Advances in Frontline Treatment for Advanced Renal Cell Carcinoma - Episode 2

Comparing Approved First-Line IO-TKI and IO-IO Combination Treatment Regimens in Advanced Clear Cell RCC

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Dr Nizar Tannir compares data among the 4 approved first-line I/O combination therapy regimens in advanced clear cell RCC.

Nizar Tannir, MD: This is a busy slide that shows a summary of data regarding efficacy. Side by side, the data relate to the 4 regimens that have been approved from the 4 phase 3 trials in the first line: CheckMate 214, KEYNOTE-426, CheckMate 9ER, and the CLEAR study. We’ll go into more detail about each phase 3 trial when we focus. My colleagues Dr Tykodi and Dr Ornstein will give us more details about the data.

To summarize the data, in the top row, you’ll see the overall survival [OS] median for each of these 4 trials and the hazard ratio. The hazard ratio is basically 0.66 to 0.73. Basically, the primary end point of the OS data is in favor of the combination arm compared with sunitinib. It’s important to mention that all 4 phase 3 trials used sunitinib as the comparator. When you look at the landmark analysis for OS at 1 year and 2 years, the data there again compared with sunitinib. All 4 regimens have superior data for OS at 1 and 2 years compared with the comparator sunitinib.

The third row is progression-free survival [PFS]. You see the hazard ratio, and then you can see that for the 3 I/O [immuno-oncology]–TKI [tyrosine kinase inhibitor] regimens—basically KEYNOTE-426, CheckMate 9ER, and CLEAR—the PFS shows superior results when it comes to intent to treat for all 3 I/O–TKI regimens. The response rate is in the lower row. CR [complete response] rate is an important efficacy end point that we look at when we think of selecting a therapy for our patients. The CR rate with sunitinib is 3% to 4%, and with the combinations, it’s 9% to 16%. Note that CheckMate 9ER has some updated data from ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] a few months ago, where the CR rate with nivolumab-cabozantinib was 12%.

In regard to the median follow-up, the study that has the longest follow-up of those 4 trials is CheckMate 214 because it was the first phase 3 trial launched, and it has a median follow-up exceeding 55 months. You can see the breakdown of favorable, intermediate, and poor risk for each of these phase 3 trials. That’s why it’s important to caution that you see those results side by side, but one shouldn’t compare across trials because the patients who were recruited to each trial are different.

For each trial, the percentage of patients with favorable risk, intermediate risk, or poor risk varies. It’s also important to note what you see at the bottom of the slide in the lower row: what happens after patients come off the study and what subsequent systemic therapy these patients received after sunitinib, for example. Subsequent therapies after the first-line therapy impacts survival. This is why one shouldn’t compare across trials. But this is a summary to give us all the important data that each trial has.

One point that isn’t on the slide but will come up in the discussion with my colleagues is the progressive disease [PD] rate. PD rate is an important factor that we sometimes use to think about what therapy to select for our patients. For CheckMate 214, for example, the progressive disease rate is in the 18%-to-20% range. For KEYNOTE-426, pembrolizumab-axitinib, progressive disease rate is 11%. With sunitinib, it’s invariably the same: 14% of patients on the sunitinib arm in these 4 phase 3 trials had progressive disease as best overall response, meaning patients didn’t have any tumor shrinkage and they had progressive disease after this first-line therapy. Note that the last 2 regimens that received FDA approval and came to the clinic—nivolumab-cabozantinib from CheckMate 9ER and lenvatinib-pembrolizumab from the CLEAR study—both have a low progressive disease rate: 5.6% with cabozantinib-nivolumab and 5.4% with lenvatinib-pembrolizumab.

Transcript edited for clarity.