Frontline Nivolumab Plus Cabozantinib Significantly Improves Survival in Renal Cell Carcinoma

Toni K. Choueiri, MD

Frontline nivolumab (Opdivo) in combination with cabozantinib (Cabometyx) demonstrated a 49% reduction in the risk of disease progression or death as treatment of patients with advanced renal cell carcinoma (RCC) and also significantly improved overall survival (OS) while doubling the objective response rate (ORR) in the first results from the phase 3 CheckMate-9ER study, which were presented during the 2020 ESMO Virtual Congress.¹

At a median follow-up of 18.1 months, the median progression-free survival (PFS) was 16.6 months with nivolumab/cabozantinib and 8.3 months with sunitinib (HR, 0.51; P <.0001). The combination was also found to have a manageable safety profile with a low rate of treatment-related discontinuations in patients with advanced RCC.

“With expanding options for patients with advanced RCC, the overall efficacy, safety, and quality of life benefits, as well as individual patient characteristics, are very important considerations when you select appropriate therapy,” lead study author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, senior physician with Dana-Farber Cancer Institute, and the Jerome and Nancy Kohlberg Chair and professor of medicine with Harvard Medical School, said in a press conference during the congress. “These results, we believe, support nivolumab and cabozantinib as a potential first-line option in patients with advanced renal cell carcinoma.”

Both nivolumab and cabozantinib are currently approved in separate indications in RCC. In April 2018, the FDA approved nivolumab plus ipilimumab (Yervoy) as a frontline treatment for intermediate- and poor-risk patients with advanced RCC. Prior to that, in 2015, the PD-1 inhibitor was approved for use as a single agent in the treatment for patients with metastatic RCC following prior antiangiogenic therapy.

In 2017, cabozantinib was approved by the FDA for use in previously untreated patients with advanced RCC and was initially approved as a treatment for those who had progressed on 1 prior antiangiogenic treatment.

Previously, results of a phase 1 study showcased clinical activity with the combination of nivolumab and cabozantinib in patients with advanced genitourinary cancers;² these data provided the rationale to study this combination in a larger trial.

In the international, randomized, phase 3 CheckMate-9ER trial, 651 patients with advanced RCC received the combination of nivolumab and cabozantinib (n = 323) or sunitinib (n = 328) in the first-line setting. Patients must have had previously untreated advanced or metastatic disease, a clear cell component, and any International Metastatic RCC Database Consortium (IMDC) risk score.

Patients were randomized in a 1:1 fashion. In the combination arm, nivolumab was given at 240 mg intravenously every 2 weeks along with cabozantinib, which was given orally at 40 mg daily. Oral sunitinib was administered at 50 mg daily on a 4-weeks-on/2-weeks-off cycle. Treatment was administered until disease progression or unacceptable toxicity.

The primary end point of the trial was PFS, while secondary end points were OS, ORR, and safety. Health-related quality of life (HRQoL) served as an exploratory end point.

The combination demonstrated a benefit across numerous subgroups, including age, sex, PD-L1 expression, bone metastases, IMDC risk group, and geographic region.

Additional results showed that the median OS was not reached in either arm, leading to a 40% reduction in the risk of death with the combination (HR, 0.60; P = .0010).

The ORR was also doubled with nivolumab/cabozantinib in this setting compared with sunitinib, at 55.7% versus 27.1%, respectively (P <.0001). In the combination arm, the complete response (CR) rate was 8.0%, the partial response (PR) rate was 47.7%, and the stable disease (SD) rate was 32.2%. Additionally, 5.6% of patients had progressive disease (PD) and 6.5% were not evaluable or not assessed. In the sunitinib arm, the CR, PR, and SD rates were 4.6%, 22.6%, and 42.1%, respectively. Moreover, 13.7% of patients had PD and 17.1% of patients were not evaluable or not assessed.

Regarding safety, the incidence of the most common, any-grade and high-grade treatment-related adverse events (TRAEs) were similar in both arms. More than 50% of patients on the combination required dose reductions of cabozantinib due to adverse effects (AEs). TRAEs led to treatment discontinuations in 15.3% of those in the nivolumab/cabozantinib arm and in 8.8% of those on sunitinib. Specifically, 3.1% of patients discontinued both nivolumab and cabozantinib due to AEs, 5.6% discontinued only nivolumab, and 6.6% discontinued only cabozantinib.

The overall rate of serious AEs was similar between the 2 groups; however, liver toxicity was more common with cabozantinib/nivolumab. Nineteen percent of patients on the combination required corticosteroids due to immune-related AEs, 4% of whom needed corticosteroids for at least 30 days.

“Overall, it seems that the combination has a manageable safety profile in patients with advanced RCC,” said Choueiri.

Beyond improved treatment response and survival benefits, the combination was found to provide an improved HRQoL compared with sunitinib. HRQoL was maintained over time with nivolumab/cabozantinib versus sunitinib, which had a consistent deterioration per Functional Assessment of Cancer Therapy- Kidney Symptom Index (FKSI)-19 total score. The between-arm differences were significant at nearly all time points.

Disease-related symptoms (DRS) also improved with nivolumab/cabozantinib. Those who received sunitinib experienced a decline per FKSI-Disease-DRS.

Dominik Berthold, CHUV, head of the Specialised Consultation for Urological Cancers Medical Oncology Service, Department of Oncology, Lausanne University Hospital in Switzerland, commented on the CheckMate-9ER trial during the press conference.

“All of this is pretty impressive,” Berthold explained. “What is the only drawback of this trial? It is probably the fact that [this combination is not] first-in-class in this equation. You have a combination of a checkpoint inhibitor and [TKI], and [already] in this indication, we have axitinib (Inlyta) and pembrolizumab (Keytruda). We also have the combination of ipilimumab and nivolumab with high response rates, and now, longer follow-up data.

“It is certainly an option for these patients,” Berthold continued. “What we still need to learn is, are there any patient populations who may benefit more from this combination than the other combinations? Cabozantinib is quite a unique TKI, which may better target [patients with] bone metastases, for example. [That is what we will need to] learn from longer follow-up.”

_References

1. _{Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(4). Abstract 696O.}
2. _{Nadal RM, Mortazavi A, Stein M, et al. Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies.J Clin Oncol. 2018;36(suppl 6):515. doi:10.1200/JCO.2018.36.6_suppl.515}