Abstract CT074: Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab ± tremelimumab vs chemotherapy.

Abstract

Background High TMB is predictive of PFS benefit with anti-PD-(L)1 ± anti-CTLA-4 therapy in mNSCLC. Preliminary results from MYSTIC (NCT02453282), an open-label, Phase III trial of first-line durvalumab (D; anti-PD-L1), ± tremelimumab (T; anti-CTLA-4), vs platinum-based chemotherapy (CT) in mNSCLC, indicate that blood TMB (bTMB, ≥16 mut/Mb; GuardantOMNI [Guardant Health]) from circulating tumor DNA (ctDNA) correlates positively with tissue (t) TMB (≥10 mut/Mb) (Spearman’s correlation coefficient = 0.6) and is predictive of survival benefit with D±T vs CT. Efficacy outcomes were assessed using additional exploratory cut-offs for bTMB and ≥10 mut/Mb for tTMB. Methods Pts with EGFR and ALK wild-type, immunotherapy/CT-naïve mNSCLC were randomized (1:1:1) to D (20 mg/kg i.v. q4w); D (20 mg/kg i.v. q4w) + T (1 mg/kg i.v. q4w up to 4 doses); or CT. bTMB was evaluated with the GuardantOMNI platform. tTMB was evaluated with the FoundationOne tissue NGS platform. bTMB cut-off was defined as ≥20 mut/Mb (bTMB≥20). Data cut-off: Oct 4, 2018 (OS); Jun 1, 2017 (PFS). Results 1118 pts were randomized. Baseline sample datasets were: bTMB 809; tTMB 460 pts, with baseline characteristics balanced between treatment arms. bTMB≥20 was associated with improved OS (D+T vs CT: HR 0.49 [95% CI 0.32, 0.74]; D vs CT: HR 0.72 [95% CI 0.50, 1.05]) and PFS (D+T vs CT: HR 0.53 [95% CI 0.34, 0.81]; D vs CT: HR 0.77; [95% CI 0.52, 1.13]); 24-mo survival: D+T 48.1% (95% CI 35.5, 59.7), D 33.8% (95% CI 23.4, 44.5) and CT 19.4% (95% CI 11.0, 29.5). Data for tTMB are shown (table). Additional cut-offs will be presented. Conclusion MYSTIC provides the most comprehensive data set to date supporting TMB as a predictive biomarker of OS benefit with immunotherapy. In exploratory analyses, bTMB≥20 was associated with OS and PFS benefit with D±T vs CT, with the greatest magnitude of benefit observed for pts receiving D+T. bTMB ≥20 mut/MbbTMB <20 mut/MbtTMB ≥10 mut/MbtTMB <10 mut/MbD+TDCTD+TDCTD+TDCTD+TDCTn6477702042091856060671048584OSMedian, mos21.912.610.08.511.011.616.618.611.98.410.113.895% CI11.4, 32.87.8, 18.68.1, 11.76.7, 9.88.9, 14.99.6, 13.19.7, 27.39.3, 22.09.1, 16.05.3, 10.36.4, 14.610.1, 16.3HR*0.490.72-1.160.93-0.720.70-1.391.26-95% CI0.32, 0.740.50, 1.05-0.93, 1.450.74, 1.16-0.48, 1.090.47, 1.06-1.00, 1.920.90, 1.77-PFSMedian, mos4.22.74.42.02.85.03.13.15.12.42.55.695% CI2.8, NR1.8, 4.44.1, 5.41.7, 2.82.2, 3.14.2, 5.51.5, 6.82.3, 12.74.2, 5.61.6, 3.01.8, 3.44.2, 7.0HR*0.530.77-1.551.19-0.970.86-1.981.49-95% CI0.34, 0.810.52, 1.13-1.23, 1.940.94, 1.50-0.63, 1.490.55, 1.33-1.42, 2.781.05, 2.13-*HRs refer to comparison of experimental regimen to CT; NR, not reached Citation Format: Solange Peters, Byoung Chul Cho, Niels Reinmuth, Ki Hyeong Lee, Alexander Luft, Myung-Ju Ahn, Paul Baas, Manuel Cobo Dols, Alexey Smolin, David Vicente, Vladimir Moiseyenko, Scott J. Antonia, Kazuhiko Nakagawa, Sarah B. Goldberg, Edward Kim, Rajiv Raja, Philip Brohawn, Delyth Clemett, Piruntha Thiyagarajah, Urban Scheuring, Feng Liu, Naiyer Rizvi. Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab ± tremelimumab vs chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT074.

Precision Medicine for NSCLC in the Era of Immunotherapy: New Biomarkers to Select the Most Suitable Treatment or the Most Suitable Patient

“…A second bTMB assay, using the 500-gene panel Guardant OMNI, was evaluated in an exploratory analysis of the randomized phase III MYSTIC trial. A bTMB ≥ 20 Mut/Mb was significantly associated with OS and PFS benefit with durvalumab ± tremelimumab compared with platinum-based chemotherapy, with the greatest magnitude of benefit observed for patients receiving dual immune checkpoint blockage (HR 0.49 and 0.72 for OS and HR 0.53 and 0.77 for PFS with durvalumab-tremelimumab and durvalumab alone, respectively) [62]. Once again, bTMB did not correlate with PD-L1 expression levels.…”

Tissue-Plasma TMB Comparison and Plasma TMB Monitoring in Patients With Metastatic Non-small Cell Lung Cancer Receiving Immune Checkpoint Inhibitors

“…It is important to note that ultimately, this trial did not show any survival difference by TMB (11). A preplanned exploratory analysis from the MYSTIC trial showed an OS benefit in patients with PTMB > 16 mutations/Mbp in front-line combined anti-PD-L1 and anti-CTLA4 immunotherapy for advanced NSCLC (31). However, the Neptune trial, which prospectively assessed the role of PTMB in this same setting with the same treatment failed to show any predictive relevance of PTMB in the primary analysis (32).…”

Mechanism- and Immune Landscape-Based Ranking of Therapeutic Responsiveness of 22 Major Human Cancers to Next Generation Anti-CTLA-4 Antibodies

“…Therefore, subsequent studies focused on the dual blockade of CTLA-4 and PD-1/PD-L1 [46]. Recently, two randomized phase III trials (CheckMate 227 and MYSTIC) showed improved activity compared with platinum-based chemotherapy only in selected patients with high tumor mutation burden with ipilimumab-nivolumab [47], while tremelimumab-durvalumab [48] failed to demonstrate any benefit in unselected patients. Therefore, a new generation of anti-CTLA-4 antibodies must show higher anti-tumor activity in order to achieve better outcomes.…”