Richard W. Joseph, MD, internist and oncologist, Mayo Clinic, discusses molecular signatures in metastatic renal cell carcinoma (mRCC).

Current molecular signatures can be used to distinguish a VEGF-based tumor from an immune tumor, says Joseph. Now that the majority of frontline treatment regimens in mRCC are combinations of immunotherapy and VEGF therapies, great signatures to distinguish between regimens are lacking. Prior to immunotherapy and VEGF combinations, PD-L1 was relatively helpful, adds Joseph; now, it’s less helpful, but not obsolete. For example, a PD-L1—positive tumor—especially in patients with sarcomatoid histology&mdash;would do better with a double immunotherapy combination. The responses that have been reported with the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) in patients with PD-L1–positive sarcomatoid tumors are very high. However, as it stands, a treatment decision should never be based solely on PD-L1, he says.

Joseph is hopeful that molecular markers will emerge, especially for PD-L1—negative patients, in whom treatment approaches between a double immunotherapy combination versus an immunotherapy/VEGF combination are not always as clear.

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Dr. Joseph on Molecular Signatures in mRCC

Richard W. Joseph, MD, internist and oncologist, Mayo Clinic, discusses the combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) in metastatic renal cell carcinoma (mRCC).

The combination of atezolizumab and bevacizumab has shown encouraging signals of activity, according to results from the phase II IMmotion150 and the phase III IMmotion151 trials. However, the primary endpoints are relatively immature. Joseph, having treated patients on the trials, explains that the combination is also 1 of the more tolerable regimens of the combinations available for patients with advanced RCC. The rate of grade 3/4 adverse events tends to be on the lower side with atezolizumab and bevacizumab compared with other combinations.

That combination, pending approval, is likely to have a prominent role in patients who are frailer and in whom maintaining a good quality of life is more of a goal, says Joseph. The complete response rates with this combination look pretty reasonable, too. If the combination is approved, it is likely to complicate the current paradigm, of which there are currently 3 combination therapies to choose from. However, another option is always a good thing for patients, concludes Joseph.

Dr. Joseph on the Combination of Atezolizumab and Bevacizumab in mRCC

Richard W. Joseph, MD, internist and oncologist, Mayo Clinic, discusses considerations for frontline therapy selection for patients with metastatic renal cell carcinoma (mRCC).

The first thing that needs to be to be taken into consideration is a patient’s risk status, whether it’s good, intermediate, or poor. Risk status was initially designed to be prognostic, but can also be used to predict biology, adds Joseph.

In addition to risk status, a patient’s comorbidities should also be used to guide therapy selection. For example, if a patient has a cardiac history, is anti-VEGF therapy the best choice? Additionally, any soft or hard contraindication to immunotherapy could help eliminate an immunotherapy-based therapy from the equation. Ultimately, the decision comes down to good clinical judgement, concludes Joseph.

Richard W. Joseph, MD, internist and oncologist, Mayo Clinic, discusses considerations for frontline therapy selection in metastatic renal cell carcinoma (mRCC).

Dr. Joseph on Factors Influencing Frontline Therapy Selection in mRCC

Richard W. Joseph, MD, internist and oncologist, Mayo Clinic, discusses the process of selecting frontline therapy in metastatic renal cell carcinoma (mRCC).

Favorable-risk patients tend to do very well with TKI monotherapy, says Joseph. For example, Joseph has had several patients who have been on a TKI for over 5 years. Despite the introduction of combinations of immunotherapy and VEGF TKIs, there remains a role for TKI monotherapy, specifically among favorable-risk patients with slow-growing disease or those who do not want the added toxicity that comes with combination therapy.

The newer combinations play a much bigger role in intermediate- and poor-risk patients, but they can also be used in favorable-risk patients. The decision is multifaceted, explains Joseph, but one of the most important considerations is patient preference. Younger, healthier patients may be willing to take on greater risk, whereas older patients may opt for a more conservative approach.

Joseph tends to favor the combination of 2 immunotherapy agents in intermediate- and poor-risk patients, so that he can turn to an anti-VEGF therapy upon disease progression. Moreover, the double immunotherapy combinations have shown a high rate of complete remissions, which may lead to durable responses and potential treatment discontinuation.

Richard W. Joseph, MD

Articles

Dr. Joseph on Molecular Signatures in mRCC

Dr. Joseph on the Combination of Atezolizumab and Bevacizumab in mRCC

Dr. Joseph on Factors Influencing Frontline Therapy Selection in mRCC

Dr. Joseph on Selecting Frontline Therapy in mRCC