GENEVA, SWITZERLAND—First line immunotherapy with durvalumab or the combination of durvalumab and tremelimumab does not improve overall survival in unselected patients with lung cancer, according to late-breaking results from the MYSTIC trial presented at the ESMO Immuno-Oncology Congress (Abstract LBA6).
The combination of immune checkpoint inhibitors and chemotherapy has been successfully tested in different trials as first-line therapy for metastatic non-small cell lung cancer (NSCLC) while the use of two immunotherapy drugs without chemotherapy has been addressed in very few studies.
“Some patients are worried about the side effects of chemotherapy and prefer to delay it. Avoiding the use of chemotherapy in the first-line setting also leaves an effective rescue option when immunotherapy fails,” noted Pilar Garrido, MD, Associate Professor of Medical Oncology at Universidad de Alcalá in Madrid, Spain, and Head of the Thoracic Tumours Unit in the Medical Oncology Department at the University Hospital Ramón y Cajal (IRYCIS), commenting on behalf of ESMO.
MYSTIC Trial Details
The MYSTIC trial enrolled 1,118 patients with metastatic NSCLC who were randomly allocated to durvalumab alone, durvalumab plus tremelimumab, or chemotherapy. The primary endpoints were overall survival for durvalumab versus chemotherapy, and overall survival and progression-free survival for durvalumab plus tremelimumab versus chemotherapy in patients with 25 percent or greater PD-L1 expression in tumor cells.
A total of 488 patients (44%) had PD-L1 expression of 25 percent or greater. Durvalumab alone or with tremelimumab did not improve overall survival or progression free survival compared to chemotherapy. “While not reaching statistical significance, durvalumab monotherapy gave a clinically meaningful median overall survival improvement of 16.3 months compared to 12.9 months with chemotherapy in patients with 25 percent or greater PD-L1 expression,” stated study author Naiyer Rizvi, MD, Director of Thoracic Oncology and Immunotherapeutics, at Columbia University Medical Center, New York.
An exploratory analysis examined survival according to high or low tumor mutational burden (TMB) in the blood—16 or more mutations per megabase was defined as “high” and less than 16 as “low.” TMB evaluation was performed in more than 70 percent of patients, of whom 40 percent had high TMB.
In patients with high TMB, overall survival was 16.5 months with durvalumab plus tremelimumab versus 10.5 months with chemotherapy, with a hazard ratio of 0.64. Overall survival with durvalumab alone was 11 months. The proportion of high TMB patients alive at 2 years was 39 percent with durvalumab plus tremelimumab, 30 percent with durvalumab, and 18 percent with chemotherapy. In those with low TMB, overall survival was 8.5 months with durvalumab plus tremelimumab, 12.2 months with durvalumab, and 11.6 months with chemotherapy.
“The results of the exploratory analysis need to be validated in a future trial,” Rizvi said. “TMB is measured with a simple blood test and might be an easy way to select patients for this treatment. The CheckMate 227 trial previously showed that first-line immunotherapy combinations work best in advanced NSCLC patients with high TMB (N Engl J Med 2018;378:2093-2104).”
Safety data were consistent with previous studies. The incidence of grade 3/4 treatment-related adverse events was 14.6 percent, 22.1 percent, and 33.8 percent with durvalumab, durvalumab plus tremelimumab, and chemotherapy, respectively.
“Immunotherapy has rapidly become a first-line treatment option in NSCLC, as shown in the 2018 ESMO Clinical Practice Guidelines for metastatic disease,” Garrido noted (Ann Oncol 2018;29(Supplement 4):iv192-iv237). “The ESMO Immuno-Oncology Congress showcases cutting-edge developments in this fast-moving field, such as the highly anticipated MYSTIC trial. The analysis shows that appropriate biomarkers are needed to select the patients most likely to benefit from combination immunotherapy in first line. The challenge now is to prospectively validate them prior to implementation in clinical practice.”