Abstract 1279: Early radiologic signal of nivolumab responsiveness after short-course oxaliplatin-based chemotherapy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC)
Authors: Meltzer Sebastian , Negård Anne , Hamre Hanne Mari , Kersten Christian , Hofsli Eva , Guren Marianne Grønlie , Sørbye Halfdan , Flatmark Kjersti , Ree Anne Hansen 
Published: June 2022

Abstract
Purpose: Immune checkpoint inhibition (ICI) may result in tumor response patterns that differ from efficacy measures of directly cytotoxic chemotherapies. Hence, the selection of patients for experimental ICI schedules, for instance in MSS-mCRC, calls for applicable and reliable signals of activity or early failure that enable treatment adaptation and maintain patient safety.
Experimental procedures: In the ongoing METIMMOX phase 2 study, we hypothesize that patients with previously untreated unresectable MSS-mCRC can obtain durable disease control to ICI when given short-course oxaliplatin-based chemotherapy (2 cycles of FLOX Q2W) before 2 cycles of nivolumab (240 mg Q2W) in a repeat sequential schedule to a total of 8 cycles. Patients have been randomly assigned to either this experimental study arm or a control arm of 8 FLOX cycles Q2W (standard-of-care; SoC), in both cases before treatment break until disease progression and reintroduction of a new treatment sequence. Radiologic response assessment is performed every 8 weeks with progression-free survival (PFS) as the primary end point.
Results: At analysis 10 November 2021, median PFS was 9.3 months (95% CI, 8.3-10.3) for SoC (n = 34) and 11.4 months (95% CI, 7.4-15.5) for the experimental therapy (n = 39) (p = 0.335; log-rank test). In the latter group, 37 patients had available response evaluation at minimum 8 weeks of study treatment, as 2 patients (compared to 4 in the control group) had discontinued treatment due to intolerable toxicity before the first post-baseline assessment. The control arm patients had deeper responses with mean 23% (SD, 19%) target lesion reduction compared to mean 8%(SD, 33%) reduction for the experimental schedule (p = 0.028; Student’s t-test). We categorized the experimental arm patients into those with ≥10% (n = 20) or &lt;10% (n = 17) target lesion reduction at 8 weeks. Median PFS for the ≥10% group was 15.2 months (95% CI, 11.4-19.0) and for the &lt;10% group 4.5 months (95% CI, 3.2-5.7), which was clearly superior and inferior to the control arm PFS (p = 0.007 for the ≥10% group and p = 0.019 for the &lt;10% group; log-rank test). Categorisation of experimental arm patients set at higher than 10% target lesion change at the first radiologic response assessment did not identify patients with longer PFS.
Conclusions: While the SoC first-line chemotherapy resulted in deeper early responses, target lesion reduction of ≥10% at 8 weeks identified MSS-mCRC patients who held ICI responsiveness evoked by short-course oxaliplatin-based chemotherapy, with significantly improved PFS compared to the SoC. An early radiologic signal of clinical activity may guide the selection of patients to the safe continuation of investigational ICI schedules; however, we do not know if adopting it may compromise prognosis for patients with early ICI failure who can proceed with SoC.
Citation Format: Sebastian Meltzer, Anne Negård, Hanne Mari Hamre, Christian Kersten, Eva Hofsli, Marianne Grønlie Guren, Halfdan Sørbye, Kjersti Flatmark, Anne Hansen Ree. Early radiologic signal of nivolumab responsiveness after short-course oxaliplatin-based chemotherapy in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1279.