Becker, Claus

11541 Background: Ripretinib (R) is a switch-control tyrosine kinase inhibitor (TKI) indicated for the treatment of patients (pts) with advanced gastrointestinal stromal tumor (GIST) after prior treatment with ≥3 TKIs. In the INTRIGUE study (NCT03673501) there was no significant difference in median PFS (primary endpoint) between R and sunitinib (S). We present exploratory analyses of tolerability data and selected pt reported outcomes (PROs). Methods: Pts were randomized 1:1 to R 150 mg QD or S 50 mg QD 4 weeks on/2 weeks off.Dose modification was allowed for toxicity management. The event of interest was severe or life-threatening (grade ≥3) treatment-related adverse event prior to progression (sTRAE). Days with at least one sTRAE were summed for all treated pts and for pts with ≥1 sTRAE event. PROs were assessed using questions from EORTC QLQ-C30 and Dermatology Life Quality Index (DLQI) at cycle 1 (C1) day 1 (D1), D15, and D29; D1 and D29 of all other cycles; as well as at end of treatment. Differences in PRO scores between baseline and later assessments were calculated across visits. Long-term data will be presented. Results: Pts receiving R (n = 223) versus (vs) S (n = 221) experienced fewer sTRAEs (24% vs 51%, respectively). For all treated pts, the mean time with sTRAEs was 11 days for R and 42 days for S (ratio 0.27, P<0.0001). For pts with ≥1 sTRAE, the mean number of days with a sTRAE was 48 days for R vs 81 days for S (ratio 0.59, p = 0.037). Completion of PRO assessments across the two treatment arms was similar (baseline: R [n = 199], S [n = 199]; C1 D29: R [n = 167], S [n = 177]). Significant differences in self-reported functioning and symptoms were observed by C1 D29. For PROs relating to commonly reported sTRAEs, except constipation, pts in the R arm reported better outcomes than pts in the S arm. Pts in the R arm reported significantly (p<0.05) less decline compared to baseline in pt-reported role function as well as less increase, or improvement, in symptoms of fatigue, appetite loss, diarrhea, nausea/vomiting, and pain vs pts in the S arm. Moderate or severe effect of skin toxicity on pt life, as measured by DLQI in the R arm (n = 165) and in the S arm (n = 175), was observed in 6.6% of pts in the R arm vs 14.8% of pts in the S arm (p = 0.015). Conclusions: In the INTRIGUE study the total number of days with sTRAEs was fewer for pts receiving R vs S. Pts in the R arm also reported significantly less decline in pt-reported role function and less increase in symptoms related to commonly reported sTRAEs, except constipation, vs pts in the S arm. Medical writing provided by Costello Medical. Clinical trial information: NCT03673501.

Background: The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events is an item library designed for eliciting patient-reported adverse events in oncology. For each adverse event, up to three individual items are scored for frequency, severity, and interference with daily activities. To align the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events with other standardized tools for adverse event assessment including the Common Terminology Criteria for Adverse Events, an algorithm for mapping individual items for any given adverse event to a single composite numerical grade was developed and tested. Methods: A five-step process was used: (1) All 179 possible Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events score combinations were presented to 20 clinical investigators to subjectively map combinations to single numerical grades ranging from 0 to 3. (2) Combinations with <75% agreement were presented to investigator committees at a National Clinical Trials Network cooperative group meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability, and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating adverse events between study arms was measured in two Phase III clinical trials (NCT02066181 and NCT01522443). Results: In Step 1, 12/179 score combinations had <75% initial agreement. In Step 2, majority consensus was reached for all combinations. In Step 3, five grades were adjusted to assure directional consistency. In Steps 4 and 5, composite grades performed well and comparably to individual item scores on validity, reliability, sensitivity, and between-arm delineation. Conclusion: A composite grading algorithm has been developed and yields single numerical grades for adverse events assessed via the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, and can be useful in analyses and reporting.

