ASCO GU 2020: Dr. Rini Highlights Key Research Efforts in Kidney Cancer

Brian Rini, MD, inaugural chief of Clinical Trials at Vanderbilt-Ingram Cancer Center, discusses some of the exciting data on kidney cancer presented at the 2020 Genitourinary Cancers Symposium.

Long-term follow-up data from the phase III CheckMate-214 trial examining nivolumab (Opdivo) plus ipilimumab (Yervoy) versus sunitinib (Sutent) in advanced renal cell carcinoma (RCC) were presented at the symposium. At a median follow-up of 42 months, median overall survival (OS) with the combination was a median of 47 months with the combination versus 26.6 months with sunitinib in intermediate- or poor-risk patients with advanced RCC (HR, 0.66; 95% CI, 0.55-0.80; P <.0001). The PFS was a median of 12.0 months versus 8.3 months with the combination and sunitinib, respectively, in this patient population. One-third of patients who start on the therapy are going to experience disease control, says Rini, which is impressive in kidney cancer. As the data set matures, Rini predicts increasing response durability will be observed with this approach.

The final analysis of the randomized, open-label, phase III CheckMate-025 trial, which compared the use of nivolumab versus everolimus (Afinitor) in patients with metastatic clear cell RCC (ccRCC) who had received previous treatment with antiangiogenic therapy, were also presented at the meeting. The median OS was 25.8 months (95% CI, 22.2-29.8) with nivolumab and 19.7 months (95% CI, 17.6-22.1) with everolimus. The hazard ratio for death with nivolumab versus everolimus was 0.73 (95% CI, 0.62-0.85; P = .0001). The ORR was greater with nivolumab than with everolimus, at 23% versus 4% (HR, 6.86; 95% CI, 4.01-11.74; P < .0001). Although in the United States there’s not as much single-agent use of nivolumab as it’s used in the up-front setting, it speaks to the value of the agent, says Rini.

Another agent that is generating excitement in the space is the oral hypoxia-inducible factor (HIF)2α inhibitor MK-6482. The agent induced a partial response rate of 24% and a disease control rate of 80% in patients with advanced ccRCC, according to data from a phase I/II trial. The median PFS was 11 months and the 12-month PFS was 49%. Twenty-nine percent of patients continued treatment beyond 12 months, and 81% of responses lasted ≥6 months. Another notable characteristic of this agent is that it’s well tolerated, says Rini. In comparison VEGF TKIs, whether used as monotherapy or in combination, are not as tolerable, adds Rini. As the field shifts to the use of more combinations, investigators must be mindful of toxicity; as such, a safe and effective drug like MK-6482 would be a major advance in the space, according to Rini.

A couple of combination studies with nivolumab were presented at the symposium. For example, first results from the phase II NIVES trial examining nivolumab in combination with stereotactic body radiotherapy (SBRT) in pretreated patients with metastatic RCC, says Rini. The ORR with the approach was 17.4% in the ITT population and the disease control rate was 58.0%. The rationale behind this approach is that radiation to the tumor will trigger antigen release, which will then increase the immune response when an immunotherapy agent is given, thus leading to more systemic antitumor immunity, explains Rini. However, it’s unclear whether the combination was any more active than what is expected with immunotherapy alone, adds Rini. More work needs to be done to explore SBRT further.

Additionally, the combination of nivolumab plus sitravatinib was found to induce a confirmed ORR of 39% and a 92% clinical benefit rate in patients with advanced ccRCC who progressed on prior VEGF-targeted therapy, according to results from a phase I/II trial. The combination led to a median PFS of 10.3 months among 38 evaluable patients. The clinical activity and preliminary PFS data exceeded the historical performance of other single-agent therapies used to treat patients with CRC, such as everolimus, cabozantinib (Cabometyx), and nivolumab. One of the fundamental questions in the field is whether the different targets and properties of TKIs affect immunomodulation differently, says Rini.

In May 2019, the combination of avelumab (Bavencio) and axitinib (Inlyta) received FDA approval for use in the frontline treatment of patients with advanced RCC. The approval was based on data from the randomized, phase III JAVELIN Renal 101 trial, and additional analyses were presented at the meeting. The trial evaluated the antitumor activity and safety of frontline avelumab combination with axitinib (Inlyta) versus sunitinib monotherapy in patients with advanced RCC. Among 560 patients with PD-L1—positive tumors, the median PFS was 13.8 months with avelumab plus axitinib compared with 7.2 months with sunitinib. In the overall population of 886 patients, the median PFS was 13.8 months compared with 8.4 months. Furthermore, the ORR was 55.2% with avelumab/axitinib and 25.5% with sunitinib in the two groups, respectively. Results presented at the symposium showed that, when broken down by prognostic risk group, the combination proved to result in longer median PFS compared with sunitinib in favorable- (not evaluable vs 13.8 months, respectively), intermediate- (13.8 months vs 8.4 months), and poor-risk patients (6.0 months vs 2.9 months).

Additional phase III trials are examining the combination of cabozantinib and nivolumab as well as lenvatinib (Lenvima) and pembrolizumab. Although data have not been released yet, Rini predicts they will perform like other TKI/immunotherapy combinations. The question of whether they’ll result in a survival advantage remains to be seen, Rini adds; however, he does not believe they will be much more effective than what has been seen with oxaliplatin plus pembrolizumab. The read out of some adjuvant trials are also anticipated within the next year or so, says Rini; these trials could potentially change the frontline treatment of these patients.

Lenvatinib has been studied in combination with pembrolizumab, which had shown the most impressive phase II activity, says Rini. In the second-line setting, the agent has been evaluated with everolimus in advanced/metastatic RCC. The initial findings of the phase Ib/II Study 111 showed that lenvatinib plus pembrolizumab (Keytruda) induced a disease control rate of 94% in patients with metastatic ccRCC who regressed following treatment with a PD-1/PD-L1 inhibitor. The ORR at week 24 was 61% and the confirmed ORR via investigator review was 64%. Based on earlier data from the trial, the FDA issued a breakthrough therapy designation to the combination for this patient population.

According to Rini, it will be interesting to see how lenvatinib/everolimus compares with lenvatinib/pembrolizumab; however, he expects that lenvatinib/pembrolizumab will be the stronger combination. Rini predicts that immunotherapy-based combinations will dominate the front-line treatment of this patient population. To date, the question of whether immunotherapy is active after immunotherapy remains unanswered.

Rini is also very involved in a Twitter group referred to as Uromigos (@Uromigos), which was started a little over 1 year ago. In collaboration with other oncologists from all over the world, Rini hopes to use this account to establish an educational scientific presence on the platform to share pertinent information with the oncology community. Since its inception, Uromigos is hosting podcasts and will be hosting online tumor boards in which they will invite patient advocacy groups to participate in important discussions, concludes Rini.