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ONCAlert | Upfront Therapy for mRCC

Factors for Choosing Frontline mRCC Treatment

Martin H. Voss, MD
Published Online:12:22 PM, Fri July 27, 2018

Martin H. Voss, MD: Following up on these new approvals, the question that obviously arises is, how do we make decisions in newly diagnosed patients who are being considered for frontline therapy in the metastatic setting? And there are certain criteria that can help with decision making. We have now touched upon risk stratification criteria several times in discussing the trials, and it’s interesting to note that the 2 new approvals in the first-line space, cabozantinib and ipilimumab/nivolumab, were granted based on trials that had a primary endpoint specifically looking at intermediate- and poor-risk patients. And, indeed, using the risk stratification of the International Metastatic Database Consortium, or the IMDC, is very helpful in patients.

The first question that I usually ask myself when I see a patient with newly diagnosed metastatic disease is, do they in fact need treatment at that point in time? And the IMDC risk stratification tool is helpful as we sometimes consider patients for active surveillance in the first-line setting. We can delay the onset of targeted therapy for some of our patients, those with indolent disease and a smaller disease burden. And the IMDC group in the past has presented data and published on this, and it’s helpful to know that patients with a low IMDC score and limited organ involvement can be considered safely. Some remain on active surveillance for extended periods of time.

Once one decides whether or not to start therapy, we can consider different standards now that are available to us. We have single-agent TKI therapy, and there are 3 TKIs that are commonly considered, now based on the approvals we have—cabozantinib, which we’ve heard about, sunitinib of course, and then lastly pazopanib. And then we now have the immunotherapy combination. So, CheckMate-214 now has introduced I-O therapy into the first-line space, which constitutes a huge change to the paradigms that we go by when we treat patients in the clinics.

To me, what is most relevant in considering all the trial data that are out there right now in the first-line space is the high complete remission rate that has been seen on the CheckMate-214 study. So, what distinctly sets this apart from the various TKI trials is that patients treated with ipilimumab/nivolumab, specifically those with intermediate- or poor-risk disease, can achieve complete remissions. And the CR rate in that patient population on CheckMate-214 was 9%, which is something that we’ve never seen in TKI trials.

The other thing that we haven't discussed yet that is very relevant is that on CheckMate-214, about 20% of the patient population had favorable-risk disease. These were not included in the primary endpoint analysis per how the trial had been set up, but, of course, in the secondary analysis, these patients were looked at separately. And much to everyone’s surprise, these patients actually did better with a kinase inhibitor. So, within CheckMate-214, about 200 patients on each arm had favorable-risk disease. And when we only look at those patients then, the objective response rate was significantly higher, north of 50%, in the sunitinib-treated patients, lower with ipilimumab/nivolumab, in the 20% range, and the same for progression-free trial. So, there were significantly better progression-free survivals for the TKI-treated patients with favorable-risk disease.

And then lastly, even if you look at overall survival landmark analysis, 12 and 18 months overall survival rates numerically favored the TKI arm, so sunitinib did better. That now is very relevant as we look at first-line therapy patients before we decide on which agent to put them on. Indeed, the first instance where now risk stratification with IMDC goes into decision making. So, a new patient should be assessed by IMDC risk stratification, patients with intermediate- and poor-risk disease, in my mind, should certainly be considered for combination immunotherapy based on the strong overall survival endpoint and the relatively high CR rates that have been seen. But it’s important to take a thorough history in terms of the patients’ prior medical problems. Patients with autoimmune disease, we know, are at higher risk for autoimmune toxicities with immune-activating agents like this and were excluded from participation in trials like CheckMate-214. So, that’s the second thing that is very relevant. Comorbidities, prior medical history should be assessed for all patients.

And then thirdly, of course, the overall burden, pace of disease, and maybe also organ distribution. Cabozantinib, which now is FDA approved in the first-line setting, has been studied extensively by its manufacturers, not only in kidney cancer but also in prior efforts in prostate cancer for its effect on bone metastases. And there is a lot of preclinical work but also clinical work that has gone into correlates of bone turnover, including osteoclast biology and so forth, that suggest that this agent, more so than others, has an effect on kidney cancer metastases in the bone. So, certainly for patients with a high burden of disease, osseous metastatic disease, this would be a very attractive agent.

