larotrectinib in more patients with TRK fusion GI cancer,” says Elena Garralda, Principal Investigator of VHIO’s Early Clinical Drug Development Group.
Results of this present analysis (3) show ORR of 33% in the 33 evaluable patients, with median time to response at 1.9 months and a median duration of response (DoR) of 7.3 months. The investigators reported particularly encouraging results in those patients with CRC with identified microsatellite instability high (MSI-H) status. In the 19 patients with CRC, ORR was 47%. Of the nine responders to-date, six were MSI-H.
“Our findings show that larotrectinib continues to achieve rapid, durable responses, extended survival and a favorable safety profile in patients with TRK fusion-positive GI cancers, particularly in those with colorectal cancer,” adds Elena Garralda.
“These results underpin the importance of identifying NTRK gene fusions in GI cancer, especially in patients with microsatellite instability high colorectal cancer. By simultaneously evaluating the efficacy of this targeted therapy across multiple GI tumor types in patients with TRK fusion GI cancers, we are increasingly delivering on the true promise of precision medicine in this particular population,” she concludes.
Two-arm, two part ‘double punch’ trial: new hope for patients with metastatic pancreatic ductal adenocarcinoma?
Also presented throughout the course of WCGIC 2022 were various innovative, novel studies including a randomized, double-blind multicenter, two-arm, two-stage trial co-led by Eileen M. O’Reilly, Memorial Sloan Kettering Cancer Center – MSKCC (New York, USA), and VHIO’s Teresa Macarulla, Principal Investigator of VHIO’s Gastrointestinal and Endocrine Tumors Group: the phase III daNIS-2 study (NCT04935359) of the anti–TGF-β monoclonal antibody NIS793 with nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine alone in patients with first-line metastatic pancreatic ductal adenocarcinoma, which is the most common type of pancreatic cancer (4).
Despite improving outcomes, current therapies for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) have a modest impact on overall survival (OS), representing an unmet clinical need. This particular tumor type has a notoriously dismal prognosis, with a median survival of 10-12 months. Poor outcomes are attributed to several factors including diagnosis at late-stage – precluding the majority of these patients from surgical resection – and cancer drug resistance to existing therapies including multi-agent chemotherapy.
“Considering the overall poor therapeutic responses observed in these patients, there is an urgent need to enhance drug efficacy, extend survival rates, and improve quality of life,” says Teresa Macarulla, a Medical Oncologist at the Vall d’Hebron University Hospital’s (HUVH) Medical Oncology Department, headed by VHIO’s Director, Josep Tabernero.
“The histopathologic feature of pancreatic ductal adenocarcinoma is abundant fibrosis within tumor tissue, which may contribute to the lack of treatment efficacy and effective penetration of therapies by hampering the intratumoral accumulation of anti-cancer medicines,” continues Teresa Macarulla.
Transforming growth factor-β (TGF-β) has been shown to play roles in the tumor microenvironment (TME), where it actively shapes the TME by interfering with the host immunity, and promoting cancer progression. Mounting evidence points to TGF-β as a master activator of cancer-related fibroblasts that lead to the development of fibrotic networks. Evidenced in preclinical models, TGF-β inhibition alters the TME to facilitate an antitumor response, reduce stromal fibrosis, and boost the efficacy of chemotherapy.
“These observations provide the rationale for pairing TGF-β-targeted therapies with chemotherapy. Specifically, this two-arm, two-part randomized study combines a promising first-in-class novel antibody specific for TGF-β, NIS793, with chemo-based therapy in previously untreated patients with metastatic disease,” adds Macarulla.
The daNIS-2 investigators will compare the efficacy of NIS793 in combination with nab-paclitaxel/gemcitabine (NG) versus NG alone. Consisting of two-stages: an initial safety run-in period followed by two-arm randomization (1:1), the aim of the first part is to assess the safety and tolerability of the treatment combination and confirm the recommended dose for the randomized phase once at least six patients have received the combination for a one-month cycle.
“The primary objective of this second stage is to evaluate the overall survival of patients receiving the NIS793 plus chemotherapy combination versus the chemo combo alone. We will seek to establish if blockade of TGFβ in combination can effectively reduce fibrosis, enhance chemo-sensitivity, and ultimately lead to improved survival and other clinically relevant outcomes in these patients,” concludes Teresa Macarulla.
This study is ongoing and will enroll patients from approximately 149 sites spanning 28 different countries. The first patient was treated in October 2021.
- LBA SO-34: Impact of BRAF-V600E mutation on immunologic characteristics of the tumor microenvironment (TME) and associated genomic alterations in patients with microsatellite instability-high (MSI-H) or mismatch-repair–deficient (dMMR) colorectal cancer (CRC). Salem, S. Kopetz, S. El-Refai, J. Tabernero, F. Sinicrope, J. Tie, T. George, E. Van Cutsem, E. Mauer, S. Lonardi, T. André, M. Overman, D. Foureau. Ann Oncol 2022 June: 33 (Suppl 4), S378.
- SO-29: Efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase fusion-positive gastrointestinal cancer: An expanded dataset. Boni, A. Drilon, J. Deeken, E. Garralda, H. Chung, I. Kinoshita, D. Oh, J. Patel, R. Xu, R. Norenberg, N. Brega, L. Dima, D. Hong, J. Berlin. Ann Oncol 2021 July: 32 (Suppl 3), S214-215. Presented at the ESMO virtual World Congress on Gastrointestinal Cancer, 30 June – 03 July 2021.
- SO-31: Long-term efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase (TRK) fusion gastrointestinal (GI) cancer: An expanded dataset.
Garralda, D. Hong, R. Xu, J. Deeken, A. Italiano, T. Liu, A. Ferrandiz, J. Patel, D. Lee, H. Chung, I. Kinoshita, J. Berlin, T. André, D. Oh, S. Leyvraz, M. Miguel, Y. Liu, R. Norenberg, M. Fellous, C. Mussi, A. Drilon, L. Shen. Ann Oncol 2022 June: 33 (Suppl 4), S370.
- P-22: Phase III study (daNIS-2) of the anti–TGF-β monoclonal antibody NIS793 with nab-paclitaxel/gemcitabine vs nab-paclitaxel/gemcitabine alone in patients with first-line metastatic pancreatic ductal adenocarcinoma.
O’Reilly, T. Golan, M. Ikeda, M. Milella, J. Taieb, Z. Wainberg, L. Wang, N. Gyambibi, E. López, K. Xu, T. Macarulla. Ann Oncol 2022 June: 33 (Suppl 4), S254.