Combinations Take Hold in Kidney Cancer

Bradley A. McGregor, MD

The recent success seen with the combinations of nivolumab (Opdivo) plus ipilimumab (Yervoy) as well as atezolizumab (Tecentriq) plus bevacizumab (Avastin) has convinced many that this is the era of combinations in kidney cancer, says Bradley A. McGregor, MD. However, the renewed interest and excitement in combinations was started by the success of the combination of lenvatinib (Lenvima) and everolimus (Afinitor), he adds.

The combination of lenvatinib and everolimus as a treatment for patients with advanced renal cell carcinoma (RCC) following prior antiangiogenic therapy was approved by the FDA in May 2016. The decision was based on a phase II trial, known as Study 205, in which the combination reduced the risk of progression or death by 63% versus everolimus alone.¹

Recently, the introduction of combination immunotherapy has made a frontline impact, with the FDA approval of nivolumab and ipilimumab for intermediate- and poor-risk patients with advanced RCC. The approval was based on data in the CheckMate-214 trial, which showed that nivolumab/ipilimumab reduced the risk of death by 32% compared with sunitinib (Sutent) in patients with metastatic kidney cancer.² Additionally, IMmotion151, which compared the combination of atezolizumab and bevacizumab with sunitinib, showed a statistically significant reduction in the risk for death or progression in patients with PD-L1—positive advanced or metastatic kidney cancer.

Nonetheless, not all patients may be ideal for combinations, says McGregor, because the addition of another agent often causes a higher rate of adverse events.

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In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, McGregor, clinical director of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and an instructor in medicine at Harvard Medical School, discussed the growth of combination therapy in the treatment of patients with kidney cancer.McGregor: When you look at kidney cancer as a whole, from 10 years ago when sunitinib was approved to where things are now, the landscape has evolved rapidly. Combination therapy is becoming the mainstay. Everyone thinks about combination therapy coming of age with nivolumab plus ipilimumab in the CheckMate-214 trial, and atezolizumab plus bevacizumab in IMmotion151. It has actually been around much longer than that with the FDA-approved combination of lenvatinib and everolimus— using a tyrosine kinase inhibitor (TKI) and an mTOR inhibitor.

This idea of combining different agents to get a synergistic effect is certainly very appealing, and it seems to be the way of the future with increased response rates. We hope that the impressive response rates seen with axitinib (Inlyta)/avelumab (Bavencio), axitinib/pembrolizumab (Keytruda), and pembrolizumab/ lenvatinib translate into similar impressive complete response (CR) rates. The hope is that with these therapies, we are offering these patients a chance for cure.

What combinations are the furthest along?

Many of the combinations now are trying to harness immunotherapy [plus other] immune-oncology agents, VEGF inhibitors, or multiple [other] TKI inhibitors.The two phase III trials that have read out are CheckMate-214 with nivolumab plus ipilimumab and IMmotion151 with atezolizumab and bevacizumab.

What was most appealing with the CheckMate-214 data were the impressive CR rates, specifically in the PD-L1—positive subgroup, at 16%. The CR rate for the PD-L1–negative group was comparable with what we see with interleukin-2.

When you look at IMmotion151, there was also an impressive CR rate at around 9% overall. The most appealing thing about this combination is the toxicity profile. It is a very well-tolerated regimen, as opposed to [nivolumab plus ipilimumab] where the data suggest the combination is [appropriate] only for intermediate- and poor-risk patients. When you look at the subset analysis of IMmotion151, you seem to have benefit across subgroups independent of their status.

We have multiple ongoing phase III trials that were inspired by phase I data. To varying degrees, all have very impressive response rates upwards of 70% to 80%. These are phase I trials, so take that with a grain of salt. Our hope is that these response rates translate into the phase III data, and hopefully improve disease control and CR rates.

Right now, the 3 TKI/immunotherapy-based trials are pembrolizumab/lenvatinib—which has only been presented and not published—and then axitinib/avelumab and axitinib/ pembrolizumab; those have both been published in the past 6 months.

At Dana-Farber Cancer Institute, we are participating in the CLEAR trial, which is pembrolizumab with lenvatinib versus lenvatinib with everolimus versus sunitinib. Additionally, there is a phase I study of nivolumab plus cabozantinib (Cabometyx) versus sunitinib.

Are there concerns with sequencing?

Could combinations with cabozantinib have potential?

Does everyone need combinations? Combinations are great, but as we have seen from these studies, combinations come with increased toxicities. About 60% of patients who take ipilimumab plus nivolumab require steroids, and some toxicities with these immunotherapy combinations approach 70%. Therefore, the question is, “Do you need to give everyone this therapy?” We have a very interesting trial that starts with nivolumab monotherapy, and then based on response, you add ipilimumab. Perhaps not everyone needs a combination, so if you can see the same response with less therapy and avoid toxicity, that is very appealing.That is going to be an important question. There will never be a head-to-head trial of nivolumab/ipilimumab versus pembrolizumab/ lenvatinib versus pembrolizumab/axitinib, so we are going to be stuck in this situation where we have all of these data. We are going to be left doing cross-trial comparisons and focusing on toxicity profiles. At the end of the day, it may come down to the patient. If you have a patient who has poorly controlled hypertension or cardiovascular comorbidities, perhaps you will be less likely to offer them a VEGF TKI and nivolumab/ipilimumab may be a better option. It will be a balancing game.One trial that is going to be opening shortly will be cabozantinib with atezolizumab. It will be a phase Ib trial; it has finished its escalation phase and is moving to the expansion phase, so it will be for a lot of patients with genitourinary malignancies. The study will be looking at bladder cancer, as well as frontline kidney cancer.

References

1. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial [published correction appears in Lancet Oncol. 2016;17(17):e270]. Lancet Oncol. 2015;16(15):1473-1482. doi: 10.1016/S1470-2045(15)00290-9.
2. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5.