First-Line Immunotherapy Combo Fails to Improve Survival in Lung Cancer Trial


Durvalumab plus tremelimumab did not meet the primary endpoint of the phase 3 MYSTIC trial evaluating improvement in overall survival and progression-free survival compared with chemotherapy.

First-line immunotherapy with durvalumab (Imfinzi, AstraZeneca) or the combination of durvalumab and tremelimumab failed to improve overall survival (OS) in patients with lung cancer compared with chemotherapy, according to new data from the phase 3 MYSTIC trial presented at the ESMO Immuno-Oncology Congress.

For the trial, 1118 patients with metastatic non-small cell lung cancer (NSCLC) were treated with either durvalumab monotherapy, durvalumab plus tremelimumab, or chemotherapy to evaluate OS and progression-free survival (PFS). Forty-four percent of patients in the study had PD-L1 expression of 25% or greater.

Durvalumab alone or in combination with tremelimumab did not improve OS or PFS compared with chemotherapy, failing to meet the trial’s primary endpoint. However, the study showed that durvalumab monotherapy did demonstrate a clinically meaningful median OS improvement of 16.3 months compared with 12.9 months with chemotherapy in patients with 25% or greater PD-L1 expression. The combination therapy had a hazard ratio of 0.65 (98.77% Cl 0.611-1.173; nominal p=0.202) with safety and tolerability profiles consistent with previous studies. The data support further analysis in exploratory subgroups, according to AstraZeneca.

In an exploratory analysis of survival according to high or low tumor mutational burden (TMB), patients with high TMB had an OS of 16.5 months with the combination therapy compared with 10.5 months with chemotherapy, with a hazard ratio of 0.62. OS with durvalumab monotherapy was 11 months. The researchers performed TMB evaluation in more than 70% of patients, of whom 40% had high TMB.

At 2 years, the proportion of patients with high TMB who were alive was 39% with durvalumab plus tremelimumab, 30% with durvalumab monotherapy, and 18% with chemotherapy. In patients with low TMB, OS was 8.5 months with durvalumab plus tremelimumab, 12.2 months with durvalumab monotherapy, and 11.6 months with chemotherapy, according to the study.

According to study author Naiyer Rizvi, MD, director of thoracic oncology and immunotherapeutics at Columbia University Medical Center, TMB could be a potential way to select patients who may benefit most from this treatment. He indicated that the CheckMate 227 trial previously showed that first-line immunotherapy combinations work best in advanced NSCLC patients with high TMB.

“The analysis shows that appropriate biomarkers are needed to select the patients most likely to benefit from combination immunotherapy in first line,” Dr Rizvi said in a press release about the findings. “The challenge now is to prospectively validate them prior to implementation in clinical practice.”


First Line Immunotherapy Combination Fails to Improve Overall Survival in Lung Cancer [ESMO press release]. ESMO’s website. Accessed December 14, 2018.

AstraZeneca provides update on the Phase III MYSTIC trial of Imfinzi and tremelimumab in Stage IV non-small cell lung cancer [news release]. AstraZeneca’s website. Accessed December 14, 2018.

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