Methods for Identifying Treatment-Emergent Symptomatic Adverse Events from the Patient Perspective with Application to the PRO-CTCAE Gina L. Mazza, Ethan Basch, Lauren J. Rogak, and Amylou C. Dueck Associate Professor of Biostatistics Mayo Clinic, Scottsdale, AZ Joint Statistical Meetings August 1, 2019 Denver, CO

Common Terminology Criteria for Adverse Events (CTCAE v5)

Hortobagyi GN, et al. N Engl J Med. 2016; 375(18):1738-1748.

Attribution (or relatedness): 1 = Unrelated 2 = Unlikely 3 = Possible 4 = Probable 5 = Definite Sharma P, et al. J Clin Oncol. 2019; 37(19):1608-1616.

How accurate is attribution? 9 double-blind placebo- controlled randomized trials Relatedness overestimated High proportion of “possibly” related Placebo arms: significant rate of related AEs Fatigue, nausea, vomiting, diarrhea, constipation, and neuropathy overly reported as related Le-Rademacher J, et al. Ann Oncol. 2017; 28(6):1183-1190.

PRO-CTCAE™ Item Library 124 patient-reported items representing 78 symptomatic adverse events (e.g., dysphagia, nausea, sensory neuropathy) Items assess frequency, severity, interference with daily activities, presence, amount Covered adverse events are drawn from the US National Cancer Institute's “Common Terminology Criteria for Adverse Events” (CTCAE) Item generation: Basch E, et al. J Natl Cancer Inst. 2014; 106(9). Cognitive testing: Hay JL, et al. Qual Life Res. 2014; 23(1):257-69. Validity, reliability, & responsiveness: Dueck AC, et al. JAMA Oncol. 2015; 1(8):1051-9.

Adverse Event Grading: Clinician-Reported versus Patient-Reported Musculoskeletal and connective tissue disorders Adverse Event Grade 1 2 3 4 5 Arthralgia Mild pain Moderate pain; limiting instrumental ADL Severe pain; limiting self care ADL - Please think back over the past 7 days: How OFTEN did you have ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS)? Never / Rarely / Occasionally / Frequently / Almost constantly What was the SEVERITY of your ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS) at their WORST? None / Mild / Moderate / Severe / Very severe How much did ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS) INTERFERE with your usual or daily activities: Not at all / A little bit / Somewhat / Quite a bit / Very much

http://healthcaredelivery.cancer.gov/pro-ctcae/

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Summary measures – max score & max baseline-adjusted score PTID W0 W1 W2 W3 Max score post-baseline Max baseline-adjusted score 001 1 3 002 4 003 2 004

Summary measures – max score & max baseline-adjusted score PTID W0 W1 W2 W3 Max score post-baseline Max baseline-adjusted score 001 1 3 002 4 003 2 004 If the max score is worst than baseline, then use max score.

Summary measures – max score & max baseline-adjusted score PTID W0 W1 W2 W3 Max score post-baseline Max baseline-adjusted score 001 1 3 002 4 003 2 004 If the max score is the same or better than baseline, then use 0.

COMET-2: Prospective Double Blind Placebo Controlled Trial Cabozantinib: 60 mg PO qd Placebo mitoxantrone: q3w IV Placebo prednisone: PO bid Castration-resistant Prostate Cancer with bone metastasis and pain despite narcotic use Prior treatment with docetaxel and either abiraterone or enzalutamide Loss of clinical benefit Randomization (1:1) Mitoxantrone: 12 mg/m2 q3w IV Prednisone: 5 mg PO bid Placebo cabozantinib: PO qd N=119 PRO-CTCAE: 12 symptomatic AEs (21 items) by automated telephone (at-home reporting), automated daily reminders followed by telephone data collection by data coordinator after 72 hours Baseline Every 3 weeks during treatment End of treatment

COMET-2 analysis details 119 patients enrolled, 117 started treatment 114 patients completed PRO-CTCAE at baseline (112 started treatment) 112 patients completed PRO-CTCAE post-baseline (all started treatment) 107 patients completed PRO-CTCAE at baseline + at least one post- baseline (all started treatment) Used as the analysis population Zeros imputed for electronically skipped items End-of-treatment questionnaire omitted from analysis (N=68)

Basch EM, et al. Eur Urol. 2018. pii: S0302-2838(18)30932-1.

