MYSTIC: TMB may affect NSCLC response to durvalumab plus tremelimumab
medwireNews: First-line treatment with durvalumab plus tremelimumab may improve survival relative to chemotherapy in patients with metastatic non-small-cell lung cancer (NSCLC) and a blood tumor mutational burden (bTMB) of at least 20 mutations/Mb, research suggests.
The phase 3 MYSTIC trial found that the anti-PD-L1/anti-CTLA-4 immunotherapy combination did not improve overall survival (OS) versus chemotherapy in all patients but halved the risk for death in those with a high bTMB.
The international study randomly assigned individuals with treatment-naïve, stage IV NSCLC who had no sensitizing EGFR or ALK genetic alterations to receive treatment with durvalumab monotherapy (20 mg/kg every 4 weeks; n=369), durvalumab at the same dose plus tremelimumab (1 mg/kg every 4 weeks, up to 4 doses; n=371), or platinum-based doublet chemotherapy (n=352).
After a median 30.2 months of follow-up, the primary endpoint of median OS among patients with tumor PD-L1 expression levels of at least 25% (n=488) did not differ significantly between the patients who received immunotherapy and those who received chemotherapy. It was 16.3 months with durvalumab, 11.9 months with durvalumab plus tremelimumab, and 12.9 months with chemotherapy.
Nonetheless, the corresponding OS rates at 2 years were 38.3%, 35.4%, and 22.7%, suggesting that durvalumab alone or in combination with tremelimumab may offer “a longer-term treatment benefit” than chemotherapy, Naiyer Rizvi (Columbia University Medical Center, New York, USA) and co-researchers report in JAMA Oncology.
In addition, exploratory analyses among 211 patients with a bTMB of at least 20 mutations/Mb showed that, in these patients, OS with durvalumab plus tremelimumab was more than double that with chemotherapy, at 21.9 versus 10.0 months, resulting in a significant hazard ratio of 0.49 in favor of the immunotherapy combination.
The combined immunotherapy response was also durable, with a 2-year OS rate of 48.1% versus 19.4% with chemotherapy.
By contrast, there was no significant difference in OS for durvalumab plus tremelimumab versus chemotherapy among the patients with bTMB below 20 mutations/Mb. There was also no difference in OS between durvalumab monotherapy and chemotherapy at bTMBs either above or below 20 mutations/Mb.
The rates of treatment-related grade 3 or worse adverse events were 14.9%, 22.9%, and 33.8% with durvalumab, durvalumab plus tremelimumab, and chemotherapy, respectively, while the rates of adverse events leading to death were 0.5%, 1.6%, and 0.9%, respectively.
Rizvi and co-authors conclude that “[t]hese findings highlight the need for further investigation and prospective validation of blood tumor mutational burden as a predictive biomarker for immunotherapy.”
In an accompanying comment, Saiama Waqar and Ramaswamy Govindan, both from Washington University School of Medicine in St Louis, Missouri, USA, note that optimal bTMB and cutoffs that are clinically useful for patient selection are currently unclear and can be highly variable.
They therefore believe “[i]t is time to bring industry and academia together to independently standardize TMB testing, similar to the efforts to standardize PD-L1 testing through the Blueprint PD-L1 assay comparison project.”
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