dm+d

28013211000001109

New Medicines

CabometyxMetastatic renal cell carcinoma - first-line in combination with nivolumab

Information

Cabometyx
XL184, XL 184
Ipsen
Exelixis

Development and Regulatory status

Launched
Launched
Launched
May 2021
May 21Licence change approved by the MHRA for use in combination with nivolumab, for the first-line treatment of advanced renal cell carcinoma in adults [9].
Mar 21Approved in EU [8].
Feb 21Recommended for EU approval by CHMP - the additional indication is "in combination with nivolumab... for the first-line treatment of adult patients with advanced renal cell carcinoma [7].
Jan 21Approved in US for in combination with nivolumab for first line treatment of advanced renal cell carcinoma [6].

Category

MET, RET and VEGFR2 inhibitor. CABOMETYX, the tablet formulation of cabozantinib, is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.
UK incidence of RCC is 12 per 100,000 people. Patients with stage 1 (39%) and 2 (16%) RCC, and some with stage 3 (26%), are candidates for surgery. Five-year survival ranges from 40-90% in stage 1-3 disease, and 10% in stage 4.
Metastatic renal cell carcinoma - first-line in combination with nivolumab
Oral

Further information

Yes

Trial or other data

Feb 21New analysis from PIII CheckMate-9ER trial shows that the combination of Opdivo (nivolumab) and Cabometyx (cabozantinib) vs. sunitinib in 1st-line treatment of advanced RCC showed sustained benefits in PFS after a median follow-up of 23.5 months. Median PFS was 17 months with the study combination vs. 8.3 months with sunitinib (HR 0.52; 95% CI: 0.43 to 0.64). The company said that this combination maintained improvements in OS, demonstrating a 34% reduction in the risk of death vs. sunitinib (HR: 0.66; 95% CI: 0.50 to 0.87). Of those on this combination, 6.6% discontinued both agents due to side effects and 9.7% discontinued OPDIVO only and 7.2% discontinued CABOMETYX only [5].
Apr 20Topline results from open-label, randomised, global PIII CheckMate 9ER trial (NCT03141177) which enrolled 701 pts with previously untreated advanced or metastatic RCC show that the primary endpoint of significantly improving PFS for the combination of cabozantinib plus nivolumab vs. sunitinib was met. Preliminary assessment shows the combination demonstrated a favourable safety profile [3,4].
May 17PIII CheckMate 9ER trial to evaluate nivolumab in combination with cabozantinib tablets or in combination with ipilimumab and cabozantinib versus sunitinib in patients with previously untreated, advanced or metastatic RCC starts (CA209-9ER; NCT03141177). The open-label trial will enrol approximately 1,014 patients in the US, Western Europe and Australia. Primary outcome is progression-free survival; collection of these data is expected to complete Feb 21 [1,2].

Evidence based evaluations

CabometyxRadioactive iodine-refractory differentiated thyroid cancer - monotherapy in patients who have progressed during or after prior systemic therapy

Information

Cabometyx
Licence extension / variation
Ipsen
Exelixis

Development and Regulatory status

Phase III Clinical Trials
Launched
Launched
May 22Approved in EU as a monotherapy for the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC), refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy [13].
Mar 22EU positive opinion granted recommending a license change to include use as monotherapy for the treatment of adult patients with locally advanced or metastatic differentiated thyroid carcinoma (DTC), refractory or not eligible to radioactive iodine (RAI) who have progressed during or after prior systemic therapy [12].
Sep 21Filed in EU; regulatory decision is anticipated H1 2022 [11].
Sep 21Approved in US by FDA for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy and who are radioactive iodine-refractory or ineligible. [9]
Jun 21Filed in US [7].
Feb 21Granted breakthrough therapy designation in the US [6].