Decreased appetite (S) 41 ( 77%) 47 ( 87%) 0.21 9 ( 17%) 11 ( 20%)  BASELINE RATES Score >0 Score ≥3 PRO-CTCAE Item Cabozantinib N ( %) Mitoxantrone-pred Fisher P Constipation (S) 43 ( 81%) 42 ( 78%) 0.81 15 ( 28%) 7 ( 13%) 0.06 Decreased appetite (S) 41 ( 77%) 47 ( 87%) 0.21 9 ( 17%) 11 ( 20%) 0.80 Decreased appetite (I) 30 ( 57%) 35 ( 65%) 0.43 8 ( 15%) 1.00 Diarrhea (F) 24 ( 45%) 22 ( 41%) 0.70 3 ( 6%) 2 ( 4%) 0.68 Fatigue (S) 52 ( 98%) 54 ( 100%) 0.50 29 ( 55%) 29 ( 54%) Fatigue (I) 51 ( 96%) 52 ( 96%) 28 ( 53%) 30 ( 56%) 0.85 Insomnia (S) 39 ( 74%) 43 ( 80%) 5 ( 9%) 0.27 Insomnia (I) 32 ( 60%) 37 ( 69%) 0.42 12 ( 23%) 0.47 Mouth or throat sores (S) 0.20 -- Nausea (F) 35 ( 66%) 39 ( 72%) 0.53 0.79 Nausea (S) 33 ( 62%) 0.31 4 ( 8%) 6 ( 11%) 0.74 Numbness/tingling in hands/feet (S) 33 ( 61%) 0.22 4 ( 7%) Numbness/tingling in hands/feet (I) 19 ( 35%) 0.33 0.72 Pain (F) 53 ( 100%) 45 ( 85%) 49 ( 91%) 0.39 Pain (S) 36 ( 68%) 36 ( 67%) Pain (I) 31 ( 57%) Rash (P) Shortness of breath (S) 25 ( 47%) 0.08 0.32 Shortness of breath (I) 19 ( 36%) 0.03 Vomiting (F) 16 ( 30%) Vomiting (S) 14 ( 26%) 0.40

Without and with baseline adjustment # of AEs with significant between-arm differences (0 vs ≥1): By investigator report (CTCAE): 0 By patient report (PRO-CTCAE without adjustment for baseline): 4 By patient report (PRO-CTCAE with adjustment for baseline): 7 Dueck AC, et al. To appear in JAMA Onc.

Large difference (impacts less severe scores more) High baseline: Low baseline: Small difference

Max baseline-adjusted vs. max change-from-baseline score   With adjustment ≥1 With adjustment ≥2 With adjustment ≥3 PRO-CTCAE Item Cabo N Mito N Cabo N ( %) Mito N ( %) Fisher P Constipation (S) 53 54 25 ( 47%) 16 ( 30%) 0.08 22 ( 42%) 12 ( 22%) 0.04 14 ( 26%) 7 ( 13%) 0.09 Decreased appetite (S) 52 34 ( 65%) 18 ( 33%) 0.002 32 ( 62%) 17 ( 31%) 0.003 20 ( 38%) 8 ( 15%) 0.008 Diarrhea (F) 42 ( 81%) 26 ( 48%) <0.001 35 ( 67%) 23 ( 44%) 6 ( 11%) Fatigue (S) 24 ( 45%) 0.17 19 ( 36%) 0.30 Insomnia (S) 22 ( 41%) 0.84 13 ( 25%) 20 ( 37%) 0.21 1.00 Mouth or throat sores (S) 33 ( 63%) 19 ( 35%) 0.006 17 ( 33%) 10 ( 19%) 0.12 6 ( 12%) 1 ( 2%) 0.06 Nausea (F) 31 ( 60%) Numbess/tingling in hands/feet (S) 28 ( 54%) 0.049 11 ( 20%) 0.02 12 ( 23%) 4 ( 7%) 0.03 Pain (F) Rash (P) 0.65 -- Shortness of breath (S) 50 29 ( 58%) 21 ( 39%) 20 ( 40%) 0.31 7 ( 14%) Vomiting (F) 9 ( 17%) 0.52 Change-from-baseline ≥1 Change-from-baseline ≥2 Change-from-baseline ≥3 0.29 3 ( 6%) 2 ( 4%) 0.68 19 ( 37%) 0.01 27 ( 52%) 0.004 4 ( 8%) 0.44 0 ( 0%) 0.49 0.07 18 ( 35%) 0.005 11 ( 22%) 0.19 15 ( 29%) 5 ( 9%) 0.20 IDENTICAL!

