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TMB as a predictor for anti-PD-1/PD-L1 response in melanoma

Over 144,000 Americans are expected to be diagnosed with melanoma this year.1 With a 15-20% 5-year survival rate for Stage IV patients, the future is not always optimistic.2 Thankfully, immunotherapy is changing that outlook. For example, one recent study found that an anti-PD-1 therapy doubled the survival rate in advanced melanoma cases.3

Still, immunotherapies may not work for everyone. Knowing who is likely to respond to immunotherapy will help ensure that these promising treatments deliver the most benefit. More informed treatment selection has the potential to steer patients away from ineffective medicines, which may reduce side effects and save both costs and disappointment. Tumor mutational burden (TMB) or mutational load is an emerging diagnostic measure that has been shown to help predict response to immunotherapy in certain cancers, including lung cancer, bladder cancer and melanoma.4, 5, 6

Foundation Medicine and our collaborators at Vanderbilt University have published new data supporting the use of TMB, as measured by our comprehensive genomic profiling assay FoundationOne®, to help predict response to anti-PD-1/PD-L1 treatment.7 These results add to the growing body of evidence that TMB may be useful for identifying patients most likely to benefit from immunotherapy and may bring us closer to our goal of impacting the greatest number of patients possible.

Previous research in melanoma has shown mutational load to be associated with clinical benefit from anti-CTLA-4 immunotherapy treatment.6 The current study sequenced melanoma samples from patients who had undergone anti-PD-1/PD-L1 treatment to determine whether TMB was correlated with that type of immunotherapy as well. Within both initial and validation cohorts (65 total patients), those who responded to treatment had higher mutational load compared to non-responders. In addition, objective response rate, progression-free survival and overall survival were superior in the high mutational load group as compared with intermediate and low mutational load groups.

Together, these data strengthen the predictive power of TMB for response to a range of existing immunotherapy options and helps to establish TMB as a clinically available tool to identify patients who are most likely to benefit from these powerful treatments.

Notes
  1. Melanoma Research Foundation. Melanoma Facts and Stats. https://www.melanoma.org/understand-melanoma/what-melanoma/melanoma-facts-and-stats. Last accessed 24 Oct 2016.
  2. American Cancer Society. Melanoma Skin Cancer. http://www.cancer.org/cancer/skincancer-melanoma/detailedguide/melanoma-skin-cancer-survival-rates-by-stage. Last accessed 24 Oct 2016.
  3. Hodi et al. Durable, long-term survival in previously treated patients with advanced melanoma (MEL) who received nivolumab (NIVO) monotherapy in a phase I trial [abstract]. American Association for Cancer Research Annual Meeting; 2016 April 16-20; New Orleans, LA. Abstract nr CT001.
  4. Rizvi et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128.
  5. Rosenberg et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920.
  6. Snyder et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. New England Journal of Medicine. 2014;371:2189-2199. Correction published in N Engl J Med. 2015 Nov 12;373:1984.
  7. Johnson et al. Targeted next generation sequencing identifies markers of response to PD-1 blockade. Cancer Immunology Research. 2016. doi: 10.1158/2326-6066.CIR-16-0143.
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