ESMO Immuno-Oncology 2018: MYSTIC: First-Line Durvalumab With or Without Tremelimumab in Metastatic NSCLC
First-line immunotherapy with durvalumab (Imfinzi) 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 by Rizvi et al at the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress 2018 (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. Commenting on behalf of ESMO, Pilar Garrido, MD, PhD, said, “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.”
MYSTIC
The MYSTIC trial enrolled 1,118 patients with metastatic NSCLC who were randomly assigned to durvalumab alone, durvalumab plus tremelimumab, or chemotherapy. The primary endpoints were overall survival for durvalumab vs chemotherapy and overall survival and progression-free survival for durvalumab plus tremelimumab vs chemotherapy in patients with 25% or greater programmed cell death ligand 1 (PD-L1) expression in tumor cells.
A total of 488 patients (44%) had PD-L1 expression of 25% or greater.
Findings
Durvalumab alone or with tremelimumab did not improve overall survival or progression-free survival compared to chemotherapy. Study author Naiyer Rizvi, MD, Director of Thoracic Oncology and Immunotherapeutics at Columbia University Medical Center, said, “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% or greater PD-L1 expression.”
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% of patients, of whom 40% had high TMB.
In patients with high TMB, overall survival was 16.5 months with durvalumab plus tremelimumab vs 10.5 months with chemotherapy (hazard ratio [HR] = 0.64). Overall survival with durvalumab alone was 11 months. The proportion of high TMB patients alive at 2 years was 39% with durvalumab plus tremelimumab, 30% with durvalumab, and 18% 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.
Dr. Rizvi said, “The results of the exploratory analysis need to be validated in a future trial. 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 [patients with] advanced NSCLC with high TMB.”
Safety data were consistent with previous studies. The incidence of grade 3/4 treatment-related adverse events was 14.6%, 22.1%, and 33.8% 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,” said Dr. Garrido, Head of the Thoracic Tumor Section, Medical Oncology Department, Ramón y Cajal University Hospital, Madrid, Spain. “The [MYSTIC trial] 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.”
Disclosure: The study authors’ full disclosures can be found at academic.oup.com.
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