CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: April 07, 2023
Expiration: April 06, 2024
What most of us unfortunately see in our medical oncology clinics is a referral for patients who have either de novo metastatic disease or recurrence after prior nephrectomy. It is important to understand the biology of the patient’s disease to determine how best to treat the patient. What oncologists have been using for many years is the IMDC criteria.14 These criteria consist of numerous clinical and laboratory values that allow for patient prognostication. The data were collected based on patients who received TKI therapy.
It was determined that risk factors for more aggressive disease biology would include a lower performance status (Karnofsky performance status <80%), time from initial diagnosis to targeted treatment of <1 year, anemia, hypercalcemia, or elevated platelet or neutrophil counts. Each of these gives the patient a point for a risk factor.
The biology for patients who have none of these risk factors tends to be favorable and correlated with a 2-year OS of 75%. With the addition of 1 or 2 risk factors, patients are categorized as intermediate risk, with a 2-year OS of 53%; 3 or more risk factors is deemed to be poor risk. These patients, unfortunately, have a more rapid and aggressive biology, with a 2-year OS of 7%.
Many people wonder if upfront nephrectomies still should be performed before starting systemic treatment in patients with advanced disease. In the days of high‑dose interleukin‑2 and interferon-γ, there were some data to suggest that cytoreductive nephrectomy did improve survival.15
Subsequently, now having used TKIs for many years, the CARMENA trial16 of sunitinib alone vs nephrectomy followed by sunitinib investigated if cytoreductive nephrectomy holds benefit in the era of TKIs. Sunitinib was found to be noninferior to nephrectomy followed by sunitinib (HR: 0.97; 95% CI: 0.79-1.19; P = .8). Based on the data from the CARMENA trial and some other data, I think the field has switched to not doing upfront cytoreductive nephrectomies for all patients.
The answer to the utility of nephrectomies in this new checkpoint inhibitor era is unknown. In my current practice, where mostly I am using checkpoint inhibitor backbones for frontline treatment of metastatic disease, I will consider either upfront cytoreductive nephrectomy or a delayed cytoreductive nephrectomy. I take into consideration the extent of the patient’s metastatic disease. For example, nephrectomy could be considered for someone with limited metastatic disease outside the kidney. However, with a higher volume of disease (moderate or extensive extrarenal disease), I commonly will initiate systemic therapy first and perform a delayed nephrectomy later pending clinical response.
It is known from the clinical trials of frontline therapy that many patients who have their kidney intact at the time of initiating systemic therapy often do not go on to achieve a complete response (CR). Ongoing clinical trials in cooperative groups are looking to better understand if a cytoreductive nephrectomy will be beneficial in the era of checkpoint inhibition (NCT04510597, NCT05753839).
The IMDC risk stratification is used to help determine frontline treatment. For IMDC favorable risk, the recommendations currently are IO/TKI combinations: pembrolizumab/axitinib, nivolumab/cabozantinib, and pembrolizumab/lenvatinib. All of these combinations have FDA approval for use in the first-line setting for patients with advanced RCC with both favorable and intermediate/poor risk. In addition to the IO/TKI combinations, dual PD-1/CTLA-4 treatment in the form of nivolumab and ipilimumab can be used for patients with intermediate and poor risk.17
CheckMate 214 was the first combination trial to be reported to show improvement in OS.18 CheckMate 214 tested the PD‑1/CTLA-4 combination of nivolumab 3 mg/kg IV every 3 weeks and ipilimumab 1 mg/kg IV every 3 weeks in the frontline setting compared with the standard of care at the time, sunitinib.
We now have 5‑year survival data to suggest that approximately 50% of patients receiving nivolumab and ipilimumab in the intention-to-treat (ITT) population were alive at year 5 and showed significant improvement in OS compared with sunitinib (HR: 0.72; 95% CI: 0.62-0.85; P <.001).
When survival benefit of this combination is assessed based on risk status, it is apparent why the PD-1/CLTA-4 combination is approved for only intermediate/poor-risk patients. Although patients with favorable-risk disease did show clinical benefit, including high CR rate, regardless of risk category, there was no improvement in OS in good risk compared with sunitinib (HR: 0.94; 95% CI: 0.65-1.37; P = .7673). In the intermediate/poor-risk group, a clear OS benefit was noted; median OS was 47 months with combination therapy vs 26.6 months with sunitinib (HR: 0.68; 95% CI: 0.58-0.81; P <.0001).
The next combination trial was KEYNOTE‑426,19,20 which assessed the VEGF TKI axitinib at 5 mg twice daily in combination with pembrolizumab 200 mg IV every 3 weeks vs sunitinib in the first-line setting for advanced or metastatic RCC. The pembrolizumab/axitinib combination showed an improvement in OS. Median OS in the ITT population was 45.7 months with pembrolizumab/axitinib vs 40.1 months with sunitinib (HR: 0.73; 95% CI: 0.60-0.88; P <.001).
