FoundationOne Heme in Patients with Lymphomas and Multiple Myeloma

Here at Foundation Medicine, we’re always excited when we can report important new data that could help improve clinical outcomes for patients. This week, at the American Society of Hematology (ASH) Annual Medical Meeting, we and our collaborators presented exciting new data supporting the use of FoundationOne Heme in cancers including diffuse large B-cell lymphoma (DLBCL), multiple myeloma and angioimmunoblastic T-cell lymphoma (AITL).

To summarize, highlights from these studies include:

• In patients with diffuse large B-cell lymphoma (DLBCL), FoundationOne Heme identified a complex genomic landscape that may impact diagnosis and prognosis, deepen the understanding of underlying biologic pathways of disease, and better guide targeted combination therapy. Additionally, the application of gene expression profiling (GEP) to this clinical platform demonstrated improved prognostic capabilities as compared to standard-of-care test methodologies such as FISH and immunohistochemistry.

• In multiple myeloma, in a study of 630 patients with various stages of disease, 63% of patients profiled with FoundationOne Heme harbored clinically relevant genomic alterations associated with either an FDA approved drug or a clinical trial, that heretofore would not have been identified through standard-of-care diagnostic testing.

• In a retrospective study of patients with angioimmunoblastic T-cell lymphoma (AITL), FoundationOne Heme identified a high frequency of co-occurring alterations in the epigenetic regulators, RhoA and TET2. These data suggest that testing for mutations in TET2 and RhoA simultaneously may have greater diagnostic utility than RhoA testing alone and may help to better inform therapeutic treatment options for patients with AITL.

FoundationOne Heme is a comprehensive genomic profile that analyzes DNA in 405 genes and RNA in 265 genes that are most commonly altered in hematologic malignancies and sarcomas. The assay provides oncologists and pathologists with molecular information that can refine diagnosis, define prognosis, and guide treatment options for patients based on the genomic profile of their cancer.

Summary of Abstracts and Key Findings:

Comprehensive Genomic Profiling of Multiple Myeloma in the Course of Clinical Care Identifies Targetable and Prognostically Significant Genomic Alterations (Abstract 369)

Historically, molecular assessment using conventional diagnostic tools and GEP has revealed multiple subgroups of multiple myeloma with distinct pathogenesis and clinical course. While these technologies have improved multiple myeloma risk assessment, they have not been able to commonly identify therapeutic targets. In this study, Foundation Medicine and its collaborators conducted comprehensive genomic profiling with FoundationOne Heme on a total of 630 patients across all stages of multiple myeloma to identify cancer-related genomic alterations, their association with disease risk and effect on patients’ clinical outcomes. Of the 630 patients profiled, 396 (62.9%) harbored clinically relevant genomic alterations, which were associated with either an FDA approved drug or a clinical trial. Key data points on targetable genomic alterations include:

• 316 patients (50.2%) had alterations in the RAS/MAPK pathway. Foundation Medicine and its collaborators recently demonstrated the clinical benefit of MEK directed therapy in this patient population.4

• 426 patients (67.6%) had alterations in epigenetic modulators. For 37 of these patients, therapy with demethylating agents was recommended.

• 39 patients (6.2%) had alterations in the mTOR pathway, suggesting potential benefit from mTOR inhibitor therapies.

Foundation Medicine also reported the following genomic trends and prognostic indicators based on the stage of the patients’ disease:

• An increasing number of mutations was observed as multiple myeloma progressed from early-stage to relapsed disease.

• Gene expression signatures were identified for patients with RAS/MAPK activation and patients with loss-of-function mutations in the DNA repair pathway, suggesting a functional relevance of these mutations. Mutations in either of these pathways were associated with significantly worse overall survival (OS).

• Presence of mutations in DNA repair genes was associated with poorer survival within the GEP-defined low-risk subgroup.

Predictive and Prognostic Significance of Comprehensive Genomic Profiling in Patients with Diffuse Large B-Cell Lymphoma (Abstract 2651)

DLBCL is the most common B-cell non-Hodgkin lymphoma (NHL) worldwide, comprising approximately 30-35% of NHL. Current standard first-line therapy affords long-term remission in only 55-60% of patients, and less than half of these cases can be treated successfully following relapse. Thus, there is a clear unmet clinical need to improve the standard of care for DLBCL patients. In this study, Foundation Medicine conducted comprehensive genomic profiling with FoundationOne Heme on cancer specimens from 125 patients with first-line and relapsed/refractory DLBCL to identify potentially clinically relevant genomic alterations.

Results showed complex molecular heterogeneity across DLBCL patients, with clinically relevant genomic alterations observed in 97 patients (78%) and potential predictive and prognostic genomic alterations identified in 99 patients (80%). Previously described genomic alterations in DLBCL were confirmed in this study, and importantly, alterations in several genes with known therapeutic associations were also detected. Other clinically relevant genomic alterations commonly associated with solid tumors, including RET, ALK, BRAF, HRAS and NRAS, were also identified in some patients.

In an application of the RNA sequencing component of FoundationOne Heme, gene expression profiling of MYC, BCL2 and BCL6 was also explored in order to analyze its role in prognostication and outcome of 184 additional patients treated at the Memorial Sloan Kettering Cancer Center. This demonstrated that over-expression of MYC, BCL2 and double-expressers (MYC and BCL2) as characterized by gene expression profiling (GEP) could serve as prognostic markers in DLBCL. High expression of MYC, BCL2 and double expressers was associated with poor prognosis; whereas, high expression of BCL6 was associated with a favorable prognosis. Survival analysis suggests GEP may improve risk stratification of DLBCL when compared to current standard-of-care methodologies such as FISH and IHC.

Comprehensive Genomic Profiling (CGP) of Angioimmunoblastic T-cell Lymphoma (AITL) to Prospectively Inform Diagnosis and Clinical Management (Abstract 3898)

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive mature T-cell lymphoma that proves difficult to diagnose and treat. Diagnosis of the disease is confounded by histologic heterogeneity and lack of sensitive diagnostic tools while, therapeutically, patients receive combination chemotherapy, which is largely ineffective. In this retrospective study of 21 patients with suspected or confirmed AITL and other T-cell neoplasms, comprehensive genomic profiling with FoundationOne Heme was conducted to determine both the genomic landscape of AITL as well as the presence of clinically relevant genomic alterations that might have the potential to improve outcomes by identifying potential targeted therapeutic agents. Key results demonstrated:

• Co-occurring mutations in RhoA and TET2 were highly associated with cases of known or suspected AITL, suggesting that the simultaneous assessment of these mutations may have greater diagnostic utility than RhoA alone as has been previously postulated.

• Mutation of IDH2 was observed at a frequency of 31%, and in all AITL samples with IDH2 mutation, RhoA and TET2 mutation also co-occurred.

• While RhoAG17V was detected in other lymphoid malignancies (MFS, MZL, CTCL), these lacked TET2 and IDH2 mutation, suggesting the specificity of the co-occurring mutations for AITL.

• The presence of IDH2 and TET2 mutations suggest potential therapeutic roles for IDH2 inhibitors and hypomethylating agents, respectively, in this aggressive lymphoma.