Cytoreductive Nephrectomy Retains Role in mRCC in the Immune Checkpoint Inhibitor Era

Ziad Bakouny, MD, MSc

Cytoreductive nephrectomy still retains a role in the treatment of patients with metastatic renal cell carcinoma (RCC), despite the emergence of effective targeted therapies and immune checkpoint inhibitors, according to Ziad Bakouny, MD, MSc; however, patient selection is key.

Data from a propensity score-based analysis showed that cytoreductive nephrectomy was associated with a significant overall survival (OS) benefit in patients with mRCC who were treated with either immune checkpoint inhibitors or targeted therapies. In the study, patients with de novo mRCC who had received a first-line systemic therapy with either an immune checkpoint inhibitor or targeted therapy were retrospectively assessed. These data were collected between 2009 and 2019 using the International Metastatic RCC Database Consortium (IMDC).

A total of 4,639 patients were included in the final cytoreductive nephrectomy analysis cohort. Of those, 4,202 patients had received previous treatment with a targeted therapy and 437 and received prior treatment with immune checkpoint inhibitors. Of the 4,202 who received targeted therapy, 2,631 underwent cytoreductive nephrectomy and 1,571 did not. Of the 437 who received prior immunotherapy, 245 had cytoreductive nephrectomy, while 192 did not.

At a median follow-up of 38.5 months, those in the targeted therapy cohort who received cytoreductive nephrectomy experienced a median OS of 26.5 months (HR, 0.48; 95% CI, 25.4-28.3) versus 10.3 months (95% CI, 9.6-11.1) in those who did not undergo cytoreductive nephrectomy. Those in the immune checkpoint inhibitor cohort with and without a cytoreductive nephrectomy experienced a median OS of 53.6 months (HR, 0.44; 95%CI, 34.3-not reached) versus 21.4 months (95% CI, 16.3-30.0), respectively.

“With the present database of this very large, retrospective study,” Bakouny explained, “there is currently no evidence to say that cytoreductive nephrectomy no longer has a place in the immune checkpoint inhibitor era, despite the fact that these systemic therapies are effective.”

In an interview with OncLive, Bakouny, a post-doctoral genitourinary oncology research fellow at Dana-Farber Cancer Institute, further discussed the controversy behind the use of cytoreductive nephrectomy in mRCC, factors to consider when selecting patients for this approach, and ongoing trials examining remaining questions in the field.

OncLive: Could you first provide some background to your research examining cytoreductive nephrectomy for patients with mRCC who had been treated with immune checkpoint inhibitors or targeted therapy?

Bakouny: Cytoreductive nephrectomy has become one of the most controversial topics in RCC and genitourinary oncology in general these days. One of the reasons is that we used to do a cytoreductive nephrectomy for patients who present with up-front metastatic disease. We mainly did this because before 2005 and [the introduction of] targeted therapies, there weren't many effective systemic therapies available for [patients with] RCC. In the cytokine era, 2 flagship randomized control trials [informed our understanding]. In 2001, research had shown a survival benefit [with] cytoreductive nephrectomy. However, in 2005, we [entered] the targeted therapy era, where we had more effective systemic therapies, such as sunitinib (Sutent) and sorafenib (Nexavar), available that were found to improve the survival of patients with this disease. As more effective systemic therapies [emerged], the question became, “Is cytoreductive nephrectomy is still relevant?”

Some very large retrospective studies have established that in the era of targeted therapies, cytoreductive nephrectomy was still effective. However, a recent, large trial called CARMENA, which randomized patients to receive either sunitinib alone or sunitinib plus cytoreductive nephrectomy, and showed that sunitinib alone was noninferior to cytoreductive nephrectomy plus sunitinib. Each of these studies, both the retrospective studies and the randomized controlled studies, have some caveats. I would always trust a randomized controlled trial more so than a retrospective study, but the randomized controlled trial, for instance, only included patients who had a relatively higher-risk disease. The median OS in that study was relatively low.

To go back to our study, we've seen [a benefit with cytoreductive nephrectomy] in the cytokine era but in the targeted therapy era, we know that it's a bit controversial. Now, [we are in the] immune checkpoint inhibitor era, where we have even more effective systemic therapies available, so is cytoreductive nephrectomy relevant at all? We set out to ask this question in this study. We used the very large IMDC database, which [includes] consecutive patients with mRCC from more than 40 centers across the world. We started with an initial consecutive series of more than 11,000 patients with mRCC. After boiling it down to our question of interest and our patient population of interest, we ended up with roughly 4,500 patients who we then divided into 2 groups: first-line targeted therapy–treated patients and first-line immune checkpoint inhibitor–treated patients. [In] each of these [cohorts], there was a subset treated by cytoreductive nephrectomy and a subset that was not treated with that approach.

