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Conditional survival and long‐term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma

Background Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow‐up of 5 years. Methods Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6‐week cycles). Efficacy was assessed in intent‐to‐treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate‐risk/poor‐risk, and favorable‐risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. Results The median follow‐up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression‐free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent‐to‐treat patients (N = 550 vs 546). Point estimates for 2‐year conditional overall survival beyond the 3‐year landmark were higher with NIVO+IPI versus SUN (intent‐to‐treat patients, 81% vs 72%; intermediate‐risk/poor‐risk patients, 79% vs 72%; favorable‐risk patients, 85% vs 72%). Conditional progression‐free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune‐mediated adverse event experience, body mass index, and age. Conclusions Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow‐up for a first‐line checkpoint inhibitor‐based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.


INTRODUCTION
Survival outcomes for patients with advanced or metastatic renal cell carcinoma (aRCC) have improved significantly in recent years, with immunotherapy-based combination regimens further prolonging survival over single-agent, targeted therapies. 1-4 However, because limited follow-up is available for most phase 3 trials of newer first-line aRCC treatments, additional analyses that comprehensively assess long-term clinical benefits in this setting remain of critical importance. Nivolumab (NIVO) plus ipilimumab (IPI) (NIVO+IPI) is approved for patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate-risk/poorrisk disease based on the primary phase 3 CheckMate 214 trial results. 2 Traditional prognostic risk models like the IMDC classification are routinely used to inform upfront prognosis and treatment decisions to help predict patient outcomes in aRCC. 5 However, such prognostic estimates based on baseline risk factors were established in the era of single-agent tyrosine kinase inhibitors and cytokines, and do not adequately address outcomes for patients with aRCC who achieve a durable response and survival benefits with immunotherapy. 6,7 As the aRCC treatment landscape evolves and long-term outcomes continue to improve, an updated prognostic framework is needed. Although clinical response and survival projections at diagnosis using standard prognostic models can help individualize therapy regimens, prognoses may change over time, particularly among patients with a poor outlook according to baseline assessments. 8,9 Conditional survival has since emerged as a clinically relevant measure of prognosis that estimates survival probability for patients as the length of survival increases in response to treatment. 9,10 Conditional survival assessments may account for the time alive since randomization or treatment initiation and can help provide critical long-term prognostic information as prespecified survival milestones are reached. Previous conditional survival analyses in patients with aRCC who received VEGF-targeted therapy demonstrated improved outcomes over time with length of survivorship. 8,11 However, limited conditional survival data exist in patients with aRCC who received NIVO monotherapy or first-line immunotherapy combinations. 11 With a minimum follow-up of 5 years, we report the longest phase 3 follow-up for a checkpoint inhibitor combination therapy in aRCC together with the first long-term conditional survival analyses of patients in CheckMate 214.

Patients and Treatment
CheckMate 214 is a global, open-label, randomized, phase 3 trial. Study design and statistical analyses details have been described previously, and additional details are included in the online Supporting Information. 12 CheckMate 214 was approved by institutional review boards or ethics committees at each site and was conducted following Good Clinical Practice Guidelines according to the International Conference for Harmonisation. All patients provided written informed consent in accordance with Declaration of Helsinki principles. This study is registered with ClinicalTrials.gov (ClinicalTrials.gov identifier NCT02231749).

Assessments
The co-primary trial end points were overall survival (OS), progression-free survival (PFS) according to an independent radiology review committee, and the objective response rate (ORR) according to the independent radiology review committee (with duration of response [DOR]) in intermediate-risk/poor-risk patients (primary), intentto-treat (ITT) patients (secondary), and favorable-risk patients (exploratory). Conditional OS, conditional PFS, and conditional response estimates, together with an evaluation of patients who had durable clinical benefits and an assessment of treatment-free interval in responders, were analyzed post hoc. Additional assessment details are included in the Supporting Methods.

