Background: Cabozantinib plus nivolumab (CN) is a 1L therapy for aRCC. In the CM9ER trial CN had superior efficacy to sunitinib (SUN) and showed HRQoL benefit. We investigated the relationship between clinical outcomes, treatment and early deterioration in HRQoL dimensions in the CM9ER population. Methods: Using the CM9ER intention-to-treat (ITT) population (median follow-up 32.9 months) we: (a) explored time-to-event outcomes for CN vs SUN (b) identified determinants of HRQoL benefit by performing ordinal regression using the 19-item Functional Assessment of Cancer Therapy – Kidney Symptom Index (FKSI-19) item scores at week 13 (c) investigated relationships between early (week 13) deterioration in FKSI-19 items and clinical outcomes using a cox proportional modeling framework. First, univariate Cox proportional hazard modeling assessed the predictiveness of early FKSI-19 item deterioration (sig. threshold p≤ 0.20). Items with significant univariate associations with the outcome were included in multivariate regression modeling (sig. threshold p≤ 0.10). Treatment and baseline stratification factors (geographic region, baseline IMDC score, PD-L1 status) remained in all models. Results: All CM9ER ITT patients (N = 651; CN, 323; SUN, 328) were included. Compared with SUN, CN patients had a longer median duration of treatment (94.6 wks vs 36.5 wks), time to disease progression (83.1 wks vs 42.1 wks) and time to first grade 3/4 adverse event (16.3 wks vs 12.0 wks). FKSI-19 items with early deterioration favoring CN vs SUN (p≤ 0.05) were: lack of energy; pain; fatigue; bone pain; weak all over; nausea; bothered by treatment side effects; able to work. The table reports variables significantly associated with clinical outcomes (p≤ 0.05). Conclusions: Early deterioration in bone pain and sleep were associated with increased risk of mortality, and early deterioration in pain with reduced risk of toxicity-related discontinuation. We found no association between early FKSI-19 item deterioration and risk of progression or tumor shrinkage. Controlling for other variables, CN (vs SUN) treatment was positively and significantly associated with increased chance of tumor shrinkage, survival and progression-free survival, independent of early HRQoL deterioration. Clinical trial information: NCT03141177.