Abstract 105P
Background
Although immunotherapies can demonstrate salutary anti-cancer effects with long-term response, unfortunately, not all patients benefit from immunotherapies. Even among patients with favorable immune biomarkers (e.g. high expression or amplification of PD-L1, MSI-high and high tumour mutation burden [TMB]), the response is about 50-60% and thus further biomarker is required.
Methods
We prospectively enrolled 105 patients with diverse metastatic malignancies who received anti-PD-1/PD-L1 based therapies and obtained serial plasma for tumour derived cell-free DNA (cfDNA) to assess variant allele frequency (VAF) and TMB (samples obtained at the day of therapy, prior to first cycle. Subsequent samples prior to the second cycle of therapy). Machine learning was applied to adjust the serial VAF changes (Adj ΔVAF). Adj ΔVAF was dichotomized by the median value (≤median [low] vs. >median [high]). Serial TMB was dichotomized by decrease/no change vs. increase before and after therapy. Clinical outcomes were correlated with the cfDNA analysis. The study was conducted under the PREDICT protocol (NCT02478931).
Results
Among 105 patients, the most common diagnosis was gastrointestinal cancers (N=33) followed by genitourinary (N=17) and gynaecological cancers (N=14): Seventy-nine patients were evaluable for clinical outcomes at the time of data cutoff. Significantly higher rate of clinical benefit from immunotherapy (defined as stable disease [SD]≥6months/ partial response [PR]/ complete response [CR]) were seen amongst patients whose Adj ΔVAF was low (low vs. high: 69.2% vs. 22.5%, odds ratio: 0.07, 95% CI: 0.01-0.58, P=0.0142 [multivariate]). This also translated into statistically better progression-free survival (PFS) and overall survival (OS) (low vs. high, PFS: hazard ratio [HR]: 0.69, 95% CI: 0.60-0.79, P<0.001, OS: HR: 0.60, 95% CI: 0.51-0.72, P<0.001 [multivariate]). Serial changes in TMB were not strongly associated with clinical outcome.
Conclusions
Among patients with metastatic solid tumours treated with anti-PD-1/PD-L1 based therapies, low Adj ΔVAF in blood-derived cfDNA was significantly associated with clinical benefit rate as well as prolonged PFS and OS.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Konica Minolta.
Disclosure
S. Kato: Honoraria (self): Roche; Advisory/Consultancy: Foundation Medicine. B. Li: Full/Part-time employment: Ambry Genetics. S.W. Cha: Full/Part-time employment: Ambry Genetics. D. Bianchi-Frias: Full/Part-time employment: Ambry Genetics. N. Kamei: Full/Part-time employment: Konica Minolta. R. Hoiness: Full/Part-time employment: Ambry Genetics. J. Hoo: Full/Part-time employment: Ambry Genetics. P.N. Gray: Full/Part-time employment: Ambry Genetics. T. Iyama: Full/Part-time employment: Konica Minolta. M. Kashiwagi: Full/Part-time employment: Konica Minolta. H-M. Lu: Full/Part-time employment: Ambry Genetics. R. Kurzrock: Research grant/Funding (institution): Incyte; Advisory/Consultancy, Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Merck Serono; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Sequenom; Research grant/Funding (institution): Foundation Medicine; Research grant/Funding (institution): Guardant Health; Research grant/Funding (institution): Grifols; Research grant/Funding (institution): Konica Minolta; Advisory/Consultancy: LOXO; Advisory/Consultancy: X-Biotech; Advisory/Consultancy: Actuate Therapeutics; Advisory/Consultancy: NeoMed; Speaker Bureau/Expert testimony: Roche; Shareholder/Stockholder/Stock options: IDbyDNA; Shareholder/Stockholder/Stock options: Curematch, Inc.