Long-Term Data Show Nivolumab/Ipilimumab as Preferred Frontline Regimen in RCC

Nizar M. Tannir, MD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) continued to showcase superior overall survival (OS) and objective responses compared with sunitinib (Sutent) in intermediate- and poor-risk patients with advanced renal cell carcinoma (RCC), according to long-term follow-up from the phase 3 CheckMate-214 trial.

At a minimum follow-up of 42 months, the median OS was 47.0 months with the combination versus 26.6 months with sunitinib in this patient population (HR, 0.66; 95% CI, 0.55-0.80; P <.0001). The objective response rate (ORR) was 42% in the combination arm versus 26% in the sunitinib arm per independent radiology review.

Additionally, the median progression-free survival (PFS) was 12.0 months in the combination arm versus 8.3 months in the sunitinib arm (HR, 0.76; 95% CI, 0.63-0.91; P <.01). At 42 months, 35% of patients in the combination arm remained progression free versus 19% in the sunitinib arm. Moreover, these responses appeared durable in the combination arm, whereby investigators reported a plateau in the PFS curve after 24 months.

Notably, the complete response (CR) rate was 10% versus 1% in patients who received the combination versus sunitinib, respectively, regardless of risk category.

“I’m confident that patients who achieve a CR, regardless of risk category, have a high likelihood of experiencing long-term remission and potential cure,” said lead study author, Nizar M. Tannir, MD, FACP.

Moreover, the incidence of all-grade treatment-related adverse events (TRAEs) in the combination arm was comparable to that in the sunitinib arm. The rate of immune-related AEs (irAEs) requiring corticosteroid use in the combination arm decreased over time. Among patients who discontinued the combination due to toxicity, OS was not negatively impacted.

“The combination of nivolumab and ipilimumab is really the regimen of choice for the first-line treatment of patients with advanced RCC,” said Tannir.

In an interview with OncLive, Tannir, professor, deputy department chair, Ransom Horne, Jr. Professorship for Cancer Research, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the 42-month follow-up results from the CheckMate-214 trial in advanced RCC and provided perspective on other approved combinations in the frontline setting.

OncLive: Were the 42-month follow-up data from the CheckMate-214 trial consistent with what we had seen previously?

Tannir: Yes; they confirmed the previous data. The survival of patients who received nivolumab/ipilimumab was superior to those who received sunitinib in the intermediate- and poor-risk population, as well as in the intent-to-treat (ITT) population.

Were the ORRs consistent with prior findings?

The ORRs in patients with intermediate- and poor-risk disease who received the combination were consistent with prior reports. [Those responses] were in the order of 42% versus 26% to 27% with sunitinib. In the ITT population, these rates were 39% and 33%, respectively.

The CR rate was 10.1% with the combination versus 1% with sunitinib in the intermediate- and poor-risk population. In the ITT population, the CR rate was 11% with the combination versus 2% with sunitinib, according to independent review. We did see concordance in ORR in the intermediate- and poor-risk population, as well as the ITT population, between investigator assessment and independent review.

We did see some discordance in patients with favorable-risk disease. This was an exploratory cohort of 249 patients. A total 125 patients received the combination, and 124 received sunitinib. The CR rate, by independent radiology committee review, was 13% with the combination versus 6% with sunitinib. By investigator assessment, the CR rate was 8%.

How did PFS differ between the 2 arms in the ITT and the different risk groups?

The PFS was longer with the combination versus sunitinib in the primary population of patients with intermediate- and poor-risk disease and the ITT population. It's important to note that the medians don’t tell the story. One of the key messages of these updated results is the PFS probabilities in the intermediate- and poor-risk and ITT populations. At 42 months, there was a plateau of the PFS Kaplan-Meier curve in patients in the combination arm, in which 35% of patients were progression free. That’s not the case with sunitinib.

Did any new safety signals emerge with the combination?

There were no new concerning safety signals. There we no additional deaths in either arm. As per the prior findings that we published in the New England Journal of Medicine in March 2018 and in Lancet Oncology just a couple months ago, there were 8 deaths in the combination arm, which translated to a 1.5% [fatality rate] and 4 deaths in the sunitinib arm, which translated to a 4.7% [fatality rate].

It’s important to note that most of the TRAEs with the combination occurred in the first 6 months of enrollment. Over time, these AEs declined. All-grade AEs were comparable in both arms. The irAEs happened in the first 4 to 6 months of treatment. Over time, those [irAEs] decreased, and the use of corticosteroids decreased.

In terms of corticosteroid use, 28.7% of patients in the combination arm received 40 mg of prednisone daily or an equivalent for any amount of time, for any duration. Nineteen percent of patients received 40 mg of prednisone daily or an equivalent for 2 weeks or longer, and 9.9% of patients received prednisone or an equivalent for more than 30 days. The rate of grade 3/4 [AEs] was lower with the combination versus sunitinib overall.

Was OS impacted among patients who discontinued the combination?

There was no negative impact with discontinuation on OS. A total 141 patients [discontinued] the combination out of 550 patients in the ITT population, translating to a 22% discontinuation rate during the induction phase or the maintenance phase after patients completed 4 cycles of the combination.

The Kaplan-Meier curve for OS [of patients who discontinued the combination] was higher than the Kaplan-Meier curve of the ITT patients. OS for patients who discontinued the combination due to toxicity was not negatively affected.

Will these data impact your current approach to frontline therapy in advanced RCC?

Yes, absolutely. The [CheckMate-214 trial] is the only phase 3 trial that has long-term follow-up. There are other regimens that are approved for the frontline treatment of patients with advanced RCC. Those 2 regimens are pembrolizumab (Keytruda) plus axitinib (Inlyta) and avelumab (Bavencio) plus axitinib.

Avelumab/axitinib did not [show a statistically significant improvement in OS in the phase 3 JAVELIN Renal 101 trial], so that regimen has fallen by the wayside. However, updated results could show OS benefit for the vaccine.

In terms of the KEYNOTE-426 trial, we only have the first [set of data] that were published a year ago in the New England Journal of Medicine. The data showed the benefit of pembrolizumab/axitinib versus sunitinib in all International Metastatic RCC Database risk subgroups, as well as an improvement in ORR and PFS. However, we don’t have long-term follow-up, so I can’t gauge whether there will be a plateau for PFS [to the extent we’ve seen with nivolumab/ipilimumab].

At the end of the day, patients would like to be cured, or at least have a durable response. A durable CR is the path to cure. The CR rate with pembrolizumab/axitinib was 5.8%. We’ll see how that rate [compares with the data from CheckMate-214] with longer follow-up. Until we see those data, it will be really hard to gauge how the combination of a TKI and PD-1/PD-L1 antibody will impact long-term survival.

Fifty-nine patients with intermediate- and poor-risk disease who received nivolumab/ipilimumab [in the CheckMate-214 trial] achieved a CR, which was just above 10%. These CRs were seen across all risk categories. The CR rate was 11% in the ITT population and 13% in patients with favorable-risk disease.

Tannir NM, McDermott DF, Escudier B, et al. Overall survival and independent review of response in CheckMate 214 with 42-month follow-up: first-line nivolumab + ipilimumab (n+i) versus sunitinib (s) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2020;38(suppl_6; abstr 609). doi:10.1200/JCO.2020.38.6_suppl609