The following is a summary extracted from a set of guidelines issued during 2022 by the American Society for Clinical Oncology (ASCO) on how to medically treat metastatic kidney cancer for patients who have clear cell carcinoma (ccRCC). The guidelines were developed by a panel of experts co-chaired by W. Kimryn Rathmell, Chair of Medicine at Vanderbilt University Medical Center, and Peter J. Van Veldhuizen, Head of the GU Medical Oncology at the University of Rochester.
What are the preferred options for first-line treatment of metastatic renal cell carcinoma for clear cell patients?
Active Surveillance
The first recommendation is for those metastatic patients who have no symptoms of disease and have a favorable histology, as indicated by the grade and stage of their tumor to be put under “active surveillance.” The objective is to delay systemic therapy for indolent disease in order to increase the quality of life of the patient and not to burden them with the side effects of the therapy.
Systemic Treatment
Patients for whom “systemic treatment” of their tumors is recommended should be evaluated to establish a risk factor category (favorable, intermediate, or poor risk for survival). The risk factor categories are determined by a set of patient characteristics that were developed by Daniel Heng et al. The evaluation system is called the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model[1] or IMDC for short. The resultant risk factor, favorable, intermediate, or poor, informs the choice of therapy to be used for each patient.
Five Combination Therapies
The panel recommended five combination therapies. Four of the combinations can be used for patients in any of the risk categories and one, the combination of two immune therapy drugs, ipilimumab (ipi) plus nivolumab (nivo) is recommended for patients with intermediate or poor-risk disease only.
This is based on the results of the CheckMate 214 trial, which compared the nivo+ipi drug combination to sunitinib. At a 42-month follow-up, intermediate and poor-risk patients taking nivo+ipi had a 52% probability of survival versus a 39% probability for intermediate and poor-risk patients taking sunitinib. Furthermore, 10.1% of the nivo-ipi patient had a complete response (CR) versus 1.4% of the sunitinib patients. In addition, 47.3% of nivo+ipi patients had grade 3 and above Adverse Events versus 64.1% of sunitinib patients. Note that the nivo-ipi combination was not recommended for the favorable risk group patients since it did not show superior performance over sunitinib for favorable-risk patients in the CheckMate 214 trial.
The other four recommendations are combinations of an immune therapy drug with a VEGF inhibitor drug.
The first combination is avelumab plus axitinib, which is based on the results of the Phase III Javelin Renal 101 trial. Half the 886 patients were randomly assigned to the avelumab+axitinib group and the other half to the sunitinib group. The median progressive-free survival (PFS) was 13.8 months for the avelumab-axitinib patients versus 8.4 months for the sunitinib patients. The Adverse Events (AEs) grade 3 and above affected about the same number of patients in each cohort, 71.2% for the avelumab-axitinib group and 71.5% for the sunitinib group. The overall survival data are still pending, but the above data were good enough for the panel to recommend the combination therapy.
Next is lenvatinib plus pembrolizumab or everolimus versus sunitinib. In the Phase III CLEAR trial, 1069 patients were randomly assigned to one of three arms of the trial: lenvatinib plus pembrolizumab, lenvatinib plus everlolimus, or sunitinib. With the primary endpoint being PFS, the lenvatinib plus pembrolizumab combination group had a PFS of 23.9 months versus 9.2 months for the sunitinib group and also had a 34% advantage over the sunitinib patients in respect to median overall survival (OS). 16.1% of the lenvatinib plus pembrolizumab group had a CR versus 9.8% of the Lenvatinib plus everolimus group versus 4.2% of the sunitinib group. The side effects of the combination therapies were high, with grade 3 or higher AEs occurring in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% in the lenvatinib plus everolimus patients, and 71.8% of the sunitinib patients leading to high drug discontinuations and dose reductions.
The third combination trial is pembrolizumab plus axitinib versus sunitinib with data coming from the 861 patient Keynote-426 Phase III trial. The pembro-axi combination was approved by the FDA in 2019, however, a recent 2021 abstract updated the survival results from a 43-month follow-up. It showed that the median OS for the pembro-axi cohort was 45.7 months, while that of the sunitinib group was 40.1 months. The median PFS was 15.7 months for pembro-axi and 11.1 months for sunitnib.
