Heightened Histological Focus Fosters Treatment Advances in Non-clear Cell RCC

Chung-Han Lee, MD, PhD

Novel combinations such as cabozantinib (Cabometyx) plus nivolumab (Opdivo) are leading to unprecedented responses in non-clear cell renal cell carcinoma (RCC), said Chung-Han Lee, MD, PhD. Findings from studies including the phase 2 PAPMET trial (NCT02761057) have not only led to a new standard of care but demonstrate the shift away from the historical paradigm of evaluating non-clear cell RCC as one disease.

“Currently, non-clear cell RCC is an incredibly exciting space. It’s nice to finally see it garner the same type of attention that clear cell kidney cancer has,” Lee said. “Multiple clinical trials [have guided us] and will continue to guide us in terms of the types of systemic responses we might end up seeing.”

In an interview with OncLive^®, Lee, a medical oncologist at Memorial Sloan Kettering Cancer Center, explained the historical barriers to treatment developments in non-clear cell RCC; highlighted the efficacy of cabozantinib plus nivolumab in patients with unclassified, translocation, papillary, and fumarate hydratase (FH)–deficient non-clear cell RCC; and elaborated on the need for increased molecular classification of the histologic subsets of non-clear cell RCC.

OncLive^®: How would you characterize the progress that has been made in clear cell RCC relative to non-clear cell RCC?

Lee: Over the past 5 or 6 years, we have seen a dramatic improvement in the treatment of clear cell kidney cancer. In that time, we’ve had multiple phase 3 clinical trials demonstrating the efficacy of an immuno-oncology–based combination over monotherapy with a TKI. Multiple studies have shown an improvement in objective response rate [ORR], progression-free survival [PFS], and overall survival [OS] with using immuno-oncology either in combination with a PD-1 inhibitor plus a CTLA-4 inhibitor, or a PD-1 inhibitor plus a TKI.

However, in comparison, non-clear cell kidney cancer has lagged. Until a couple of years ago, the primary NCCN [National Comprehensive Cancer Network]–recommended first-line therapy was a single agent TKI plus a drug like sunitinib [Sutent]. It’s exciting to now see multiple clinical trials slowly read out within non-clear cell with novel agents that have demonstrated additional efficacy.

Why has drug development lagged behind clear cell RCC?

Part of what contributes to the difficulty of drug development within non-clear cell kidney cancer is the relative rarity of the different histologies. Non-clear cell [is a term that covers] a diverse set of histologies. It is a compilation of any histology besides clear cell RCC.

In fact, the eligibility criteria for most phase 3 clinical trials define clear cell RCC as any histology with a degree of a clear cell component. Anything that doesn’t fall within that category can be considered non-clear cell kidney cancer.

Along with that, we’ve also seen an evolution in how we think about the sub-classification of [non-clear cell RCC]. Historic classifications include papillary, chromophobe, and unclassified RCC, as well as other subsets, such as medullary kidney cancer and collecting duct kidney cancer. Now we’re starting to see increases in molecular classification and starting to have more defined subsets within non-clear cell RCC. Because of the diversity and rarity of non-clear cell RCC, seeing specific drugs targeted to these molecular subsets is difficult.

Could you elaborate on how the results of the PAPMET trial led to the replacement of sunitinib as the standard of care?

The PAPMET trial was a pivotal study that changed the standard of care for non-clear cell kidney cancer. It’s one of the few randomized clinical trials available that has demonstrated improved efficacy for a specific subset of non-clear cell RCC. This was a large clinical trial run across about 65 centers across the United States, which enrolled patients with papillary histology.

Patients were randomized to cabozantinib, crizotinib [Xalkori], and savolitinib vs sunitinib. This trial demonstrated improved efficacy with cabozantinib vs sunitinib with an improvement in PFS.

The investigators of this clinical trial deserve much credit [because they were able to] enroll all these patients from molecularly selected and/or histologically selected subsets into a study that showed a benefit in this patient population. It takes a lot of commitment for centers to adequately stratify these types of patients, especially those with rare histologies. Because of this trial, cabozantinib received an NCCN designation as a regimen for papillary RCC.

You were a coauthor on a study evaluating cabozantinib, the current standard of care, plus nivolumab in patients with non-clear cell RCC and genomic correlates. What was the rationale this combination?

