Examining TKI Combinations in Advanced RCC - Episode 4

FDA-Approved TKI/IO Combinations in mRCC

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Hutson and Choueiri elaborate on the FDA-approved TKI + ICI combinations and their data from the following trials: KEYNOTE-146, JAVELIN Renal 101, and CheckMate-9ER.

Thomas E. Hutson, DO, PharmD: Yeah, absolutely. It sealed the role of checkpoint inhibitors as a primary therapy for the disease. We know that it’s coming after the approval…of combination immune agents, like the ipilimumab-nivolumab regimen that you mentioned before. But we had wondered what would be the role of a TKI [tyrosine kinase inhibitor]. Toni just mentioned all the preclinical and basic science research suggesting that certain TKIs have immunomodulating properties, plus the underlying basic biology that we understood of the cancer, that continue to inhibit VEGF are going to be important if the mutation that results in the majority of is VHL related. This was a major trial to show us that this combination of a TKI plus an I/O [immuno-oncology] is going to have additive benefits that are going to push up response rates. From the original report, we had 9% complete response rates. We had overall tumor response rates.… We saw a median progression-free survival increase to 15.4 months when it was compared with sunitinib as a control. We saw for the first time that combining an I/O and a TKI together produced a benefit for us. That has entered the frontline setting as a viable therapeutic option. Unlike some of the concerns, and we could debate whether immune approaches have a role in the favorable-risk person, the I/O-TKI seem to have shown benefit across all risk groups. That was also something that we gleaned from this trial.

Toni K. Choueiri, MD: In both studies, the pembrolizumab-axitinib and avelumab-axitinib started at the same time from phase 1 and went through phase 3. The differentiator was the avelumab axitinib. First, avelumab is a PD-L1, not a PD-1 inhibitor. That’s the first thing. Both studies went from phase 1 in untreated patients, who showed significant but more direct activity, to phase 3. With avelumab, the activity from phase 1 in clear-cell RCC [renal cell carcinoma] was shown in terms of response rate to be higher in PD-L1 positive. Unlike KEYNOTE-426, the end point of PFS [progression-free survival] and OS [overall survival]—2 co-primary end points—were in PD-L1–positive population, which ended up in phase 3 being over 60% of patients. 

You asked about PD-L1 as biomarker. Each drug has its own PD-L1 definition. Avelumab was thought to be a bit of a differentiator compared with others because it’s unique and can mediate ADCC [antibody-dependent cell-mediated cytotoxicity] because it retained this native FC region. Overall, the study met its primary end point of PFS. And it ended up that PD-L1—positive or not—didn’t make a difference. Response rate also was doubled. The differentiator, unfortunately, is that whether in the PD-L1 positive or in the ITT [intent to treat], the combo of avelumab-axitinib still does not have an overall survival advantage over sunitinib. The final analysis did not happen yet. Therefore, despite the FDA approval of this TKI-I/O combination, it does not have an OS advantage.

This brings memories from the phase 1 of cabozantinib a long time ago. It’s been a journey, and I’m happy that now it’s the first line, 1 of the standards with nivolumab. We learned that this could be from another phase 1—by Dr Andrea Apolo at the NCI [National Cancer Institute]—that they could be combined. That’s the first thing. We settled on a 40-mg dose of cabozantinib, which is not the FDA starting dose of 60 mg with monotherapy. The study had a primary end point of PFS, and it did meet the primary end point with a hazard ratio of 0.5. Also, we had an OS advantage with a 40% decrease in the risk of death. The responses were doubled. The CRs [complete responses] were higher, and there were quite interesting quality-of-life data. One of the interesting things we insisted on initially was the first disclosure of the result That was at ESMO [European Society for Medical Oncology Congress] 2020… We insisted on having some quality of life. Patient-reported outcomes are the voice of the patient. We introduced 2 metrics, the FKSI-19 [revised Kidney Symptom Index] and DRS [disease-related symptoms]. Those supported the combination of cabozantinib-nivolumab over sunitinib. More recently, there was way more quality of life presented at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium], going in the same direction that cabozantinib-nivolumab is superior to sunitinib. All the end point that we had, to my knowledge, were met.

This transcript was edited for clarity.