CheckMate 9ER compared nivolumab 240 mg IV every 2 weeks plus oral cabozantinib 40 mg once daily with sunitinib for treatment of first-line metastatic RCC. At ASCO GU 2023, the 3‑year survival data for CheckMate 9ER21 were presented. At the 36‑month mark, 58.7% of patients in the ITT population receiving the IO/TKI combination were alive compared with 49.5% in the sunitinib arm, yielding a median OS of 49.5 months with nivolumab/cabozantinib vs 35.5 months with sunitinib (HR: 0.70; 95% CI: 0.56-0.87).
Finally, the most recent IO/TKI combination studied in first-line advanced RCC was in the CLEAR trial. The CLEAR trial had 3 arms: lenvatinib 20 mg once daily plus pembrolizumab 200 mg IV every 3 weeks, lenvatinib 18 mg once daily plus everolimus 5 mg daily, and sunitinib 50 mg once daily.22 Compared with sunitinib, patients who received lenvatinib/pembrolizumab had longer OS (HR: 0.66; 95% CI: 0.49-0.88; P = .005).
There are several treatment options in the frontline setting, which is so wonderful for our patients but does make selecting therapy challenging. Although cross-trial comparisons are limited in usefulness because of their differences, this table helps to summarize the key trials in the frontline settings. To highlight a few differences in these studies, there was some variation in the biology of the patients enrolled. For example, the studies with the most patients with poor‑risk disease were CheckMate 21418 and CheckMate 9ER.23 Among the IO/TKI combination studies, CheckMate 9ER had fewer patients with previous nephrectomies at 69% vs 74% and 83% in the CLEAR and KEYNOTE-426 studies, respectively. The number of treatment discontinuations across the trials varied slightly, as well.18,20,22,23
The overall response rates (ORRs) across the IO/TKI trials are in a similar range—between 56% and 71%. However, the ORR in the ipilimumab/nivolumab trial was 39%, which corresponded with a higher rate of primary progressive disease of 18% vs the IO/TKI combination trials.18,20,22,23 If there is concern for rapidly progressive disease, an IO/TKI combination may be preferred.
When considering frontline treatment and the use of IO/IO, sometimes the concern is about the primary progressive disease rate of 18%. More recently, a triplet combination has been studied to investigate if there is benefit of PD-1/CTLA-4 inhibition with a TKI in the upfront setting. COSMIC‑313 is a randomized, placebo-controlled phase III study of nivolumab and ipilimumab with or without cabozantinib in first-line intermediate/poor-risk advanced RCC.24 Updated data for COSMIC-313 were presented at ASCO GU 2023. The primary endpoint of PFS was met in the ITT population (HR: 0.74; 95% CI: 0.58-0.94). Of interest, in the subgroup analysis by IMDC risk group, benefit was maintained in the intermediate-risk group (HR: 0.68; 95% CI: 0.54-0.86), but the same benefit was not shown in the poor‑risk group (HR: 0.93; 95% CI: 0.64-1.35).
Although this trial certainly met its primary endpoint with PFS, the CR rate was lower at 3% compared with some of the other combination trials mentioned previously. There is a lot of discussion as to why the CR rate was lower, including that many more patients on COSMIC‑313 had their primary kidney tumor in place.
The other large consideration in this clinical trial was how to safely give a triplet in the frontline setting, as numerous treatment‑related AEs (TRAEs) led to treatment discontinuation.24 In the intermediate-risk group, 51% of patients who received triplet therapy had a TRAE that led to discontinuation of ≥1 of the 3 drugs, and 14% of patients experienced a TRAE that led to discontinuation of all 3 agents.
There is a question as to whether potential treatment tolerability issues led to a lack of efficacy. Overall, I think we have learned a lot from this clinical trial, and I look forward to seeing future results as the data mature.
In making treatment decisions in the frontline setting between these IO/TKI regimens or the PD-1/CTLA-4 combination, the first thing to assess is IMDC criteria and understanding that the biology of favorable‑risk disease is perhaps really driven in an angiogenic manner. Thus, it makes sense that those patients do well with a TKI in their backbone.
I think about patients and their symptoms and how quickly a response is needed. If the patient is symptomatic and a quick response is necessary, I use a regimen with a TKI, knowing that the time to response is typically quicker and less likely to have primary progressive disease.
If a patient has perhaps a lower volume of disease and is not symptomatic, subgroup analyses have suggested that a PD‑1/CTLA-4 combination—where we have the longest survival data and even treatment‑free survival data—can be beneficial, for example, in those with lung-only disease.
In terms of selecting one IO/TKI combination over another, there are no head-to-head trial comparisons of the different options, so there is not a hard-and-fast rule. We will discuss the AE profiles in more detail later in this module, but potential toxicities and patient comorbidities are key decision points to take into consideration. For example, if I have a frail or older patient for whom I am worried about TKI tolerability and toxicities, the short half-life of axitinib is a nice benefit. If a patient has uncontrolled hypertension or numerous antihypertensives on their medication profile, all of the current TKIs can cause hypertension, but lenvatinib has the highest incidence, so I would be more cautious. If adherence is a concern, lenvatinib and cabozantinib are administered once daily vs axitinib, which is twice daily.
During upfront treatment selection, I also take into consideration what I potentially could administer in the second-line setting. I want to have as many options as possible and be cognizant of what clinical trials could be available for the patient at the time of progression.
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