What evidence is there for the use of cabozantinib in the treatment of clear-cell carcinoma of the uterus?

What evidence is there for the use of cabozantinib in the treatment of clear-cell carcinoma of the uterus?

Comment by InpharmD Researcher

Evidence for the specific use of cabozantinib in patients with clear-cell carcinoma of the uterus is limited and reported only in subpopulation cohort groups. These studies found cabozantinib alone or with nivolumab to potentially improve progression-free survival for various histologies of endometrial cancer, but specific outcomes for clear-cell patients remain unreported.

Background

An ongoing randomized, phase 2 study (NCT03367741) is evaluating the efficacy of combination cabozantinib-nivolumab compared to nivolumab monotherapy in patients with advanced, recurrent metastatic endometrial cancer, including stage III-IV uterine corpus carcinoma. Patients are randomized to one of two arms to receive either 1) cabozantinib orally once daily on days 1-28 and nivolumab intravenously on days 1 and 15, then on day 1 beginning cycle 5 or 2) nivolumab monotherapy. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients were followed up for up to 12 weeks. Outcomes assessed include progression-free survival and overall response rate. The estimated completion date is February 2025. [1]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What evidence is there for the use of cabozantinib in the treatment of clear-cell carcinoma of the uterus?

Level of evidence

B - One high-quality study or multiple studies with limitations Read more→

Please see Tables 1-2 for your response.

Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer
Design	Open-label, phase II, randomized clinical trial N = 77
Objective	To assess the efficacy and safety of nivolumab plus cabozantinib versus nivolumab alone in immuno-oncology (IO)-naive recurrent endometrial cancer (EC), and the efficacy of the combination in disease that had progressed after IO
Study Groups	Arm A: cabozantinib (40 mg/day on days 1-28) + nivolumab (240 mg on days 1 and 15) in 28-day cycles (N = 36) Arm B: nivolumab (240 mg on days 1 and 15) in 28-day cycles (N = 18) Arm C: cabozantinib (40 mg/day on days 1-28) + nivolumab (240 mg on days 1 and 15) in 28-day cycles in patients previously treated with IO (N = 23)
Inclusion Criteria	Eastern Cooperative Oncology Group (ECOG) performance status 0-2, diagnosis of measurable disease according to Response Evaluation Criteria in Solid Tumors RECIST; version 1.1), and radiologic progression after at least one line of previous platinum-based chemotherapy.
Exclusion Criteria	Prior cabozantinib treatment; known brain metastases; concomitant treatment with therapeutic doses of anticoagulant; recent bleeding history or tumor invading the gastrointestinal tract; tumor encasing blood vessels; radiographic evidence of cavitating pulmonary lesions; history of bowel obstruction within the preceding 3 months; history of autoimmune disease; or concomitant treatment with steroids within 7 days before the first dose
Methods	Response was assessed by CT scan every 8 weeks. Adverse events were graded using Common Terminology Criteria for Adverse Events (CTCAE). If patients experienced toxicity, the cabozantinib dose could be reduced one level to 20 m daily. Patients in Arm B could cross over to Arm C at the time of progression, provided they still met the eligibility criteria for the exploratory post-IO cohort.
Duration	24 months
Outcome Measures	Primary: Progression-free survival (PFS), defined as the interval between randomization and disease progression or death from any cause, whichever occurred earlier. Secondary: RECIST-defined ORR, overall survival (OS), and safety.
Baseline Characteristics		Arm A: cabozantinib + nivolumab (N = 36)	Arm B: nivolumab (N = 18)	Arm C: cabozantinib + nivolumab (N = 23)
	Age, years	67	66	66
	ECOG performance status, n(%) 0 1 2	13 (36%) 19 (53%) 4 (11%)	10 (56%) 8 (44%) 0	14 (61%) 9 (39%) 0
	Clear cell histology	5 (14%)	0	0
	Mismatch repair system status Intact High microsatellite instability	34 (94%) 2 (6%)	18 (100%) 0	18 (78%) 5 (22%)
	Prior treatment lines 2 ≥ 3	19 (53%) 17 (47%)	6 (33%) 12 (67%)	9 (39%) 14 (61%)
Results	Endpoint	Arm A: cabozantinib + nivolumab (N = 36)	Arm B: nivolumab (N = 18)	Arm C: cabozantinib + nivolumab (N = 20)	p-Value
	Median PFS, months (90% confidence interval [CI])	5.3 (3.5 to 9.2)	1.9 (1.6 to 3.4)	--	0.09
	Recist-defined ORR	25%	11%	25%	--
	Median OS, months	13.0 (10.2 to 18.4)	7.9 (6.1 to not estimatable)	--	--
Adverse Events	Common adverse events included diarrhea, elevated liver enzymes, fatigue, and hypertension. Serious adverse events occurred in 31% of Arm A, 0% of Arm B, and 33% of Arm C.
Study Author Conclusions	Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.
InpharmD Researcher Critique	Limitations include the choice of control arm and potential imbalance in prior therapy between groups. The confidence interval was established at 90%, along with a 0.10 significance level, which is an abnormal analysis for measurement.

