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PURPOSE We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status. METHODS Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life. RESULTS At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed. CONCLUSION With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer. [Media: see text]

Score reproducibility is an important measurement property of fit-for-purpose patient-reported outcome (PRO) measures. It is commonly assessed via test-retest reliability, and best evaluated with a stable participant sample, which can be challenging to identify in diseases with highly variable symptoms. To provide empirical evidence comparing the retrospective (patient global impression of change [PGIC]) and current state (patient global impression of severity [PGIS]) approaches to identifying a stable subgroup for test-retest analyses, 3 PRO Consortium working groups collected data using both items as anchor measures.The PGIS was completed on Day 1 and Day 8 + 3 for the depression and non-small cell lung cancer (NSCLC) studies, and daily for the asthma study and compared between Day 3 and 10. The PGIC was completed on the final day in each study. Scores were compared using an intraclass correlation coefficient (ICC) for participants who reported "no change" between timepoints for each anchor.ICCs using the PGIS "no change" group were higher for depression (0.84 vs. 0.74), nighttime asthma (0.95 vs. 0.53) and daytime asthma (0.86 vs. 0.68) compared to the PGIC "no change" group. ICCs were similar for NSCLC (PGIS: 0.87; PGIC: 0.85).When considering anchor measures to identify a stable subgroup for test-retest reliability analyses, current state anchors perform better than retrospective anchors. Researchers should carefully consider the type of anchor selected, the time period covered, and should ensure anchor content is consistent with the target measure concept, as well as inclusion of both current and retrospective anchor measures.

LBA9025 Background: In CheckMate 227 part 1 (NCT02477826), 1L NIVO + IPI demonstrated long-term, durable survival benefit vs platinum-doublet chemo in patients (pts) with metastatic NSCLC regardless of tumor programmed death ligand 1 (PD-L1) expression level. Here we present the longest reported follow-up (5 y) of a phase 3 trial of 1L combination immunotherapy in metastatic NSCLC. Methods: Adults with previously untreated stage IV or recurrent NSCLC, no known EGFR/ ALK alterations , and an ECOG performance status ≤ 1 were enrolled and stratified by histology. Pts with tumor PD-L1 ≥ 1% were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W), or chemo. Pts with tumor PD-L1 < 1% were randomized 1:1:1 to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Pts were treated until progression, toxicity, or ≤ 2 y for immunotherapy. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and a novel efficacy endpoint, treatment-free interval. Treatment-free interval was measured in pts who discontinued study therapy (for any reason including treatment completion) and was defined as the time from last study dose to start of subsequent systemic therapy or death, whichever occurred first. Results: Minimum follow-up was 61.3 mo (database lock, Feb 15, 2022). In pts with tumor PD-L1 ≥ 1% (N = 1189), continued long-term OS benefit was seen with NIVO + IPI vs chemo (HR, 0.77 [95% CI, 0.66–0.91]); 5-y OS rates were 24% (NIVO + IPI), 17% (NIVO), and 14% (chemo). OS benefit also continued in pts with tumor PD-L1 < 1% (N = 550) for NIVO + IPI vs chemo (HR, 0.65 [95% CI, 0.52–0.81]); 5-y OS rates were 19% (NIVO + IPI), 10% (NIVO + chemo), and 7% (chemo). Clinical benefit with NIVO + IPI vs chemo was observed across additional efficacy endpoints in the overall population and in pts alive at 5 y (table). PFS, ORR, and DOR with NIVO and NIVO + chemo will be presented. Among pts alive at 5 y in the NIVO + IPI group, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) remained treatment-free ≥ 3 y after discontinuing study therapy; median (range) duration of NIVO ± IPI therapy was 17.7 (0-25.5) mo (PD-L1 ≥ 1%) and 9.5 (0-25.1) mo (PD-L1 < 1%). No new safety signals were observed. Conclusions: With a 5-y minimum follow-up, NIVO + IPI continues to provide long-term, durable clinical benefit vs chemo in previously untreated pts with metastatic NSCLC, regardless of PD-L1 expression. NIVO + IPI led to increased 5-y survivorship; the majority of these pts were treatment-free for ≥ 3 y post-treatment discontinuation. Clinical trial information: NCT02477826. [Table: see text]

