Expert Insights on the Evolving Treatment Paradigm During Kidney Awareness Month

In 2021 alone, about 76,080 people will be diagnosed with kidney cancer. Additionally, an expected 13,780 people are expected to die from the disease this year alone.¹

March is Kidney Awareness Month. Currently, there are 37 million people in the United States living with chronic kidney disease.¹ Kidney cancer specifically is among the 10 most common cancer in both women and men. Currently, the lifetime risk of developing kidney cancer is 2.02% for men and 1.03% for women. Most individuals with kidney cancer are older, with the average age of diagnoses being 64. According to the American Cancer Society (ACS), the disease is very uncommon in people younger than 45.2 The current overall 5-year survival rate for kidney cancer is 75%. For localized kinder cancer, the 5-year survival rate is 93% while for distant kidney cancer it is 13%.³

The rate of kidney cancer has been rising since the 1990s, according to the ACS. However, the trend is starting to level off, most likely due to the rise of imaging tests such as CT scans, which are able to detect cancers that may have not been found otherwise. Additionally, improved therapies like platelet–derived growth factor receptor (PDGFR) inhibitors have helped contribute to improved and stable survival rates.²

In an interview with Targeted Oncology, Walter M. Stadler, MD, an oncologist at the University of Chicago and a member of the Medical Steering Committee for the Kidney Cancer Association, discussed recent updates and changes in the kidney cancer landscape.

TARGETED ONCOLOGY: How has the setting of kidney cancer changed over the last few years?

STADLER: Well, I think that if I zoom out a little bit here and look at what's happened over the last few decades, it's been nothing short of remarkable. I started my career with essentially no active therapies, aside from high-dose IL-2 [interleukin 2], which was very toxic and benefited only a very small proportion of patients. We now have a number of VEGFR inhibitors, we have a number of immune checkpoint inhibitors, and we have hypoxia-inducible factor (HIF) inhibitors emerging very rapidly. So, the fact that we've moved from essentially no therapy to trying to discuss which one of several treatments might be best for a specific patient is quite an impressive development over the last 2 decades.

TARGETED ONCOLOGY: What therapies do you prefer to use for patients in this setting in the first line?

STADLER: In the first line setting, we think about [patients with] good prognosis versus intermediate/poor prognosis. For good prognosis patients, our options include surveillance because some of these patients do well for long periods of time. [Our options] also include metastatic site directed therapy with either surgery or radiotherapy, and more specifically for the latter stereotactic body radiotherapy. Finally, it includes single agents for which there's good data with VEGFR inhibitors as well as combination therapy with an immune checkpoint inhibitor [PD-1] inhibitor plus a VEGFR inhibitor.

For initial therapy of intermediate and poor prognosis patients, what we're really looking at is either combination treatment with a PD-1 checkpoint inhibitor and a VEGFR inhibitor, or dual checkpoint inhibitor therapy with a CTLA-4 and a PD-1 inhibitor for which, the only combination that's available is ipilimumab [Yervoy] and nivolumab [Opdivo].

TARGETED ONCOLOGY: Can you discuss the phase 3 trial of the HIF-2α inhibitor, MK-6482, in this space?

STADLER: It was refreshing to see that a HIF inhibitor was developed and shows clear patient benefit. One thing that we've learned is that VHL mutations and pathway alterations are the pathognomonic definition for clear cell renal cell carcinoma. One of the major impacts of that alteration is upregulation of the HIF transcription factor. For many years, this was considered to be therapeutically not targetable. We now have a drug; it actually works, it actually leads to tumor shrinkages. A phase 3 trial to determine whether MK-6482 can improve survival versus standard everolimus is now ongoing and many of us are hopeful that the trial will be positive.

TARGETED ONCOLOGY: What other single agent or combination regimens have shown promise in this setting?

STADLER: Well, I think that now that we have a couple of different agents, one of the things showing promise is the combination of a HIF inhibitor and a VEGFR inhibitor. There are also ideas about combining HIF inhibitors and immunotherapy. Additionally, there are other immunotherapy agents out there, including an IL-2 receptor agonist that has some nice preliminary data. So, there are thus a number of additional approaches, especially in the immune therapy area, that we are hopeful will make a useful contribution for patients.

TARGETED ONCOLOGY: Which upcoming trials are you looking forward to?

STADLER: There are a number of exciting trials currently ongoing. These include combination immunotherapy plus a VEGFR inhibitor, as well as the addition of the HIF inhibitor that I've mentioned. We are participating in one such umbrella trial sponsored by Merck, but others are available. These kind of combination approaches is what I believe the future holds.

TARGETED ONCOLOGY: What are some unmet needs that are still present in in kidney cancer?

STADLER: Well, fundamentally, we're not curing patients. While we are often treating patients for many years. We're really not making the cancer go away and stay away. I think that really should be the goal. I think that's what patients expect of us and would like us to do. The 'cure' word was not something we used to throw around very easily, but I think that there is a potential for that.

TARGETED ONCOLOGY: Is there anything else you'd like to highlight in this setting?

STADLER: I think that one of the things that we've discussed a lot is that we have several agents that are very similar—we have several VEGFR tyrosine kinase inhibitors, we have several PD-1 pathway inhibitors, and frankly, the similarities between drugs in each class are much greater than any differences. So that allows us to mix and match and to begin to think about addressing cost issues. These medications are extremely expensive. They're not only expensive to the health system in general, they're also expensive to patients in regard to out-of-pocket expenses. There is real financial toxicity. Patients and families are being significantly impacted, up to and including bankruptcy, as a result of these therapies. From a health system perspective, the money that we spend on maintaining patients on expensive treatment is essentially money that we cannot spend in other areas.

If one has multiple agents in the same class that work similarly, we should be able to force the manufacturers to compete on price. Our system doesn't support that. Additionally, many of the PD-1 pathway inhibitors are likely over-dosed. More specifically, we probably don't need to give them as frequently to have the same impact. There may also be scenarios where we can discontinue treatment, especially for the PD-1 pathway inhibitors, and still not have an adverse impact on patients. This is going to become increasingly important over time; we just can't simply spend [up to] $50,000 a month on treating individual patients. That needs to change.

TARGETED ONCOLOGY: Do you have a method for escalating or de-escalating therapies for patients right now?

STADLER: I think that the major driver for dose adjustment continues to be toxicity. I think all of us who use these therapies have, for example, utilized intermittent treatment with the VEGFR inhibitors. I think that for the PD-1 checkpoint inhibitors, we are investigating this concept of longer intervals between dosing, which we think will preserve efficacy and at the same time save costs.

The fact that we're discussing these kinds of things makes me highly enthusiastic, and I think is something that our patients are really are thankful for.

_References:

_{1. National Kidney Month 2021. National Institutes of Health. Accessed March 25, 2021. https://bit.ly/39dhseO}

_{2. Key Statistics About Kidney Cancer. American Cancer Society. Accessed March 25, 2021. https://bit.ly/2PaGtjX}

_{3. Survival Rates for Kidney Cancer. American Cancer Society. Accessed March 25, 2021. https://bit.ly/3rlKDCN}