Back Back
TKIs in Era of Immunotherapy
Renal Cell Carcinoma in Transition: Role of TKI-Based Therapy in the Era of Immunotherapy

Released: April 03, 2017

Expiration: April 02, 2018

Activity Information

Activity

Progress
1
Course Completed

Case Study: First-line Options
A 64‑year‑old man received a nephrectomy for localized renal cell carcinoma (RCC). Six months later, he was found to have lung metastases and was started on sunitinib.

The current standard for first‑line treatment of RCC is either sunitinib or pazopanib, based on the phase III COMPARZ trial results that showed that both TKIs produced equivalent PFS and OS. Although sunitinib and pazopanib remain reasonable choices for initial systemic therapy, other first-line agents are expected to become available in the near future.

Promising combination regimens are being explored in the first-line setting and include phase III studies of atezolizumab plus bevacizumab, ipilimumab plus nivolumab, and avelumab plus axitinib, all being compared with sunitinib. The phase II IMmotion150 trial compared atezolizumab (an anti–PD-L1 antibody) plus bevacizumab (an anti-VEGF antibody) vs atezolizumab vs sunitinib in treatment-naive advanced RCC (N = 305). Efficacy analysis in the overall patient population showed similar PFS (the primary endpoint) between all treatment arms (HR: 1.10 for the combination vs sunitinib). However, in patients who expressed higher levels of PD-L1, there was an improvement in PFS with atezolizumab plus bevacizumab vs sunitinib (HR: 0.64; P = .095). This is very encouraging, and a phase III study comparing this combination to sunitinib in patients with untreated metastatic RCC is under way that could affect treatment in the first‑line setting.

The combination of ipilimumab plus nivolumab—2 checkpoint inhibitors—has also been explored in patients with metastatic RCC who have had no previous systemic therapy for metastatic disease in the phase II CheckMate 016 trial, which showed a promising ORR of 40%. This combination is now being compared with sunitinib in the phase III CheckMate 214 study.

In the phase III JAVELIN Renal 101 study, axitinib plus avelumab (a VEGF‑TKI and PD‑L1 inhibitor combination) is being compared with sunitinib in the first-line setting.

In addition to combination approaches, the phase II CABOSUN trial comparing cabozantinib with sunitinib in the first-line treatment setting for intermediate-risk or poor-risk RCC showed superior clinical efficacy with cabozantinib. Safety profiles between these 2 agents were comparable, and once more mature OS analysis is available, cabozantinib may also be a potential first-line treatment option for this patient population.

I expect a paradigm shift in the first‑line therapy setting within the next 2 years, particularly regarding treatment approaches with immune checkpoint inhibitors, but at least for now, sunitinib and pazopanib remain the standard of care in this setting and are considered equivalent in terms of efficacy.

Case Study: Second-line Options
The patient was started on sunitinib and continued therapy for 12 months without progression. At that time, he developed progressive lung nodules and mediastinal lymphadenopathy. He had an ECOG PS of 0 (ie, very healthy) with normal renal function and no comorbid conditions other than controlled mild hypertension (which may be due to sunitinib). He is deemed to have intermediate-risk disease.

Currently used second-line options for metastatic RCC include axitinib, cabozantinib, nivolumab, lenvatinib/everolimus, and everolimus alone. When considering each of these agents, I would recommend cabozantinib for this patient based the patient’s disease and characteristics. First, let’s talk about the large phase III METEOR trial, which compared cabozantinib with everolimus as second-line therapy after previous progression on a first-line VEGF-TKI in patients with metastatic RCC. In this study, cabozantinib produced the longest median PFS seen with a second-line monotherapy to date in metastatic RCC (7.4 months with cabozantinib vs 3.9 months with everolimus). In an unplanned second interim analysis of OS, cabozantinib also increased the median OS vs everolimus (21.4 vs 16.5 months, respectively). In a subgroup analysis, it was clear that the patients who benefited most had intermediate to good risk. The PFS HRs, strongly favoring cabozantinib over everolimus, were 0.54 for good-risk patients and 0.57 for intermediate-risk patients. By contrast, the PFS HR for patients with poor risk was 0.78. A caveat is that these small subgroups were not powered individually for PFS and OS benefit.

