Promising Combinations Surpass Standard of Care in Advanced Renal Cell Carcinoma

Bradley McGregor, MD

Bradley McGregor, MD

Combination regimens may be replacing the gold standard, sunitinib (Sutent), for the treatment of patients with renal cell carcinoma (RCC), according to Bradley McGregor, MD.

Multiple studies have shown combinations of checkpoint inhibitors and chemotherapy prolong progression-free survival (PFS) and improve overall survival (OS) in patients with RCC. In the CheckMate 214 study of nivolumab (Opdivo) plus ipilimumab (Yervoy) versus sunitinib (NCT02231749) in advanced disease patients, those who received the combination achieved higher OS rates at 18 months(75% vs 60%) and objective response rates (42% vs 27%;P<.001) compared with patients treated with sunitinib only.¹

Another trial, the JAVELIN Renal 101 trial (NCT02684006), compared avelumab (Bavencio) plus axitinib (Inlyta) to sunitinib in the same patient population. It demonstrated that combination therapy had a median PFS of 13.8 months, which was significantly higher than with sunitinib monotherapy, which was 7.2 months.²The phase Ib KEYNOTE-426 trial of pembrolizumab (Keytruda) plus axitinib versus sunitinib alone (NCT02853331) showed both a longer PFS (15.1 vs 11.1 months) and OS (89.9% vs 78.3%). The combination, pembrolizumab/axitinib also reached a higher objective response rate of 59.3% (95% CI, 54.5%-63.9%) compared with 35.7% (95% CI, 31.1%-40.4%) with sunitinib alone.³

These combinations are highly active; however, McGregor admitted that they do not work for all patients. In patients with certain morbidities, like hypertension or arthritis, these regimens may do more harm than good. &ldquo;It comes down to looking at the patient and finding the regimen that works best for them,&rdquo; he said. &nbsp;

For some patients, sunitinib monotherapy may be the best option, and although the combination therapies are promising, sunitinib is still active in this patient population.

In an interview withTargeted Oncologyat the2019Kidney Cancer Research Summit, McGregor, clinical director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, discussed emerging combinations and novel agents for the treatment of RCC.

TARGETED ONCOLOGY: What were you excited to see during the first Kidney Cancer Research Summit?

McGregor: Overall, we've had remarkable advances in kidney cancer over the past couple of years. Going back to ESMO 2017, when we had the first data for nivolumab and ipilimumab, this showed improvement in OS in those with intermediate and poor-risk disease. Since then we've presented data for both axitinib/avelumab, and pembrolizumab/axitinib, showing improvement in PFS across risk groups. [The combination of] pembrolizumab and axitinib showed an improvement in overall survival across risk groups. We have had this revolution of therapy where tyrosine kinase inhibitor (TKI) monotherapy, which used to be that gold standard for kidney cancer, is being replaced by newer agents that hopefully have more durable response rates. But, at the end of the day, not everyone responds to these agents, and as we start using immunotherapy and more potent TKIs in the frontline setting, I think we're left with the question of what happens to those patients who don't respond?

We need ongoing research. This symposium is focusing on that research. We're looking for novel targets and new ways we can attack kidney cancer because as well as we're doing, we're not doing this for everyone. Some patients don't respond to these great combinations and we need to do better. This meeting is focusing on those approaches.

TARGETED ONCOLOGY: Has the emergence of multiple combinations for kidney cancer made treatment decisions more complicated?

McGregor: Absolutely. We have 3 large trials that were comparing combination regimens versus sunitinib monotherapy. All 3 combinations were able to outperform sunitinib in various ways, but they weren't compared head-to-head. How does one choose between nivolumab and ipilimumab versus pembrolizumab/axitinib versus axitinib/avelumab? It's challenging and I think right now if you're going to be encouraged by the data from axitinib/avelumab, while it&rsquo;s probably one of the best-tolerated regimens with only 11% of patients needing high-dose steroids, it doesn't have an OS benefit yet, but that could change with longer survival. We're left with only 2 agents that improve OS in the frontline versus sunitinib. Granted nivolumab/ipilimumab goes with intermediate or poor-risk disease whereas pembrolizumab/axitinib is across all risk groups.

It comes down to a discussion with the patient about what's important to them. Axitinib/nivolumab has the highest rate of immune-related adverse events, up to 35% require high-dose steroids and 60% required some form of steroids. Although we're not supposed to compare trial to trial, it did seem to have the highest complete response (CR) rate, which was close to 10%. That's important. We may say a DPR is just as good as a CR, a patient feels good when you say "hey, the CT scan says it's all gone." That's something to think about.

