Agarwal Expands on Sequencing Options in mRCC

Neeraj Agarwal, MD

With more than 11 therapies FDA approved for patients with metastatic renal cell carcinoma (mRCC), sequencing therapies has become a challenge for many clinicians. For those who progress on frontline therapy, the most effective second-line therapy, according to Neeraj Agarwal, MD, is cabozantinib (Cabometyx).

“If somebody is progressing on a first-line VEGF tyrosine kinase inhibitor (TKI) or immunotherapy, the best drug I can think of is cabozantinib, which is an inhibitor of VEGF, cMET, and AXL,” said Agarwal, associate professor, Division of Oncology, Department of Medicine, at the University of Utah School of Medicine, Huntsman Cancer Institute.

Cabozantinib holds frontline and second-line indications for patients with advanced RCC. The TKI was initially approved in April 2016 for patients with mRCC following 1 prior antiangiogenic therapy. The decision was based on data from the phase III METEOR trial, which indicated a 49% reduction in the risk of disease progression or death with cabozantinib versus everolimus (Afinitor). Moreover, the median progression-free survival (PFS) was 7.4 months versus 3.9 months, respectively (HR, 0.51; P <.0001). Additionally, the TKI demonstrated a 4.9-month extension in the median overall survival (OS) compared with everolimus.

OncLive^®: How has mRCC treatment changed over the past decade?

What are some sequencing considerations?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Agarwal discussed his preferred sequencing strategies in the treatment of patients with mRCC.Agarwal: It’s amazing to see how much has changed in the last 10 years. Just 10 years ago, all we had was interferon or high-dose interleukin therapy. Since the approval of sorafenib (Nexavar)—the first VEGF TKI to be approved for these patients—we have seen more than 10 agents get approved. We continue to see new approvals every 6 months now, [and it has become] very challenging [to figure] how to sequence these agents and how to maximize their efficacy so that we can improve the OS and quality of life for our patients.I would divide these agents into 4 major classes. First, there are agents that target VEGF; these would be the VEGF TKIs or VEGF antibodies, such as sunitinib (Sutent), pazopanib (Votrient), sorafenib, or bevacizumab (Avastin). The second class is of the second-generation VEGF inhibitors, such as cabozantinib, which also have activity against other tyrosine kinases. Cabozantinib also inhibits AXL and cMET. There is lenvatinib (Lenvima), which also inhibits FGFR, which is considered to be among the resistance mechanisms for VEGF blockade.

The third category is mTOR inhibitors, which are, frankly, no longer used in most of these patients. The fourth and most novel class is the checkpoint inhibitors, which include ipilimumab (Yervoy), a CTLA-4 inhibitor, and nivolumab (Opdivo), a PD-1 inhibitor.

As far as sequencing is concerned, I always remind myself of the data from The International Metastatic Renal Cell Carcinoma Consortium led by Toni Choueiri, MD, of Dana- Farber Cancer Institute and Daniel Heng, MD, of the Tom Baker Cancer Centre. I’m part of the consortium, and we just published a paper that shows how many real-world patients are able to get second- and third-line therapy.

The results were very telling. We started with more than 7000 patients who were newly diagnosed and received first-line therapy for metastatic RCC. Only 50% of patients received second-line therapy, and fewer than 8% of patients received fourth-line therapy. The message I got from these data was that we need to use the most effective therapy at a given time point for each given patient. Otherwise, it is very possible that the patient may not see the second- or third-line therapy.

When I look at somebody who has progressed on a VEGF TKI, I want to use the most effective second-line therapy or salvage therapy. I would call it salvage therapy because all these agents are not only approved for those who have failed first-line therapy, they’re approved for patients who have progressed on multiple lines of therapy.

How have combination regimens played a role in sequencing?

As a monotherapy, cabozantinib is still associated with the longest second-line or third-line PFS. That is very important for me because a long PFS means the patient is going to be alive for that amount of time and also is more likely to see the subsequent line of therapy.The combination of lenvatinib with everolimus was approved by the FDA based on data from a phase II trial; it was a 3-arm trial comparing the use of lenvatinib with that of everolimus and of lenvatinib plus everolimus. There were 50 patients in each arm. If you look at the data carefully, lenvatinib was not superior to everolimus in terms of PFS, which was the primary endpoint of the study. The FDA approved the combination of lenvatinib and everolimus based on its superiority for PFS compared with everolimus alone.

What is the greatest unmet need in this population?

What do we get from this combination? There is increased efficacy. The median PFS was 12 to 13 months versus 4 to 5 months with everolimus monotherapy. However, 2 drugs mean more toxicity and more cost. Given this, I still prefer cabozantinib for frail patients who are progressing on first-line therapy. When these patients progress on cabozantinib, I tend to go with the combination of lenvatinib and everolimus [assuming] they can tolerate or afford the combination.There’s unmet need all over. It’s great to see that OS has gone up from 1 year to almost 3 to 4 years. I ’m happy with the progress that has been made, but I’m not satisfied. We need to keep moving toward developing more exciting drugs and more combinations. More importantly, we need to develop biomarkers to minimize cost and toxicity and improve patient selection.

The combination of ipilimumab and nivolumab has already been approved by the FDA in the first-line setting. I [believe] axitinib (Inlyta) with avelumab (Bavencio) and axitinib with pembrolizumab (Keytruda) will be approved in 2019. When you talk about patients who are progressing on these drugs, the only drug I can think of is cabozantinib. Cabozantinib is obviously superior to conventional VEGF TKIs, such as sunitinib or, in the context of the METEOR trial, everolimus; it is a monotherapy which is better than dual therapy. [Cabozantinib monotherapy is better than] combination therapy with lenvatinib and everolimus, in terms of cost and toxicity. [Again], you can always use [that combination] later.

Choueiri TK, Escudier B, Powles T, et al; METEOR Investigators. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814- 1823. doi: 10.1056/NEJMoa1510016.