Following Up on the MYSTIC Trial

Researchers focused on a subset of patients with high tumor mutational burden using a 20-mutation-per-megabase threshold and found significant improvement in progression-free survival and overall survival.

In further analysis from the phase III MYSTIC trial, investigators examined the relationship between STK11,KEAP1, and ARID1A mutations and chemotherapy outcomes/prognostic factors in patients with metastatic non–small-cell lung cancer (NSCLC). Findings were presented on September 8, 2019, at the International Association for the Study of Lung Cancer (IASLC) 2019 World Conference on Lung Cancer (WCLC) held in Barcelona.

“The STK11-KEAP1 mutations … influence outcomes and need to be factored into our analysis of TMB [tumor mutational burden] and other outcomes of lung cancer,” said primary author Naiyer A. Rizvi, MD, Director of Thoracic Oncology, Division of Hematology/Oncology, Columbia University Medical Center, New York. “STK11-KEAP1 are sort of bad actors in terms of lung cancer outcomes [as supported by current knowledge]."

The MYSTIC trial was a phase III trial comparing durvalumab monotherapy or durvalumab-tremelimumab with chemotherapy as first-line treatment in patients with metastatic or locally advanced NSCLC with epidermal growth-factor receptor and anaplastic lymphoma kinase wild-type. In the update, Naqvi et al. focused on a subset of patients with high tumor mutational burden using a 20-mutation-per-megabase threshold and found significant improvement in progression-free survival and overall survival. The analysis was performed with a plasma assay utilizing a 500-gene panel with a one-megabase footprint.

Patients with mutations in STK11 or KEAP1 exhibited decreased median overall survival in all experimental groups. Furthermore, in patients given durvalumab plus tremelimumab, survival benefits were seen in those with ARID1A mutations.

Rizvi provided some insight regarding the effects of immunotherapy in these patients.

“There seems to be some possible effect with immunotherapy in these patients although when one looks at the overall survival, they still continue to be fairly poor,” he said.  

In the study population that could be evaluated (n=943), the prevalence of the STK11 mutations was 16%, the prevalence of the KEAP1 mutation was 18%, and the prevalence of the ARID1A mutation was 12%.  Of note, STK11 and KEAP1 are relatively common and the third and fourth most common mutations in lung cancer after p53 and KRAS.

ARID1A patients are about 10% of the population and seem to do particularly well with durvalumab- tremelimumab,” he said. “The key finding is the ARID1A  response in the durvalumab- tremelimumab patients was a pretty impressive response rate as well as overall survival in this patient population.”

 “Interestingly, with the durvalumab-tremelimumab combination with the ARID1A mutations, [patients] seem to do much better with a response rate of 51 percent,” Rizvi said. “Intriguingly, the STK11-KEAP1 mutations did seem to fair a little bit better in terms of response rate versus chemotherapy or durvalumab with the combination durvalumab-tremelimumab. Again, the numbers are small so it’s hard to make too much of that...I think the take home message is that that these STK11-KEAP1 mutations are prognostic for [less] … I think that these exploratory analyses can help us to think about how to use TMB and outcomes in lung cancer patients in future trials.”