Transcript edited for clarity.

Martin H. Voss, MD: Following up on these new approvals, the question that obviously arises is, how do we make decisions in newly diagnosed patients who are being considered for frontline therapy in the metastatic setting? And there are certain criteria that can help with decision making. We have now touched upon risk stratification criteria several times in discussing the trials, and it’s interesting to note that the 2 new approvals in the first-line space, cabozantinib and ipilimumab/nivolumab, were granted based on trials that had a primary endpoint specifically looking at intermediate- and poor-risk patients. And, indeed, using the risk stratification of the International Metastatic Database Consortium, or the IMDC, is very helpful in patients.

The first question that I usually ask myself when I see a patient with newly diagnosed metastatic disease is, do they in fact need treatment at that point in time? And the IMDC risk stratification tool is helpful as we sometimes consider patients for active surveillance in the first-line setting. We can delay the onset of targeted therapy for some of our patients, those with indolent disease and a smaller disease burden. And the IMDC group in the past has presented data and published on this, and it’s helpful to know that patients with a low IMDC score and limited organ involvement can be considered safely. Some remain on active surveillance for extended periods of time.

Once one decides whether or not to start therapy, we can consider different standards now that are available to us. We have single-agent TKI therapy, and there are 3 TKIs that are commonly considered, now based on the approvals we have—cabozantinib, which we’ve heard about, sunitinib of course, and then lastly pazopanib. And then we now have the immunotherapy combination. So, CheckMate-214 now has introduced I-O therapy into the first-line space, which constitutes a huge change to the paradigms that we go by when we treat patients in the clinics.

To me, what is most relevant in considering all the trial data that are out there right now in the first-line space is the high complete remission rate that has been seen on the CheckMate-214 study. So, what distinctly sets this apart from the various TKI trials is that patients treated with ipilimumab/nivolumab, specifically those with intermediate- or poor-risk disease, can achieve complete remissions. And the CR rate in that patient population on CheckMate-214 was 9%, which is something that we’ve never seen in TKI trials.

The other thing that we haven't discussed yet that is very relevant is that on CheckMate-214, about 20% of the patient population had favorable-risk disease. These were not included in the primary endpoint analysis per how the trial had been set up, but, of course, in the secondary analysis, these patients were looked at separately. And much to everyone’s surprise, these patients actually did better with a kinase inhibitor. So, within CheckMate-214, about 200 patients on each arm had favorable-risk disease. And when we only look at those patients then, the objective response rate was significantly higher, north of 50%, in the sunitinib-treated patients, lower with ipilimumab/nivolumab, in the 20% range, and the same for progression-free trial. So, there were significantly better progression-free survivals for the TKI-treated patients with favorable-risk disease.

And then lastly, even if you look at overall survival landmark analysis, 12 and 18 months overall survival rates numerically favored the TKI arm, so sunitinib did better. That now is very relevant as we look at first-line therapy patients before we decide on which agent to put them on. Indeed, the first instance where now risk stratification with IMDC goes into decision making. So, a new patient should be assessed by IMDC risk stratification, patients with intermediate- and poor-risk disease, in my mind, should certainly be considered for combination immunotherapy based on the strong overall survival endpoint and the relatively high CR rates that have been seen. But it’s important to take a thorough history in terms of the patients’ prior medical problems. Patients with autoimmune disease, we know, are at higher risk for autoimmune toxicities with immune-activating agents like this and were excluded from participation in trials like CheckMate-214. So, that’s the second thing that is very relevant. Comorbidities, prior medical history should be assessed for all patients.

And then thirdly, of course, the overall burden, pace of disease, and maybe also organ distribution. Cabozantinib, which now is FDA approved in the first-line setting, has been studied extensively by its manufacturers, not only in kidney cancer but also in prior efforts in prostate cancer for its effect on bone metastases. And there is a lot of preclinical work but also clinical work that has gone into correlates of bone turnover, including osteoclast biology and so forth, that suggest that this agent, more so than others, has an effect on kidney cancer metastases in the bone. So, certainly for patients with a high burden of disease, osseous metastatic disease, this would be a very attractive agent.

Transcript edited for clarity.
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