First-Line Immunotherapy Is Associated With Worse Survival Outcomes in Synchronous mRCC

The time to treatment failure (TTF) following immunotherapy was among patients with synchronous metastatic renal cell carcinoma (mRCC) vs those who had metachronous disease, according to findings from a retrospective study that were presented at the 2023 Kidney Cancer Research Summit.¹

After first-line treatment, the median TTF was 9.0 months in patients with synchronous disease vs 19.8 months in those with metachronous disease (HR, 1.37; 95% CI, 0.98-1.92; P = .064), with a log-rank P value of .064.¹

“[This is the] first study to report the negative impact of synchronous mRCC vs metachronous mRCC on outcomes in patients treated with first-line immune checkpoint inhibitor–based combinations,” Georges Gebrael, of the Division of Medical Oncology in the Department of Internal Medicine at the University of Utah Huntsman Cancer Institute in Salt Lake City, wrote in a presentation of the data.

According to the Surveillance, Epidemiology, and End Results registry, localized RCC, defined as that confined to the primary disease site, comprises 66% of diagnosed RCC cases; regional RCC, defined as disease that has spread to the regional lymph nodes, comprises 16% of diagnosed cases; distant RCC, defined as disease that has metastasized, comprises 15% of diagnosed cases; and 3% of diagnosed RCC cases are unknown/unstaged.²

A Swedish population-based study investigating the occurrence of local recurrences and metastases in patients with primary nonmetastatic RCC found that 20% of patients initially diagnosed with localized RCC between 2005 and 2009 subsequently progressed to having metachronous disease, defined as having metastatic disease during 5-year follow-up.³ Another study, which characterized overall survival (OS) and TTF in patients with mRCC who received TKIs, found that patients with primary, or synchronous, mRCC were more likely to have poorer outcomes when treated with TKIs than those with metachronous mRCC.⁴

Gebrael and colleagues aimed to determine whether metachronous or synchronous mRCC affected survival outcomes in patients who had received immune checkpoint inhibitor–based combinations in the frontline setting.1

Eligible patients included those with a confirmed mRCC diagnosis who had received a first-line regimen including a PD-1, PD-L1, or CTLA-4 inhibitor. Patients were excluded if they had missing data regarding the date of their initial RCC diagnosis or the date of their metastatic disease diagnosis.

In this study, synchronous disease was defined as the presence of metastatic lesions at or within 3 months of a patient’s initial RCC diagnosis. Metachronous disease was defined as the presence of metastatic disease diagnosed beyond 3 months from a patient’s initial RCC diagnosis.

The end points of this study were TTF, OS, and disease control rate (DCR).

In total, 97 patients with metachronous disease and 126 patients with synchronous disease were enrolled. Patients in the metachronous and synchronous cohorts had median ages of 65.0 years (interquartile range, 58.0-72.0) and 62.0 years (interquartile range, 55.0-70.0), respectively (P = .06). Additionally, 68% (n = 66) and 67% (n = 85) of patients in the metachronous and synchronous cohorts were male, respectively, and 32% (n = 31) and 33% (n = 41) of patients were female, respectively (P > .09). Of the patients in the metachronous and synchronous cohorts, 89% (n = 85) and 79% (n = 97), respectively, had clear cell histology.

Regarding International Metastatic RCC Database Consortium (IMDC) risk criteria, of the patients in the metachronous and synchronous cohorts, respectively, 13.4% (n = 13) and 94% (n = 118) had initiated treatment less than 1 year after their initial RCC diagnosis (P < .001), 5.2% (n = 5) and 11% (n = 14) had a Karnofsky Performance Score of less than 80 (P = .114), 36% (n = 35) and 55% (n = 69) had low hemoglobin (P = .006), 8.9% (n = 8) and 7.7% (n = 9) had high calcium (P = .756), 2.1% (n = 2) and 16% (n = 20) had high neutrophils (P < .001), and 3.1% (n = 3) and 21% (n = 26) had high platelets (P < .001). In total 14% (n = 14) and 84% (n = 81) of patients in the metachronous cohort had favorable-risk and intermediate/poor-risk disease per IMDC, respectively, and 4.8% (n = 6) and 94% (n = 119) of patients in the synchronous cohort had favorable-risk and intermediate/poor-risk disease, respectively. The P value for IMDC risk was .016.

Brain, bone, or liver metastases developed in 45.36% (n = 44) of patients in the metachronous cohort and 45.23% (n = 57) of patients in the synchronous cohort (P = .87). In total, 96.9% (n = 94) and 43.7% (n = 55) of patients in the metachronous and synchronous cohorts, respectively, had prior nephrectomy (P < .001).

The median OS was 28.0 months in patients with synchronous disease vs 50.9 months in those with metachronous disease (HR, 2.23; 95% CI, 1.36-3.65; P = .001), with a log-rank P value of .0011. When adjusted in a multivariable analysis, the hazard ratio (HR) for synchronous vs metachronous disease was 1.96 (95% CI, 1.17-3.27; P = .010). When adjusted for age at the time of first-line treatment initiation, sex, histology, and IMDC risk, the HRs were 1.01 (95% CI, 0.99-1.03; P = .416), 1.08 (95% CI, 0.66-1.76; P = .761), 0.54 (95% CI, 0.31-0.93; P = .026), and 1.62 (95% CI, 0.63-4.18; P = .315), respectively.

The DCRs were 62% in patients with synchronous disease vs 86% in those with metachronous disease (P = .001). Of the 119 evaluable patients in the synchronous cohort, 4% (n = 5), 24% (n = 28), 34% (n = 41), and 38% (n = 45) achieved a complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), respectively, and 7 patients were not assessed. Of the 88 evaluable patients in the metachronous cohort, 6% (n = 5), 30% (n = 26), 51% (n = 45), and 14% (n = 12) achieved a CR, PR, SD, or PD, respectively, and 9 patients were not assessed. When adjusted in a multivariable analysis, the HR for synchronous vs metachronous disease was 0.29 (95% CI, 0.13-0.64; P = .002). When adjusted for age at the time of first-line treatment initiation, sex, and histology, the HRs were 1.03 (95% CI, 1.00-1.06; P = .084), 1.08 (95% CI, 0.52-2.26; P = .838), and 3.04 (95% CI, 1.33-6.95; P = .008), respectively.

Gebrael cited the retrospective nature of this study and its small sample size as key limitations of this research.

“Further validation is needed in larger prospective datasets,” Gebrael concluded. “These data could inform future clinical trial designs.”

References

1. Gebrael G, Meza K, Li X, et al. Impact of synchronous vs. metachronous mRCC on outcomes in patients treated with first line immune-checkpoint inhibitors-based combinations. Presented at: 2023 Kidney Cancer Research Summit; July 13-14, 2023; Boston, MA.
2. Cancer stat facts: kidney and renal pelvis cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed July 17, 2023. https://seer.cancer.gov/statfacts/html/kidrp.html
3. Dabestani S, Thorstenson A, Lindblad P, et al. Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study. World J Urol. 2016;34(8):1081-1086. doi:10.1007/s00345-016-1773-y
4. Donskov F, Xie W, Overby A, et al. Synchronous versus metachronous metastatic disease: impact of time to metastasis on patient outcome-results from the International Metastatic Renal Cell Carcinoma Database consortium. Eur Urol Oncol. 2020;3(4):530-539. doi:10.1016/j.euo.2020.01.001