Abstract PS13-09: Chemotherapy-induced nausea and vomiting (CINV) risk after prior breakthrough CINV: Unmasking the false average
Authors: Navari Rudolph M , Binder Gary , Molassiotis Alexander , Roeland Eric , Ruddy Kathryn J. , LeBlanc Thomas W. , Kloth Dwight D. , Sebastiani Silvia , Dimberg Lina Y. , Schmerold Luke M. , Liu Xing , Schwartzberg Lee 
Published: February 2021

Abstract
Background: Although many studies have demonstrated consistent levels of effectiveness of CINV prophylaxis for the entire study population across multiple chemotherapy cycles, rarely have studies reported how each patient’s risk of subsequent CINV differs based on prior cycle breakthrough CINV with the same prophylaxis. We lack data on whether prophylaxis continues to fail in the same group of patients each cycle, or whether failure is random with each subsequent cycle. We sought to evaluate individual patients’ risk of repeat CINV in each subsequent chemotherapy cycle. Methods: In a prospective, 4-cycle CINV prophylaxis trial of oral or intravenous combination netupitant/palonosetron (NEPA) + dexamethasone (day 1) for patients with breast cancer receiving anthracycline + cyclophosphamide (AC), we defined CINV as vomiting or use of rescue medication during days 1-5 after chemotherapy. Patients without CINV were classified as complete response (CR); the rest as treatment failure (TF). We analyzed patients’ sequences of CR and TF, and compared CR or TF for cycles 2-4 based on cycle 1 outcomes, using chi-square statistics. To provide context, we performed a post-hoc similar analysis of results reported by Herrstedt et al [2005] from a clinical trial of ondansetron + aprepitant (APR) for patients with breast cancer receiving 4 cycles of AC. Results: The 402 female patients in the NEPA trial received a total of 1,299 cycles. In cycle 1, 99 (24.6%) patients experienced TF (TF1); over all 4 cycles, TF occurred 253 times (19.5%). Patients with CR in cycle 1 (CR1) had a ≥92% rate of CR in cycle 2; their rates of repeat CR were similar in each subsequent cycle. Patients with TF1 had nearly equal risk of CR or TF in cycle 2 (45:55); thereafter 85% of this TF1 subgroup repeated their cycle 2 outcome (CR or TF) in cycles 3 and 4. Over all cycles of NEPA, patients with CR1 subsequently had CR in &gt;90% of cycles 2-4; those with TF1 subsequently had TF in 49.8% of cycles 2-4 (p&lt;0.0001) (see Table). We separately examined Herrstedt’s evaluation of 433 patients across 1537 cycles with APR. In cycle 1, TF was seen 213 times (49.2%), with TF reported in 46.7% of cycles 1-4. We found that patients with CR1 had an 80.5% rate of CR in cycle 2 and repeat CR rates were higher in subsequent cycles. Patients with TF1 had TF in cycle 2 (TF2) at a rate of 78.4%, with 76.6% TF3 and 72.7% TF4. For APR, CR1 resulted in subsequent CR in 78.6% of cycles 2-4 while patients with TF1 again had TF in 74.8% of cycles 2-4 (p&lt;0.0001). Patients with TF1 were more likely to later drop from the study (see Table). Notably, among those with CR1 after APR, the few patients who later had TF in any cycle, had a subsequent repeat failure rate similar to those with TF1. Conclusions: When patients receiving guideline-recommended triple antiemetic prophylaxis successfully avoided CINV in their first cycle of HEC, they had 80-95% likelihood of repeating that success in later cycles. After NEPA, those whose prophylaxis failed in cycle 1 did not face a similar high risk of repeat failure in cycle 2. The pattern of repeat failure after aprepitant was different, with a high repeat failure risk starting in cycle 2. These findings strongly suggest that consistent population average CR rates reported across cycles may mask a higher repeat failure rate for individual patients that experience cycle 1 CINV, particularly for aprepitant. Further study of this phenomenon is needed for other HEC regimens, and to confirm the lack of high repeat failure seen in cycle 2 for NEPA.
Repeat CINV in Later Cycles, Based on Cycle 1 ResultsNEPAAprepitant + OndansetronInitial Cycle Result (n/total initial cycles)CR1 (303/402)TF1 (99/402)CR1 vs TF1 (P value)CR1 (220/433)TF1 (213/433)CR1 vs TF1 (P value)Subsequent CR cycles (n, % of total subseq. cycles)636 (93.0%)107 (50.2%)&lt;0.0001464 (78.6%)124 (25.2%)&lt;0.0001Subsequent TF cycles (n, % of total subseq. cycles)48 (7.0%)106 (49.8%)126 (21.4%)370 (74.8%)Total subsequent cycles (n, % of total subseq. cycles)684 (100%)213 (100%)590 (100%)494 (100%)Dropped vs ITT* (n, % ITT cycles)225 (24.8%)84 (28.3%)0.226370 (10.6%)145 (22.7%)&lt;0.0001* The NEPA trial was closed when the last patient completed the first cycle, resulting in an artificially high proportion of patients that did not complete 4 cycles.
Citation Format: Rudolph M Navari, Gary Binder, Alexander Molassiotis, Eric Roeland, Kathryn J. Ruddy, Thomas W. LeBlanc, Dwight D. Kloth, Silvia Sebastiani, Lina Y. Dimberg, Luke M. Schmerold, Xing Liu, Lee Schwartzberg. Chemotherapy-induced nausea and vomiting (CINV) risk after prior breakthrough CINV: Unmasking the false average [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-09.