Bradley McGregor, MD

Bradley A. McGregor, MD, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School, discusses current and future second-line therapy options following frontline tyrosine kinase inhibitor (TKIs) and immunotherapy (IO) for patients with advanced renal cell carcinoma (RCC).

The choice of second-line therapy is based on limited data since frontline IO/TKI combinations are relatively new. McGregor says cabozantinib (Cabometyx) is a strong single-agent option based on how it performed as a comparator arm in the CANTATA trial (NCT03428217). Lenvatinib (Lenvima) and everolimus (Afinitor) are also a second-line option.

More trials are ongoing to research the optimal treatment following IO/TKI frontline therapy. McGregor says there were impressive results for lenvatinib plus pembrolizumab (Keytruda) in patients who had received prior IO. The currently-enrolling CONTACT-03 trial (NCT04338269) is investigating cabozantinib plus atezolizumab (Tecentriq) versus cabozantinib alone. Another trial accruing patients is the TiNivo-2 trial (NCT04987203) of tivozanib (Fotivda) plus nivolumab (Opdivo) versus tivozanib in the second line.

A phase 3 trial (NCT04586231) of belzutifan (Welireg) plus lenvatinib versus cabozantinib is ongoing, as well as a phase 3 trial (NCT04195750) of belzutifan versus everolimus.

These trials will show whether additional immunotherapy is effective in patients who are refractory or relapsed following frontline IO/TKI.

If a patient does not receive cabozantinib in the frontline setting, I think given immediate results and what we saw in the CANTATA tracking, cabozantinib is a very appropriate option as well as lenvatinib and everolimus given the phase 2…improvement in survival versus everolimus, so I think either one of those would be a reasonable option. Obviously, if they received cabozantinib frontline, I'm going to use lenvatinib/everolimus, and if they received lenvatinib/pembrolizumab in the frontline, I'm going look at cabozantinib. I think we certainly need to do better and there are multiple trials ongoing in this frontline.

 One of the questions we don't really know the answer is if you progress on IO, is there a role for continuing IO? We've seen some pretty impressive results for the combination of lenvatinib and pembrolizumab for patients who progress on prior immunotherapy: response rates over 50%. Is that from lenvatinib or is that truly from the combination? There are multiple trials ongoing: the [CONTACT-03] trial looking in cabozantinib and atezolizumab versus cabozantinib that has completed accrual. Right now, the TiNivo-2 trial looking at tivozanib versus tivozanib and nivolumab for patients who have progressed on immunotherapy even at frontline or second-line setting is currently accruing. There are other trials looking at adding belzutifan to lenvatinib versus cabozantinib. And then we look forward the results of the phase 2 trial of belzutifan versus everolimus in the treatment refractory setting.

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Bradley A. McGregor, MD, discusses current and future second-line therapy options following frontline tyrosine kinase inhibitor and immunotherapy for patients with advanced renal cell carcinoma.

Current and Potential Second-Line Therapies Following IO/TKI in RCC

Bradley A. McGregor, MD, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and instructor in medicine at Harvard Medical School, discusses new trials of intensified combination regimens for frontline treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma (RCC).

The current frontline therapy for intermediate- and poor-risk patients is a choice between immunotherapy (IO) and tyrosine kinase inhibitor (TKI) combinations or the IO/IO combination of ipilimumab (Yervoy) plus nivolumab (Opdivo). Ipilimumab/nivolumab tends to offer more durable responses but a lower objective response rate than IO/TKIs.

McGregor says some randomized trials are attempting to improve on the outcomes of IO/IO and IO/TKI combinations through intensified therapy. This includes the COSMIC-313 trial (NCT03937219) comparing cabozantinib (Cabometyx), nivolumab, and ipilimumab versus nivolumab/ipilimumab alone. Additionally, the 3-arm MK-6482-012 trial (NCT04736706) will evaluate lenvatinib (Lenvima)/pembrolizumab (Keytruda) versus lenvatinib, pembrolizumab and belzutifan (Welireg), versus pembrolizumab/lenvatinib plus quavonlimab, a novel anti­–CTLA-4. The PDIGREE trial (NCT03793166) will add cabozantinib after an initial treatment of nivolumab/ipilimumab.

