Cabometyx Improves Survival Without Progression in Previously Treated Advanced NETs

Cabometyx (cabozantinib) provided a survival benefit without disease progression compared with placebo in patients with advanced neuroendocrine tumors (NETs) whose disease progressed following prior therapy, according to recent study findings.

Results from the phase 3 CABINET trial, which were presented during the 2023 ESMO Congress, demonstrated that patients with advanced NETS whose disease progressed after a prior therapy had a significant improvement in progression-free survival(PFS; the time during and after treatment when a patient with cancer is alive without disease worsening) after treatment with Cabometyxversus placebo.

In particular, NETsrefers to a tumor that forms from cells that release hormones into the blood as a result of a signal from the body’s nervous system, according to the National Cancer Institute. These tumors typically create high amounts of hormones, which can lead patients to experience several different symptoms.

At a median follow-up of 13.9 months, patients with extra-pancreatic NETs (epNETs) who received the tyrosine kinase inhibitor (129 patients) experienced a median PFS of 8.3 months versus 3.2 months with placebo (68 patients). Additionally, at a median follow-up of 16.7 months, patients with pancreatic NETs (pNETs) achieved a median PFS of11.4 monthsversusthree months in the Cabometyx(62 patients) and placebo (31 patients) arms, respectively.

“There’s an unmet need for new treatment options for patients with advanced NETs,” Dr. Jennifer A. Chan, clinical director of the Gastrointestinal Cancer Center and director of the Program in Carcinoid and Neuroendocrine Tumors at Dana-Farber Cancer Institute in Boston, and associate professor of medicine at Harvard Medical School, said during the presentation. “Multiple studies have shown that VEGF pathway inhibitors are active against NETs.”

CABINET enrolled patients with well- to moderatelydifferentiated, grade 1 to 3 NETs (tumors considered low grade to high grade). Patients needed to have disease progression within 12 months prior to treatment assignment and have disease progression after or intolerance of at least one prior FDA-approved systemic therapy, excluding somatostatin analogs (a synthetic version of somatostatin, which potentially slows down hormone production to control symptoms). Concurrent use of somatostatin analogs was permitted if administered at a stable dose for at least two months.

Patients in both the epNETs and pNETs subgroups were randomly assigned to receive either Cabometyxor placebo until disease progression. The primary endpoint was PFS, and secondary endpoints included overall survival (OS; the time from treatment initiation when a patient with cancer is still alive), objective response rate (the percentage of patients with a partial or complete response to treatment), safety and tolerability.

In the epNETs group, at the start of the study, patients in the Cabometyxand placebo arms both had a median age of 66 years. Most patients in both arms had an ECOG performance status of 1 (restricted in strenuous activity; 64% versus 52%), well-differentiated disease (cancer cells that resemble normal cells from where they grew; 79% versus 84%), grade 2 disease (intermediate-grade tumors; 63% versus 66%) and received concurrent treatment with somatostatin analogs (62% versus 65%). The median number of prior lines of therapy received was twoin both groupsand the median time from diagnosis to treatment assignment was 87 months versus 83 months, respectively.

Similarly, in the pNETs group, patients in the Cabometyxand placebo arms had a median age of 60 years versus 64 years, respectively. Most patients in both arms were men (56% versus58%), had well-differentiated disease (90% versus97%), had grade 2 disease (63% versus63%)and received prior treatment with somatostatin analogs (97%versus94%). The median number of prior lines of therapy received was threeversustwo, respectively, and the median time from diagnosis to random assignment was 84 months versus 83 months.

In the epNETs cohort, patients in the Cabometyxand placebo arms underwent a median number of five and three cycles of therapy, respectively. At the data cutoff, 22% and 16% remained on treatment, respectively. Reasons for treatment discontinuation included disease progression (36% versus 50%), side effects (20% versus 15%), consent withdrawal (9% versus 4%), alternate therapy (3% versus 1%), physician decision (2% versus 6%) and death (5% versus 3%).

In the pNETs cohort, patients in the Cabometyxand placebo arms underwent a median number of seven and four cycles of therapy, respectively. At the data cutoff, 24% and 13% of patients remained on treatment, respectively. Reasons for treatment discontinuation included disease progression (35% versus 71%), AEs (16% versus 0%), consent withdrawal (5% versus 10%) and intercurrent illness (5% versus 3%).

Additional data from the study revealed that the median OSin the epNETs cohort was 21.9 months versus 22.4 months in the Cabometyxand placebo arms, respectively. In the pNETs cohort, the median OS was 43.5 months versus 31 months in theCabometyxand placebo arms, respectively.

In terms of safety, patients in the Cabometyx(124 patients) and placebo (63 patients) arms of the epNETs cohort experienced severe (59.7% versus 33.3% respectively), life-threatening (7.3% versus 1.6%)and fatal(8.9% versus 7.9%)side effects. Commonly occurring severe or worse side effectsconsisted of high blood pressure (27.4% versus 4.8%), fatigue (13.7% versus 7.9%) and diarrhea (10% versus 3%). Investigators noted that of the 11fatal side effectsthat were observed in the Cabometyxarm, events were unrelated or unlikely to be related to treatment in eight patients and possibly related in three patients.

In the pNETs cohort, patients in the Cabometyxarm (60 patients) experienced severe (56.7%), life-threatening (8.3%) and fatal (3.3%) side effects; those in the placebo arm (30 patients) experienced severe side effects(43.3%). The most common severe or worseside effects included high blood pressure (26.7% versus 20% respectively), fatigue (13.3% versus 3.3%) and high glucose levels (8.3% versus 10%). The fatalside effectsin the Cabometyxarm were determined to be unrelated to treatment.

“The interim analyses and both of the cohorts showed a statistically significant and clinically meaningful difference in PFS in patients treated with (Cabometyx),” Chan concluded. “Based on these results, the DSMB voted unanimously to stop accrual to the trial, unblind all patientsand all those receiving placebo to crossover to (Cabometyx). The(side effects) that we observedwere consistent with the known safety profile of cabozantinib. Based on these results, (Cabometyx)may become a new treatment option for patients with previously treated,progressive NETs.”

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