Max baseline-adjusted vs. max change-from-baseline score   With adjustment ≥1 With adjustment ≥2 With adjustment ≥3 PRO-CTCAE Item Cabo N Mito N Cabo N ( %) Mito N ( %) Fisher P Constipation (S) 53 54 25 ( 47%) 16 ( 30%) 0.08 22 ( 42%) 12 ( 22%) 0.04 14 ( 26%) 7 ( 13%) 0.09 Decreased appetite (S) 52 34 ( 65%) 18 ( 33%) 0.002 32 ( 62%) 17 ( 31%) 0.003 20 ( 38%) 8 ( 15%) 0.008 Diarrhea (F) 42 ( 81%) 26 ( 48%) <0.001 35 ( 67%) 23 ( 44%) 6 ( 11%) Fatigue (S) 24 ( 45%) 0.17 19 ( 36%) 0.30 Insomnia (S) 22 ( 41%) 0.84 13 ( 25%) 20 ( 37%) 0.21 1.00 Mouth or throat sores (S) 33 ( 63%) 19 ( 35%) 0.006 17 ( 33%) 10 ( 19%) 0.12 6 ( 12%) 1 ( 2%) 0.06 Nausea (F) 31 ( 60%) Numbess/tingling in hands/feet (S) 28 ( 54%) 0.049 11 ( 20%) 0.02 12 ( 23%) 4 ( 7%) 0.03 Pain (F) Rash (P) 0.65 -- Shortness of breath (S) 50 29 ( 58%) 21 ( 39%) 20 ( 40%) 0.31 7 ( 14%) Vomiting (F) 9 ( 17%) 0.52 Change-from-baseline ≥1 Change-from-baseline ≥2 Change-from-baseline ≥3 0.29 3 ( 6%) 2 ( 4%) 0.68 19 ( 37%) 0.01 27 ( 52%) 0.004 4 ( 8%) 0.44 0 ( 0%) 0.49 0.07 18 ( 35%) 0.005 11 ( 22%) 0.19 15 ( 29%) 5 ( 9%) 0.20 Difficult or impossible to achieve in patients with pre-existing symptoms at baseline

Does max score or max baseline-adjusted score (0 vs ≥1) better differentiate between arms? Difference in area under the ROC curves significant for: Decreased appetite severity: ΔAUC=0.12, 95% CI 0.03-0.12, p=0.008 Shortness of breath severity: ΔAUC=0.09, 95% CI 0.01-0.18, p=0.04 Shortness of breath interference: ΔAUC=0.09, 95% CI 0.01-0.17, p=0.03 Median ΔAUC across the 21 items = 0.04 (range: -0.03 to 0.12) Significant overall effect: ΔAUC = 0.03, 95% CI 0.01-0.05, p=0.004

Is the baseline adjustment method ready for primetime? Replicated in three other trials to date See Gounder MM et al. (N Engl J Med. 2018; 379[25]:2417-2428) for published application However, open questions remain Impact of reduced variability Ceiling effect – what if patients all start at scores of 3 or 4? Intended to identify harms (so may not work well for improving symptoms) Interpretability, best language for labeling tables/graphics Baseline subtraction changed to baseline adjusted Worsened from baseline? Highest or worse?

Concluding thoughts Baseline adjustment appears to better identify treatment harms than maximum score Recommend longitudinal depictions to supplement tabular summary baseline adjustment method Advanced analytics (e.g., model-based analysis) are more sensitive for detecting differences between arms, but are less “user friendly” The future: NCI Tolerability MoonshotSM Consortium Standardized analysis and reporting

Thanks! dueck@mayo.edu @BiostatGirl SAS & R code forthcoming (https://github.com/biostatgirl)