“At least the PFS data are very compelling for TMB being a predictive marker…especially for nivolumab/ipilimumab,” Baik said.
However, Bristol-Myers Squibb recently withdrew their supplemental biologics license application to the FDA for the combination of nivolumab and ipilimumab for the treatment of patients with advanced NSCLC with high TMB.6
While she said that not much information is known yet, as several pieces of data from the trial are still pending, she noted that more recent data did not show a different in overall survival between patients according to TMB status—and not all patients had TMB-evaluable tumors.7
“I think we need the full data set to really make sense of the data.”
Overall, Baik suggested that literature is consistent in showing that high TMB is associated with a clinical response to immune checkpoint inhibition therapy. Additionally, she suggested that TMB and PD-L1 are likely complementary biomarkers, reflecting activity at different steps of the immunity cycle.
“With all of this, the million-dollar question is, ‘Is TMB ready to be used in the clinic?’ There are varying opinions on this out there, but my personal opinion is: not yet,” she commented.
Challenges also exist for implementing TMB in clinical use, Baik noted, as there is not a great degree of standardization between assay results.
Baik explained how she currently stratifies her patients with lung cancer for chemotherapy and/or immunotherapy based on current information with TMB and PD-L1. For patients with “hot” or inflamed tumors, which demonstrate both high PD-L1 expression and TMB, she gives anti–PD-1 monotherapy. For patients with high PD-L1 expression but low TMB, she gives chemoimmunotherapy. For those with high TMB but low or negative PD-L1 expression, she gives chemoimmunotherapy or anti–PD-1/CTLA-4 therapy. Moreover, for patients with “cold” or noninflamed tumors that demonstrate both low TMB and low or negative PD-L1 expression, she administers chemotherapy with or without immunotherapy, or possibly cellular immunotherapy.
Concluding, Baik said that what is most important with regard to the future use of biomarkers for immunotherapy, is rigorous validation before they are to be used in the clinic.
- Chan TA, Yarchoan M, Jaffee E, et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol. 2019;30(1):44-56. doi: 10.1093/annonc/mdy495.
- Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128. doi: 10.1126/science.aaa1348.
- Carbone DP, Reck M, Paz-Ares L, et al; CheckMate 026 Investigators. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415-2426. doi: 10.1056/NEJMoa1613493.
- Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378:2093-2104. doi: 10.1056/NEJMoa1801946.
- Borghaei H, Hellmann MD, Paz-Ares LG, et al. Nivolumab (Nivo) + platinum-doublet chemotherapy (Chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: results from CheckMate 227. J Clin Oncol. 2018;36(suppl; abstr 9001). doi: 10.1200/JCO.2018.36.15_suppl.9001.
- Bristol-Myers Squibb Reports Fourth Quarter and Full Year Financial Results. Bristol-Myers Squibb. Published January 24, 2019. https://bit.ly/2FMWGpr. Accessed January 24, 2019.
- Bristol-Myers Squibb Provides Update on the Ongoing Regulatory Review of Opdivo Plus Low-Dose Yervoy in First-Line Lung Cancer Patients with Tumor Mutational Burden ≥10 mut/Mb. Bristol-Myers Squibb. Published October 19, 2018. https://bit.ly/2ySdgOC. Accessed January 28, 2019.