For now, McGregor feels that if a patient needs a response in the first line, an IO/TKI would be used. But if he thought a patient could continue to be treated, if they do not respond to frontline therapy, he would choose ipilimumab/nivolumab and then a second-line TKI.

 When we look at intermediate/poor-risk disease, obviously I think therapy is indicated. There are trials ongoing to see: Can we improve upon the IO/TKI doublets or nivolumab/ipilimumab? So COSMIC-313 has accrued; this was limited in intermediate/poor disease and looked at combination of cabozantinib and nivolumab/ipilimumab versus nivolumab/ipilimumab. So can we get the increased response rate on the TKI/IO combinations with the durability of nivolumab/ipilimumab? We look forward to those results.

There's an ongoing trial with lenvatinib and pembrolizumab versus lenvatinib, pembrolizumab and CTLA-4 versus lenvatinib, pembrolizumab, and belzutifan that is currently accruing. So I think it'd be really important to think about this idea of intensification.

Until we know if intensification is going to be important, we're left with IO/IO versus IO/TKI. And that's where, if I have a patient who I feel that they have progressive disease as their best response, they can likely go on to a TKI. I'm going to think about nivolumab/ipilimumab. I strongly support the ongoing PDIGREE trial, which starts with nivolumab and ipilimumab, and then based on response, will look at adding cabozantinib to nivolumab versus nivolumab alone, so this [would be an] adaptive approach. I think those are going to be really important data to help us further improve care for our patients.

Bradley A. McGregor, MD, discusses new trials of intensified combination regimens for frontline treatment of patients with intermediate- or poor-risk advanced renal cell carcinoma.

Ongoing Trials Investigate Intensified Frontline Therapy for RCC

Bradley McGregor, MD, clinical director, Lank Center for Genitourinary Oncology, senior physician, Dana-Farber Cancer Institute, and instructor of medicine, Harvard Medical School, discusses the ongoing COSMIC-313 trial (NCT03937219) of cabozantinib (Cabometyx), ipilimumab (Yervoy), and nivolumab (Opdivo) in patients with renal cell carcinoma (RCC).

COSMIC-313 is a randomized trial of this combination compared with nivolumab and ipilimumab. In this setting, there are many different VEGF inhibitors and immune-oncology (IO) combinations with slightly different toxicity profiles and different drugs. There are also IO-IO combinations—for these, it seems like there are a group of patients who have a durable response and are able to go off of therapy, according to McGregor. It is uncertain if this response will be seen with VEGF and IO combinations since those data are still maturing. With IO-IO combinations for patients with RCC, over 20% have progressive disease as their best response.

McGregor says the hope with COSMIC-313 is that the triplet combination of nivolumab and ipilimumab with cabozantinib will be able to overcome the progressive disease as best response for these patients. He also hopes that this combination will maintain a point where patients can continue on therapy and have durability of their response.

Bradley McGregor, MD, discusses the ongoing COSMIC-313 trial of cabozantinib, ipilimumab, and nivolumab in patients with renal cell carcinoma.

Combination of Cabozantinib/Ipilimumab/Nivolumab Investigated in RCC

Bradley McGregor, MD, clinical director of Lank Center for Genitourinary Oncology, senior physician at Dana-Farber Cancer Institute, and instructor of Medicine at Harvard Medical School, discusses the CheckMate-9ER trial (NCT03141177) of nivolumab (Opdivo) plus cabozantinib (Cabometyx) versus sunitinib (Sutent) in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC).

This trial enrolled patients from all of the International Metastatic RCC Database Consortium risk groups. The number of patients in each risk were comparable to real-world practice according to McGregor, with 20% to 25% having favorable risk, about 60% having intermediate risk, and about 20% having poor risk. The patients were evenly distributed through the United States, Europe, and the rest of the world.

