TKI/Immunotherapy Combos Dominate Frontline Metastatic RCC Management

ALTHOUGH CHOOSING AMONG AVAILABLE options has proven particularly challenging in the frontline treatment of patients with metastatic renal cell carcinoma (RCC), one thing is clear: Novel combination regimens are the future, according to Claud M. Grigg Jr, MD.

“All patients with clear cell RCC, unless they have a true contraindication to an immune checkpoint inhibitor [ICI], really should be receiving some kind of combination therapy in the frontline setting, with the exception of the very rare favorablerisk patients,” said Grigg. “[We should be] ensuring that these patients aren’t receiving TKI [tyrosine kinase inhibitor] monotherapy anymore. The choice among combination therapies is still a difficult one to make and I don’t believe that there is necessarily a correct answer for all patients, but all should be receiving some kind of combination.”

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on genitourinary malignancies, Grigg, a medical oncologist at Levine Cancer Institute, part of Atrium Health, highlighted different frontline combination regimens that are improving outcomes for patients with metastatic RCC.

OncLive^®: With the emergence of novel combination regimens, there has been a shift away from monotherapy approaches in the first-line setting. Could you speak to the significance of the CheckMate 214 trial?

Grigg: CheckMate 214 [NCT02231749] was really the first major trial to examine a combination therapy in the frontline setting. Here, the combination of 2 ICIs, nivolumab [Opdivo] and ipilimumab [Yervoy], was compared with sunitinib [Sutent] in its standard 4-weeks-on, 2-weeks-off schedule. The [doublet] was associated with an improvement in overall survival [OS]. We have the longest follow-up for this study [of the frontline combination trials], at more than 40 months, and many of the responses reported are still durable to this day. The OS benefit continues to be evident as time goes on and follow-up continues.

Immunotherapy in combination with VEGF TKIs has also been shown to improve outcomes for patients. How do you differentiate among these regimens in practice?

We now have 2 approved VEGF inhibitor and immunotherapy combinations and we’re anticipating a third and potentially a fourth combination in the [near future].* That being said, it’s becoming a very confusing space for many clinicians to differentiate among all these different regimens. Certainly, the idea of combining a VEGF receptor inhibitor with an ICI has had a tremendous impact on our patients. The objective response rates [ORRs] and radiographic response rates are really tremendous with these combinations. We’ve seen response rates ranging from 50% to 60% [with these approaches]. The rate of tumor [reduction] is approximately 90% to 95% with these regimens. The majority of our patients achieve at least some benefit from these combinations. In terms of understanding the differences among these options, we don’t have a lot of answers; hopefully, we will in the coming years.

One such combination was evaluated in the KEYNOTE-426 trial. What was learned from this research?

In the KEYNOTE-426 trial [NCT02853331], investigators compared a combination [composed] of the PD-1 checkpoint inhibitor pembrolizumab [Keytruda] and axitinib [Inlyta], given at its standard dose of 5 mg twice daily, versus sunitinib, given on a 4-weeks-on, 2-weeks-off schedule. Although axitinib can be titrated up and down, it generally is started at that dose. That combination was associated with improvements in OS, progression-free survival [PFS], and ORR. With longer-term follow-up of a median of 30 months, the improvements in OS and PFS persist.

The toxicity with this regimen seems to be fairly manageable and predictable. We tend to see the same safety profile that we observe with either drug alone. Namely, [we see] autoimmune toxicities with pembrolizumab and standard TKI toxicities with axitinib. Compared with sunitinib, the toxicity profile [of the combination] appears to be comparable or better in some ways. This is certainly a very effective and promising regimen for the frontline setting.

What has been reported with the combination of avelumab (Bavencio) plus axitinib in patients with metastatic disease? How does it compare with other TKI/immunotherapy combinations in this space?

Interim results from the JAVELIN Renal 101 trial [NCT02684006] were released at [around the same] time, although they have a shorter follow-up compared with KEYNOTE-426. This was a similar study comparing the PD-L1 inhibitor avelumab with the same dose of axitinib versus the same standard dosing of sunitinib. This study was also positive, at least in terms of PFS. The OS data did seem to show a trend toward improvement, although the results are not mature yet. We also saw a very high ORR, around 52%. Improvement in PFS and toxicity profiles were comparable [with what has been seen] with the other TKI/ immunotherapy combinations.

The FDA granted a priority review designation to a supplemental biologics application and supplemental new drug application for nivolumab plus cabozantinib (Cabometyx) based on data from the pivotal CheckMate 9ER trial (NCT03141177). What is the hope for this regimen? How does it measure up against the other regimens?

We are looking forward to seeing the publication of the results from this trial; the findings [reported thus far have been] very impressive. At an early follow-up time, we saw improvements in OS and PFS. The PFS was essentially doubled, with the most impressive PFS hazard ratio of all the TKI/immunotherapy combinations. We can’t directly compare this study against others because the study populations aren’t necessarily comparable. Nonetheless, the improvements in PFS and OS [represent] good news.

Also, no unexpected toxicities have been reported with the combination compared with nivolumab or cabozantinib alone. As such, [this doublet] should be a welcome addition to the first-line treatment [arsenal].

Are you excited about any other TKI/ immunotherapy combinations under exploration?

We saw a press release on the combination of lenvatinib [Lenvima] with immune checkpoint inhibition, [which appears to have been] a positive trial. We look forward to seeing the [full] results. Certainly, newer agents [are also emerging] in the pipeline; specifically, agents targeting HIF-2α have generated a lot of excitement. Several combination studies are being planned, but many of them are still quite a bit away from [revealing] any results.

How have these regimens performed in patients with favorable-risk disease? What are some of the challenges faced with this subset?

The favorable-risk population is a challenge because these patients have a really good prognosis by definition and are expected to live a long time. Detecting any improvements in OS can [require] a really long follow-up time. Thus far, at least in some of our subgroup analyses from studies that have longer follow-up like KEYNOTE- 426, we haven’t seen a true differentiation in terms of OS between TKI/immunotherapy combinations versus TKI monotherapy.

Additionally, [regarding] CheckMate 214, the subgroup analysis for the favorable-risk population showed that PFS and ORR favored the TKI versus the immunotherapy/ immunotherapy combination. Some of the extended follow-up has suggested no improvement in terms of OS [with the combination] and perhaps even a slight favoring of OS for the TKI monotherapy. At this point, favorablerisk patients should receive TKI monotherapy or [a TKI] in combination with an ICI. [As for which,] I don’t believe that we’ve fully answered that question yet.

What is needed in order to move the needle forward?

The frontline space is becoming crowded. We’re learning that all our drugs that work well in the later settings also work well in the frontline setting. Unfortunately, although responses can occur once resistance develops to any individual TKI, they are often less robust. With each line of TKI, we see diminishing response and benefit.

What we really need are new drugs that have a new mechanism of action. We’re all looking forward to hearing the results of some of the metabolically targeted drugs. We know that the glucose metabolism pathway is very important in clear cell RCC. [We’re also excited about] the drugs that are targeting HIF-2α, which is a key component of the von Hippel-Lindau inactivation in clear cell disease. Having new drugs with new mechanisms of action will be key to the future.

Editor’s Note: This interview was conducted prior to the 2021 Genitourinary Cancers Symposium.