Choueiri Covers CABOSUN Excitement and Beyond in RCC

Toni K. Choueiri, MD

The potential practice-changing CABOSUN findings presented at the 2017 ESMO Congress validated the investigator-assessed results the oncology community learned of more than 1 year prior. With an independent review, frontline treatment with cabozantinib (Cabometyx) was found to demonstrate superiority in progression-free survival (PFS) over sunitinib in patients with advanced renal cell carcinoma (RCC).

Specifically, findings showed that cabozantinib-treated patients had a median PFS of 8.6 months versus 5.3 months for patients treated initially with sunitinib, representing a 52% reduction in the hazard for progression or death.

The independent review of the data confirmed the primary analysis of the CABOSUN randomized trial, which showed a median PFS of 8.2 months with cabozantinib and 5.6 months with sunitinib by investigator assessment (HR, 0.66; 95% CI, 46%-95%; 1-sided P = .012).

Additionally, an updated review of overall survival (OS) did show a numerical advantage in favor of cabozantinib, but the difference did not achieve statistical significance. This was also consistent with the initial investigator review of survival.

OncLive: Could you recap the main findings from the CABOSUN trial?

In an interview with OncLive during the 2017 ESMO Congress, Toni K. Choueiri, MD, director of the Kidney Cancer Center at Dana-Farber Cancer Institute, shed light on the excitement surrounding the CABOSUN and CheckMate-214 trials, and why the future of the RCC field lies in novel combination regimens.Choueiri: At the 2016 ESMO Congress, we presented CABOSUN results in the plenary session and we showed that, for the first time, a VEGF tyrosine kinase inhibitor (TKI) had antitumor activity, and it did provide superior PFS over sunitinib in metastatic RCC of intermediate and poor risk. The analysis was investigator-assessed, so what we did this time is provide an independent review with more follow-up for OS and [investigated] MET as a biomarker in the study.

How do you see these findings shaking up the standard of care for patients with RCC?

What are the next steps? Will a phase III trial be required to submit for frontline approval?

We also saw subgroup analyses of the METEOR trial at this meeting. What are the data coming out from that?

Can you comment on the data from CheckMate-214, another pivotal trial presented at this meeting?

Like the investigator assessment, we had similar findings in the independent review and the median PFS was not different. The hazard ratio was even lower, around 0.48, with cabozantinib providing superior PFS compared with sunitinib. The responses were double with cabozantinib. This study was not powered for OS benefit, but the OS also was trending in the right direction. The updated toxicity profile data from both drugs were not different between both arms. There is potential for cabozantinib to be an option in the frontline setting. Currently, this drug is approved in patients who progress after VEGF TKI, anti-VEGF therapy, or antiangiogenic therapy. Although CABOSUN is still a randomized phase II and not phase III study, you have a study that showed, by both investigator and by independent review, superiority for the primary endpoint of PFS. It could become an option in intermediate- and poor-risk patients that are systemic therapy—naïve. This is a good question. I don't know. There are other examples, such as the lenvatinib (Lenvima)/everolimus (Afinitor) combination, which was approved in the second-line setting based on phase II data. That was for a drug that was new to the field, where here you have a drug that already is used in the second-line setting, so I don’t know if they will require a phase III trial. The [independent] center review is likely required and that was done, which was what we presented at the 2017 ESMO Congress.For the past year, we have been presenting a subgroup analysis of patients with prior nephrectomy. We looked at patients who had their first TKI, whether pazopanib (Votrient) or sunitinib. An interesting analysis was presented by Dr Thomas Powles and looked at patients who progressed on prior immune checkpoint blockers, received cabozantinib, and the effect was even more pronounced. We also presented the quality of life (QOL) metrics from METEOR that showed a somewhat similar QOL profile compared with everolimus. This is big news in the field. For the first time in the frontline setting, an immunotherapy combination had 2 of the 3 coprimary endpoints met. Responses were higher than sunitinib, and we just realized that even the OS was in favor of the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) and a lot of things need to be taken into consideration.

First, the primary endpoint was like CABOSUN—in the intermediate- and poor-risk group. It would be important to look at the good-risk group in CheckMate-214. On CABOSUN, the team did not have any patients at good risk, but there is a subset on CheckMate-214, so it would be important to look at the good-risk group. The toxicity profile would be important, especially to know how many patients ended up receiving steroids, etc.

With all of the new agents emerging, will there still be a place for temsirolimus or everolimus?

The important thing is that these are all options that didn’t exist a few years ago for patients, and it is better to have an embarrassment of riches than struggle on what drug to use, because most of them have minimal efficacy. Now, we have combinations, we have cabozantinib, and other drugs. A lot of ongoing studies are combining TKIs with PD-1 and PD-L1 inhibitors; they are either starting accrual, or about to finish, or are midway through. It is an exciting field, and the next couple of years are going to be very important. Less and less. The responses were less than 10%, and, in the everolimus study, the comparator was placebo—something we don’t do now. In the temsirolimus study, the comparator was interferon. However, the combination of everolimus and lenvatinib packaged together is active; the drug is approved in the second-line setting and it’s being tested in the frontline setting as part of the CLEAR trial by Eisai. That will test the combination of pembrolizumab (Keytruda) plus lenvatinib, or lenvatinib/everolimus versus sunitinib [NCT02811861]. In combination, yes [these drugs might have a role].

