The following article features coverage from the American Society of Clinical Oncology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Results of a retrospective cohort study of patients with solid tumors treated with immune checkpoint inhibitors (ICIs) showed improved overall survival (OS) in those who had inactivating mutations in genes encoding for components of the mammalian SWI/SNF complex, including the BAF (BRG1/hBRM-associated factor) and polybromo-BAF (PBAF) complexes. The findings from this study were presented at the 2019 American Society of Clinical Oncology Annual Meeting.1

Although immunotherapies targeting inhibitory T-cell receptors have been associated with durable responses in subsets of patients across many different cancer types, the majority of patients do not respond to these treatments. Hence, the identification of biomarkers of response and resistance to ICIs remains an active area of research.

A previous study of patients with clear cell renal cell carcinoma identified inactivating mutations in PBRM1 as potential biomarkers for improved outcomes in patients treated with ICIs.2 The PBRM1 gene encodes for a component of the PBAF complex, a tumor suppressor that is part of the mSWI/SNF chromatin remodeling complex; other genes associated with mSWI/SNF include PBRM1, SMARCA4, SMARCB1, ARID1A, ARID1B, and ARID2.

In this study, databases from the Dana-Farber Cancer Institute (DFCI), Boston, Massachusetts, were interrogated to obtain clinicopathologic data for patients with several types of solid tumors characterized by any truncating mutation or homozygous deletion in PBRM1, SMARCA4, SMARCB1, ARID1A, ARID1B, and ARID2 who had received treatment with ICIs. Wild type controls did not have these mutations.

Of the 7121 patients with the relevant types of tumors (including colorectal cancer, non-small cell lung cancer, melanoma, renal cell carcinoma, and urothelial carcinoma) who were treated with an ICI in the metastatic setting, 245 patients had metastatic disease characterized by a specified alteration in the targeted genes, and these patients were histology-matched with 431 patients who did not have an alteration in any of the targeted genes.

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Alterations in genes associated with the PBAF complex (ie, PBRM1, ARID2) were most common in renal cell carcinoma and melanoma, whereas BAF-related alterations (ARID1A, ARID1B) were most common in colorectal cancer, esophagogastric cancer and urothelial cancer.

Key findings of the study included a median OS of 18.7 months and 11.4 months (hazard ratio [HR], 0.30; 95% CI, 0.10-0.89; P =.03); and not reached and 10.9 months (HR, 0.33; 95% CI, 0.16-0.7; P =.004); for patients with colorectal cancer and renal cell carcinoma, respectively (with and without disease characterized by 1 or more of the targeted alterations).  However, alterations in these genes were associated with worse OS in patients with non-small cell lung cancer (HR, 1.44; 95% CI, 1.06-1.96; P =.018).

While these results suggest a relationship between mutations in key genes encoding for components of the PBAF and BAF complexes and improved OS in patients with certain solid tumors receiving ICIs, the study presenter, Dr Sarah Abou Alaiwi, stated that “there is a need for more work to discern the biology of mSWI/SNF and its interaction with checkpoint inhibitors.”

Read more of Cancer Therapy Advisor‘s coverage of ASCO’s annual meeting by visiting the conference page.

References

  1. Abou Alaiwi S, Nassar A, El Bakouny Z, et al. Association of polybromo-associated baf (PBAF) complex mutations with overall survival (OS) in cancer patients (pts) treated with checkpoint inhibitors (ICIs). Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 3, 2019; Chicago, IL. Abstract 103.
  2. Miao DMargolis CAGao W, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018;359:801-806.