Cabozantinib Shows Potential for Treating Papillary RCC Population

Sumanta Kumar Pal, MD

Cabozantinib (Cabometyx) showed superior progression-free survival (PFS) over sunitinib (Sutent) for the treatment of patients with advanced papillary renal cell carcinoma (RCC) in the SWOG 1500 trial (NCT02761057), showing potential for filling an area of unmet need.

SWOG 1500 is a randomized, open-label phase 2 trial that compared sunitinib to cabozantinib, crizotinib (Xalkori), and savolitinib for the treatment of patients with papillary RCC. The primary end point of the study was PFS. Secondary end points include response rate, overall survival, and toxicity. Other outcomes include MET mutation rate and the assessment of type 1 and type 2 renal papillary cancer.

During the study, patients were assigned to receive 1 of the 4 study drugs. Patients in the sunitinib arm received the agent on days 1-28 of a 42-day cycles in the absence of disease progression or unacceptable toxicity. Patients in the other 3 arms received their assigned drug on days 1-42 of each 42-day cycle. 

Between April 2016 and December 2019, 152 patients were assigned into 1 of 4 groups. However, 5 patients were deemed ineligible, dropping the number in the analysis down to 147. Both savolitinib and crizotinib groups were halted after a futility analysis as no improvement in PFS were seen. The median PFS for the cabozantinib group was 9.0 months (95% CI, 6-12). For the sunitinib group, it was 5.6 months (95% CI, 3-7; HR, 0.60, 0.37-0.97, one-sided P = .019). The response rate for cabozantinib was also significantly longer than that of sunitinib, 23% versus 4% (2-sided P = .010).

Sumanta Kumar Pal, MD, a medical oncologist at the City of Hope Cancer Center, discussed the SWOG 1500 trial, the potential of cabozantinib for the treatment of papillary RCC, and the future of RCC care in an interview with Targeted Oncology^TM.

TARGETED ONCOLOGYTM: Can you discuss the idea of the SWOG 1500 trial?

PAL: The SWOG 1500 trial is a randomized study that looks at sunitinib versus 3 other potential MET-targeted therapies cabozantinib, savolitinib, and crizotinib in patients with metastatic papillary kidney cancer. The study was really designed to look at the primary end point of PFS, and the study ultimately was quite positive [in the] comparison of cabozantinib versus sunitinib.

TARGETED ONCOLOGYTM: Could you go into how the 4 drugs were chosen for the study?

PAL: The path towards choosing the 4 drugs for the study was quite interesting. We actually began with a very simple design of sunitinib versus cabozantinib. And then, as time went on, the study expanded actually through the advice of the National Cancer Institute and other groups, to include multiple inhibitors. Ultimately, as studies go, it's very difficult to enlist a number of agents—6, 7 therapies—within the context of 1 study. So, the study design filtered down to the forum design with the 3 MET inhibitors cabozantinib, crizotinib, and savolitinib.

TARGETED ONCOLOGYTM: More broadly, could you talk a bit about the papillary RCC patient population and what makes this a more difficult cancer type to treat?

PAL: I would argue that papillary RCC really represents an area of unmet need. The outcomes that we see for our patients with papillary kidney cancer are nowhere near as transformed as the outcomes for our metastatic clear cell patients with the advent of novel therapies. So, I think that studies that are really dedicated to papillary kidney cancer are still warranted, and fortunately, SWOG 1500 fits the bill for one such study that really takes aim at this population.

TARGETED ONCOLOGYTM: Can you explain the purpose and design of the SWOG 1500 trial?

PAL: The study design of SWOG 1500 was really intended to address PFS for patients with metastatic papillary kidney cancer. We wanted to see if we could push the needle forward by getting away from a pure VEGF inhibitor like sunitinib, which at the time was a very reasonable standard, and potentially supplanting it with therapies that actually were targeting MET. We know that many patients with papillary RCC either have MET alterations, either gene mutations or copy number alterations, and perhaps targeting MET using some of these small molecules [would be] an effective strategy to abrogate signaling and improve outcomes.

So, we arrived at savolitinib based on data that me and Toni Choueiri, MD of the Dana-Farber Cancer Institute and others, have published in the Journal of Clinical Oncology.2 Looking at this drug in a single-arm phase 2 study (NCT02127710) seemed to have activity, particularly in MET-altered patients. There was an EORTC CREATE trial (NCT01524926) that looked at the drug crizotinib in patients with papillary kidney cancer and showed some responses again, primarily in the context of MET-altered patients.3 And then, finally, we know that cabozantinib has activity across the board in patients with RCC. There have been some retrospective efforts that showed efficacy in papillary disease. I think what the space really begged for was a randomized trial design and compared all of those, and that's what SWOG 1500 really addresses.