4502 Background: In CM 214, when compared to sunitinib (S), nivolumab plus ipilimumab (N+I) was associated with both clinical benefit and improved HRQoL as first-line treatment for intermediate/poor (I/P)-risk patients (pts). This analysis investigates the direct association between HRQoL and clinical outcomes in aRCC pts. Methods: I/P-risk population included 425 and 422 pts in the N+I and S arms, respectively. HRQoL was assessed using the FKSI-19 (Total Score and Disease Related Symptoms [DRS]). Three separate analyses (A, B, and C) were conducted. A: Changes in individual item scores from baseline to last assessment prior to progression were descriptively assessed. B: For each FKSI-19 score, multivariable Cox regression, adjusted for treatment and stratification factors, was used to evaluate the prognostic significance of baseline and time-dependent HRQoL scores in separate models. Hazard ratios (HR) were calculated based on the risk of death per improvement in HRQoL scores, defined using the clinically meaningful change threshold (5 points for FKSI-19 Total and 3 points for DRS). Pts with overall survival (OS) events were censored if their survival event was not within 12 weeks of the last available HRQoL assessment. C: The association between HRQoL change status (ie, improvement or maintenance vs. worsening from baseline in the FKSI-19 Total Score), irrespective of treatment arm, and OS was further assessed using a landmark analysis at the month 6 (mo-6) landmark. Additional landmark time points were explored in sensitivity analysis. Results: Items related to fatigue and perceived bother of the side-effects of treatment had the largest percentage of pts worsening prior to progression. In both baseline and time-dependent HRQoL analyses, OS was independently associated with both HRQoL measures. Higher (better) baseline scores were associated with significantly reduced risk of death (HR [95% CI] for FKSI-19 Total Score and DRS was 0.83 [0.80-0.87] and 0.80 [0.76-0.84], respectively). Every 5-point increase (improvement) in FKSI-19 Total Score and 3-point increase in DRS was associated with a 31% decreased risk of death ( P < 0.01). At mo-6, 301 pts showed improvement or maintenance in HRQoL. Pts with improved/stable HRQoL had a 52% reduction in risk of death compared to pts who had worsened (HR 0.48 [95% CI: 0.39-0.59]). Conclusions: Results demonstrate there is an association between HRQoL and clinical outcomes in CM 214. Baseline HRQoL scores are a potential predictor for survival in aRCC, and HRQoL changes are informative for pts’ expected survival. HRQoL change status at mo-6 was significantly and positively associated with subsequent survival. Thus, patient-reported outcomes may be useful for both describing pt experience in clinical trials and providing valuable clinical insights during routine practice. Clinical trial information: NCT02231749.

307 Background: Nivolumab + ipilimumab (N+I) demonstrated durable, long-term survival in the phase 3 CheckMate 214 trial as first-line treatment for intermediate/poor (I/P)-risk patients (pts) with aRCC. After a minimum follow-up of 5 years, N+I maintained superior overall survival and response benefits vs sunitinib (S) in both I/P-risk pts and across all randomized pts. We report the HRQoL results from the 5-year follow-up. Methods: Pts were randomized 1:1 to receive N 3 mg/kg + I 1 mg/kg every 3 weeks (wks) for 4 cycles followed by N 3 mg/kg every 2 wks or S 50 mg/d orally for 4 wks (6-wk cycle). HRQoL was assessed using the FKSI-19, FACT-G, and EQ-5D-3L instruments at baseline (BL) and on day 1 of wks 1 and 4 of the first 2 cycles, on day 1 of wks 1 and 5 of the next 2 cycles, and on day 1 of wk 1 of subsequent cycles. The analyses included mixed-model repeated measures (MMRM) for change from BL across 59 months (while on-treatment) and time to confirmed deterioration (TCD). Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat”, “quite a bit”, and “very much”). Results: 1096 pts were randomized to N+I (I/P-risk: 425; favorable [F]-risk: 125) and S (I/P-risk: 422; F-risk: 124). In the overall and I/P-risk populations, N+I pts reported improved mean FKSI-19 total scores over time compared with a decline observed with S. Overall changes from BL through 59 months favored N+I over S with significant differences between arms observed for all outcomes (Table). Median TCD was significantly longer with N+I vs S for all FKSI-19 scores, as well as FACT-G total and physical domains for both populations ( P < 0.05). Pts in the N+I arm were 76% (odds ratio [95% CI]: 0.24 [0.16–0.35]) and 73% (0.27 [0.18–0.40]) less likely to be notably bothered by side effects than pts in the S arm in the total and I/P-risk populations, respectively. Conclusions: Pts reported HRQoL benefits with N+I vs S. Treatment with N+I showed a decreased risk of being bothered by treatment side effects and of experiencing clinically meaningful deterioration in HRQoL in contrast with S. These results suggest that the superior efficacy of N+I over S comes with the additional benefit of improved long-term HRQoL. Clinical trial information: NCT02231749. [Table: see text]

