Efficacy of Nivolumab/Ipilimumab May Change Timing of Cytoreductive Nephrectomy in Advanced RCC

Hiroshi Kikuchi, MD, PhD

Roughly 50% of patients with clear cell renal cell carcinoma (RCC) responded to the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) in a Japanese study, and varied responses occurred in those with nonclear cell histology.¹

The data which were presented during the 2021 American Urological Association Annual Meeting signal a changing role for the timing of cytoreductive nephrectomy for patients with advanced RCC.

A total of 27 patients treated with the combination were included in the analysis; 19 patients had clear cell RCC and 8 patients had nonclear cell RCC. Among all patients 48.1% of patients had a partial response; the partial response rate was 52.6% for those with clear cell histology and 37.5% for those with nonclear cell histology. No patients had a complete response.

Further, 3 patients with clear cell RCC experienced tumor reduction of at least 50% or decreased to 4 cm in diameter or less had no viable tumor cells and their tumors did not have regrowth during the follow-up period.¹

“From [the results] of this study we propose the timing and indication of cytoreductive nephrectomy,” said Hiroshi Kikuchi, MD, PhD, a member of the Department of Renal and Genitourinary Surgery at the Hokkaido University Graduate School of Medicine in Sapporo, Japan in a poster presentation. “We could judge the primary tumor response at 4 months from the [initiation] of nivolumab plus ipilimumab treatment. If there is no response, consider [cytoreductive nephrectomy] before or after second-line treatment. However, if there is significant response, there is no need to rush to cytoreductive nephrectomy.”

Cytoreductive nephrectomy has been the standard-of-care for patients with advanced RCC. However, data from the CARMENA trial (NCT00930033) demonstrated that immediate cytoreductive nephrectomy should no longer be considered the standard in patients with intermediate- and poor-risk metastatic RCC when medical treatment is required.^2,3 Reassessment is needed, and it should rather be considered in a patient-tailored manner.⁴

In the study, investigators evaluated if treatment with nivolumab plus ipilimumab contributed to changes in primary tumor sizes prior to cytoreductive nephrectomy in 51 patients with metastatic RCC or unresectable RCC. Significant response was defined as primary tumor reduction in size by 30% or more.¹

The median age in the subgroup was 66 years (range, 52-78). The median primary tumor size at baseline was 9.3 cm (range, 3.9-13.7).

At baseline, 13 patients (48.1%) were classified into the IMDC intermediate-risk group, and 14 patients (51.9%) were in the IMDC poor-risk group. Additionally, the median number of IMDC risk factors found in patients was 3 (range, 1-6). Of those patients with non-clear cell RCC, 2 presented with chromophobe RCC, 1 with mucinous tubular and spindle cell carcinoma, and 5 were unclassified.

The identified sites of metastases included: lung (70.4%), lymph nodes (70.4%), bone (25.9%), liver (25.9%), pancreas (18.5%), adrenal (14.8%), pleura/diaphragm (14.8%), brain (7.4%), muscle (7.4%), heart (3.7%), kidney (3.7%), and retroperitoneum (3.7%).

The median follow-up was 9.3 months (range, 0.8-25.3). Of the nonresponders 7 had stable disease and 7 had progressive disease; 5 of the patients with disease progression had nonclear cell RCC and all patients with stable disease had clear cell RCC.

Investigators reported a detailed analysis for 6 patients who underwent cytoreductive nephrectomy of the 10 responders.

Patients 1, 3, 4, and 5 had clear-cell RCC, and patients 2 and 6 had an unclassified disease type.

Patient 3 had a primary tumor size of 8.4 cm prior to receiving immune-checkpoint inhibitors (ICI). After 1 cycle of nivolumab plus ipilimumab and 13 cycles of single-agent nivolumab a –61.90% change in tumor size was recorded. Prior to surgical compete resection the tumor was 3.2 cm. Patient 4 received 4 cycles of the combination and 1 cycle of nivolumab for a tumor reduction of 6.0 cm to 3.1 cm (––48.33%).

Patient 5 had the greatest reduction in tumor size (–64.21%) and received 4 cycles of nivolumab plus ipilimumab and 4 cycles of nivolumab. The primary tumor size was reduced from 9.5 cm to 3.4 cm prior to surgical complete resection.

Patient 6 received 4 cycles of the combination therapy and 7 cycles of nivolumab for a tumor reduction of –43.01%; specifically, a reduction from 9.3 cm to 5.3 cm.

Patient 2 had the lowest reduction in primary tumor size. Specifically, after 2 cycles of nivolumab plus ipilimumab, a –35.62% reduction in tumor size was recorded with a decrease from 7.3 cm to 4.7 cm prior to cytoreductive nephrectomy.

Contrastingly, the 13.7 cm primary tumor of patient 1, who had clear-cell RCC, increased in size by 0.73% after 4 cycles of nivolumab plus ipilimumab and 1 cycle of nivolumab. The patient received axitinib (Inlyta) as a second-line treatment before cytoreductive nephrectomy, which was conducted 8.1 months after initial treatment. Patient 1 had an initial primary tumor size of 13.7 cm, which was recorded as 11.4 cm prior to surgery.

An analysis of the relationship between primary tumor reduction and patient backgrounds was also conducted and included inflammatory markers. Kikuchi said. “IMDC risk score [P = .6714] and [increased C-reactive protein] CRP scores [P = .8521] were not significantly different between responders and nonresponders.”

Additionally, a comparison evaluation showed that the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio tended to decrease in responders compared with nonresponders among the clear-cell RCC patient population (P = .0944; P = .0691). The platelet-to-lymphocyte ratio significantly decreased in responders in this cohort (P = .0391). According to Kikuchi, these inflammation markers may be predictive factors of treatment responses in primary tumors.

Although further studies are needed, the results suggest the importance of considering cytoreductive nephrectomy from radiological and pathological viewpoints, Kikuchi noted.

_References

_{1. Kikuchi H, Osawa T, Matsumoto R, et al. Efficacy of nivolumab plus ipilimumab in primary tumor as first-line therapy in the patients with advanced renal cell carcinoma. J Urol. 2021;206(suppl 3):259. doi:10.1097/JU.0000000000001995.16}

_{2. Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology guidelines for cytoreductive nephrectomy in patients with synchronous metastatic clear-cell renal cell carcinoma. Eur Urol. 2018;74(suppl 6):805-809. doi:10.1016/jeuroro.2018.08.008}

_{3. NCCN. Clinical Guidelines in Oncology. Kidney cancer, version 2.2022. Accessed September 10, 2021. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf}

_{4. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675}