Lee Explores Treatment Options in Second- and Third-Line RCC

Chung-Han Lee, MD, PhD

During a Targeted Oncology Case Based Peer Perspective event, Chung-Han Lee, MD, PhD, a medical oncologist in the Genitourinary Oncology Service, at Memorial Sloan Kettering Cancer Center in West Harrison, NY, discussed the case of a 57-year-old woman with clear cell renal cell carcinoma (ccRCC).

Targeted Oncology™: What is the rationale for the use of targeted therapies in RCC?

LEE: When we think about the rationale for targeted therapy in RCC, a lot of this is centered around VHL [von Hippel–Lindau] disease, with RCC the most common cause of death. [Mutations in the VHL tumor-suppressor gene] lead to constitutive activation of the HIF [hypoxia-inducible transcription factor pathway], leading to growth factor production of VEGF.

The rationale for targeting the mTOR signaling pathway is that the mTOR axis is critical for thinking about downstream targeting from different receptor carcinogen kinases, which can be important for contributing to growth and proliferation. Some of the next-generation TKIs [tyrosine kinase inhibitors] target MET, AXL, and FGFR. Cabozantinib [Cabometyx] blocks the MET- and AXL-receptor tyrosine kinases, in addition to VEGFR 1 through 3; lenvatinib [Lenvima] blocks FGFR 1 through 4.

[If we] think about ways of further addressing the antiangiogenic potential of these different treatments, there is some speculation that there are also receptor tyrosine kinases on the different immune cells. Whether…there is some cooperation between the lenvatinib and the cabozantinib or axitinib [Inlyta] with the checkpoint inhibitors, remains to be better understood.

Could tumor mutational burden serve as a biomarker in RCC?

One of the things that we always think about when considering checkpoint inhibitors is using tumor mutational burden as a possible biomarker to determine whether patients will respond to [them]. What is unique about RCC is that, despite high objective response rates, we do not see a huge number of somatic mutations. That is still poorly understood. Why is RCC immunoresponsive? I think that we have a lot of data, going back to the interferon days, demonstrating that there is this immune reaction. But it doesn’t seem to be driven by mutational load.

Please describe the standard frontline treatments for patients with poor- and intermediate-risk clear cell RCC.

When we think about cross-trial comparisons, we have a few different clinical trials. There is the combination of axitinib and pembrolizumab [Keytruda] versus sunitinib [Sutent] with a hazard ratio of overall survival of 0.53 [NCT02853331],¹ the combination of axitinib and avelumab [Bavencio] with a hazard ratio of 0.78 [NCT02684006],² and the combination of ipilimumab [Yervoy] and nivolumab [Opdivo] with a hazard ratio of 0.68 [NCT00098657].³

Cabozantinib was also compared [with] sunitinib in the frontline setting, in the CABOSUN trial [NCT01831902], with a hazard ratio of 0.81, but not reaching clinical significance or statistical significance in that setting.⁴ These trials demonstrate that a few agents have been a little bit better than sunitinib.

Please describe the findings from KEYNOTE-426.

The KEYNOTE-426 [NCT02853331] data evaluated the combination of axitinib and pembrolizumab versus sunitinib.⁵ [The investigators reported] that even before the first scans, the separation of survival curves occurred prior to the 3-month mark. The only way that this is possible is if there are early deaths related to treatment. These are the people who are not making it to second-line therapy. This is where [we consider] the overall clinical picture; whether…people are going to make it to second-line therapy is a way that we can often think about how to prioritize response rate versus durability. Currently, follow-up for the axitinib and pembrolizumab combination is not far enough [along] for us to know what the long-term effects are, given that there’s a lot of censoring beyond the 24-month mark. So, we’ll have to see, with longer-term follow-up, whether…that overall survival curve flattens out or is going to be similar to what we see with single-agent TKI therapy [with] continued decline over time.

Looking specifically at people with intermediate and poor risk, the curves probably separate even [more quickly] as we eliminate all the people with favorable risk disease. I think that this is reflected by the higher response rate when we use a TKI and immuno-oncology combination versus a single-agent TKI. We saw an 8% complete response [CR] rate associated with the axitinib and pembrolizumab [combination], compared with a 2% CR rate associated with sunitinib. I think that there is a lot of debate about whether…CR is a good end point. But, from a patient standpoint, patients often feel happy to see a disease that was there shrink to a size that we can no longer see it.

CheckMate 214 (NCT02231749) was updated at the Genitourinary Cancers Symposium this year. How do you interpret the findings?

We now have a 42-month minimum follow-up for these patients. We are seeing the curves start to flatten out, beyond the 30- and 40-month mark, with a significant hazard ratio.⁶ If you look early on, [there is] no separation of the curves until a bit later. You’re losing a significant portion of patients by not being able to make it to second-line therapy. You’re talking about 10% of people who pass away within the first 6 months.

The progression-free survival [PFS] curve is, in some ways, perhaps one of the most interesting [findings] about the ipilimumab and nivolumab combination. If you get beyond the 30-month mark there seem to be few people who progress afterward. However, [looking at] sunitinib, there seems to be less durability, for even those [patients who] respond, and, over time, we see continued trickling down and people ultimately progressing, even with people [who were] long-term responders.