The fourth recommendation is the combination of nivolumab plus cabozantinib versus sunitinib using the 651 patient, Phase III CheckMate 9ER trial. At a follow-up of 18 months, the PFS for nivo+cabo was 16.6 months versus 8.3 months for sunitinib. The probability of survival at 12 months was 85.7% for nivo+cabo and 75.6% for sunitinib with a hazard ratio (HR) for death of 0.60, or a 40% higher probability of the nivo+cabo group having survived at the 12-month date. 75.3% of the nivo+cabo patients had Adverse Events of grade 3 or higher versus 70.6% of the sunitnib patients, although a higher quality of life (HRQoL) was reported by the nivo+cabo group.
The question is which of the above combination choices to select for a particular patient comes down to the side effects profile of the therapies, the patient’s comorbidities, the experience of the oncologists with the recommended therapies, and the differential in costs of the therapies. This is especially true since the drug companies haven’t yet developed biomarkers that would inform oncologists as to which patients would benefit from which therapies based on the tumor characteristics.
For patients with comorbidities that could make the combination therapies intolerable, the panel recommended the use of selected monotherapies such as sunitinib, pazopanib (Votrient), cabozantinib, or pembrolizumab.
Recommended Monotherapies
For a select number of patients, the panel “weakly” recommended the use of high-dose Interleukin-2 (IL-2), a cytokine therapy the first approved, in 1992, for kidney cancer. In a 120-patieent trial, the response rate (ORR) was 25% with 13 patients (11%) maintaining PFS at 3 years. The median OS was 42.8 mos. IL-2 was the only FDA-approved therapy from 1992 to 2006 and was known to have a small minority of patients who had long-term durable responses. However, it comes with substantial toxicity so the prospective user must be quite healthy, aside from the cancer, and it must be administered by a doctor and facility that are very experienced with its application so that they can manage the complications effectively.
What are the preferred options for second-line and above treatment of metastatic renal cell carcinoma for clear cell patients?
The first recommendation is the use of nivolumab or cabozantinib for patients who progressed on a VEGFR TKI alone. In the 658-patient METEOR trial, the median OS favored cabozantinib at 20.4 mos. to everolimus at 17.1 months. In the 821-patient CheckMate025 trial, OS favored nivolumab to everolimus, 25.8 mos. to 19.7 months, respectively. The panelists complained that, in second-line therapy, there are often no head-to-head trials comparing effective therapies, as, for example, there is no second-line trial comparing nivolumab versus cabozantinib. They strongly recommend that patients enter clinical trials.
Another recommendation for patients who progressed on a nivo-ipi combination would be to take a VEGF targeted therapy like cabozantinib or the combination of lenvatinib and everolimus. Since the combo therapies suggested for first-line are relatively new, there isn’t much evidence of what to take after they fail. One notable exception is tivozanib, which, in the TIVO-3 trial that tested tivozanib versus sorafenib on a 350-patient sub-group that had progressed after having taken an immune therapy drug and a targeted therapy combination. Thus, testing these drugs in what was essentially a third or fourth-line treatment, tivozanib did significantly better than sorafenib in progression-free survival by 5.6 mos.to 3.9 mos. The most significant grade 3 or 4 adverse event was hypertension, showing up on 20% of tivo patients and 14% of sorafenib patients. These results led to FDA approval for tivozanib for use in refractory kidney cancer.
Focus on Treating the Metastasis Directly Rather than Systemic Treatment
For patients with limited progression of metastasis, the patient may opt for local therapy such as radiation (like stereotactic ablative body radiotherapy (SABR)), ablation, cryotherapy, or metastasectomy. Patients electing to treat the metastasis directly may elect to combine it with immunotherapy. Subsequent treatment with TKIs is not recommended as, for example, sorafenib and pazopanib have been shown to have no effect.
There have been a couple of prospective trials in which the patient has oligoprogressive disease, meaning the number of metastatic sites is limited and progressing slowly, but the systemic therapy is otherwise effective. In a 30-patient Phase II trial of oligometastatic patients, SABR therapy was utilized to remove the metastases. At a median 17.5-month follow-up, the 1-year PFS was 64% of patients. The authors of the study reported that SABR could be used in place of systemic therapy.
SABR therapy has been gaining in popularity especial among patients of advanced age and those with comorbidities who may find systemic medical therapy intolerable, however, younger patients may opt for metastasectomy especially where the resected tissue must be preserved for histological analysis.
For bone and brain metastasis and for sarcomatoid carcinomas, consult the original ASCO document, Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline at https://ascopubs.org/doi/full/10.1200/JCO.22.00868
[1] Note that the Heng risk factors were formulated during the targeted therapy era (the use of TKIs) and there are no comparative risk factor systems for immunotherapy treatment.
Source
Journal of Clinical Oncology, Vol 40, No. 25, September 1, 2022
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