Regarding combinations, are there some checkpoint inhibitors that have synergy when added to other agents?

Secondly, there is a small group of patients who have an alteration in the mTOR pathway—TSC1/TSC2—and we know from several series that these patients may have a better outcome to an mTOR inhibitor. Thus far, this has been accepted. There are some trials looking at drugs that target the pathway perhaps in the more effective way—targeting TORC1, TORC2, and other elements of the pathway. Hopefully, these will pan out. The initial experience hasn’t been as positive, but there are other drugs and combinations coming with this pathway. First of all, you have 2 drugs that work. You have to combine whether there is synergy or not. But, we hope here that 1 plus 1 is not 2, but that it is 3 or 4. There is synergy if you look at the preclinical data.

Also, when you inhibit AXL and MET, for example, with cabozantinib and a VEGF ligand with bevacizumab (Avastin), the immune modulator is more prime. There are some data coming, especially with atezolizumab (Tecentriq) and bevacizumab (Avastin).

At the end of the day, what matters is the responses and the clinical activity. It looks like there is some synergy, especially when you combine TKIs, for example. One TKI, axitinib (Inlyta), was combined with the PD-L1 inhibitor avelumab (Bavencio), as well as [with] the PD-1 inhibitor pembrolizumab. The responses are really high—between 60% and 70%, and over 70% with pembrolizumab. Now, at least there could be some synergy and the combination seems to be at least tolerated with full-dose axitinib. Not surprisingly, both combinations are moving to phase III trials and are accruing.

Therefore, if these trials are positive, and then you have nivolumab/ipilimumab, how are you going to choose and based on what? Then comes the cost and the toxicity profile, and we hope the biomarker. That is very important. Is it going to be something as simple and what we are used to, like PD-L1 immunohistochemistry? Or, is it going to be in all-comers? Some of these studies are stratifying for PD-L1 and others are not, so it’s going to be very interesting. It may get confusing in the next 4 or 5 years. However, again, these are active therapies. Patients, at the end of the day, will live longer.

There are also combination therapies for RCC patient populations that are an unmet need. Can you speak to research on radium-223 dichloride (Xofigo) in kidney cancer? One of the unmet needs in kidney cancer are bone metastases. We have shown in the past that they have a worse survival and they benefit less from VEGF TKIs, such as sunitinib. One of the things we also presented at the 2017 ESMO Congress is a feasibility study with Drs Dominick Bosse and Rana McKay of combining the VEGF TKIs with radium-223, which is approved in the treatment of metastatic castration-resistant prostate cancer with bone metastases.

Why is there such a small percentage of patients with RCC who enroll on clinical trials?

Kidney cancer is more lytic disease in the bone rather than blastic, but there is some evidence that there is some element of bone formation. The combination was well tolerated and it’s feasible. We did not have a control arm to look at elements of clinical efficacy compared with TKI alone. We saw modulation of the bone biomarker, which is encouraging. You cannot say for sure that this is from the addition of radium-223. It could be the TKI alone. However, at the same time, this is tolerated and hopefully we will move to the next level with a larger study—especially in an unmet need. We have a problem. Patients should be on clinical trials. Now, we are learning. Look at CABOSUN and CheckMate-214; look at all of the studies being presented. There are more studies being presented at the 2017 ESMO Congress. This is the way that we learn, we can’t assume that we have to stop here. Remember, metastatic RCC is largely incurable and, in addition, is lethal.

Therefore, we have to try. We have to do better, and we can do better with clinical trials. Combinations are coming and they should be tried. The minority of patients—the latest estimate is around 5%—go on clinical trials. I am not saying that every patient should be on a trial. There are a lot of problems sometimes for a patient to be on trial. Many community centers don’t have trials and there is distance for travel. Eligibility is more important; a patient doesn’t usually fit and might have organ dysfunction.

However, 5% is a problem. Dr Danny Heng and I both co-lead The International Metastatic Renal Cell Carcinoma Database Consortium, and we looked at thousands of patients. We said to ourselves, if we apply the eligibility criteria of the study that looked at sunitinib versus pazopanib to our database, two-thirds of patients would be eligible; 67% and the rest will not be. If 67% become eligible, then let’s say 50% would be on trial. However, 5% is actually very low in the United States. We could do better. Doubling that number to 10% would make a lot of strides. Even if we don’t come up with a new drug that is totally new, at least we will have answers.

Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy doe patients (pts) with metastatic renal cell carcinoma (mRCC). In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA38.