Alternatively, some patients are scared of immune-related events and they like the idea of oral therapy and they want to take that. It does come down to a discussion with the patient about which regimen fits in best with their lifestyle and what's important to them. Some patients may say, &ldquo;I don't want to take a pill." Maybe another patient has bad hypertension or cardiomyopathy in which case, you should be worried about giving them prolonged axitinib. It comes down to looking at the patient and finding the regimen that works best for them.

TARGETED ONCOLOGY: Are there patients you still prescribe sunitinib to?

McGregor: There are certain patients who you'd be worried about giving immunotherapy to. I have patients come into the clinic and they have serious deformities from rheumatoid arthritis. While we are intrigued by the idea of immunotherapy, if we have another option that can work for these patients that doesn&rsquo;t have that risk of autoimmune complications, I think that's appealing. If you look at the data in clinical practice, some people do well with TKI monotherapy.

What we need to do as we move forward is, [find] those biomarkers that assess what's going on. Toni Choueiri, MD, presented data at ASCO this year looking at avelumab plus axitinib versus sunitinib in the JAVELIN Renal 101 trial. It showed that there seems to be this VEGF signal that patients do well with sunitinib alone and better than the combination of axitinib and avelumab. We need to find those biomarkers to say who's going to do well with monotherapy, or who has that VEGF-driven tumor. We had a hint of that with the nivolumab/ipilimumab data and we see that those patients with good risk seem to have a better PFS and response rate with sunitinib compared with nivolumab and ipilimumab.

This is something that is evolving and is exciting as we look toward the future.

TARGETED ONCOLOGY: What are some other combination regimens that are being explored that look promising?

McGregor: The recently opened COSMIC trial is fascinating. It's going to be the first trial comparing the combination of nivolumab and ipilimumab versus nivolumab/ipilimumab with cabozantinib (Cabometyx). That will be interesting. We've seen that VEGF plus immuno-oncology (IO) therapy works with single-agent PD-1, and the great thing about ipilimumab is that it has durability, so maybe by adding that VEGF2 with nivolumab/ipilimumab, we'll have better response rates.

There are ongoing trials looking at NKTR-214, which is a pegylated interleukin-2. There are lots of different combinations that we're looking at to try to hopefully improve response rates. We are also trying to manage the safety profile because our goal in these situations is to give patients the best quality of life for as long as possible.

TARGETED ONCOLOGY: What other novel agents are under investigation?

McGregor: I think one of the more exciting agents is the glutaminase inhibitor. There&rsquo;s the recently accrued CANTATA trial, which is looking at cabozantinib with or without that glutaminase inhibitor. There is a lot of interest in HIF-2 inhibition. There's a compound exploring HIF-2 inhibition. Data was presented at the International Kidney Consortium last year showing that these regimen have activity in heavily treated patients.

We're looking at these novel approaches and, on top of that, we're looking at the mechanisms of resistance so that we can maybe combine agents earlier in different combinations to overcome those resistances.

TARGETED ONCOLOGY: What research is ongoing at Dana-Farber Cancer Institute in this space?

McGregor: We are actively involved in a lot of these clinical trials. We've been looking at non-clear cell RCC and we presented some data earlier this year on the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) in non-clear cell RCC. This is a trial of 60 patients that included those with non-clear cell disease or those with greater than 20% sarcomatoid differentiation, independent of histology. What we showed was that this combination is highly active with response rates close to 30% in all-comers with good activity and a minimal toxicity profile. While atezolizumab/bevacizumab is not an approved combination for treatment in clear cell kidney cancer at this time, other VEGF and IO combinations are approved. Our data has the activity of IO plus VEGF combinations, independent of histology. I think it's intriguing and we're looking to build upon the data with other trials.

TARGETED ONCOLOGY: What are prognostic differences between clear-cell and non-clear cell kidney cancer? What are some challenges with treating these histologies?

McGregor: There has been lots of research on this and, unfortunately, patients with non-clear cell histology have worse outcomes than their clear-cell counterparts, stage for stage. There's an unmet need for our patients.

When you look at non-clear cell histology, it's a diverse group. Papillary is nowhere near the same as medullary, collecting duct, or a translocation. A lot of these basket trials include all clear cell patients, and while I think that's the best way to get these patients on trials, these are very different biologies. It's something that needs to be looked at individually. That's been done to an extent with the ongoing PAPMET trial looking at those with papillary RCC and saying if this is aMET-driven process, let's try to attack MET with different MET inhibitors.

We have a long way to go in the treatment of our patients with non-clear cell RCC.

References

1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378:1277-1290. doi: 10.1056/NEJMoa1712126.
2. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.N Engl J Med. 2019;380:1103-1115. doi: 10.1056/NEJMoa1816047. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.N Engl J Med. 2019;380:1116-1127. doi: 10.1056/NEJMoa1816714.