In terms of with longer follow-up, the CR rates, as nebulous of an end point as that is, we see that it is quite similar among people of all risk categories. Based off some of the exploratory analyses, the label is intermediate and poor risk; however, there is some argument for using the ipilimumab and nivolumab combination even within the favorable-risk group. I definitely see people who do that and feel strongly about that.

What are the next treatment options available to the patient?

This patient ended up receiving axitinib and pembrolizumab combination as up-front therapy. She had, initially, stable disease. She did notice some moderate diarrhea, as diarrhea is often a dose-limiting toxicity related to axitinib, and then some mild fatigue. However, she was one of the unlucky few who noticed rapid progression of disease at the 3-month mark, with increasing back pain, mild nausea, weight loss. Growth of her lung nodules, and new lymph nodes are enlarged, where she used to be KPS [Karnofsky performance status] 90, and now she has the ECOG performance status of 1, or 70%. This is a case in which she has worsening performance status, and there [are] new lesions, and they’re bigger. But, [progression] is often not as clear-cut as this.

What do you think of the answers to this poll?

These comments are reflective of our conversation. Most people would choose a single-agent TKI in this setting. It sounds [as though], from a consensus standpoint, everyone had thought about using cabozantinib, at least in the discussion.

In this setting, which is the second-line setting, some of these [responses] would probably make less sense. I think that there would be very few of us who would give nivolumab as monotherapy after the axitinib/pembrolizumab combination. Granted, they are technically different drugs, but I think that most of us would be worried about doing that. Cabozantinib has a category 1 [classification], along with axitinib having category 1, and lenvatinib/everolimus has a category 1 indication. All [these agents] demonstrate efficacy in the post-VEGF-targeted therapy space. The data that we have for the post-TKI/immuno-oncology regimen [are] a lot more limited. I think that there is a lot of extrapolation that we do based off of the TKI monotherapy experience.

For second-line therapy, what are things that you typically prioritize when making treatment decisions?

I make the treatment decision based on performance status, although I’m worried about sometimes overshooting. The other thing I think about, because the half-lives are fairly long for a lot of these TKIs, I talk to the patient and say that the dose ramps up over the course of the next couple of weeks, and if you feel terrible at day 3, you’re going to fall apart at day 7. I usually try to make a guess on what I think [is] the dose that they’re going to settle out at.

What is your experience with using lenvatinib/ everolimus? How would you sequence this regimen?

Most people are using lenvatinib/everolimus in the third-line setting, with a couple of people thinking about using it in the second-line setting. Some start the combination at a reduced dose.

Toxicity is an issue with this regimen, as demonstrated in a phase 2 trial [NCT01582009]. I would say that my own personal experience is I have had few patients who have been able to tolerate it, or have been able to stay on the 18-mg dose, especially in the second-line plus setting. I often go in a bit lower, and it’s often a guess whether…they’re [to receive] lenvatinib at 10 mg versus 14 mg. If you give someone a high dose, and you make them very sick, they are going to quit on you almost immediately. And then, it’s just a horrible experience for everyone. For specific adverse effects, diarrhea is significant.

For patients who experience diarrhea, how do you decide which drug to alter when using the combination?

I go lower than 5 mg on the everolimus. That’s 1 place in which maybe I’m different. There is an everolimus 2.5-mg dose, and because of the half-life I’ve even given everolimus 5 mg every other day. Sometimes that does help with the tolerability related to it. In my experience, it’s more of a stomatitis issue, stomatitis or decrease of counts that makes me think that this is the everolimus that was triggering the issues, or peripheral edema. A lot of the [gastrointestinal] toxicity related to TKI therapy can be reduced with prophylaxis and the dose reduction.

I definitely [recommend] dexamethasone mouth rinses—that’s usually my first step. So, basically Biotene mouthwashes, salt mouthwashes, and steroid mouthwashes, before I start thinking about dose reduction. If that’s not enough, then I lower the dose. Usually, my approach has always been: What’s the maximum supportive therapy I can give to the patient before lowering the dose?

If I begin the starting dose at 18 mg, then the first dose reduction is 14 mg, then 10 mg and then 8 mg. For people who’ve been very sensitive to the drug, I have gone as low as 4 mg on it and have seen durability and maintenance of their response even at the 4 mg dose. Those are select cases.

_References:

_{1. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127. doi:10.1056/ NEJMoa1816714}

_{2. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115. doi:10.1056/ NEJMoa1816047}

_{3. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115-124. doi:10.1056/ NEJMoa065044}

_{4. Choueiri TK, Hessel C, Halabi S, et al. Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): progression-free survival by independent review and overall survival update. Eur J Cancer. 2018;94:115-125. doi:10.1016/j. ejca.2018.02.012}

_{5. Plimack ER, Rini BI, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): updated analysis of KEYNOTE- 426. J Clin Oncol. 2020;38(suppl 15):5001. doi:10.1200/JCO.2020.38.15_suppl.5001}

_{6. Tannir NM, McDermott DF, Escudier B, et al. Overall survival and independent review of response in CheckMate 214 with 42-month follow-up: first-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2020;38(suppl 6):609. doi:10.1200/JCO.2020.38.6_suppl.609}