Among a select group of patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with the biologic durvalumab was not associated with statistically significant improvements in overall survival versus chemotherapy in the international randomized MYSTIC trial.
Treatment with durvalumab (Imfinzi, AstraZeneca) was associated with a numerically reduced risk of death in patients with 25% or more of tumor cells expressing programmed cell death 1 or its ligand (PD-L1), with a 24-month overall survival rate of 38.3% observed in these patients, compared to 22.7% of patients treated with standard chemotherapy.
The MYSTIC trial results, published online April 9 in JAMA Oncology, have clinical implications for the treatment of metastatic NSCLC, wrote researcher Naiyer Rizvi, MD, of Columbia University Medical Center, New York City, and colleagues.
“Although patients with PD-L1 tumor cells (PD-L1 TC) between 25% and 49% had a reduction in the risk of death equivalent to patients with PD-L1 TC ≥50%, they had improved outcomes compared with patients with PD-L1 TC <25%, indicating that a PD-L1 TC ≥25% is an appropriate cut-off point for durvalumab monotherapy in patients with metastatic NSCLC,” they wrote.
An exploratory analysis also identified a blood tumor mutational burden (bTMB) threshold of at least 20 mutations per megabase as predictive of optimal clinical benefit for treatment with the combination of durvalumab and tremelimumab, compared to standard chemotherapy.
The researchers concluded that “further investigation and prospective validation of bTMB as a predictive biomarker for benefit with immunotherapy are warranted.”
The researchers noted that early studies suggest tumor mutational burden, either measured using tissue (tTMB) or blood TMB, is a key indicator of response to PD-L1 therapies.
“However, to our knowledge, a predictive effort of tTMB on overall survival benefit with immunotherapy vs chemotherapy has not been shown in NSCLC.”
They added that more recent studies suggest that bTMB may obviate certain “logistic and technical challenges associated with tTMB measurement.”
Durvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks PD-L1 binding to PD-1 and GD80, and it has been approved for the treatment of patients with unresectable, stage III NSCLC without disease progression after platinum-based chemoradiotherapy.
The drug has shown clinical activity in patients with advanced NSCLC in combination with tremelimumab in phase 1 and phase 2 trials.
The open-label MYSTIC trial was conducted at 203 cancer treatment centers in 17 countries, and it included treatment-naive patients with metastatic NSCLC who had no sensitizing EGFR or ALK genetic alterations.
A total of 1118 patients were randomized (1:1:1) to receive treatment with durvalumab (20mg/kg every 4 weeks), durvalumab (20mg/kg every 4 weeks) plus tremelimumab (1mg/kg every 4 weeks, up to 4 doses), or platinum-based doublet chemotherapy.
The primary end points, assessed in patients with 25% of tumor cells expressing PD-L1, were overall survival (OS) for durvalumab vs chemotherapy, and OS and progression-free survival (PFS) for durvalumab plus tremelimumab versus chemotherapy. Analysis of blood tumor mutational burden (bTMB) was exploratory.
Among the main study findings:
Among 488 patients with ≥25% of tumor cells expressing PD-L1, median OS was 16.3 months (95% CI, 12.2-20.8) with durvalumab versus 12.9 months (95%CI, 10.5-15.0) with chemotherapy (hazard ratio [HR], 0.76; 97.54% CI, 0.56-1.02; P=0.04 [non-significant]).
- Median OS was 11.9 months (95% CI, 9.0-17.7) with durvalumab plus tremelimumab (HR vs chemotherapy, 0.85; 98.77% CI, 0.61-1.17;P=0.20).
- Median PFS was 3.9 months (95% CI, 2.8-5.0) with durvalumab plus tremelimumab versus 5.4 months (95% CI, 4.6-5.8) with chemotherapy (HR, 1.05; 99.5% CI, 0.72-1.53;P=0.71).
Among 809 patients with evaluable bTMB, those with a bTMB ≥20 mutations per megabase showed improved OS for durvalumab plus tremelimumab versus chemotherapy (median OS, 21.9 months [95% CI, 11.4-32.8] vs 10.0 months [95% CI, 8.1-11.7]; HR, 0.49; 95% CI, 0.32-0.74).
Fifty-five of the 369 patients treated with durvalumab (14.9%) had treatment-related adverse events of grade 3 or higher, compared to 85 (22.9%) of 371 patients who received treatment with durvalumab plus tremelimumab, and 119 (33.8%) of 352 patients who received treatment with chemotherapy.
Adverse events leading to death were reported in 0.5%, 1.6% and 0.9% of patients treated with durvalumab, durvalumab plus tremelimumab and chemotherapy, respectively.
“Whereas durvalumab plus tremelimumab did not statistically significantly improve OS or PFS vs chemotherapy in patients with PD-L1 TC ≥25%, the combination showed clinical activity in patients with bTMB ≥20 mut/Mb” the researchers wrote.
In an accompanying editorial, Saiama Waqar and Ramaswamy Govindan, MD, wrote that to their knowledge, “the MYSTIC study is the first to prospectively demonstrate a correlation between TMB and overall survival with immune checkpoint inhibitor therapy in the first-line treatment setting, and it also showed a correlation between blood TMB and tissue TMB testing in the 352 matched samples tested (Spearman ρ = 0.6; Pearson r = 0.7).”
They wrote that testing for blood or tissue TMB is likely to be limited at present, and they concluded that “it is time to bring industry and academia together to independently standardize TMB testing, similar to efforts to standardize PD-L1 testing through the Blueprint PD-L1 assay comparison project.”
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The phase 3 MYSTIC study did not meet its primary end points of improved overall survival with durvalumab versus chemotherapy in metastatic NSCLC patients with ≥25% of tumor cells expressing PD-L1.
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Exploratory analyses identified a blood tumor mutational burden threshold of ≥20 mutations per megabase for optimal survival benefit with durvalumab plus tremelimumab.
Salynn Boyles, Contributing Writer, BreakingMED™
The MYSTIC study was funded by AstraZeneca.
Researcher Naiyer Rizvi reported receiving personal fees from AstraZeneca, and other pharmaceutical companies, grants from Bristol-Myers Squibb, equity in Bellicum, Brooklyn Immunotherapeutics and Gristone. Dr. Rizvi also has a patent pending for PCGT/US2015/062208 with royalties paid.
Other MYSTIC researchers also reported receiving personal fees or other fees from AstraZeneca and other pharmaceutical companies.
Cat ID: 24
Topic ID: 78,24,730,24,192,925