Category

MET, RET and VEGFR2 inhibitor
Differentiated tumours (papillary or follicular) are highly treatable and usually curable. Poorly differentiated tumours (medullary or anaplastic) are much less common, are aggressive, metastasise early and have a much poorer prognosis. 70% of thyroid cancers are papillary and 10% are follicular. The annual incidence data for thyroid cancer in the UK from 2008 show 5.1 per 100,000 for women and 1.9 per 100,000 for men [1].
Radioactive iodine-refractory differentiated thyroid cancer - monotherapy in patients who have progressed during or after prior systemic therapy
Oral

Further information

Yes

Trial or other data

Sep 21Positive final results from the pivotal PIII COSMIC-311 trial announced for cabozantinib. An updated analysis for the primary endpoint of ORR favored cabozantinib at 11% vs. 0% for placebo. Median overall survival was 19.4 months with cabozantinib and not estimable for pts treated with placebo (HR: 0.76; 95% CI: 0.45–1.31).Median PFS for treatment with cabozantinib was 11 months vs. 1.9 months with placebo. At a median follow-up of 10.1 months, cabozantinib reduced the risk of disease progression or death vs. placebo (hazard ratio [HR]: 0.22; 96% CI: 0.15–0.32). Subgroup analyses demonstrated that cabozantinib improved PFS vs. placebo irrespective of prior exposure to lenvatinib and/or sorafenib. [10]
Jul 21Interim analysis (n=187) of PIII COSMIC-311 study shows cabozantinib significantly prolongs progression-free survival vs placebo (5.7 vs 1.9 months; HR 0.22; 96% CI 0.13–0.36). Objective response was reported in 15% on cabozantinib & 0% on placebo (p=0.028) but didn’t meet prespecified significance level [8].
Dec 20Exelixis announce positive data from planned interim analysis of PIII COSMIC-311 trial. Interim analysis (n=300) found that cabozantinib significantly improved PFS vs placebo (risk of disease progression or death reduced by 78% (HR 0.22; 96% CI[0.13–0.36]; p<0.0001) [5].
Jul 20PIII COSMIC-311 completed enrolment of the first 100 patients in the trial in Feb 2020 and Exelixis plans to conduct an analysis in these first 100 patients for the co-primary endpoint of ORR, and an interim analysis of PFS in the second half of 2020. It further expects to reach total enrolment of 300 patients for the trial in the H2 20. Collection of primary outcome data is due to complete this month [3,4].
Oct 19PIII COSMIC-311 study is recruiting [2].
Oct 18PIII COSMIC-311 study to evaluate the effect of cabozantinib compared with placebo on progression free survival (PFS) and objective response rate (ORR) in subjects with Radioiodine-Refractory Differentiated Thyroid Cancer (DTC) who have progressed after prior VEGFR-Targeted therapy starts (NCT03690388). 300 patients aged 16 years or older will be recruited from countries including the US, EU & UK. Collection of primary outcome data (progression-free survival and objective response rate) is due to complete Jul 20 [2].

Evidence based evaluations

CabometyxMetastatic renal cell carcinoma - cabozantinib plus nivolumab following first-line nivolumab and ipilimumab

Information

Cabometyx
Licence extension / variation
Ipsen
Exelixis

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

MET, RET and VEGFR2 inhibitor. CABOMETYX, the tablet formulation of cabozantinib, is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.
RCC accounts for 80-90% of kidney cancers in the UK. In 2012, there were 7,366 (4,625 male and 2,741 female) new cases of kidney cancer registered in England. Approximately 17% of patients present with metastatic disease and around half of the remainder will progress to advanced disease. 58% of patients with advanced disease receive targeted therapies, of whom 62% go on to receive second line therapy.
Metastatic renal cell carcinoma - cabozantinib plus nivolumab following first-line nivolumab and ipilimumab
Oral

CabometyxRenal cell carcinoma, intermediate- or poor-risk advanced or metastatic - first-line in combination with nivolumab and ipilimumab

