Cabozantinib Combinations Generate Excitement in RCC

Rana R. McKay, MD

Since the FDA approval of cabozantinib (Cabometyx) for use patients with in renal cell carcinoma (RCC), research efforts have been examining the agent in combination with immunotherapy and dual immunotherapy to further improve patient outcomes, according to Rana R. McKay, MD.

“The treatment landscape for patients with advanced RCC has been rapidly evolving. Historically, the standard frontline treatment for those with advanced disease has been single-agent VEGF inhibition,” said McKay. “Over the past several years, we've seen a series of studies that have explored combination treatment strategies, such as dual-immunotherapy combinations or immunotherapy/VEGF combinations, that have revolutionized the way that we treat this patient population.”

Results from the phase II CABOSUN trial demonstrated that frontline cabozantinib was superior to sunitinib (Sutent) in patients with advanced RCC, showing a median progression-free survival (PFS) of 8.6 months versus 5.3 months per independent review committee (IRC); this translated to a 52% reduction in the risk of progression or death (HR, 0.48; 95% CI, 0.31-0.74; P = .0008).¹ The objective response rate with cabozantinib was 20% versus 9% with sunitinib. Moreover, at a median follow-up of 34.5 months, the median overall survival (OS) was 26.6 months compared with 21.2 months with cabozantinib and sunitinib, respectively (HR, 0.80; 95% CI, 0.53-1.21).²

The use of TKI combinations is rapidly expanding in RCC, with several trials evaluating cabozantinib combinations, added McKay. For example, cabozantinib is being examined in combination with the PD-L1 inhibitor atezolizumab (Tecentriq) in the phase Ib COSMIC-21 trial.

Additionally, the CheckMate-9ER trial (NCT03141177) is examining the combination of cabozantinib plus nivolumab (Opdivo) versus sunitinib in treatment-naïve patients with advanced or metastatic RCC. Depending on the results, the trial could potentially shift the current standard of care for frontline RCC therapy, according to McKay.

In an interview with OncLive, McKay, a medical oncologist and assistant professor of medicine at the University of California, San Diego Health, discussed the evolving role of cabozantinib in the RCC treatment paradigm and the research being done examining novel combinations.

OncLive: What are some of the newest options available for patients with RCC? How has treatment evolved in recent years?

McKay: Data [from recent] studies highlight that patient survival [and] responses are improving [with combinations]. To date, the 3 combinations that have been approved for use in the United States include the combination of nivolumab plus ipilimumab (Yervoy), based on data from CheckMate-214; pembrolizumab (Keytruda) plus axitinib (Inlyta) based on data from KEYNOTE-426; and axitinib plus avelumab (Bavencio) based on data from JAVELIN Renal 101.

Cabozantinib recently emerged as a promising frontline treatment in RCC. How is cabozantinib unique compared with other agents in the space?

Cabozantinib is a TKI that, in addition to blocking VEGF, also blocks MET, which is a known mechanism of resistance to VEGF inhibition. Initially, cabozantinib was approved for use in the second-line space, based on data from the METEOR trial. Patients who received a prior VEGF inhibitor were randomized to receive either cabozantinib or everolimus. Results from the study demonstrated improvements in response, PFS, and OS in [this patient population].

Due to the efficacy observed with cabozantinib in the second-line and its ability to overcome resistance to VEGF inhibition, the drug was evaluated in the frontline space via a large phase II study that was conducted by the Alliance [for Clinical Trials in Oncology; the effort was led by] Toni Choueiri, MD, of Dana-Farber Cancer Institute. In this trial, patients who had intermediate- or poor-risk disease based on International Metastatic RCC Database Consortium criteria were randomized to receive cabozantinib compared with sunitinib. Results demonstrated a significant improvement in ORRs and PFS in patients who received frontline cabozantinib, thus presenting another treatment option to those with newly diagnosed disease.

Cabozantinib appears to have particular activity in patients who have bone metastases, given that bone metastases tend to have increased expression as MET. Existing data support [the agent’s] use in all-comers, but specifically in that subset of patients. [Cabozantinib] also serves as a treatment option for patients who are not able to receive dual immunotherapy combinations or immunotherapy plus VEGF combinations.

What are some of the trials investigating cabozantinib in combination with other agents?

Several trials are exploring various combinations of cabozantinib with immunotherapy. The phase Ib COSMIC-021 trial is evaluating the combination of cabozantinib with atezolizumab, which is a PD-L1 inhibitor. There is suspected synergy between cabozantinib and checkpoint inhibition, and the data show a signal of efficacy with the combination of these agents. A larger phase III trial that is currently being designed and launched is evaluating cabozantinib with or without atezolizumab in the second-line setting, following immunotherapy or immunotherapy/VEGF therapy. The trial is [enrolling] patients with clear cell, unclassified, and papillary histology, [and seeks to address] the unmet need of the patient population with non-clear cell RCC. There is rationale for combining cabozantinib with immunotherapy.

Additionally, in the frontline space, several trials are currently evaluating different treatment strategies that utilize cabozantinib. For example, we are eagerly awaiting the data from the CheckMate-9ER trial of nivolumab plus cabozantinib in this space. Additionally, COSMIC-313 is examining the combination of nivolumab plus ipilimumab with or without cabozantinib in the frontline.

