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Evidence Mounts for Tumor Mutational Burden as Biomarker of Immune Checkpoint Inhibitor Benefit in NSCLC


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The search for biomarkers to identify patients who are likely to respond to immunotherapy continues. According to biomarker tissue and blood analysis of patients enrolled in the phase III MYSTIC trial, high tumor mutational burden in both tissue and blood identified patients with non–small cell lung cancer (NSCLC) who gained a survival benefit from first-line treatment with the programmed cell death ligand 1 (PD-L1) inhibitor durvalumab vs chemotherapy.1 Low tumor mutational burden predicted better survival with chemotherapy. The biomarker study was independent of the overall results of the MYSTIC trial, which showed no difference in survival between the two treatments.


Tumor mutational burden was predictive of an overall survival benefit with first-line durvalumab and durvalumab plus tremelimumab in metastatic NSCLC.
— Solange Peters, MD, PhD

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Patients with the cutoff of tissue tumor mutational burden ≥ 10 mutations/megabase of DNA (mut/Mb) had a median overall survival of 18.6 months with durvalumab, 16.6 months with durvalumab plus the cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) antibody tremelimumab, and 11.9 months with chemotherapy. The difference between the durvalumab groups and chemotherapy did not reach statistical significance. Patients with lower tumor mutational burden (ie, < 10 mut/Mb) did better with chemotherapy alone.

“Tumor mutational burden was predictive of an overall survival benefit with first-line durvalumab and durvalumab plus tremelimumab in metastatic NSCLC. In tissue tumor mutational burden greater than or equal to 10 mut/Mb, overall survival was improved with durvalumab with or without tremelimumab vs chemotherapy, but the small data set limits interpretation,” said lead author Solange Peters, MD, PhD, of the University Hospital Center Vaudois and Lausanne University, Switzerland. Dr. Peters presented these findings from the biomarker study at the 2019 Annual Meeting of the American Association for Cancer Research (AACR).1

Additional analysis found that tumor mutational burden greater than or equal to 20 mut/Mb was associated with improved survival with durvalumab vs chemotherapy. “We observed markedly improved overall survival and greater clinical benefit with durvalumab plus tremelimumab vs chemotherapy, indicating the potential contribution of tremelimumab in this setting,” she noted.

The results of the exploratory analysis support the prospective study of blood tumor mutational burden as a predictive marker for immunotherapy, Dr. Peters added.

MYSTIC Details

The phase III MYSTIC trial randomly assigned 1,118 patients with stage IV NSCLC to 1 of 3 treatment arms for first-line therapy: durvalumab, durvalumab plus tremelimumab, or platinum-based chemotherapy. Patients were enrolled regardless of the level of PD-L1 expression.

“For the primary endpoint, a significant difference favoring durvalumab over chemotherapy was not met in patients with PD-L1 ≥ 25%,” Dr. Peters told listeners. “Durvalumab did bring a clinically meaningful 3-month survival benefit, but it was not statistically significant.”

Overall survival according to tissue and blood tumor mutational burden were exploratory endpoints. “Tumor mutational burden is a predictive biomarker of a survival benefit from immunotherapy that is independent of PD-L1 expression,” she explained. “However, tumor mutational burden had not previously been studied to show a survival benefit for immune checkpoint inhibitor vs chemotherapy.”

High Tumor Mutational Burden

  • In patients with non–small cell lung cancer (NSCLC), high tumor mutational burden in tissue and blood predicted a survival benefit with durvalumab vs chemotherapy.
  • Patients whose tumors were of low tumor mutational burden did not benefit from an immune checkpoint inhibitor and appear to do better on chemotherapy.
  • Blood tumor mutational burden correlates with tissue tumor mutational burden and is easier and faster to obtain.
  • Tumor mutational burden and programmed cell death ligand 1 are independent biomarkers and identify different patients.
  • Prospective validation of blood tumor mutational burden as a predictive biomarker is needed.

“Measuring tumor mutational burden is invasive and requires acquiring sufficient tissue with a sufficient turnaround time. We use a cutoff of 10 mut/Mb based on data from CheckMate 558,” stated Dr. Peters. “Measuring blood tumor mutational burden from circulating DNA is easier, faster, less invasive, and possibly more representative of the heterogeneity of metastatic lesions,” she added.

Tissue tumor mutational burden can be measured by the next-generation sequencing platform from Foundation Medicine. “Blood tumor mutational burden was evaluated for the first time in MYSTIC, using a Guardant sequencing platform that comprises a 500-gene panel. In a subset of patients with matched tissue and blood samples, blood tumor mutational burden showed good correlation with tissue tumor mutational burden,” Dr. Peters told the audience.

In the 31.2% of patients with matched specimens of blood and tissue, a correlation was observed between the two tests. The median overall survival was similar using blood and tissue tumor mutational burden analysis.

Several Thresholds Assessed

The investigators used several thresholds for blood tumor mutational burden, including > 16 mut/Mb. “We found better survival compared to chemotherapy in all patients defined as high tumor mutational burden irrespective of the threshold chosen,” Dr. Peters said.

Then they looked at blood tumor mutational burden ≥ 20 mut/Mb as a threshold. Again, they found superior survival with high tumor mutational burden and a significant benefit with durvalumab plus tremelimumab vs chemotherapy using this higher threshold.

In patients with high blood tumor mutational burden > 20 mut/Mb, 2-year overall survival was 48% with the combination, 34% with durvalumab alone, and 19% with chemotherapy. “In patients with blood tumor mutational burden < 20 mut/Mb, no significant survival difference was observed with immunotherapy, and chemotherapy is still a good option,” she said.

“PD-L1 and blood tumor mutational burden are independent biomarkers for survival. They do not correlate. You look at different patients when you use these biomarkers,” she told listeners.

No difference was observed in safety outcomes when patients with high tumor mutational burden were compared with the overall study population.

“Based on this exploratory analysis, further investigation and prospective validation of tumor mutational burden in the blood as a predictive biomarker for immune checkpoint inhibitor therapy are warranted, and this marker should be evaluated in as many clinical trials as possible across different tumor types,” Dr. Peters stated. 

DISCLOSURE: Dr. Peters has received educational grants, provided consultation, attended advisory boards, and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, and Takeda, from whom she has received honoraria.

REFERENCE

1. Peters S, Cho BC, Reinmuth N, et al: Tumor mutational burden as a biomarker of survival in metastatic non-small cell lung cancer: Blood and tissue TMB analysis from MYSTIC, a phase III study of first-line durvalumab + tremelimumab vs chemotherapy. 2019 AACR Annual Meeting. Abstract CT074. Presented April 1, 2019.


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