Cabozantinib Displays Activity as Combination Component and Monotherapy in Second-Line Advanced RCC

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Cabozantinib (Cabometyx) with or without atezolizumab (Tecentriq) was safe and effective for the second-line treatment of patients with advanced renal cell carcinoma (RCC), irrespective of prior immunotherapy or TKI therapy, according to findings from the phase 3 CONTACT-03 trial (NCT04338269) presented during the 2025 ASCO Annual Meeting.

Data from a post-hoc subgroup analysis revealed that among patients treated with atezolizumab plus cabozantinib (n = 129) or cabozantinib alone (n = 107), outcomes were consistent regardless of prior immunotherapy-based combinations used in the first-line setting.

Among patients previously treated with any immunotherapy combination regimen, treatment with atezolizumab/cabozantinib or cabozantinib alone elicited a median progression-free survival (PFS) of 10.2 months (95% CI, 8.3-10.6) vs 10.4 months (95% CI, 8.0-12.5), respectively (HR, 1.03; 95% CI, 0.75-1.41; P = .8746). The respective 6-, 12-, and 18-month rates between the cabozantinib combination and monotherapy arms were 73.6% vs 69.6%, 38.0% vs 44.6%, and 22.6% vs 30.1%, respectively.

In those treated with a dual immunotherapy regimen, the median PFS was 10.4 months (95% CI, 8.3-12.7) with the combination regimen (n = 80) vs 10.5 months (95% CI, 8.1-14.0) with the monotherapy (n = 70; HR, 1.01; 95% CI, 0.67-1.51; P = .9806). The respective 6-, 12-, and 18-month rates were 77.8% vs 70.0%, 42.6% vs 47.7%, and 27.9% vs 33.3%.

Furthermore, among those previously treated with immunotherapy and a TKI, the median PFS was 10.2 months (95% CI, 7.1-10.5) vs 10.4 months (95% CI, 6.3-12.5) in the combination (n = 49) and monotherapy (n = 37) arms, respectively (HR, 1.06; 95% CI, 0.64-1.77; P = .8150). The respective 6-, 12-, and 18-month rates were 66.9% vs 68.7%, 30.0% vs 38.8%, and 13.7% vs 24.1%.

Additionally, the median overall survival (OS) outcomes were similar between treatment arms. In patients previously treated with any immunotherapy combination regimen, the median OS with the combination was 24.3 months (95% CI, 20.2-not estimable [NE]) vs NE (95% CI, 18.3-NE) with cabozantinib monotherapy (HR, 0.82; 95% CI, 0.54-1.26; P = .3684). The respective 6-, 12-, and 18-month OS rates were 89.0% vs 88.4%, 75.5% vs 67.7%, and 64.0% vs 61.4%.

Among those previously treated with a dual immunotherapy regimen, the median OS in the combination therapy and monotherapy arms was 24.3 months (95% CI, 19.2-NE) vs NE (16.5-NE; HR, 0.77; 95% CI, 0.45-1.30; P = .3222). Additionally, the 6-, 12-, and 18-month rates were 92.3% vs 86.9%, 79.3% vs 65.6%, and 65.0% vs 59.6%, respectively.

In those previously treated with immunotherapy and a TKI, the median OS was NE (95% CI, 17.1-NE) with cabozantinib/atezolizumab vs 20.7 months (95% CI, 15.3-NE) with cabozantinib alone (HR, 0.92; 95% CI, 0.45-1.86; P = .8078). Furthermore, the respective 6-, 12-, and 18-month rates were 83.7% vs 91.5%, 69.4% vs 71.5%, and 63.1% vs 64.6%.

“Results from this post hoc subgroup analysis of [the phase 3 CONTACT-03 trial] suggest that [second-line] cabozantinib is effective in patients with advanced RCC previously treated with [first-line immunotherapy] combination regimens,” Cristina Suárez, MD, PhD, genitourinary oncologist and clinical investigator of the Vall d’Hebron Institute of Oncology in Barcelona, Spain, wrote in the presentation with study coinvestigators. “The results of this analysis can help inform clinicians making [second-line] treatment decisions for patients with disease progression on contemporary [first-line immunotherapy]-containing combinations.”

Patients treated with cabozantinib alone or in combination with atezolizumab had a median age of 60 years (range, 33-89) vs 62 years (range, 36-83), 76% vs 72% were male, and 67% vs 71% had a Karnofsky score of 100 or 90. A total of 71% vs 63% received a prior nephrectomy, and 12% vs 11% had sarcomatoid features. Between the 2 arms, 67% vs 68% had an IMDC score of 1 or 2.

The most common sites of metastases in the respective arms included lung (65% vs 58%), lymph node (55% vs 46%), bone (36% vs 30%), liver (25% vs 20%), and adrenal gland (24% vs 15%). The median duration of most recent first-line immunotherapy regimen was 5.8 months (range, 0.2-51.4) vs 7.2 months (range, 1.4-46.6), respectively. The most common best responses to the most recent immunotherapy included disease progression (40% vs 32%) and stable disease (32% vs 39%), with 17% vs 22% of patients experiencing a partial response (PR).

The phase 3 CONTACT-03 study evaluated patients with locally advanced or metastatic RCC and radiographic tumor progression on or following adjuvant, first-line, or second-line immunotherapy. The end points of the unplanned post hoc subgroup analysis included PFS by blinded independent central review (BICR), OS, objective response rate (ORR), and duration of response (DOR) per BICR, as well as safety.

Additional efficacy data revealed that in the monotherapy and combination arms, the ORR was 36% vs 37%, all of which consisted of PRs. Among patients previously treated with dual immunotherapy, the ORR was 38% vs 45% in the respective arms, and for those previously treated with immunotherapy and a TKI, the ORR was 31% vs 25%. The median DOR in each arm with any immunotherapy combination regimen, a dual immunotherapy regimen, and immunotherapy plus a TKI was 15.1 months (95% CI, 10.3-NE) vs 10.5 months (95% CI, 8.0-NE), 15.1 months (95% CI, 8.4-NE) vs 11.7 months (95% CI, 7.4-NE), and 17.3 months (95% CI, 8.2-NE) vs 10.4 months (95% CI, 6.2-NE).

Any-grade treatment-related adverse effects (TRAEs) occurred in 98% of the monotherapy group and 95% of the combination group. Additionally, the respective grade 3/4 TRAE and serious TRAE rates in each arm were 48% vs 58% and 13% vs 25%. Notably, no grade 5 TRAEs occurred in the monotherapy arm, but 3 (2.3%) patients in the combination arm had grade 5 TRAEs.

AEs leading to dose modification occurred in 87% and 92% of the cabozantinib alone and cabozantinib/atezolizumab arms. In the combination arm, 89% of AEs leading to dose reduction were related to cabozantinib, and 62% were related to atezolizumab. AEs leading to discontinuation occurred in 4.7% and 17.0% of the respective arms, with 9.4% related to cabozantinib and 12.0% related to atezolizumab in the combination arm.

Reference

Suárez C, Choueiri TK, Albiges L, et al. Efficacy and safety of second-line cabozantinib ± atezolizumab for patients with advanced renal cell carcinoma after progression on immuno-oncology combinations: subgroup analysis of CONTACT-03. J Clin Oncol. 2025;43(suppl 16):4523. doi:10.1200/JCO.2025.43.16_suppl.4523