Sunitinib Generates Clinical Activity After Immunotherapy Failure in Metastatic Renal Cell Carcinoma

Second-line sunitinib (Sutent) appeared to have clinical activity following failure on frontline immunotherapy in patients with metastatic renal cell carcinoma (mRCC), according to a retrospective study presented in a poster during the 35th Annual European Association of Urology Virtual Congress.

Although immunotherapy has become the standard of care for the frontline treatment of patients with mRCC, treatment sequencing remains a challenge as there have not been any guidelines or regulatory policies addressing optimal sequencing approaches. Targeted therapies have been associated with improvements in both progression-free survival and overall survival (OS), as well as a favorable toxicity profile and improved health-related quality of care. However, minimal research exists related to second-line sunitinib after progression on immunotherapy.

The purpose of this study was to determine the clinical effectiveness of the VEGFR tyrosine kinase inhibitor (TKI) either alone or in combination with nivolumab (Opdivo) and ipilimumab (Yervoy) as treatment of patients with mRCC.

The median OS was 17.1 months (95% CI, 11.8-35.2) among patients who received second-line sunitinib, and the 1-year OS rate was 64.3% (95% CI, 48.2-76.6). Among patients who had received prior ipilimumab and nivolumab, the median OS was 18.3 months (95% CI, 9.2-not evaluable [NE]), and the 1-year OS rate was 72.7% (95% CI, 46.0-87.7). Among those treated previously with immunotherapy and a VEGFR TKI, the median OS was 17.1 months (95% CI, 9.5-NE), and the 1-year OS rate was 52.6% (95% CI, 28.3-72.1). There was not a statistically significant difference in the median OS for patients treated with prior immunotherapy plus VEGFR TKI versus ipilimumab plus nivolumab (P =.39).

The objective response rate (ORR) was 28.6% among all patients who received second-line sunitinib. The ORR in the nivolumab plus ipilimumab arm was 44.0%, and the ORR in the immunotherapy plus VEGFR TKI arm was 16.7%. The difference between these 2 arms was not statistically significant (P =.10).

In the overall population, the best response was a partial response, which occurred in 14 patients (28.6%), while 19 patients had stable disease (38.8%) and 16 had progressive disease (32.7%). In the nivolumab plus ipilimumab arm and the immunotherapy plus VEGFR TKI arm, the best responses were partial responses, occurring in 11 (44.0%) and 3 (16.7%), while stable disease was reported in 8 patients (32.0%) versus 9 (50.0%) and progressive disease in 6 (24.0%) and 6 (33.3%), respectively.

The median time to treatment discontinuation (TTD) was 5.4 months (95% CI, 4.2-9.6). Among patients who had received prior nivolumab plus ipilimumab, the median TTD was 5.6 months (95% CI, 4.1-NE), and the median TTD in the immunotherapy plus VEGFR TKI arm was 7.2 months (95% CI, 3.4-10.2). The difference in median TTD was not statistically significant in immunotherapy plus VEGFR TKI arm compared with the nivolumab plus ipilimumab arm.

The primary reason for treatment discontinuation among 40 patients who had discontinued was disease progression on sunitinib, which was the case in 60.0% of the patients. Additionally, 35.3% in the nivolumab plus ipilimumab arm discontinued due to toxicity while 52.9% discontinued due to disease progression. Among patients in the immunotherapy plus VEGFR TKI arm, 86.7% discontinued treatment due to disease progression.

The majority of patients in this study were non-white (70.7%) and male (76.7%). Sixty-one patients (92.4%) had clear cell pathology. The number of metastases was 1 in 6 patients (9.4%), 2 in 16 (27.6%), 3 in 13 (22.4%), and 4 or more in 8 (13.8%), while the number of metastases was unknown in 21 patients (36.2%). The location of the metastases was primarily lung (47.9%), lymph nodes (32.9%), and bone (26.0%), while other locations included liver (15.1%), brain (9.6%), adrenal gland (8.2%), pancreas (6.8%), and other (15.1%).

The multi-institutional cohort study was conducted at select centers from the International Metastatic Renal Cell Carcinoma Database Consortium. To be included in the study, patients had to have been treated with second-line sunitinib after prior treatment with immunotherapy in the frontline setting. Prior immunotherapy treatments included combination ipilimumab plus nivolumab, immunotherapy plus a VEGFR TKI therapy, or immunotherapy monotherapy.

The median age among the 73 patients included in the study was 61.5 years, and according to IMDC risk score in 63 patients, 7 (11.1%) were favorable risk, 34 (54.0%) were intermediate risk, and 22 (34.9%) were poor risk. First-line treatment with combination nivolumab plus ipilimumab was the most common prior immunotherapy (53.4%), while 30.1% had received immunotherapy plus VEGFR TKI, and 16.4% had received immunotherapy alone. The median treatment duration was 12.6 months with immunotherapy plus VEGFR TKI and 6.3 months with nivolumab and ipilimumab.

Overall, statistical differences were not observed for the median OS, median TTD, and ORR between the nivolumab plus ipilimumab and the immunotherapy plus VEGFR TKI arms, but this may have been due to the small sample size. Larger studies are needed to confirm these findings. More research is necessary to determine optimal treatment sequencing approaches after progression on frontline immunotherapy, the study authors concluded.

_Reference

_{Wells JC, Dudani S, Gan CL, et al. Real-world clinical effectiveness of second-line sunitinib following immune-oncology therapy in patients with metastatic renal cell carcinoma. Presented at: 35th Annual European Association of Urology Congress; July 20-26, 2020; Virtual. Poster 721.}