Mao discusses the best management strategy for a patient with clear cell RCC

During a tweet, Shifeng S. Mao, MD, PhD and Targeted Oncology Twitter followers discussed the case of a 59-year-old woman with clear cell renal cell carcinoma and the best treatment options for the condition. patient.

Targeted Oncology was joined on Twitter by Shifeng S. Mao, MD, PhD, Chair of the Urologic Oncology Team at the Allegheny Health Network Cancer Institute and Associate Professor of Medicine at Drexel University College of Medicine, for a discussion on the treatment of a 59-year-old man. woman with clear cell renal cell carcinoma (RCC).

Prior to the discussion, Targeted Oncology followers shared their thoughts in a Twitter poll regarding which front-line 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 respondents voted for nivolumab plus ipilimumab (Yervoy) and 5.4% voted for the other.

Among those 5.4% of voters who answered “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 intermediate risk metastatic clear cell CRC. 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 showed improved overall survival…Based on response rate, pembrolizumab plus lenvatinib has the best overall response rate [ORR] and full answer [CR] so far, although the follow-up is relatively short and the rate of adverse events (AEs) 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 a good performance status, I would choose a combination with a high response rate and/or a high disease control rate even though the risk of IE might be higher “, said Mao during the chat.

Mao pointed to 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. It also noted the PDIGREE trial (NCT03793166) for first-line RCC that begins by treating intermediate/low-risk patients with ipilimumab and nivolumab induction for 4 cycles, and the PIVOT 09 study (NCT03729245 ) comparing nivolumab plus bempegaldesleukin (NKTR-214: BEMPEG) with sunitinib (Sutent) or cabozantinib.

With the immense progress being made for RCC patients, Mao explained his excitement for what more can be done. “The treatment of mRCC has evolved rapidly over the past 10 years. It is one of the most exciting areas of oncology. As a GU oncologist, I am proud to be part of it,” Mao added.

In an interview with Targeted OncologyTM after the chat, Mao discussed his choices for treating this patient in more detail and explained what research he hopes will further shape the kidney cancer field.

Targeted oncology: What do you think of this RCC case?

Mao: Basically, this is a middle-aged African American woman with metastatic renal cell carcinoma who developed metastases within a year of surgery. The hemoglobin was a little low, so there are 2 criteria she meets. It belongs to the medium risk category. In this situation, the treatment options are wide open with 4 main options.

What do you think of the poll question? How did you arrive at your answer?

This is a patient with intermediate risk metastatic clear cell CRC. 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 test. All showed improved overall survival.

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

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

There is no big simple answer to this question. Based on the AE profile, ipilimumab plus nivolumab appears to have fewer grade 3-4 AEs compared to TKI/ICI combinations. Based on response rate, pembrolizumab plus lenvatinib has the best rate of ORT and CR to date, although the follow-up is relatively short and the rate of AE is high. Based on improvement in OS, cabozantinib plus nivolumab appears to have the best performance. The ipilimumab/nivolumab combination is only approved for intermediate and low risk groups, while the TKI/ICI combinations are approved for all risk categories.

The choice of any combination would depend on patient factors in terms of comorbidities, performance status, organ function, and physician factors including prescribing habits and experience. As noted, the TKI/ICI combination provides a higher response rate. However, if the pathology report shows signs of sarcomatoid differentiation predicting a better response to ICI, the ICI/ICI combination, i.e. ipilimumab plus nivolumab, will be preferred. If the patient cannot be treated with immunotherapy due to comorbidity, cabozantinib monotherapy agent may be considered.

What recent data has been influential in this space?

We see a new trial update with longer tracking and over time. This data tends to be updated every 6-12 months as they go to national meetings and give the updated data. Although network meta-analysis is not the best way to compare one trial to another, using statistical and mathematical methods to balance bias in an attempt to make comparisons to some degree can help dissect the effectiveness of different treatments. From a survival perspective, cabozantinib/nivolumab appears to be a winner. From a response perspective, lenvatinib and pembrolizumab appear to be winners, and for adverse events, ipilimumab plus nivolumab appears to have comparatively fewer adverse events.

What are you most looking forward to learning about the future of RCC?

The future is bright. Renal cell carcinoma is one of the rapidly growing cancers in this area. It is a relatively smaller area compared to breast cancer, colorectal cancer, or lung cancer, as the number of patients with metastatic RCC is much less when considering national cancer incidence . RCC is much weaker than breast cancer, lung cancer, colorectal cancer. However, the field is making a lot of noise because all these important advancements are in progress. Besides combinations and development of immunotherapy, and combination immunotherapy plus ITK. There are other newer drugs that have been evaluated in clinical trials. These are things we look forward to.

For those who can’t argue, what do you think are the main takeaways from this case?

We are very excited about what is happening. Certainly, there are many unmet needs on the ground. There is still one area where, although response rates are high, we are still seeing patients progress. So we still need better drugs. We need to develop more effective and less toxic drugs. We have to be smart about what medicine to use. A combination approach is great, but at the same time you have to use the right ones.

For example, adding pembrolizumab to this particular patient, is she really going to respond or will lenvatinib or cabozantinib work? There is a theory that when you combine the 2, the immunotherapeutic response might be higher. But there are patients who may never respond to immunotherapy, so how do you know? This is an area of ​​active research. Research is ongoing to find a biomarker that will predict response to immunotherapy versus anti-angiogenesis therapy using ITK.

Hopefully in the future, with these handy tools, we will be smarter in terms of which combination to choose or whether we should use a certain combination. Maybe we can just use immunotherapy alone or TKI alone. This will be something that will hopefully happen in the future.

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