TARGETED ONCOLOGYTM: What were the results of the trail?

PAL: The results of SWOG 1500 underscored an improvement in PFS. With cabozantinib over sunitinib, we saw that cabozantinib had a PFS of 9 months, as compared to 5.5 months with sunitinib. This was a statistically significant benefit. And furthermore, we saw quite the opposite result on the other MET inhibitor arms. We saw that crizotinib and savolitinib actually failed to improve PFS and, in fact, PFS looked to be inferior. Those studies actually closed at the time of a futility analysis. It's probably too early to say much about overall survival in the study and the numbers are quite small to assess that. I will say that we saw some fairly compelling data when it came to response rates. We saw a response rate of 23% with cabozantinib versus 4% with sunitinib, so marked differences in terms of response. And we saw complete responses with cabozantinib, which we didn't see in the context of the other drugs on the trial.

TARGETED ONCOLOGYTM: Could you go over the safety profile of cabozantinib?

PAL: Cabozantinib has been very well established across multiple prior studies. We've seen an array of [adverse effects], including hand-foot syndrome, hypertension, fatigue. And I would say that the toxicity profile that we elicited in SWOG 1500 is really no different. We've been fortunate to also have prior trials in clear cell disease, led by Toni Choueiri, MD, that compares cabozantinib to sunitinib in the front-line setting. And you can see in that context really no differences in the safety profile we elicited versus the safety profile that they elicited.

TARGETED ONCOLOGYTM: In terms of the study overall, was there anything that surprised you or anything that stood out to you?

PAL: I think the SWOG 1500 trial really does establish a current standard of care for patients with papillary kidney cancer. If you have this disease, no doubt, you should receive therapy with cabozantinib. The emerging question that arises is whether or not one should receive immunotherapy in combination with cabozantinib for papillary disease. I think 1 trial that will help shed light on that as a follow up study to SWOG 1500, is a study that’s looking at cabozantinib with or without atezolizumab (Tecentriq) and I think that that trial is really going to shed a lot of light in terms of what agent we should be using in combination with cabozantinib, and if any at all.

TARGETED ONCOLOGYTM: What are the next steps with this research?

PAL: The results from SWOG 1500 beg for a follow-up study that evaluates the role of immunotherapy. So, to that point, we're really already constructing the PATMET 2 clinical trial, if you consider SWOG 1500 to be PATMET 1. So that study will test cabozantinib either by itself or with immunotherapy. Benjamin Maughan MD, PharmD, from the University of Utah, is going to be designing that trial. I think it's going to go a long way to addressing the question of whether or not immunotherapy is a real contributor to patients with papillary disease.

TARGETED ONCOLOGYTM: What other treatments and combinations are being explored in papillary RCC that are of interest?

PAL: I will say that Tom Powles, MBBS, MRCP, MD, of the Barts Cancer Institute has presented some really compelling data in papillary kidney cancer looking at the combination of savolitinib and durvalumab (Imfinzi). It'd be interesting to look at that regimen, perhaps even more specifically in a MET-altered population just based on the biology that they've elicited there. So, I think that that study in particular might be helpful.

Beyond looking at papillary kidney cancer, there's certainly rationale to look more broadly across the spectrum of patients with papillary disease and non-clear cell diseases. I would say that chromophobe disease is an area that warrants further interest. There are studies that are ongoing with translocation RCC, looking at axitinib (Inlyta) with nivolumab (Opdivo). So, there's many stones left unturned in non-clear cell kidney cancer.

_REFERENCES:

1. _{Pal S, Tangen C, Thompson I, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703. doi:10.1016/S0140-6736(21)00152-5}

2. _{Choueiri TK, Plimack E, Arkenau HT, et al. Biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer. J Clin Oncol. 2017;35(26):2993-3001. doi:10.1200/JCO.2017.72.2967}

3. _{Schöffski P, Wozniak A, Escudier B, et al. Crizotinib achieves long-lasting disease control in advanced papillary renal-cell carcinoma type 1 patients with MET mutations or amplification. EORTC 90101 CREATE trial. Eur J Cancer. 2017;87:147-163. doi:10.1016/j.ejca.2017.10.014}