For our study, we wanted to investigate cabozantinib as the current standard of care for certain subsets of non-clear cell kidney cancer. [We were also interested in determining the efficacy of cabozantinib plus nivolumab in non-clear cell RCC, as this combination has demonstrated superior efficacy over sunitinib in clear cell RCC.] In clear cell RCC, [cabozantinib plus nivolumab] has shown improved OS, PFS, and ORR over sunitinib in a relatively sick cohort of patients.

Historically speaking, we have seen a decline in treatment efficacy when comparing clear cell data with non-clear cell data. But, given the efficacy of the regimen and the benefit within papillary RCC, we were interested in seeing whether this combination would be highly efficacious within this cohort.

In this study, we subdivided non-clear cell kidney cancer. Historically speaking, non-clear cell RCC has [been a category composed of different histologies], but we think there are some differences between the histologies that could lead to variability in terms of the treatment benefit. For cohort 1, we grouped together unclassified, papillary, translocation, and FH-deficient non-clear cell RCC. We also made a smaller cohort with only chromophobe non-clear cell RCC. We felt that doing this type of stratification gave us more biologic separation between the histologies, and we were curious to see whether this type of biologic separation would translate into differences in efficacy.

What was seen in this trial in terms of efficacy?

In cohort 1, that larger, broader cohort, we saw an ORR of [47.5%], which, although it’s hard to make comparisons across multiple studies, is among the highest ORRs that we’ve seen within a non-clear cell kidney cancer cohort.

In contrast, in the chromophobe cohort, we didn’t see any types of objective responses. There is much speculation about why that might be the case. The biology portion needs to be worked out further, but the difference we saw was striking. Part of the reason we decided to group together many histologies within the same cohort [in cohort 1] was because there’s probably much histopathologic overlap between them. Depending on the institute, [different pathologists may make different calls during diagnosis]. We decided, for better ease of comparison, to group them together and study them collectively.

What might explain the different responses?

We started to do genomic analyses on the cohort of patients who have responded. Granted, the numbers are small given this was a small phase 2 study. However, we did see some molecular changes that seem to be associated with responses. Nearly all patients who have FH deficiencies or mutations within NF2 had an objective response.

Although our numbers are small, this information is hypothesis-generating. Going forward, we should conduct a larger trial to see whether some of these results can be validated in larger cohorts. We also need to go back into the lab to understand whether certain mutations can be drivers for response in ways that we don’t yet understand. There’s a lot of work to be done to try to understand that biology.

Did you observe any new or surprising safety signals?

Large phase 3 clinical trials have already been done with the combination, and no new safety signals were identified [in our trial]. Overall, cabozantinib plus nivolumab remains well tolerated, with adverse effects that are consistent with what we would expect to see with TKIs and PD-1–based immuno-oncology therapy.

What is next for this regimen? Do you see it ultimately replacing cabozantinib in the NCCN guidelines?

We hope guideline agencies will vote [in favor of including cabozantinib plus nivolumab in the guidelines], as we see high levels of efficacy with this regimen. Hopefully, at the next NCCN guideline meeting, this regimen will be reviewed, now that the paper has been published in the JCO.

For next [steps with] this regimen, we’re looking at further expanding our clinical trial to gain more information and hopefully do further correlative analysis. The next part, beyond doing our initial look at targeted exome sequencing and looking at the genomic changes, is to then also understand what immunologic changes may have happened that can contribute to the responses. Our hope is that we can get this regimen approved and into the hands of more physicians and patients to improve patient outcomes.

What else is exciting to you about the research landscape in RCC?

One such regimen that we are interested in [in non-clear cell RCC] is lenvatinib [Lenvima] plus pembrolizumab [Keytruda]. That [combination is being studied in] an ongoing clinical trial, and hopefully we will soon have results to see whether a different TKI and immuno-oncology regimen may also show high levels of efficacy.

Also [of interest in clear cell RCC] is triplet therapy. The results of these studies are not yet available, so we don’t know whether a triplet is better than a doublet within clear cell RCC. However, there is a non-clear cell study looking at the combination of cabozantinib, ipilimumab [Yervoy], and nivolumab. If that [combination is shown to be] both safe and tolerable, it could be encouraging.