Statistical Analysis
Conditional survival was analyzed using a landmark approach based on Kaplan-Meier estimates and was calculated for patients who were either alive, progression free, or in response at 1-year increments from time zero. Conditional OS, conditional PFS (time zero was the date of randomization for both), and conditional response (time zero was the date of first confirmed response) were assessed until death or censoring at the date of last followup. Data from patients who died before the landmark timepoint or whose follow-up interval was less than the landmark time were excluded. Statistical analysis details for OS, PFS, ORR, and health-related quality of life (HRQoL) were previously reported, and additional information is included in the Supporting Information.
With NIVO+IPI, point estimates for 2-year conditional PFS were higher or remained stable from time zero

Conditional OS in Subgroups
Point estimates for conditional OS with NIVO+IPI varied to some extent across age groups in ITT patients at time zero yet were stable or consistently higher with NIVO+IPI at each subsequent year of conditional survival regardless of IMDC risk group, except for favorable-risk patients younger than 65 years ( Fig. 6A; see Supporting Table 5). Point estimates for conditional OS with NIVO+IPI in ITT patients were similar regardless of body mass index (BMI), grade ≥3 immunemediated adverse event (AE) experience, or tumor PD-L1 expression and were either higher or stable at each subsequent year of survival in each subgroup (Fig. 6B-D; see Supporting Table 5). Point estimates for conditional OS with NIVO+IPI in intermediate-risk/poor-risk patients were also higher or stable from time zero at each subsequent year of survival regardless of BMI, grade ≥3 immune-mediated AEs, or tumor PD-L1 expression and generally remained high (approximately ≥80%) at 3 years in favorable-risk patients (see Supporting Table 5). Point estimates for conditional OS with NIVO+IPI remained high (>96%) in ITT patients who had a CR from all landmark timepoints assessed ( Fig. 6E; see Supporting Table 5); similar trends were observed in patients who had a CR regardless of IMDC risk group (see Supporting  Table 5). Point estimates for conditional OS with SUN were higher or remained stable at each subsequent year of survival from time zero across all subgroups among ITT and intermediate-risk/poor-risk patients, except for patients aged 75 years and older (see Supporting Table 6). Interestingly, point estimates for conditional OS with SUN decreased with subsequent years of survival across almost all subgroups in favorable-risk patients, except for those with tumor PD-L1 expression ≥1% and those who achieved a CR.

Durable Clinical Benefit
More patients achieved a CR and did not progress with NIVO+IPI (n = 53 of 550; 9.6%) versus SUN (n = 13 of 546; 2.4%). Among complete responders without progression, baseline characteristics were largely similar to those of ITT patients in the NIVO+IPI arm. However, a higher proportion of complete responders without progression in the SUN arm had just 1 site with target/nontarget lesions at baseline ( Few patients discontinued treatment because of maximum clinical benefit in either treatment arm (NIVO+IPI, n = 18; SUN, n = 7) (see Supporting Fig. 1). Among this small subgroup, all 18 patients in the NIVO+IPI arm, versus 4 patients in the SUN arm, achieved an objective response: 5 versus 2 patients had CRs, respectively; 13 versus 2 patients had a partial response, respectively; and zero versus 3 patients had stable disease, respectively. The median duration of study therapy among these patients was 32.8 months (Q1-Q3, 24.2-45.1 months) in the NIVO+IPI arm and 7.8 months (Q1-Q3, 6.5-19.1 months) in the SUN arm.
With 5 years of follow-up, the overall difference in the mean change from baseline between treatment arms was statistically significant in favor of NIVO+IPI according to the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Kidney Symptom Index total and disease-related symptoms subscale scores (P < .05) in both ITT patients and intermediate-risk/poor-risk patients (see Supporting Table 8).