11535 Background: Ripretinib is a novel switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits KIT and PDGFRA kinase signaling through a dual mechanism of action. In INVICTUS (NCT03353753), a randomized, double-blind, placebo-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs placebo and had a favorable overall safety profile in patients previously treated with ≥3 prior TKIs. Methods: As part of the INVICTUS trial, patient reported outcome (PRO) measures were collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). In prespecified and additional analyses, ANCOVA models were built to compare changes from baseline to cycle 2 day 1 (C2D1) for PRO measures within the ripretinib and placebo arms and determine the difference between treatment arms. PRO measures included the EQ5D visual analogue scale (VAS) and the C30 physical functioning (PF) and role functioning (RF) scales (all scores range from 0–100; higher scores are better). The C30 overall health and overall QoL questions were also assessed (scores range from 1–7; higher scores are better). Fixed effects included treatment arm, number of previous anticancer treatments (3 vs ≥4), and ECOG score at baseline (0 vs 1/2). Results: Overall, 129 patients were randomized and 128 received treatment (85 to ripretinib 150 mg QD; 43 to placebo). All PRO p-values are nominal, and no statistical significance is being claimed. VAS scores improved an average 3.7 points from baseline to C2D1 with ripretinib vs an average decline of 8.9 with placebo (P = 0.004; improvement or no change, 67% vs 41% of patients, respectively). Similarly, the average PF score improved 1.6 points with ripretinib and decreased 8.9 with placebo (P = 0.004; improvement or no change, 68% vs 44%). RF scores also improved an average of 3.5 points with ripretinib vs a decrease of 17.1 with placebo (P = 0.001; improvement or no change, 77% vs 50%). For the overall health and overall QoL questions, scores increased with ripretinib an average of 0.20 and 0.28, respectively, and decreased 0.78 and 0.76 with placebo (both P = 0.001; improvement or no change, 74% vs 47% and 79% vs 59%, respectively). Conclusions: Based on the 5 PRO measures assessed, when compared with placebo and best supportive care, ripretinib provided patient-benefit in advanced GIST with PRO measures of role and physical function, VAS, overall health, and overall QoL remaining stable. Clinical trial information: NCT03353753 .

7018 Background: Standard reporting of symptomatic adverse events (AEs) in oncology relies on clinicians to rate patient (pt) experience using CTCAE; each symptom is represented by a single graded item. To capture direct pt experience, NCI developed PRO-CTCAE to supplement CTCAE. In PRO-CTCAE, the pt answers up to 3 questions per AE about a symptom’s frequency, severity and interference with daily activities. To align PRO-CTCAE with CTCAE, we developed an algorithm for mapping sets of questions for an AE to a single composite numerical grade. Methods: We used a 5-step process. (1) All 187 possible PRO-CTCAE score permutations were presented to clinical investigators to subjectively map permutations to single numerical grades (range 0-3). (2) Permutations with < 75% agreement were presented to investigator committees at a National Clinical Trials Network meeting to gain majority consensus via anonymous voting. (3) The resulting algorithm was refined via graphical and tabular approaches to assure directional consistency. (4) Validity, reliability and sensitivity were assessed in a national study dataset. (5) Accuracy for delineating AEs between study arms was measured in 2 phase III clinical trials (Alliance for Clinical Trials in Oncology A091105 and Exelixis COMET-2). Results: (1) 12/187 score permutations had < 75% initial agreement. (2) Majority consensus was reached for all permutations. (3) 5 mappings were adjusted to assure directional consistency. (4) Composite grades for 46/59 (78%) AEs were higher in pts with ECOG performance status 2-4 vs 0-1 (median effect size 0.23 [range -0.49-0.73]; 32/59 effect size ≥0.2; 25/59 p< 0.05), similar to when conducting analysis on individual unmapped items. The test-retest reliability for 24 selected composite grades ranged from 0.57-0.96 (median intraclass correlation coefficient [ICC] 0.77) with 18/24 (75%) grades having ICC ≥0.7. Median (range) standardized response means in pts reporting worsening, no change, and improvement were 0.20 (0.03-0.34), -0.06 (-0.20-0.03) and -0.12 (-0.32-0.06). (5) Pattern, directionality and statistical significance of between-arm differences in both trials were preserved with composite grades as compared to individual unmapped items. Conclusions: A composite grading algorithm for PRO-CTCAE was rigorously developed and validated. PRO-CTCAE composite grades may be useful in analyses to provide a single metric for each pt-reported AE for trial and real-world reporting. Support: UG1CA189823; U01CA233046; HHSN261200800043C; Bayer (A091105); https://acknowledgments.alliancefound.org .