Brian I. Rini, MD
Although the VEGF TKI tivozanib (Fotivda) demonstrated superior progression-free survival (PFS) and tolerability compared with sunitinib (Sutent) in the TIVO-3 study, its role remains unclear following the FDA’s recommendation to not submit a new drug application (NDA) of tivozanib for patients with highly refractory, advanced or metastatic renal cell carcinoma (RCC).
In January 2019, the FDA stated that Aveo Oncology, the developer of tivozanib, should not submit the NDA following the preliminary overall survival (OS) findings from the phase III TIVO-3 trial in this patient population, adding that the data do not alleviate their concerns regarding a potential detriment in OS, which were outlined in a complete response letter issued in June 2013.1
Aveo Oncology previously stated that it plans to make an NDA filing decision following the availability of additional mature OS results.
In the international, multicenter, open-label, controlled TIVO-3 trial, 322 patients with refractory advanced RCC were randomized to receive tivozanib hydrochloride or sorafenib (Nexavar). The primary endpoint was progression-free survival (PFS), and secondary endpoints were objective response rate (ORR), OS, and duration of response.
Results showed that the median PFS was 5.6 months with tivozanib compared with 3.9 months with sorafenib (HR, 0.73; 95% CI, 0.56-0.94; P
= .0165), and the ORRs were 18% versus 8%, respectively (P
= .02); all were partial responses.2
In the preliminary analysis of the OS endpoint, results showed a hazard ratio >1. In interim OS findings presented at the 2019 Genitourinary Cancers Symposium, the median OS was 16.4 months with tivozanib and 19.7 months with sorafenib (HR, 1.12; 95% CI, 0.84-1.51; P
However, Brian I. Rini, MD, professor of medicine at Cleveland Clinic, suggested that tivozanib may also be the best-tolerated VEGF TKI.
“In the future, this may make it a good partner for immunotherapy combinations, but even given by itself, most of its toxicity is on target,” Rini said.
Immunotherapy and TKI combinations were among the highly anticipated presentations at this year’s symposium, including KEYNOTE-426, which evaluated pembrolizumab (Keytruda) and axitinib (Inlyta) in patients with metastatic RCC (mRCC). In that study, the combination was associated with a 47% reduction in the risk of death compared with sunitinib alone (HR, 0.53; 95% CI, 0.38-0.74; P
These findings led to the FDA granting a priority review designation in February 2019 to a supplemental biologics license application for the regimen as a frontline treatment for patients with advanced RCC.
In an interview with OncLive
, Rini discussed the next steps with tivozanib and immunotherapy/TKI combinations in patients with mRCC.
OncLive: Could you discuss the background and the findings for TIVO-3?
: TIVO-3 was a phase III trial of tivozanib versus sorafenib. These drugs had previously been compared in the frontline setting, in a trial called TIVO-1, now many years ago. What was seen in that trial were advantages to tivozanib in responses and PFS, but it looked like sorafenib was maybe the favorite in OS. For that reason, the drug was not FDA approved in the United States, although it was approved in Europe many years later. In order to look at this comparison again, we did this TIVO-3 trial in patients with refractory RCC.
Patients with mRCC who have had 2 or 3 prior regimens—mostly VEGF inhibitors or prior immunotherapy—were randomized 1:1 to receive tivozanib or sorafenib. They were followed for progression. What it showed was that tivozanib led to a significant PFS advantage compared with sorafenib; it was a nearly 6-month PFS with tivozanib compared with about 4 months for sorafenib. There was also a response rate advantage of 18% versus 8% [in favor of tivozanib]. Overall survival (OS) is still immature; it will be followed up later this year.
Two other things are impressive. One is that the durability of responses with tivozanib were quite unusual for a TKI. These drugs can create high responses, but they are often short-lived. If you look at the curves in the data in durability of response, they appear to be quite durable with tivozanib.
Some of that might be linked to my second comment, which is that the drug is really well tolerated—possibly the best-tolerated TKI. Sorafenib is a dirtier drug, leading to rash, diarrhea, fatigue, and things like that. Tivozanib is a really clean and well-tolerated drug, and for the subset of patients who respond, they can do well for quite a long time.
