Choi, Haesun

498 Background: Radiotherapy-based metastasis-directed therapy (MDT) has emerged as a viable treatment paradigm for oligometastatic clear cell renal cell carcinoma (ccRCC). However, the optimal integration of MDT with frontline immune checkpoint inhibition (ICI) is unclear, especially in light of the M1 NED subgroup analysis of KEYNOTE-564 suggestive of a larger benefit from adjuvant pembrolizumab. Here, we sought to compare the effects of MDT with or without pembrolizumab on clinical and translational outcomes among patients with oligometastatic ccRCC enrolled on two prospective phase II trials. Methods: We undertook an exploratory cohort study of two prospective, single-arm, investigator-initiated phase II trials. The RAPPORT trial (NCT02855203) assigned 30 patients to radiotherapy-based MDT followed by pembrolizumab 200 mg Q3W for eight cycles (MDT+ICI cohort). The MD Anderson trial (NCT03575611) assigned 121 patients to serial MDT (which was almost exclusively radiotherapy-based) without systemic therapy (MDT cohort). For both trials, eligibility criteria consisted of 1 to 5 ccRCC metastatic lesions amenable to MDT. For the present analysis, the primary endpoint was progression-free survival (PFS), prospectively defined by RECIST v1.1 and analyzed using Cox regression. Peripheral blood flow cytometry obtained at baseline, end of MDT in both cohorts (after 1 cycle of ICI in the MDT+ICI cohort), and after completion of all treatment in both cohorts (3 months in the MDT alone cohort and 12 months in the MDT+ICI cohort) was compared using adjusted linear mixed effect models. Results: A total of 150 patients were included for analysis (MDT+ICI: 30; MDT: 120). Median follow-up time was 34 months (MDT+ICI: 28; MDT: 36). At enrollment, the MDT+ICI cohort had a larger number of metastases (median 3 vs 1). Adjusted for prognostic factors, median PFS was 28 months after MDT+ICI and 17 months after MDT (HR, 0.57; 95% CI: 0.31 to 0.998; P = 0.049). Induction of activated systemic CD8 + T cells (ICOS + ) was observed in both cohorts following MDT; however, this increase was greater in the MDT+ICI cohort. Moreover, there was evidence of decreased systemic CD8 + T cell immunosuppression (CD73 + ) following treatment cessation in the MDT+ICI group. Conclusions: To our knowledge, this is the largest prospective analysis of MDT for ccRCC in the ICI era. The addition of maintenance ICI to MDT may improve clinical outcomes in patients with oligometastatic ccRCC. Greater immunomodulatory signals were observed with MDT+ICI, providing a mechanistic link to the clinical benefits. The ASTROs trial (NCT06004336) randomizing patients with oligometastatic ccRCC to MDT with or without pembrolizumab has been initiated to test the hypotheses generated by the present study. Clinical trial information: NCT02855203 and NCT03575611 .

BackgroundUncertainty regarding the reproducibility of the apparent diffusion coefficient (ADC) hampers the use of quantitative diffusion‐weighted imaging (DWI) in evaluation of the prostate with magnetic resonance imaging MRI. The quantitative imaging biomarkers alliance (QIBA) profile for quantitative DWI claims a within‐subject coefficient of variation (wCV) for prostate lesion ADC of 0.17. Improved understanding of ADC reproducibility would aid the use of quantitative diffusion in prostate MRI evaluation.PurposeEvaluation of the repeatability (same‐day) and reproducibility (multi‐day) of whole‐prostate and focal‐lesion ADC assessment in a multi‐site setting.Study TypeProspective multi‐institutional.SubjectsTwenty‐nine males, ages 53 to 80 (median 63) years, following diagnosis of prostate cancer, 10 with focal lesions.Field Strength/Sequence3T, single‐shot spin‐echo diffusion‐weighted echo‐planar sequence with four b‐values.AssessmentSites qualified for the study using an ice‐water phantom with known ADC. Readers performed DWI analyses at visit 1 (“V1”) and visit 2 (“V2,” 2–14 days after V1), where V2 comprised scans before (“V2pre”) and after (“V2post”) a “coffee‐break” interval with subject removal and repositioning. A single reader segmented the whole prostate. Two readers separately placed region‐of‐interests for focal lesions.Statistical TestsReproducibility and repeatability coefficients for whole prostate and focal lesions derived from median pixel ADC. We estimated the wCV and 95% confidence interval using a variance stabilizing transformation and assessed interreader reliability of focal lesion ADC using the intraclass correlation coefficient (ICC).ResultsThe ADC biases from b0–b600 and b0–b800 phantom scans averaged 1.32% and 1.44%, respectively; mean b‐value dependence was 0.188%. Repeatability and reproducibility of whole prostate median pixel ADC both yielded wCVs of 0.033 (N = 29). In 10 subjects with an evaluable focal lesion, the individual reader wCVs were 0.148 and 0.074 (repeatability) and 0.137 and 0.078 (reproducibility). All time points demonstrated good to excellent interreader reliability for focal lesion ADC (ICCV1 = 0.89; ICCV2pre = 0.76; ICCV2post = 0.94).Data ConclusionThis study met the QIBA claim for prostate ADC. Test–retest repeatability and multi‐day reproducibility were largely equivalent. Interreader reliability for focal lesion ADC was high across time points.Level of Evidence1Technical EfficacyStage 2TOC CategoryPelvis