Conference Coverage

MYSTIC trial: bTMB correlates with tTMB, predicts survival in mNSCLC



– Blood tumor mutational burden (bTMB) predicts survival benefit in metastatic non–small cell lung cancer (mNSCLC) patients treated with first-line durvalumab plus tremelimumab versus platinum-based chemotherapy, according to findings from the open-label, phase 3 MYSTIC trial.

Frontline Medical News

Dr. Solange Peters

Specifically, in patients with bTMB based on circulating tumor DNA at levels of 20 mutations (mut)/megabase (Mb) or greater, overall survival (OS) was significantly improved with durvalumab alone and with durvalumab plus tremelimumab versus chemotherapy (hazard ratios, 0.74 and 0.49, respectively). Progression-free survival (PFS) was also improved (HRs, 0.76 and 0.53, respectively), Solange Peters, MD, PhD, reported at the annual meeting of the American Association for Cancer Research.

Among patients with bTMB less than 20 mut/Mb, the corresponding OS hazard ratios were 1.55 and 1.26, and the corresponding PFS hazard ratios were 1.22 and 1.16, said Dr. Peters, director of teaching and patient care in the area of medical oncology and thoracic malignancies at Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland) University, and president-elect of the European Society for Medical Oncology.

Study subjects were 1,118 patients with immunotherapy- and chemotherapy-naive EGFR and ALK wild-type mNSCLC who were randomized 1:1 to receive either the programmed death–ligand 1 (PD-L1) agent durvalumab, durvalumab plus the anti-CTLA4 agent tremelimumab, or chemotherapy. At a tissue TMB (tTMB) level of 10 mut/Mb or greater, those who received either durvalumab or durvalumab plus tremelimumab had better OS than did those who received chemotherapy (HRs, 0.70 and 0.72, respectively).

Further, bTMB levels of at least 16 mut/Mb correlated positively with tTMB (Spearman correlation coefficient, 0.6; Pearson correlation coefficient, 0.7), she said, adding that survival probability at 24 months was 41.7% with durvalumab plus tremelimumab versus 35.0% with durvalumab alone and 22.7% with chemotherapy in this patient subgroup.

“When you look at the subgroup of patients with lower number of mutations than 10, this phenomenon is not observed. If anything should be potentially stressed about these hazard ratios – all above 1 – is potentially that chemotherapy represents a better option in this patient population,” she said.

Treatment included intravenous durvalumab at a dose of 20 mg/kg every 4 weeks with or without IV tremelimumab at a dose of 1 mg/kg every 4 weeks for up to four doses (372 and 374 patients, respectively), or platinum-based chemotherapy (372 patients).

“Durvalumab ... is already approved for unresectable stage 3 NSCLC and has shown clinical activity in heavily pretreated patients with mNSCLC in the context of phase 2 and 3 previously presented trials,” Dr. Peters said, noting that the multicenter MYSTIC trial was designed to assess its potential role in the treatment of all-comers with stage IV disease.

Overall survival data from the study were presented at the 2018 ESMO Immuno-Oncology Congress, and showed that the primary endpoint of superiority of durvalumab or durvalumab plus tremelimumab versus chemotherapy for OS in patients with high PD-L1 expression (at least 25% of tumor cells expressing PD-L1) was not met. There did, however, appear to be a clinically meaningful 3-month survival benefit (HR, 0.76) with durvalumab, she said.

The idea of combining durvalumab with tremelimumab was based on the potential for “antitumor activity via nonredundant pathways,” she noted, further explaining that the interest in determining whether bTMB correlates with tTMB relates to the rapid availability and less invasive nature of the latter and the fact that bTMB measured from circulating tumor DNA, “biologically speaking, may be more representative of the heterogeneity of metastatic lesions in the context of an advanced disease.”

The current findings are from exploratory analyses looking at OS based on bTMB and tTMB at varying levels to “better understand optimal outcomes and potential contributions of tremelimumab,” she said, noting that survival benefit was observed in all subgroups defined by a high TMB (equal to or greater than vs. less than 4, 8, 12, 16, and 20 mut/Mb).

Outcomes using the bTMB cutoff of 16 or greater mut/Mb were also presented at the ESMO meeting, and showed an OS benefit with durvalumab and durvalumab plus tremelimumab versus chemotherapy in those patients; the finding was more pronounced with durvalumab plus tremelimumab (HR, 0.82 and 0.62, respectively), and the effect increased with increasing bTMB levels.

“Based on that, we decided to [use the 20 mut/Mb or greater] cutoff to conduct a subsequent analysis,” Dr. Peters said, noting again the “very significantly improved” OS and PFS for combined treatment versus chemotherapy with 20 or greater versus less than 20 mut/Mb, and the value of chemotherapy in those with lower bTMB.

Tumor response was also better with durvalumab plus tremelimumab versus chemotherapy at this cutoff; objective response rates were 29.9% and 48.4% with durvalumab and durvalumab plus tremelimumab, respectively, versus 21.4% with chemotherapy.

“Again, under this threshold [less than 20 mut/Mb], it looked like chemotherapy was offering a better response rate with 31.4% as compared to 20% and less for the immunotherapy strategy,” she said.

Also of note, the percentage of patients remaining in response at 6 and 12 months was much better in those who received immunotherapy with durvalumab plus tremelimumab versus chemotherapy; this was more pronounced in those with high TMB (85.6% vs. 14.4% at 6 months; 81.7% vs. 7.2% at 12 months).

No differences were seen in toxicity patterns in the subgroup of patients with bTMB greater than 20 mut/Mb when compared with the overall safety population from MYSTIC, she added.

“Based on this exploratory analysis, further investigation and prospective validation of bTMB as a predictive biomarker for immunotherapy is warranted and should potentially be evaluated in as many as possible future clinical trials looking at immunotherapy across various solid tumors,” Dr. Peters said.

MYSTIC is sponsored by AstraZeneca. Dr. Peters reported relationships – including receipt of honoraria or consulting fees, receipt of grant/research support, and/or speaking engagements – with numerous pharmaceutical companies.

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