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High TMB Predicts Response to Pembrolizumab

Tissue tumor mutation burden (tTMB) has been under study for some time as a biomarker that could predict which patients are most likely to respond to immunotherapy.

In June, it was approved by the US Food and Drug Administration as a biomarker for pembrolizumab (Keytruda) use in patients with advanced cancers who have progressed on prior therapy.

Now the data supporting that approval have been published in Lancet Oncology.

They come from analysis of outcomes from 790 patients who participated in the phase 2 KEYNOTE-158 study of treatment with pembrolizumab in 10 tumor-type-specific groups.

The results show better responses in patients who had a high tissue TMB (≥10 mutations per megabase), which was found in 102 (13%) of the 790 participants.

The majority of these patients (87%) did not have high tTBM.

Of the 102 patients with high tTMB, 29% achieved an objective response to pembrolizumab compared with 6% in the non-tTMB-high group. In addition, the median duration of response was not reached in the tTMB-high group vs 33.1 months in the non-tTMB-high group.

An expert not involved with the study was enthusiastic about the results.

“This gives clinicians treating patients with any metastatic solid tumor the possibility of offering immunotherapy with pembrolizumab to those whose tumors have a TMB greater than 10 mutations per megabase,” said Matthew R. Zibelman, MD, assistant professor, Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

“The real win here is not for clinicians but for the patients who may get access to this drug with an opportunity for a meaningful response, ” he said.

TMB is essentially a measurement of the number of somatic mutations within a tumor and defined as the total number of somatic mutations per coding area of a tumor genome, he explained.

“Currently, its use as a predictive marker to choose treatment remains investigational in most clinical settings,” Zibelman told Medscape Medical News. “This testing is becoming standard in most commercially available next-generation sequencing platforms offered, and has been looked at as a potential biomarker in several tumors, including non-small cell lung cancer and melanoma,” he added.

Zibelman suggested that the results should now be implemented into clinical practice. “Testing should be offered to all patients with metastatic solid tumors, particularly those without prior approvals for immunotherapy agents specific to their indication,” he said.

“Clear Advantage”

“The higher the TMB, the greater the number of neoantigens expressed by the tumor, enhancing the probability of cancer cells being recognized by the immune system. This simple but captivating rationale likely underlies the clear advantage from pembrolizumab treatment found for patients with tTMB-high tumors, in terms of objective response and duration of response,” writes Melissa Bersanelli, MD, Medical Oncology Unit, University Hospital of Parma, Italy, in an accompanying editorial.

The authors showed the usefulness of tTMB status even in tumors that are well known to be poorly immunogenic, such as small cell lung cancer, she noted.

However, in this setting of rare tumors where there are few viable options and limited