Risk Assessment and Diagnostic Work-up

EP: 1.The Biology of RCC and Improved Treatment Outcomes

EP: 2.Tumor Biology in Favorable to Poor-Risk RCC

EP: 3.Improved Outcomes With Novel and Combination Therapies

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EP: 4.Risk Assessment and Diagnostic Work-up

EP: 5.Newly Diagnosed RCC: KEYNOTE-426 and CheckMate-214

EP: 6.The Role of VEGF TKI Monotherapy

EP: 7.Impact of the Phase 3 CheckMate 9ER Trial on Practice

EP: 8.The Role of Combination Treatment in RCC

EP: 9.The Future Treatment Landscape of RCC

EP: 10.Emerging Therapies for Relapsed/Refractory MRCC

Robert Alter, MD: As we talk about how patients present and our initial assessment, we medical oncologists are getting the patient handed to us, so we have the diagnosis. Going to the primary care physicians and community oncologists when a patient presents to you as an unknown primary care patient, the typical laboratory work would be a chemistry panel, including an LDH [lactate dehydrogenase], a CBC [complete blood count], and a urinalysis. Suspicion for having a renal mass leads to a CT scan of the abdomen and pelvis, sometimes an MRI, a chest x-ray, and sometimes a CT scan of the chest. If it’s clinically appropriate based on the patient, you could do bone scanning, imaging of the head, and a core biopsy.

The challenges we have occur when patients present with a renal mass or renal tumors and have symptoms such as hematuria, IVC [inferior vena cava] thrombus, bone metastasis, painful metastasis, decreasing functional performance status, and extensive disease. Oftentimes, it’s not so simple that can just take our time and let these diagnoses evolve and have the opportunity to make therapeutic decisions. We somehow have to believe that there is a way of gauging patients by tumor volume as well as some of the parameters that are given to us.

Dating to the early use of immunotherapy, the first risk classification we had when it came to utilizing patient prognostic features would be the MSKCC [Memorial Sloan Kettering Cancer Center Risk Score], or the risk categorization on patients based on the data utilizing interferon in patients postnephrectomy. In those patients, through Dr Bob Motzer’s guidance, and through the Cytokine Working Group, they discussed the best ways of assessing these patients. They looked at parameters, including time from initial diagnosis to initial treatment, lab studies of LDH, calcium level, and hemoglobin. They were also looking at a patient’s functional performance status and using those 5 tools to categorize patients who have a favorable risk to patients who have no risk factors. Patients will be intermediate risk if they have 1 or 2 risk factors, and then patients who have more risk factors would be categorized as patients with poor risk.

Through the IMDC [International Metastatic Renal Cell Cancer Database Consortium Criteria], they substituted out the LDH, maybe through inconsistencies or through utilizing better ways of assessing the tumor burden, and they now incorporate the white blood cell count and platelet count, so neutrophilia as well as thrombocytosis would now be substituted for that. In those patient-risk categorizations, they are recognizing that these factors can sometimes predict survival as well as, through the NCCN [National Comprehensive Cancer Network] Guidelines, guide us about how to use treatments in a therapeutic fashion based on the analysis.

We’ll talk also about the CheckMate-214 trial as well as the KEYNOTE-426 trial.

Michael Atkins, MD: I personally reject the IMDC risk categorization for making choices between the 2 regimens that you just discussed: nivolumab-ipilimumab and axitinib-pembrolizumab. I know that the NCCN makes recommendations, but those recommendations are not based on the data; they’re based on the ways in which the trials were designed rather than the results of those trials. Once again, these models were developed for VEGF receptor TKI [tyrosine kinase inhibitor] therapies, which were almost invariably noncurative. When you’re seeing patients and you have potentially curative treatments, you should be using those treatments first rather than going to palliative therapies as your first option.

My approach when I’m seeing a patient is to ignore the NCCN Guidelines and decide first whether a patient needs therapy. If they do, then I need to determine whether they’re a candidate for either a protocol or for immunotherapy. If they need therapy and are candidates for immunotherapy, meaning they don’t have a reason why they can’t receive a checkpoint inhibitor and don’t have an alternative clinical trial for which they’re eligible, I will start them on nivolumab-ipilimumab with the hope of curing them. I will then leave other treatments that are less likely to produce durable benefit for patients who don’t have complete response or durable response to up-front immune therapy.

Robert Alter, MD: You mentioned active surveillance before. I find that active surveillance is probably the most difficult conversation to have with patients who are referred to a medical oncologist. They are being told by a neurologist or a primary care doctor that they already have disease with metastases, whether it’s before or after they’ve had a cytoreductive nephrectomy, and they may even be asymptomatic where the volume is nominal, and there may be small pulmonary lesions. Your first recommendation is to watch and repeat the scan in 3 months, and they are flabbergasted at how they were told they have metastatic carcinoma and you wish to observe it. You bring up a great point. Despite the painful conversation, you have to convince them that we’re taking care of the patient beforeworrying about the disease.

I agree with you. Through our high-dose IL-2 system, we were still holding on to those small groups of patients who were having complete, durable remissions with great quality of life; they had the ability not to endure toxicities of therapy while still being able to have survival. The approach should always be about reaching for the stars with the least toxic therapy. Using combination immunotherapies in an up-front regimen, even in patients who are favorable risk, may still be an excellent option as your first-line therapy.

Michael Atkins, MD: Yes. Going back to the days of high-dose IL-2, the patients who we would now label favorable risk had the most durable benefit with immunotherapy. In the trial I presented at ASCO [American Society of Clinical Oncology Annual Meeting] this year looking at nivolumab monotherapy in patients with metastatic kidney cancer as first-line treatment, which you participated in as well, we had a 50% response rate in the favorable-risk group of patients with over 13% complete responses with just nivolumab monotherapy. There wasn’t a single patient with favorable risk who progressed at the 12-week first scan and wouldn’t have been able to receive a subsequent therapy with a TKI after progression. If they were tolerating nivolumab well, for ipilimumab-nivolumab, we also saw another 13% of patients respond when we added ipilimumab to the nivolumab in the crossover group. A number of those patients who were who were favorable risk in that trial are likely off-treatment and doing well without evidence of disease or at least without evidence of disease progression just from nivolumab monotherapy. To me, it is still not fair that we don’t have an FDA-approved immunotherapy-alone strategy for patients with favorable risk based just on the design of the trial.

Robert Alter, MD: That’s right. If we want to talk about the data we’ve been seeing over the last 2 or 2½ years, in CheckMate-214, KEYNOTE-426, and JAVELIN Renal 101, and in CheckMate 9ER soon, we see that we’re not sitting here using single-agent TKIs anymore. We’ve stepped up a bit. The expectations for these patients are not just to have responses. We’re looking for durable responses, and we’re looking for overall survival. We should still think about a backbone, and we should think about how our patients are still looking for complete remission.

Transcript Edited for Clarity