Merck's Two Trials Show No Correlation Between TMB Levels and Patient Outcomes with Keytruda-Based Therapy

Compiled by Fan Dongdong

To Secure a Share of the Lucrative Non-Small Cell Lung Cancer Market, Some Immuno-Oncology Companies Have Turned to Studying the Biomarker Tumor Mutational Burden (TMB). However, Recent Data from Lung Cancer Giant Merck Sharp & Dohme (MSD) Cast Doubt on the Utility of This Biomarker.

At the World Conference on Lung Cancer held in Barcelona last Sunday, MSD presented the results of two exploratory analyses, which suggested that tumor mutational burden (TMB) does not appear to determine which patients benefit from the Keytruda plus chemotherapy combination.

MSD analyzed tumor mutational burden (TMB) data from patients in its Phase 2 KEYNOTE-021 and Phase 3 KEYNOTE-189 studies, both of which evaluated the immuno-oncology flagship therapy Keytruda in combination with chemotherapy for the treatment of previously untreated non-small cell lung cancer (NSCLC) patients. In both trials, the efficacy of the combination regimen was consistent across patients with varying TMB levels, and MSD did not identify a significant correlation between TMB and the ability of the treatment combination to elicit patient responses, delay disease progression, or prolong survival.

Dr. Roy Baynes, Senior Vice President and Head of Global Clinical Development at MSD, stated, “The evidence confirms that treatment outcomes are indeed not influenced by tumor mutational burden (TMB) status. KEYNOTE-189 reinforces the strength of Keytruda in combination with chemotherapy as a first-line treatment regimen for lung cancer. This important dataset, along with these new exploratory results, will provide valuable guidance for academic researchers and clinicians who have a keen interest in the role of tumor mutational burden (TMB).”

Since the advent of immunotherapy in clinical practice, tumor mutational burden (TMB) has emerged in recent years as a robust predictive biomarker, second only to PD-L1. TMB reflects the number of gene mutations present in the tumor tissue of patients. A higher number of mutated genes in tumor tissue increases the likelihood of generating more abnormal proteins, which are more readily recognized by the patient’s immune system. This recognition activates the patient’s endogenous anti-tumor immune response, thereby enhancing the overall efficacy of exogenous tumor immunotherapy.

Baynes stated that these new findings are good news for Merck Sharp & Dohme (MSD), as they clearly indicate that all patients who can tolerate chemotherapy should receive combination therapy with Keytruda. However, this trial data is not a positive sign for companies seeking to use tumor mutational burden (TMB) to stratify patient subgroups. More unfortunately for these companies, there was also little evidence last year to suggest that TMB has a significant impact on final patient outcomes.

This is not the first time that tumor mutational burden (TMB) has encountered a setback. In its CheckMate-227 trial, Bristol-Myers Squibb found that among patients with non-small cell lung cancer (NSCLC) whose TMB exceeded 10 mutations per Mb, the combination of Opdivo and Yervoy more than tripled the one-year progression-free survival rate (42.6% vs. 13.2%). This trial was also the first prospective clinical study to confirm that TMB can serve as a predictive biomarker for the efficacy of immunotherapy.

Based on the CheckMate-227 trial results demonstrating that Opdivo in combination with Yervoy significantly improved progression-free survival compared to chemotherapy, Bristol Myers Squibb submitted a supplemental Biologics License Application (sBLA). However, in March 2019, new data revealed no significant difference in overall survival outcomes between patients with high or low tumor mutational burden (TMB). Following discussions with the U.S. Food and Drug Administration, Bristol Myers Squibb announced the withdrawal of its application.

Baynes added that this does not mean the role of tumor mutational burden (TMB) in treatment selection has come to an end. “We still consider tumor mutational burden (TMB) an important area of research, and MSD is also conducting relevant studies.”

Reference Source: Merck analyses throw doubt on new biomarker's utility