Daniel M. Geynisman, MD, on Optimal Therapy Selection in RCC

At 2022 ASCO GU, Daniel M. Geynisman, MD, spoke with CancerNetwork® about his strategy for treating renal cell carcinoma across lines of therapy.

Following the 2022 Genitourinary Cancer Symposium, CancerNetwork® spoke with Daniel M. Geynisman, MD, associate professor in the Department of Hematology/Oncology and vice chair of the Quality Improvement Program at Fox Chase Cancer Center in Philadelphia, Pennsylvania, about updates in the treatment of patients with renal cell carcinoma (RCC) and how he is choosing to treat his patients in the frontline setting and beyond.


It’s a crowded space; there are many options, which is wonderful for our patients. [Treatment] has really changed over the last 5 years. Remember, 5 years ago, this was a TKI [tyrosine kinase inhibitor]–based space. All frontline patients were receiving single-agent tyrosine kinase inhibitors and then switched to IO/IO [immunotherapy], with ipilimumab [Yervoy] plus nivolumab [Opdivo] for the intermediate-high risk patients, and then shortly thereafter IO/TKI [as in] PD-1 or PD-L1 inhibitors with a TKI for all patients with favorable, intermediate, and poor [risk].

The standard of care now for frontline therapies is either IO/IO, or IO/TKI. Certainly, for intermediate-, high-, and favorable-risk patients it is most often IO/TKI. There are caveats to that, but that’s the general paradigm. How you decide for most patients between IO/IO and IO/TKI is dependent on patient preferences. It’s dependent on extent of disease, other comorbidities that patients have, and what side effects they’re willing to potentially incur. There are physician preferences, and what some oncologists believe is a better frontline regimen, but there are really pluses and minuses to both combinations. For example, the ipilimumab/nivolumab combination has the longest follow-up data and approximately a third of patients have not required other therapy after being treated with it [in clinical trials], so it has that nice tail of the curve. However, on the flip side, the IO/TKI combinations have a much higher response rate. If you’re looking for a good and deep immediate response in somebody who has high-volume disease and you’re worried about their symptoms, IO/TKI may be very reasonable. If you have someone who is not symptomatic and has relatively low-volume disease, they might be a great patient for pure immunotherapy. There’s a wide spectrum there, and at the end of the day, both are appropriate. What’s most important to know is that single-agent TKI is not appropriate for almost any patient unless they’re truly not candidates for immunotherapy. That’s the key takeaway for me.

In the second-line space, there are multiple options, and they depend somewhat on what you use in your frontline space. For example, if you had a pure immunotherapy treatment in the frontline space, you’re obviously going to go to a TKI in the second-line space. You may use a TKI by itself, like cabozantinib [Cabometyx] or you may use the combination of a TKI and an mTOR inhibitor like lenvatinib [Lenvima] and everolimus [Afinitor]. You may enroll a patient in a clinical trial that is investigating further immunotherapy at a time of progression, for example combining a TKI with immunotherapy versus the TKI alone. Probably around the corner, not too far from now, there is going to be the approval of the HIF2-a inhibitor belzutifan (Welireg), and that may be an option for this second- or third-line space. We always encourage clinical trials. Again, there are options. If you’ve had an IO/TKI in the frontline, it gets a little bit more challenging because the patient has seen a drug in each of the categories, but most people will go into a second-line TKI. For example, if you were treated with pembrolizumab [Keytruda] and axitinib [Inlyta] in the frontline setting, you go to cabozantinib in the second-line setting.