Cabozantinib RCC Benefit Highlighted as Frontline Approval Approaches

Michael R. Harrison, MD

The multikinase inhibitor cabozantinib (Cabometyx) remains to be the sole oral drug to meet 3 clinical trial endpoints of progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) in patients with advanced renal cell carcinoma (RCC), Michael R. Harrison, MD, noted in a presentation at the 35th Annual CFS^® meeting.¹

The benefit with cabozantinib was seen in the pivotal phase III METEOR trial, which led to the FDA approval of cabozantinib in April 2016 for patients with advanced renal cell RCC who have received prior therapy.

The FDA approval timeline of tyrosine kinase inhibitors (TKIs) for patients with advanced RCC in the “post-cytokine era” started with sorafenib (Nexavar) in December 2005, followed by sunitinib (Sutent), pazopanib (Votrient), axitinib (Inlyta), cabozantinib, and lenvatinib (Lenvima) plus everolimus (Afinitor). The RCC paradigm also includes mTOR inhibitors temsirolimus (Torisel) and everolimus (Afinitor), the anti-VEGF therapy bevacizumab (Avastin) and the PD-1 inhibitor nivolumab (Opdivo).

“It’s a pretty complex landscape,” said Harrison, a medical oncologist at Duke Cancer Institute.

Cabozantinib’s indication is specifically for patients with advanced RCC who have received prior treatment with an antiangiogeneic agent. Resistance to VEGFR inhibitors is also associated with increased MET and AXL signaling, which promotes tumor growth, angiogenesis, metastasis, and invasion into nearby tissues.

“We also know that when VEGF is inhibited, resistance to those VEGF inhibitors is driven by increased MEK and AXL signaling,” said Harris.

Preclinical models have shown that cabozantinib is designed to inhibit the MET and AXL receptors.

In the open-label, phase III METEOR trial, 658 patients with advanced clear cell RCC who progressed on or within 6 months of a prior VEGF TKI were randomized 1:1 to receive cabozantinib at 60 mg once daily (n = 330) or everolimus at 10 mg once daily (n = 328).² Crossover was not permitted; the primary endpoint was PFS confirmed by an independent radiology review committee (IRRC), with secondary endpoints being OS and ORR.

"Importantly, this trial was powered to demonstrate an OS benefit if there was one to be seen,” Harris explained.

In the primary PFS analysis, which was conducted in the first 375 patients randomized to treatment, the median PFS was nearly doubled with cabozantinib over everolimus, at 7.4 months and 3.8 months, respectively (HR, 0.58; 95% CI, 0.45-0.74; P <.0001).

“Of course, findings showed a 42% risk reduction in progression, and that was highly statistically significant,” he added.

Additionally, there was a median improvement in OS with cabozantinib versus everolimus at 21.4 and 16.5 months, respectively, leading to a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.53-0.83; P = .0003). The ORR confirmed by IRRC was 17% with cabozantinib and 3% with everolimus (P <.0001).

There were a number of hypothesis-generating subgroup analyses of the METEOR trial published in Lancet Oncology that were generally consistent with overall results from the phase III study, Harris said. Some of the subgroup populations were small, he noted, and are not considered substantial evidence of efficacy.

Key differences, however, can be found in patients with varying levels of MET status. In comparison of cabozantinib with everolimus, the HRs for OS were 0.55 for patients with high levels of MET expression (95% CI, 0.31-0.99) and 0.72 for low MET status (95% CI, 0.52-1.00). HRs for PFS for high MET expression was 0.41 (0.24-0.68) and 0.58 for low MET expression (95% CI, 0.43-0.79).

The HRs for OS were also noticeably different overall in patients with bone and visceral metastases (HR, 0.45; 95% CI, 0.28-0.72) and without (HR, 0.73; 95% CI, 0.57-0.93). It was a similar trend for PFS—for those with both metastases, the HR was 0.26 (95% CI, 0.16-0.43) and 0.56 without them (95% CI, 0.45-0.70).

“The caveats, of course, are that we are not supposed to make definitive conclusions based on subgroup analyses, but I think they are interesting to think about when we're thinking about the patient sitting in front of us and what might be the most beneficial choice for that patient,” he said.

The piece of data to focus on, Harrison added, would be the overall HRs of 0.66 for OS and 0.51 for PFS.

“Are there any groups that appear to be better? You focus your eyes on the OS column,” he said. “You can see that nothing really stands out in this group. The key thing in all of these is that cabozantinib appears, pretty uniformly, to benefit all patients no matter what characteristic you looked at.”

The safety profile of cabozantinib is consistent with adverse events (AEs) with other VEGFR TKIs, Harrison said. In METEOR, all-grade AEs were diarrhea (74%), palmar-plantar erythrodysesthesia syndrome (PPES)/hand-foot syndrome (42%), fatigue (56%), and hypertension (39%). The rates of grade 3/4 AEs that were more than 10% of patients were diarrhea (11%) and hypertension (16%) compared with that of everolimus (2% and 3%, respectively).

“The key thing is recognizing that cabozantinib has a pretty typical profile of AEs for a VEGF receptor TKI,” Harrison said. “[These are] things like diarrhea, nausea, vomiting, decreased appetite, hand-foot syndrome, [and] hypertension. The grade 3/4 AEs were relatively uncommon.”

Patients should be monitored for increased liver function tests (AST/ALT) as well as abnormal blood cell counts, which can be associated with cabozantinib treatment.

In METEOR, dose withholds, reductions, and discontinuations were used to managed AEs. Withholding cabozantinib is instructed for grade 4 AEs, as well as for grade 3 or intolerable grade 2 AEs that cannot be managed with dose reductions or supportive care measures.

The most common reasons for dose reductions in the cabozantinib arm (60%) over everolimus (24%) were diarrhea, PPES, fatigue, and hypertension. Cabozantinib was discontinued in 10% of patients, equal to discontinuations with everolimus, most frequently due to decreased appetite (2%) and fatigue (1%).

“The key thing about hypertension is just to realize that it’s going to occur and to plan for it,” said Harrison on the common AEs. “If you have patients who have hypertension at baseline, you want to get them under good control before starting cabozantinib and then watching them pretty closely. Diarrhea, similarly, can be managed with supportive care and so can, in some cases, hand-foot syndrome.”

Based on the METEOR findings, the NCCN Clinical Practice Guidelines were updated in August 2017 to include cabozantinib as a category 1, preferred subsequent therapy in patients with advanced clear cell RCC previously treated with an antiangiogeneic agent. The recommended dose is 60 mg once daily; this can be reduced to 40 mg and then 20 mg for tolerability issues.

“Patients should receive it preferentially over everolimus,” said Harrison.

Cabozantinib could soon see an indication in the frontline setting for this patient population, as well. The agent was granted a priority review designation by the FDA for a supplemental new drug application for previously untreated patients with advanced RCC.

The application is based on results from the phase II CABOSUN trial, in which cabozantinib reduced the risk of progression or death by 34% versus sunitinib as a first-line treatment for patients with metastatic RCC.³ The median PFS was 2.6 months longer with cabozantinib versus sunitinib, at 8.2 versus 5.6 months (HR, 0.66; 95% CI, 0.46-0.95; P = .012). Under the Prescription Drug User Fee Act, the FDA is scheduled to make its decision on the application by February 15, 2018.

References

1. Harrison M. Clinical review of Cabometyx: a treatment standard for advanced renal cell carcinoma. In: Proceedings from the 35th Annual Chemotherapy Foundation Symposium; November 8-10, 2017; New York, New York.
2. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823.
3. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591-597. doi:10.1200/JCO.2016.70.7398.