Furthermore, a large cooperative group trial chaired by Tian Zhang, MD, of the Duke Cancer Institute, along with Choueiri, is looking at an adaptive-based approach to immunotherapy. All patients will start on treatment with nivolumab/ipilimumab, and then, based on their response to therapy, they will be randomized to either continue nivolumab or have cabozantinib added to nivolumab.

What is known about the safety of some of these combinations?

The safety profiles of the combinations differ. When we look at the safety profiles of VEGF-targeted therapies, they tend to be predictable and dose dependent. [Safety] improves when the drug is discontinued or [the dose is] modified. When we look at toxicities associated with immunotherapy, at the present time, we don't have any strategies to predict who is going to develop [an event] or not. The toxicity does not appear to be dose dependent and [these events] generally happen at any time, although you cannot predict the timing. When we look at data from KEYNOTE-426 with the combination of pembrolizumab plus axitinib, there are some nuances about immunotherapy and VEGF combinations. Some symptoms could be related to either the immunotherapy agent or the VEGF agent. For example, hepatitis could be related to the immunotherapy agent or axitinib. Similarly, diarrhea could be related to either of the agents, as well.

The beauty about axitinib is that it has a very short half-life; it can be easily discontinued and you can very closely monitor for resolution of toxicity before triggering the use of steroids or other immune-modifying agents. However, the [regimen] requires a lot of close monitoring; the grade 3/4 toxicity is supposed to be higher with the combination of immunotherapy plus VEGF.

When we look at the dual immunotherapy combinations, such as nivolumab plus ipilimumab, it appears that approximately one-third of patients require the use of high-dose steroids to treat what may be an immune-related adverse event, whether that be colitis, pneumonitis, hepatitis, or other immune-mediated phenomenon. The toxicity seems to occur early, within the first 6 months of treatment. There is not necessarily time [for the events to] be chronic in nature, barring those patients who require chronic steroid use for different therapies.

The safety profiles of these agents are very different and require very close communication with the care team of the patient, including involvement of the nursing staff who sometimes are on the front lines with triaging symptoms for patients. If patients enter into a different care facility, make sure that the facility knows the drugs that they are taking. A lot of education is needed between the patient and the multidisciplinary team that's caring for them with regard to these combinations.

If the combination of nivolumab plus cabozantinib were approved down the line, would this cause any disruptions in sequencing?

We are eagerly awaiting the results of the CheckMate-9ER trial, which is examining the combination of nivolumab plus cabozantinib. If this trial were to be positive, it's going to throw another wrench into the treatment landscape of metastatic RCC because there would be a fourth regimen that will be approved for use in the frontline space. Additionally, if cabozantinib is being use in the frontline space, it might create complications regarding the second-line strategy.

That being said, the field is moving toward the use of combinations early and up front in an attempt to overcome resistance. Some patients may not have the opportunity to receive a second-, third-, or fourth-line drug depending on their disease course. If we can improve the options available in the frontline space, the hope is that we never need to answer the question about second-line therapy because we’ll be doing frontline treatment very well. Should this combination be approved, it is going to create some complexity with regard to how we will strategize therapies post-cabozantinib.

What are your thoughts on the new drug application submitted to the FDA for tivozanib (Fotivda) in relapsed/refractory RCC?

It's exciting to see that tivozanib was submitted to the FDA for approval. Persistence is key when it comes to this agent. Multiple points exist along the trajectory of the development of this drug; there has been hurdle after hurdle. [We know that it] is an effective VEGF TKI that has demonstrated clear efficacy for [patients with] advanced RCC. As such, we await the decision of the FDA regarding this agent.

Are any biomarkers under exploration in this disease?

Many biomarkers have been investigated in the context of large phase III trials in advanced RCC. Largely, PD-L1 status has been looked at. The assays that were used in the context of these phase III trials all differ because they all define positivity in a different kind of way. Additionally, the number of patients who were deemed to be biomarker-positive based on PD-L1 status all differed from around 25% to upward of 60%, depending on the trial. We still have a lot to do with regard to biomarker research.

Presently, it does not seem that PD-L1 status is a purely predictive biomarker. Other biomarkers are also being explored, specifically tumor mutational burden, CD8, tumor cell infiltration, and novel signatures. RNA signatures of immune response or immunogenicity have also been examined, as well.

Another biomarker that has been explored, but is not typically considered to be a biomarker, is histology. For example, we’re realizing that patients who have sarcomatoid histology appear to do better with immunotherapy-based therapies and have very dramatic responses. [Histology] is not a classic biomarker but is a histologic biomarker that has been very clinically meaningful.

There is still a lot to come with regard to the development and identification of biomarkers in RCC, specifically with regard to predictive biomarkers that will help guide therapy. I would implore the field to develop standardized strategies around these biomarkers so that every single trial doesn't use a different biomarker. We need to use biomarkers that can be applied across trials so we can utilize them in clinical practice.

References

1. George DJ, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib for previously untreated patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk: subgroup analysis of progression-free survival (PFS) and objective response rate (ORR) in the Alliance A031203 CABOSUN trial. J Clin Oncol. 2018;36(suppl 6; abstr 582). doi: 10.1200/JCO.2018.36.6_suppl.582
2. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94(115-125). doi: 10.1016/j.ejca.2018.02.012