The first question we asked in this very large series was: Who are the patients who are getting cytoreductive nephrectomies? We found that these were patients who were younger, had lower-risk disease, and tended to have some adverse histologic features. This is potentially because systemic therapies are not very effective for patients with such features. Then, the meaty question was: Is cytoreductive nephrectomy still associated with an OS benefit in the immune checkpoint inhibitor–treated patients? We found that the same signal we had seen in the targeted therapy era, we saw again in the immune checkpoint inhibitor era. We tried to be very diligent in how we corrected for confounding factors because we know that this is an important issue with retrospective studies.

As such, we did 2 analyses: a propensity-based analysis and a multivariable analysis. Both [analyses] found that the benefit with cytoreductive nephrectomy observed in immune checkpoint inhibitor–treated patients was similar to that observed in the targeted therapy era.

Going forward, we want to have very well-designed, randomized controlled trials to precisely ask this question, such as the PROBE trial and the CYTOSHRINK study, which is using stereotactic body radiotherapy (SBRT), but it’s a similar concept because it's targeting the primary lesion. Many other trials are ongoing, as well. I look forward to [hearing more from] these trials and until then, we're trying to provide evidence to see whether we should continue cytoreductive nephrectomy. I believe that given our data, there is no evidence to the contrary.

How would you categorize the current state of cytoreductive nephrectomy? What factors are you considering when determining whether a patient is a candidate for this approach?

That's the most important question [that we need to consider]—especially in clinical practice. We've [come] from an era where cytoreductive nephrectomy was kind of a ubiquitous therapy. We didn't have any effective therapies available, so [we would give this to] every patient who would come in. As we see effective systemic therapies emerge, we're going to [increasingly use cytoreductive nephrectomy in] more selected populations. This is what [data from] the CARMENA study suggested, as 1 of their subgroup analyses showed that patients with 1 IMDC criteria seemed to benefit from cytoreductive nephrectomy. However, the trial had not been powered for that specific subgroup. We see the same signal in our data, as well.

Patients are actually receiving this [approach] in practices throughout the world. We have a very large dataset across the world from 40 academic institutions, and we do see that the patients who are receiving cytoreductive nephrectomy are those who have the lowest-risk disease. From a scientific clinical perspective, it makes sense that patients who have lower metastatic burden, patients who have oligometastatic disease, those whom we could render without evidence of disease, and patients [for whom] we could render no evidence of disease (NED) with a metastasectomy and a cytoreductive nephrectomy, plus or minus some systemic therapy, are the patients who would benefit most. Although factors like normal hemoglobin and normal calcium have been shown to correlate with good prognosis in patients in general, these are patients who would not progress and would be perfect for a cytoreductive nephrectomy, at least until we have other evidence to suggest otherwise in this era.

Are any other prospective trials beyond CARMENA ongoing that are looking at cytoreductive nephrectomy in combination with other therapies?

A few clinical trials are currently ongoing. The PROBE trial is looking at up-front nivolumab (Opdivo)/ipilimumab (Yervoy) and deferred cytoreductive nephrectomy. Additionally, the CYTOSHRINK trial is also looking at up-front nivolumab/ipilimumab and SBRT; although this is not cytoreductive nephrectomy, the primary lesion is being targeted with SBRT, so it is a similar concept. Another trial from Europe is being done, and that's also [examining] up-front nivolumab/ipilimumab and deferred cytoreductive nephrectomy.

Many of these trials are now looking at deferred, as opposed to up-front, cytoreductive nephrectomy; this is somewhat different from what the CARMENA trial [has done] and it is slightly similar to what the SURTIME trial had originally done.

As such, many of these trials are now looking at very effective regimens, such as nivolumab/ipilimumab or other immune checkpoint inhibitor-based regimens, getting a deep partial response, and then just removing the remaining bulky mass and trying to render the patient NED, which makes a lot of sense.

Reference

Bakouny Z, Xie W, Dudani S, et al. Cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI) or targeted therapy (TT): a propensity score-based analysis. J Clin Oncol. 2020;38(suppl 6):608. doi:10.1200/JCO.2020.38.6_suppl.608