Information

Cabometyx
Licence extension / variation
ipsen
Exelixis

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

MET, RET and VEGFR2 inhibitor. CABOMETYX, the tablet formulation of cabozantinib, is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 60 mg orally, once daily.
Renal cancers account for approximately 2-3% of all malignancies, with the highest incidence in Western countries. Males are more likely to be affected than females, with a ratio of 1.5:1. The incidence of kidney cancer begins to rise after the age of 40 and is highest in people aged between 60 and 70 years. Several risk factors have been identified, particularly smoking and obesity [1].
Renal cell carcinoma, intermediate- or poor-risk advanced or metastatic - first-line in combination with nivolumab and ipilimumab
Oral

Cabometyx Metastatic castration-resistant prostate cancer (mCRPC) in men who have previously been treated with one, and only one, novel hormonal therapy - in combination with atezolizumab

Information

Cabometyx
Licence extension / variation
Ipsen
Exelixis

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

MET, RET and VEGFR2 inhibitor
Prostate cancer is the most common cancer in men and makes up 26% of all male cancer diagnoses in the UK. The age-standardised incidence of prostate cancer in England in 2016 was 173.7 per 100,000 in 2016 [1].
Metastatic castration-resistant prostate cancer (mCRPC) in men who have previously been treated with one, and only one, novel hormonal therapy - in combination with atezolizumab
Oral

CabometyxNon-small cell lung cancer (NSCLC) - second-line with atezolizumab in patients previously treated with an immune checkpoint inhibitor

Information

Cabometyx
Licence extension / variation
Ipsen
Exelixis

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials

Category

MET, RET and VEGFR2 inhibitor. CABOMETYX, the tablet formulation of cabozantinib, is available in 20 mg, 40 mg or 60 mg doses. The recommended dose is 40 mg orally, once daily.
There were 46,403 new cases diagnosed in the UK in 2014. NSCLC accounts for 85% of cases [1]. The five-year survival rate for patients with NSCLC is 24%, but that rate falls to just 6% for those with advanced or metastatic disease. More than half of lung cancer cases are diagnosed at an advanced stage [2].
Non-small cell lung cancer (NSCLC) - second-line with atezolizumab in patients previously treated with an immune checkpoint inhibitor
Oral

CabometyxAdvanced neuroendocrine tumours after progression on everolimus

Information

Cabometyx
XL184, XL 184
Ipsen
Exelixis

Development and Regulatory status

None
None
Phase III Clinical Trials

Category

MET, RET and VEGFR2 inhibitor
PNETs can be divided into functional (exhibit a distinct clinical syndrome due to hormone hypersecretion) and non-functional tumours. Population-based studies have assessed the incidence of PNETs as 0.2-0.4 per 100,000 [1]. Carcinoid tumours are rare, slow-growing tumours that originate in cells of the diffuse neuroendocrine system. Carcinoid tumours are the most common NETs. Annual incidence is approximately 3 per 100,000 per year [2].
Advanced neuroendocrine tumours after progression on everolimus
Oral

Cabometyx Advanced hepatocellular carcinoma (HCC) - first-line in combination with atezolizumab or as monotherapy

Information

Cabometyx
Licence extension / variation
Ipsen
Exelixis

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Apr 22Development discontinued; removed from pipeline [7].
Mar 22With disappointing final data from the PIII COSMIC-312 study, Exelixis has decided not to file a supplemental New Drug Application to the US FDA [6].

Category

A small molecule that inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumour growth and angiogenesis, pathologic bone remodeling, and metastatic progression of cancer.
HCC is the most common type of primary liver cancer. In the UK there are about 1,500 deaths per year from HCC. It is thought that HCC may be diagnosed more frequently in the UK over the next few years due to the hepatitis C epidemic.
Advanced hepatocellular carcinoma (HCC) - first-line in combination with atezolizumab or as monotherapy
Oral

Further information

Yes

Trial or other data

Mar 22Results from the final analysis of the second primary endpoint of overall survival (OS) from the PIII COSMIC-312 trial announced. The final analysis showed neither improvement nor detriment in OS for cabozantinib in combination with atezolizumab vs sorafenib [6]

Evidence based evaluations