My second choice for the case patient would be nivolumab. The phase III CheckMate-025 trial comparing nivolumab with everolimus also showed impressive efficacy for patients with metastatic RCC who progressed on or after previous antiangiogenic therapy. However, a subgroup analysis of the CheckMate-025 trial showed that nivolumab worked best in patients with poor risk, with an OS HR of 0.48 favoring nivolumab over everolimus for these patients compared with 0.81 and 0.80 for intermediate-risk patients and good-risk patients, respectively. Of course, these subgroup analyses in the METEOR and CheckMate-0125 trials are not powered to adequately assess PFS or OS benefit and cross trial comparisons are fraught with fundamental issues, but there will likely not be a trial directly comparing cabozantinib with nivolumab. Therefore, these subgroup analyses are all we can use to select optimal therapy for individual patients and suggest that for favorable-risk and intermediate-risk patients, cabozantinib may be a superior option to nivolumab.

Patients who are working full time and have a good PS typically like to be active and minimize hospital visits. If they are receiving an oral medication like cabozantinib, they come for the clinic visits every 4-6 weeks. If they are receiving nivolumab, they must receive infusions in the hospital every 2 weeks, for at least 1-2 hours, in addition to the doctor’s visit every 4 weeks. Since our case patient was treated with sunitinib with minimal adverse events from TKI therapy, he is likely to have a good quality of life on cabozantinib. In addition, cabozantinib is associated with the longest PFS as monotherapy in this setting (7.4 vs 4.5 months with nivolumab).

In my personal experience, although there are now numerous choices for subsequent lines of therapy in RCC, a subset of patients will never receive their next line of therapy, particularly if they have rapid disease progression. Although our case patient has a good PS, he does have disease progression in his mediastinal lymph nodes, which can be a concern. So, the focus of therapy for these patients should be on disease control and choosing therapy with the best chance of a response or disease stability, which is why I would recommend that he receive cabozantinib instead of nivolumab. Primary progressive disease (no response, no stable disease) as the best response to therapy is critical to selecting subsequent treatments and was more common with nivolumab (35%) than cabozantinib (14%).

Regarding the other potential second-line options, I use axitinib in the second-line setting for patients who received first-line high-dose IL‑2 (used in select patients with a good PS and normal organ function) based on the phase III AXIS study of axitinib vs sorafenib as second-line therapy for metastatic RCC (N = 723). Subgroup analyses from this trial suggested that patients who received first-line VEGF TKI (sunitinib) had only a minimal median PFS improvement with second-line axitinib (4.8 vs 3.4 months with sorafenib; HR: 0.74) whereas patients who received first-line high-dose IL‑2 had an improved benefit (12.1 vs 6.5 months, respectively; HR: 0.46). Axitinib is also the best tolerated VEGF TKI in my experience, and for patients concerned about maintaining quality of life, axitinib is a good choice.

The combination of lenvatinib plus everolimus is also approved for patients with advanced RCC following 1 previous antiangiogenic therapy based on phase II data showing an impressive median PFS of 14.6 months. However, as a combination regimen, there are more associated adverse events than with the monotherapies. I consider cabozantinib preferable to lenvatinib/everolimus for this reason. That said, I use lenvatinib/everolimus for patients in the second-line setting who did not respond to a first-line VEGF TKI for more than 6 months and have rapidly progressive, high‑burden, high‑volume disease. I also use this regimen for patients who have progressed on both cabozantinib and nivolumab.

Looking Forward
As discussed earlier, it is likely that at least 1 PD-1 pathway inhibitor will be approved in the first‑line setting, and the question will then become: What do we do in the second line? There are no data supporting sequential use of multiple immune checkpoint inhibitors. Therefore, the TKIs cabozantinib and axitinib will become the preferred second‑line choice. However, if the CABOSUN trial data result in FDA approval of cabozantinib as first‑line therapy, patients having received cabozantinib as first-line treatment may still be able to use nivolumab as second‑line therapy.

So, depending on which trials are positive or which of these agents are FDA approved in the near future, the sequencing of therapy may change. Ultimately, more robust biomarkers are needed to optimize treatment selection for patients with advanced RCC. Although data have emerged suggesting associations between biomarkers and outcomes (eg, tumor PD-L1 expression), not a single biomarker has been validated. More importantly, we need specific biomarkers that can identify who is not going to respond to a given agent. Until those biomarkers are available, we have to rely on cross-trial comparisons of subgroup analyses, which are less than ideal.

How are you using these newer agents in your clinical practice? Check out CCO’s online treatment decision tool to help you rapidly select individualized treatment options based on your patient’s specific characteristics and share your experience in the comment box below.