Discordance between central versus local response assessments in neuroendocrine tumor (NET) patients (pts) enrolled in A021202.
Authors: Geyer Susan Michelle , Mahoney Michelle R. , Asmis Timothy R. , Hall Nathan , Karovic Sanja , Knopp Michael V. , Kumthekar Priya , Nixon Andrew B. , O'Reilly Eileen Mary , Schwartz Lawrence Howard , Strosberg Jonathan R. , Meyerhardt Jeffrey A. , Maitland Michael L. , Bergsland Emily K. 
Published: January 2021

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Background: Assessment of tumor response in extrapancreatic NETs with metastases can be very challenging. Previous studies suggest a high degree of discordance between local and central imaging reviews, which has implications for clinical practice and trial design. Methods: Serial images archived from a randomized phase II trial (A021202) of pazopanib vs placebo in progressive non-pancreatic NETs were evaluated by central review, with real-time review conducted at the time of locally interpreted progressive disease (PD). The primary endpoint of the trial was progression-free survival (PFS) by central review. Discordances between central (Alliance Imaging Core Laboratory) and local (investigator-reported) reviews were assessed. Scan-level and pt-level results across both treatment arms were evaluated. Kappa tests were used to test concordance based on source of review. Results: 151 pts had a total of 724 scans with response adjudication by both local and central RECIST review. Discordance was observed in both directions. Overall, 20% of scans (143/724) had discordant classifications. The most common discordances were: stable disease (SD) on local vs. PD on central review (82/143=57%), and PD on local vs. SD on central review (32/143=22%). On a pt level, 78 of 151 pts (52%) had discordant reviews; 8 had >1 type of discordance. Overall, 30% of pts (N=45) had a determination of PD on central review, but SD or better on local review, potentially resulting in excessive exposure to therapy. In contrast, 20% (N=30) were classified as PD on local read but SD or better on real-time central review (which did not necessarily translate into an abbreviated course of treatment). Cohen’s kappa statistics revealed only moderate concordance between local and central reviewers both at the scan (K=0.48, 95% CI: 0.42 – 0.55) and pt (K=0.41, 95% CI: 0.32 – 0.5) levels, with no significant influence by treatment arm, primary tumor site, tumor functionality, histology, differentiation or primary disease spread. Conclusions: Discordance was observed in both directions, where 30% of pts were potentially kept on study drug too long (based on central read), and 20% would have been taken off study treatment early for local PD were it not for real-time central review. Although this bidirectional discordance did not affect the overall findings of the PFS outcome between arms in the trial, these analyses highlight the high prevalence of discordance, the potential to negatively influence treatment duration in both directions, and the need for more straightforward methods of assessing treatment response in carcinoid. Support: U10CA180821, U10CA180882, U24CA196171; NETRF Investigator Award; https://acknowledgments.alliancefound.org Clinical trial information: NCT01841736.