With effective TKIs already available in this space, what was the rationale for exploring tivozanib?
The real question is, "Do we actually need another TKI in this space?" I would argue that patients always need more treatment options. They always need effective options that are less toxic than existing drugs. Therefore, even though I would agree that this isn't an advance like we're going to see with immuno-oncology agents, it's an advance because there is always room for a well-tolerated, effective agent in the treatment of cancer—always.
What are the next steps with these data?
Hopefully, when the OS data come through, it will lead to an FDA approval of tivozanib in the United States. Again, this drug is not currently approved in the United States, but it is in Europe. The next steps, as I touched on previously, would be to combine it with immuno-oncology compounds to try and extend its benefit.
If tivozanib did get FDA approval, would it simply be physician's choice of which TKI to use?
If this drug were FDA approved tomorrow, it would be used a lot in the refractory setting, which is appropriate because that is the patient population in TIVO-3. I would use it after a TKI/immunotherapy combination, which is going to become the frontline standard of care. It [would] definitely find good use.
Speaking of immunotherapy/TKI combinations, what were your biggest takeaways from the KEYNOTE-426 trial?
KEYNOTE-426 was a global, randomized phase III study looking at the combination of axitinib, a very potent VEGF TKI, and pembrolizumab, a PD-1 inhibitor. This combination had shown great activity in an earlier study, so it moved into the phase III trial compared with sunitinib, which is sort of the old standard of care now.
The results were really astounding; the hazard ratio for survival was 0.53, which is the lowest hazard ratio for any kidney cancer study ever. This is true for any endpoint let alone survival. That's the most important thing, right? We want patients living longer. There were also advantages in PFS and response rate. The PFS was the longest reported at over 15 months, and response rate was the highest reported at nearly 60%. This is just a really robust regimen for efficacy, clearly better than sunitinib. As I mentioned before, it will become the standard of care.
When combining TKIs with immunotherapy, what are the key things to consider?
When you combine 2 drugs, it is always going to be more toxic than 1 drug. You are taking 2 classes of drugs, so you can get 2 classes of toxicity, so to speak. Fortunately, both drugs by themselves are pretty well tolerated. Axitinib is one of the better-tolerated TKIs—high blood pressure, diarrhea, and fatigue are the main toxicities. Pembrolizumab has the normal immune-mediated toxicity, but as a monotherapy it is very well tolerated. As a combination, [the toxicities seen] were saw as expected. Contrasting that, if you look at the ipilimumab (Yervoy) plus nivolumab (Opdivo) regimen, you get a lot of inflammatory toxicity upfront. It is more drawn out with this combination.
What other updates from the 2019 Genitourinary Cancers Symposium were you excited about?
The CheckMate-214 study presented a 30-month minimum follow-up update, with some data in intermediate- and poor-risk patients as well as favorable-risk. There were some interesting data there just giving us a longer follow-up, which is going to be important to look at for all of these immunotherapy regimens. The JAVELIN Renal 101 study of avelumab (Bavencio) and axitinib was very similar to KEYNOTE-426, and we saw some subset data presented at this meeting. These are all building blocks toward what we hope will become standard-of-care regimens.
What does this all mean for the outlook of patients with RCC?
They are living longer. When I started 20 years ago, the median OS for these patients was about 1 year. Sunitinib was FDA approved on OS data that were 2 years. We haven't even hit median OS with the current generation of immunotherapy trials, but we know they are almost twice as good as sunitinib. We are going to see median OS reach almost 4 years in this disease. That is basically a quadrupling of survival. This is not long enough, obviously, but it is definitely remarkable.
- AVEO Oncology Announces NDA Timing Update. Aveo Oncology. Published January 31, 2019. https://bit.ly/2WAkAtd. Accessed January 31, 2019.
- Rini B, Pal S, Escudier B, et al. TIVO-3: A phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). J Clin Oncol. 2019;37(suppl 7; abstr 541). doi: 10.1200/JCO.2019.37.7_suppl.541.
- Powles T, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): phase III KEYNOTE-426 study. J Clin Oncol. 2019;37(suppl 7; abstr 543). doi: 10.1200/JCO.2019.37.7_suppl.543.