References:

Lheureux S, Matei DE, Konstantinopoulos PA, et al. Translational randomized phase II trial of cabozantinib in combination with nivolumab in advanced, recurrent, or metastatic endometrial cancer. J Immunother Cancer. 2022;10(3):e004233. doi:10.1136/jitc-2021-004233

Phase II Trial of Cabozantinib in Recurrent/Metastatic Endometrial Cancer: A Study of the Princess Margaret, Chicago and California Consortia (NCI9322/PHL86)
Design	Non-randomized, multi-center, single-arm Phase II trial N= 102
Objective	To evaluate the efficacy and toxicity of cabozantinib in women with recurrent/metastatic endometrial cancer after chemotherapy
Study Groups	Study patients (N= 102) Exploratory cohort (n= 32) Carcinosarcoma (n= 19) Other (n= 13)
Inclusion Criteria	Women ≥18 years, prior chemotherapy for metastatic disease or recurrence within a year of adjuvant chemotherapy, histological diagnosis, measurable disease, ECOG ≤2, life expectancy ≥3 months, normal organ and marrow function
Exclusion Criteria	Therapeutic anticoagulation, recent GI bleeding, pulmonary hemorrhage, active brain metastases, uncontrolled illness, pregnancy, uncontrolled hypertension, active hepatitis
Methods	Patients received cabozantinib 60 mg orally daily on a 28-day cycle; response was assessed per RECIST v1.1; adverse events were graded per CTCAE v4.0 Patients were divided into two cohorts, the experimental and the exploratory group. The exploratory cohort included patients with carcinosarcoma and clear cell. Specifically, 5 patients had clear cell, and were supposedly included in the "Other" group which will be the focus of this table.
Duration	Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death
Outcome Measures	12-week progression-free survival (PFS), partial response
Baseline Characteristics		Carcinosarcoma (n= 19)	Other (n= 13)
	Age, years	64	63
	ECOG PS 0 1 2	10 9 0	6 7 0
	Chemotherapy 1 line 2 lines > 2 lines	16 3 0	10 3 0
Results	Endpoint	Carcinosarcoma (n= 19)	Other (n= 13)
	12-week PFS	8	7
	Partial response	1	1
	Median PFS, months	3.0 (2.5 to 4.6)
Adverse Events	Common toxicities: hypertension, fatigue, diarrhea, nausea, hand-foot syndrome Serious events: GI perforation/fistula, thromboembolism, bleeding
Study Author Conclusions	Cabozantinib shows activity in serous and endometrioid endometrial cancer, supporting further evaluation in genomically characterized cohorts. Potential increased response in tumors with CTNNB1 mutation or concurrent KRAS and PTEN/PIK3CA mutations.
InpharmD Researcher Critique	There is limited insight regarding the results of patients specifically will clear cell, as they were likely complied in the "Other" category of patients.

References:

Dhani NC, Hirte HW, Wang L, et al. Phase II Trial of Cabozantinib in Recurrent/Metastatic Endometrial Cancer: A Study of the Princess Margaret, Chicago, and California Consortia (NCI9322/PHL86). Clin Cancer Res. 2020;26(11):2477-2486. doi:10.1158/1078-0432.CCR-19-2576