323 Background: In CheckMate 9ER, patients (pts) with aRCC were randomized 1:1 to nivolumab 240 mg IV Q2W + cabozantinib 40 mg PO QD (N+C; n = 323) or sunitinib (S) 50 mg PO (4 weeks of 6-week cycles; n = 328). As reported previously, at a median follow-up of 18.1 months, N+C led to superior progression-free and overall survival and more favorable HRQoL than S. We report results of HRQoL analyses for 32.9-months follow-up. Methods: Disease-related symptoms (DRS) were evaluated using the FKSI-19 instrument and HRQoL with the EQ-5D-3L visual analogue scale (VAS). Change from baseline (BL) was assessed using mixed-model repeated measures (MMRM), adjusting for baseline scores and stratification factors, and included all common timepoints (at BL and every 6 wks) through week 151. Time to deterioration analysis was conducted for first (TFD), confirmed (TCD) and definitive (TDD) deterioration events using Kaplan-Meier estimates and Cox proportional hazards models. Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat”, “quite a bit”, and “very much”). HRQoL endpoints were exploratory and P-values are nominal and descriptive. Results: Group mean scores over time show that HRQoL was maintained or improved from BL with N+C while reductions were observed with S. Overall changes from BL though week 151 favored N+C with nominal significant differences between treatments observed for all scores except functional well-being (FWB; Table). Similarly, decreased risk of deterioration was observed with N+C vs S for all scores except FWB, irrespective of the deterioration definition used (TFD, TCD, TDD). Pts in N+C arm were 48% (odds ratio: 0.52 [95% CI, 0.35-0.77]) less likely to be notably bothered by side effects than pts in S arm. Conclusions: Pts continued to report improved HRQoL with N+C compared to S. Treatment with N+C reduced the risk of meaningful deterioration in HRQoL scores, regardless of the definition of deterioration and showed a decreased risk of being bothered by treatment side effects in contrast to S. These results suggest that the superior efficacy of N+C over S with the additional benefit of improved HRQoL is maintained with longer follow-up. Clinical trial information: NCT03141177. [Table: see text]

262 Background: This analysis evaluated HRQoL as exploratory endpoints in CheckMate 648, a randomized, open-label, global Phase 3 study, evaluating treatment with N+I, N+CT and CT alone in inoperable advanced, recurrent, or metastatic ESCC. Methods: The effects of N+I vs N+CT vs CT on HRQoL were assessed using the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) (including the GP5 item to assess impact of side effects) and EQ-5D-3L. A mixed model for repeated measures was used to evaluate longitudinal changes from baseline (BL) and differences between treatment groups. Comparison of the risk of being bothered by the side effects of treatment was estimated for the GP5 using generalized estimating equation (GEE). Time to confirmed deterioration (TTCD) was assessed using Kaplan-Meier plots along with Cox proportional hazard models. Analyses were conducted on both the all-randomized population and the subset of patients with PD-L1 expression ≥1%. Results: 970 pts were randomized 1:1:1 to N+I (n=325), N+CT (n=321), or CT (n=324). 90% of pts completed both a BL and at least one on-treatment assessment and were included in the PRO analysis population. FACT-E (all randomized pts). Study showed similar BL scores across all 3 treatment groups. Changes from BL showed a trend towards better HRQoL for pts treated with N+I and N+CT compared to CT alone, however these results were not statistically significant. Patients treated with N+I had significantly decreased risk of experiencing bother associated with the side effects of treatment than patients treated with either N+CT or CT. TTCD analysis demonstrated delayed deterioration for pts treated with N+CT vs CT. Findings for PD-L1 ≥1% subpopulation were similar to all randomized pts. Conclusions: In pts with inoperable advanced, recurrent, or metastatic ESCC, HRQoL is maintained throughout treatment with N+I and N+CT. Trends towards better HRQoL and decreased risk of deterioration were observed with N+I and N+CT compared to CT alone. Clinical trial information: NCT03143153. [Table: see text]