Mao Discusses the Best Management Strategy for a Patient With Clear Cell RCC

Targeted Oncology was joined on Twitter by Shifeng S. Mao, MD, PhD, chair of the Allegheny Health Network Cancer Institute urological oncology team and associate professor of medicine at Drexel University College of Medicine, for the discussion of treating a 59-year-old woman with clear-cell renal cell carcinoma (RCC).

Prior to the discussion, Targeted Oncology followers shared their thoughts in a poll on Twitter regarding which frontline therapy they would be most likely to recommend for this patient. Responders were split between axitinib (Inlyta) plus pembrolizumab (Keytruda; 32.4%) and cabozantinib (Cabometyx) plus nivolumab (Opdivo; 32.4%). Another 29.7% of responders voted for nivolumab plus ipilimumab (Yervoy) and 5.4% voted for the other.

Among these 5.4% of voters who responded “other” was Mao. He noted that the best choice for this patient is the combination of lenvatinib (Lenvima) and pembrolizumab.

“This is a patient with metastatic clear cell RCC of intermediate risk. Currently, combination therapy is preferred.There are 4 options available, including ipilimumab plus nivolumab based on CheckMate 214 [NCT02231749], pembrolizumab plus axitinib based on Keynote-426 [NCT02853331], cabozantinib plus nivolumab based on CheckMate 9ER [NCT03141177], and pembrolizumab plus lenvatinib based on CLEAR [Study 307]/KEYNOTE-581 trial [NCT02811861]All of them showed improvement of overall survival…Based on the response rate, pembrolizumab plus lenvatinib has the best overall response rate [ORR] and complete response [CR] rate so far although the follow-up is relatively short and adverse event (AE) rate is high.”

Some factors that influenced Mao's choice of treatment for this patient were her age, performance status, risk factors, and disease burden.

“For a patient with a high disease burden but with good performance status, I would choose a combination with a high response rate and/or high disease control rate even though the AE risk might be higher,” stated Mao during the chat.

Mao highlighted excellent data from ongoing trials in the RCC space, including the COSMIC-313 trial comparing cabozantinib plus ipilimumab plus nivolumab to ipilimumab plus nivolumab in patients with metastatic RCC. He also noted the PDIGREE trial (NCT03793166) for first line RCC which starts with treating patients of intermediate/poor risk with ipilimumab and nivolumab as induction for 4 cycles, and the PIVOT 09 study (NCT03729245) comparing nivolumab plus bempegaldesleukin (NKTR-214: BEMPEG) with either sunitinib (Sutent) or cabozantinib.

With the immense amounts of advances for patients with RCC, Mao explained his excitement for what more can be done. “Treatment for mRCC has evolved rapidly over the last 10 years. This is one of the most exciting fields in oncology. As a GU oncologist, I am proud to be part of it,” added Mao.

In an interview with Targeted OncologyTM following the chat, Mao further discussed his choices for treatment of this patient and explained what research he hopes will further shape the kidney cancer field.

Targeted Oncology: What were your thoughts on this RCC case?

Mao: Basically, she is a middle aged, African American female with a metastatic renal cell carcinoma who developed metastasis within 1 year following surgery. Hemoglobin was a little bit low, so there are 2 criteria that she meets. She belongs to the intermediate risk category. In that situation, the treatment options are wide open with 4 main options.

What were your thoughts on the polling question? How did you come to your answer?

This is a patient with metastatic clear cell RCC of intermediate risk. Currently, combination therapy is preferred.There are 4 options available, including ipilimumab plus nivolumab based on CheckMate 214, pembrolizumab plus axitinib based on Keynote-426, cabozantinib plus nivolumab based on CheckMate 9ER, and pembrolizumab plus lenvatinib based on CLEAR/KEYNOTE-581 trial. All of them showed improvement in overall survival.

Except for ipilimumab plus nivolumab, the 3 TKI/ICI [tyrosine kinase inhibitor/immune checkpoint inhibitor] combinations showed improvement of PFS and significantly better ORR. There are differences in follow-up duration, and proportion of patients of different IMDC [International Metastatic RCC Database Consortium] risk categories. For instance, Checkmate-214 and Checkmate-9ER included more patients of intermediate and poor risk categories, while Keynote-426 and Keynote-581 included more patients of favorable risk. It would be difficult to compare these trials.

How did you decide to choose lenvatinib and pembrolizumab for this patient?

There is no simple great answer to this question. Based on the AE profile, ipilimumab plus nivolumab seems to have less grade 3-4 AE compared to the TKI/ICI combinations. Based on the response rate, pembrolizumab plus lenvatinib has the best ORR and CR rate so far, although the follow up is relatively short and AE rate is high. Based on the OS improvement, cabozantinib plus nivolumab seems to have the best performance. The ipilimumab/nivolumab combination is only approved for the intermediate and poor risk groups while the TKI/ICI combinations are approved for all risk categories.

Choosing any combination would depend on patient factors in terms of comorbidities, performance status, organ function and physician factors including prescribing habits, and experience. As said, the TKI /ICI combination provides a higher response rate. However, if the pathology report shows evidence of sarcomatoid differentiation which would predict a better response to ICI, ICI/ICI combination, i.e., ipilimumab plus nivolumab would be preferred.If the patient cannot be treated with immunotherapy due to comorbidity, cabozantinib as a single agent can be considered.

What recent data has been influential in this space?

We see a further update of trials with longer follow-up and as time goes by. These data tend to get updated every 6 to 12 months as they go to national meetings and give the updated data. While the network meta-analysis is not the best way to compare trial to trial, using statistical, mathematical ways to kind of balance the bias to try to make comparisons to some extent can help to dissect the efficacy of different treatments. From a survival standpoint, cabozantinib/nivolumab seems to be a winner. From a response perspective, lenvatinib and pembrolizumab seems to be a winner, and for adverse events, ipilimumab plus nivolumab seems to have comparatively less adverse events.

What do you most look forward to learning about in the future of RCC?

The future is bright. Renal cell carcinoma is 1 of the fast-evolving cancers in this field. It is a relatively smaller field compared with breast cancer, colorectal cancer, or lung cancer because the number of patients with metastatic RCC is much less if you look at the national cancer incidence. RCC is much lower than breast cancer, lung cancer, colorectal cancer. However, the field is making a lot of noise because all this important progress is being made. Besides the combinations and development of immunotherapy, and the combination immunotherapy plus TKI. There are some other newer drugs that have been undergoing evaluation in clinical trials. Those are some things we're looking forward to.

For those unable to make the chat, what do you think are the key takeaways of this case?

We are very excited with what is going on. Certainly, there are a lot of unmet needs in the field. There is still an area where even though the response rates are high, we still see patients progressing. So, we still need better drugs. We need more efficacious and less toxic drugs to be developed. We need to be smart about which drug to use. A combination approach is great, but at the same time, you need to use the right ones.

For example, by adding pembrolizumab to this particular patient, is she really going to respond to it or is lenvatinib or cabozantinib going to work? There is a theory that when you combine the 2, the immunotherapy response could be higher. But there are patients who may never respond to immunotherapy, so how do we find out? This is an area of active research. There's some ongoing research to find a biomarker that will predict response to immunotherapy vs anti-angiogenesis therapy using TKI.

Hopefully in the future with those tools handy, we will be smarter about it in terms of which combination to choose or determining if we have to use a certain combination. Maybe we can just use immunotherapy alone or TKI alone. That will be something that hopefully will happen in the future.