We’re moving on to some of the newer combinations and the combinations presented. Eric, could you talk to us a bit about the belzutifan-cabozantinib combination that we saw?

There are multiple efforts now. Belzutifan is a HIF-2α inhibitor. We got it approved last year for von Hippel-Lindau disease. There’s a robust program with this compound with combinations with various TKIs [tyrosine kinase inhibitors] as well as I/O [immuno-oncology] therapy. We don’t have any good biological rationale necessarily for combining HIF-2α with a TKI or with immunotherapy, but the clinical trials are proceeding.

This is a 35-patient phase II trial [DOI: 10.1056/NEJMoa2103425] in which individuals—mostly good-risk patients, previously untreated—received a combination of belzutifan 120 mg by mouth per day plus cabozantinib 40 mg. The primary end point was objective response, and the objective response rate was very good, 57%, and the PFS [progression-free survival] is an intriguing 30 months. Those are cool data; however, there are a couple of caveats. First, if you look at the second-line cabozantinib-belzutifan data, we have a progression-free survival of around 13 months and an objective response rate in the high-20% range, which is almost identical to belzutifan monotherapy. These wonderful data that we see—how much are driven by belzutifan alone? How much is cabozantinib adding to it? It’s a cautionary note as we start piling drugs upon drugs, as oncologists do.

Let’s go around the table randomly. Ben, what about the PDIGREE trial? Do you know much about that PDIGREE study? What’s your take on it?

This is an ongoing clinical trial effectively using response adaptation: how much should we intensify therapy vs continuing with somewhat less intensified therapy. Patients with previously untreated metastatic clear-cell kidney cancer are enrolled in the trial, and they’re started on their treatment of ipilimumab-nivolumab. Depending on that response, at 3 months, they get moved to 1 of 3 cohorts. If they have progressive disease, then they move to second-line cabozantinib. If they have a complete response, then they continue on nivolumab maintenance because you would do a standard of care.

Then there’s the mainstream section. If they don’t have progression and they don’t have complete response, and they have stable disease or partial response, then that group of patients is under investigation in this clinical trial. That group of patients then gets randomized to continuing nivolumab maintenance or the addition of cabozantinib-nivolumab to see if we can, with the intensification, further improve their response and durability. It has a couple of unique advantages of trying to minimize toxicity as opposed to intensifying and doing triplet therapy from the beginning. It also leverages some of these theoretical immunomodulatory effects of cabozantinib.

Ulka, we’ll move to you. Are you going to go with bempegaldesleukin—bempegaldesleukin IL-2 plus nivolumab? We’ve got a press release saying the trial is not as positive as it was been presented at the meeting. Tell me a little about what’s going on.

Bempegaldesleukin is a PEGylated interleukin that was investigated in combination with nivolumab. It showed preliminary but really promising efficacy in the phase 2 setting in combination. It was never investigated as a single agent in metastatic kidney cancer. The combination was compared with sunitinib or cabozantinib; the majority of patients were randomized to sunitinib. The combination did not show improvement in efficacy. There’s no difference in terms of parameters of efficacy, response rates, PFS, etc, compared with single-agent VEGF TKI.

The first immune combination hasn’t been successful. It had a lot of success, but now it’s struggling a bit. Is the tide changing?

It’s a disappointment. I don’t know the exact reasons for it.

Can I push you on a different study, the CA209-8Y8 trial? That’s nivolumab vs ipilimumab-nivolumab. Does that trial worry you?

Chances are, it’s not going to show that single-agent nivolumab isn’t similar to ipilimumab-nivolumab. There was the OMNIVORE study, and HCRN [Hoosier Cancer Research Network] conducted a study. Both seem to agree on up-front nivolumab, and then if you try to add ipilimumab, you salvage a small proportion of patients. You never can get to that up-front robust response rate.

There’s refinement to the immune combinations but not huge progress. That’s fair.

Videos

An expert panel reviews novel first-line doublet therapies being studied in patients with advanced clear cell renal cell carcinoma. 

First-Line Therapy in Advanced Clear Cell RCC: Novel Doublet Regimens

Vaishali Sanchorawala, MD, director of Stem Cell Transplantation program at Boston Medical Center, director of Amyloidosis Center at Boston University School of Medicine, and secretary of the International Society of Amyloidosis for the term 2020-2022, discusses the impact of renal and cardiac response on survival in patients with light chain (AL) amyloidosis. 

Research from 2 international collaborative studies presented during the 2021 International Myeloma Workshop 2021 examined the graded renal response criteria and revised renal progression criteria for AL amyloidosis, as well as the graded cardiac response criteria and the impact of depth of cardiac response on survival, according to Sanchorawala. 

Results showed that a deeper cardiac response was associated with improved overall survival (OS), Sanchorawala says. Additionally, deeper renal response correlated with improved OS, as well as renal survival which translated to a decreased risk for renal replacement therapy, Sanchorawala concludes.

Vaishali Sanchorawala, MD, discusses the impact of renal and cardiac response on survival in patients with light chain amyloidosis. 

Vaishali Sanchorawala, MD

Articles

First-Line Therapy in Advanced Clear Cell RCC: Novel Doublet Regimens

Dr. Sanchorawala on the Impact of Depth of Renal and Cardiac Response on Survival in AL Amyloidosis