2019 ASCO Annual Meeting!
Session: Developmental Immunotherapy and Tumor Immunobiology
Type: Poster Session
Time: Saturday June 1, 8:00 AM to 11:00 AM
Location: Hall A
Molecular circulating tumor DNA response to identify long-term survival in patients receiving immunotherapy with initial radiologic stable disease.
Developmental Immunotherapy and Tumor Immunobiology
2019 ASCO Annual Meeting
Poster Board Number:
Poster Session (Board #190)
J Clin Oncol 37, 2019 (suppl; abstr 2546)
Author(s): Matthew David Hellmann, Qu Zhang, Shaad Essa Abdullah, Jamie E. Chaft, Neil Howard Segal, Chen Gao, Phillip A. Dennis, Brandon W. Higgs; Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; AstraZeneca, Gaithersburg, MD; MedImmune, Gaithersburg, MD
Background: Early on-treatment changes in ctDNA may identify responders to immunotherapy and complement radiologic assessment of benefit. Here we investigate how early changes in ctDNA associate with long-term survival following treatment with immunotherapy, and if differential patterns in molecular ctDNA response (MCR) among patients with radiologic stable disease (SD) at first on-treatment scan could identify patients deriving benefit from treatment. Methods: Paired pre- and on-treatment (week 6-8) plasma samples from 3 cohorts of patients treated with durvalumab (D) +/- tremelimumab (D+T) were evaluated (NCT01693562, NCT02087423, NCT02261220). CtDNA was profiled with the 73-gene Guardant 360 assay. Nonsynonymous variants were summarized per patient to calculate variant allelic frequency changes (dVAF) and on-treatment variant allele frequency (pVAF). A combination of dVAF and pVAF was used to define MCR. Results: The reduction of ctDNA (dVAF<0) and undetectable on-treatment ctDNA (pVAF=0) were each associated with improved OS and PFS. An optimal threshold for MCR was determined from one cohort, then applied to the other cohorts. MCR associated with significantly improved PFS and OS across all three cohorts (Table). MCR was then applied to a pooled subgroup of patients with initial radiologic SD from all three cohorts (n=78). Patients with radiologic SD and MCR were significantly more likely than those without MCR to achieve radiologic CR or PR (pooled Odds ratio 12.7, p<0.001), had improved PFS (stratified pooled HR 0.36, p<0.001), and improved OS (stratified pooled HR 0.38, p=0.005). Conclusions: MCR is an early on-treatment tool that may identify patients with improved long-term survival and patients with radiologic SD who derive clinical benefit from immunotherapy. MCR may be a supportive endpoint in prospective clinical trials. MCR and survival benefit.
|MCR, n (%)||34 (47)||28 (39)||16 (44)|
|PFS HR (95% CI)||0.28 (0.16,0.50)⁂||0.40 (0.22,0.73)⁑||0.12 (0.05,0.32)⁂|
|OS HR (95% CI)||0.25 (0.13,0.49)⁂||0.34 (0.14,0.83)*||0.15 (0.05,0.44)⁂|
*<0.05, ⁑<0.01, ⁂<0.001