DISCUSSION
With a minimum 5 years of follow-up in CheckMate 214, NIVO+IPI demonstrated long-term efficacy benefits versus SUN in ITT patients, establishing new benchmarks for the magnitude and durability of benefits possible using first-line, immunotherapy-based combinations for patients with aRCC. Notably, OS benefits with NIVO+IPI versus SUN were observed in the ITT population and in both IMDC intermediaterisk and poor-risk subgroups. Median OS was reached with NIVO+IPI in ITT patients for the first time and was numerically longer for the NIVO+IPI arm versus the SUN arm regardless of IMDC risk group. In addition, the ORR was higher in ITT patients, and the DOR was notably longer with NIVO+IPI versus SUN regardless of IMDC risk group. PFS probabilities appeared to stabilize above approximately 30% for both ITT patients and intermediate-risk/poor-risk patients after 3 years. Although the ORR was higher with SUN among favorable-risk patients, 5-year OS, PFS, and CR rates and DOR probabilities were all numerically higher with NIVO+IPI versus SUN in this subgroup. The proportion of patients who maintained a CR with NIVO+IPI was also relatively high versus SUN, yet responses were durable in those who had a CR in both treatment arms. In addition, approximately one-half of all responders experienced a treatment-free interval without initiating subsequent therapy in the NIVO+IPI arm. The overall incidence of treatmentrelated AEs remained consistent with previous reports, and no new safety signals emerged. 2,12 Together with improved efficacy and safety benefits, NIVO+IPI treatment led to fewer symptoms and better HRQoL outcomes compared with SUN, further substantiating the long-term benefits of NIVO+IPI for patients with aRCC. Of note, 75% of treated patients in the NIVO+IPI arm discontinued therapy by approximately 22 months, in alignment with the protocol amendment allowing for optional discontinuation of study treatment after 2 years; this approach has become common in clinical practice. However, the optimal duration of immunotherapy remains an important clinical question and continues to be investigated.
Conditional survival analyses estimate the probability of remaining event free (ie, remaining alive, progression free, or in response) for a defined period of time beyond reaching a landmark study milestone. These analyses are a novel, clinically relevant method to predict continued survival and response benefits as patients reach or exceed annual landmarks, thus providing meaningful insights for clinicians and patients. 10 In our analysis, point estimates for conditional OS with NIVO+IPI were higher or remained stable at each subsequent year of survival between randomization and the 3-year landmark in ITT and intermediate-risk/poorrisk patients, and point estimates for conditional OS were higher for NIVO+IPI versus SUN at 3 years regardless of IMDC risk group. In favorable-risk patients, conditional OS in those who received NIVO+IPI remained high over time, whereas conditional point estimates mostly declined with subsequent years of survival in those who received SUN. These data highlight that survival benefits with NIVO+IPI are largely durable with extended follow-up, regardless of IMDC risk group. Furthermore, point estimates for conditional OS were higher or remained steady at each subsequent year of survival with NIVO+IPI in ITT patients stratified by age, BMI, grade ≥3 immune-mediated AEs, and tumor PD-L1 expression and remained consistently high in patients who achieved a CR, indicating that none of these baseline characteristics precluded patients from achieving durable survival benefits with NIVO+IPI.
The conditional survival analyses presented here only considered patients who were alive, progression free, or in response at a certain landmark timepoint, thus excluding those who died or were censored before the landmark time. In addition, these analyses were post hoc and descriptive and were intended to provide relevant information for possible scenarios that physicians and patients face, but not for inferential purposes. Limitations of the conditional survival analyses reported in this study include the increasingly small ITT patient numbers as the 3-year landmarks were reached in the SUN arm and at later timepoints within some subgroups in both arms. Furthermore, because the conditional survival analyses were exploratory in nature, additional findings from other phase 3 prospective studies are needed to confirm the treatment effects reported in this analysis. Further investigation of long-term efficacy in patients with aRCC treated with a first-line tyrosine  kinase inhibitor who subsequently receive either immunotherapy or antiangiogenic therapy in the refractory setting would help to shed light on which patient populations are likely to experience durable outcomes. Finally, it is important to point out that although baseline characteristics for this patient subgroup were largely balanced at the start of the trial, there may be imbalances in some clinical characteristics for those patients who remained alive at the landmark timepoints assessed, potentially affecting outcomes in the conditional survival analyses. Along these lines, the natural history of disease for patients with aRCC may vary considerably, depending on the biology of individual disease and the behavior of the tumor (aggressive vs indolent), both underlying the patient's response to therapy and also potentially affecting conditional survival outcomes. 15 In summary, the current results establish the durability of clinical benefit observed with NIVO+IPI over SUN in patients who have aRCC after a minimum follow-up of 5 years. In addition, results from the first  R  e  l  b  a  r  o  v  a  F  k  s  i  R  r  o  o  P  /  e  t  a  i  d  e  m  r  e  t  n  I  T  T  I   80   40   1 year  2   long-term conditional survival analyses in CheckMate 214 show that most patients who remain alive or in response at the 3-year landmark will remain alive or in response at 5 years with NIVO+IPI. These data provide a new prognostic framework critical to the improved clinical management of patients with aRCC in the current era.