The data from the initial analysis showed that there was a marked improvement in progression-free survival (PFS) at a median follow-up of 18 months. This improvement produced a hazard ratio of 0.51, with a median PFS of 16.6 months with the combination versus 8.3 months with sunitinib. The overall survival has not been reached in either group, but the hazard ratio favors the combination at 0.60. McGregor says the P value was also statistically significant. The subgroups also favored nivolumab and cabozantinib in this study.

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Bradley McGregor, MD, discusses the CheckMate-9ER trial of nivolumab plus cabozantinib versus sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma.

CheckMate-9ER Shows Efficacy of Nivolumab/Cabozantinib Combo in RCC

Bradley McGregor, MD, clinical director, Lank Center for Genitourinary Oncology, senior physician, Dana-Farber Cancer Institute, and instructor of medicine, Harvard Medical School, discusses a small study that evaluated the combination of atezolizumab (Tecqntriq) and bevacizumab (Avastin) for the treatment of patients with non-clear cell renal cell carcinoma (RCC).

As much as the treatment landscape has evolved for advanced RCC over the last several years, these efforts have been mainly focused on clear cell RCC, says McGregor. The majority of trials exclude patients with non-clear cell variant histology RCC, but retrospective data have shown these patients tend to do worse.

In an investigative response trial, McGregor says the combination of atezolizumab plus bevacizumab was evaluated in this patient population of 60 patients, 42 of which had variant histology RCC and 18 had clear cell RCC with sarcomatous differentiation.

About half of the patients with variant histology RCC had received prior systemic therapy, McGregor notes. The overall response rate in all patients was 33% and 26% independent of histologic type. McGregor says the patients with chromophobe had the lowest response rate, but the regimen was well-tolerated with minimal grade 3 or higher adverse events.

Bradley McGregor, MD, discusses a small study that evaluated the combination of atezolizumab and bevacizumab for the treatment of patients with non-clear cell renal cell carcinoma.

Using Combination Therapy as Treatment of Non-Clear Cell RCC

Bradley McGregor, MD, clinical director of Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, discusses a trial investigating atezolizumab (Tecentriq) and bevacizumab (Avastin) in patients with metastatic renal cell carcinoma (RCC) and variant histologies and/or sarcomatoid features.

McGregor thinks that much of the data over the last few years has been focused on clear cell RCC, with trials like CheckMate-214; data from studies of pembrolizumab (Keytruda) and axitinib (Inlyta), or axitinib and nivolumab (Opdivo) excluded patients with non-clear cell and variant histology RCC. These patients do not do as well as patients with clear cell RCC, so McGregor and his colleagues started an investigator&rsquo;s response trial. The purpose of this trial was to evaluate the combination of a VEGF inhibitor and an immune checkpoint blockade in patients with variant histologies or clear cell histology with sarcomatoid features.

The trial had a total of 60 patients, who received atezolizumab and bevacizumab based on the IMmotion 150 and 151 data. McGregor say this regimen was appealing because it was well tolerated by patients in those trials. Patients in this trial were given the standard dose of atezolizumab and 15 mg/kg of bevacizumab every 3 weeks. Patients were allowed to have prior therapy, which he says was unique for this setting. Over 1 and a half to 2 years, the study enrolled the 60 patients; 42 patients had variant histology RCC and 18 had clear cell RCC with sarcomatoid differentiation.

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Bradley McGregor, MD, discusses a trial investigating atezolizumab and bevacizumab in patients with metastatic renal cell carcinoma and variant histologies and/or sarcomatoid features.

Bradley McGregor, MD | Authors

Articles

Current and Potential Second-Line Therapies Following IO/TKI in RCC

Ongoing Trials Investigate Intensified Frontline Therapy for RCC

Combination of Cabozantinib/Ipilimumab/Nivolumab Investigated in RCC

CheckMate-9ER Shows Efficacy of Nivolumab/Cabozantinib Combo in RCC

Using Combination Therapy as Treatment of Non-Clear Cell RCC

Atezolizumab and Bevacizumab Studied in Patients With Metastatic RCC