dm+d

29874611000001101

New Medicines

KisplyxAdvanced renal cell carcinoma in adults - first-line in combination with pembrolizumab

Information

Kisplyx
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

Launched
Launched
Launched
November 2021
Nov 21MHRA approves a new indication, for treatment of adults with advanced renal cell carcinoma in combination with pembrolizumab, as first-line treatment [16].
Nov 21Approved in the EU [15]
Oct 21Recommended for EU approval by CHMP – the extension to the existing indication is “treatment of adults with advanced renal cell carcinoma in combination with pembrolizumab, as first-line treatment [14].
Aug 21FDA approves the combination of lenvatinib plus pembrolizumab for first-line treatment of adult patients with advanced RCC. This review used the Real-Time Oncology Review (RTOR) pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA assessment. The FDA approved this application approximately 1 month ahead of the FDA goal date. It had priority review status in addition to breakthrough therapy status [13].
Apr 21Company has submitted data for combination therapy with pembrolizumab; not yet everolimus [12].
Apr 21Filing accepted in the US [12].
Mar 21Filing accepted in the EU [12].
Jan 18Awarded Breakthrough Designation in the US [5].
Sep 16PIII study 307 starts [1].

Category

A multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of several receptors involved in tumour proliferation.
Renal cell carcinoma comprises more than 90% of all malignancies of the kidney and is thought to affect 338,000 people worldwide [1].
Advanced renal cell carcinoma in adults - first-line in combination with pembrolizumab
Oral

Further information

Yes

Trial or other data

Jun 21Company announces new analysis evaluating health-related quality of life based on pt-reported outcomes shows the combination therapy improved quality of life measures for pts vs chemotherapy (sunitinib) [11]
Apr 21Results of PIII CLEAR study (NCT02811861) reported in NEJM [10].
Feb 21PIII RCT CLEAR (n=1069) reported longer progression-free survival with lenvatinib plus pembrolizumab (median, 23.9 vs. 9.2 months; HR 0.39; 95%, 0.32 to 0.49; P<0.001) and lenvatinib plus everolimus (median, 14.7 vs. 9.2 months; 0.65; 0.53 to 0.80; P<0.001) vs sunitinib [9].
Nov 20Manufacturers report positive results from PIII KEYNOTE-581/CLEAR trial. Study (n=1050) found these combination regimens improved PFS (primary endpoint), OS and objective response rate vs sunitinib as first-line treatment for patients with advanced renal cell carcinoma [8].
Aug 19PIII CLEAR study has finished recruiting [7].
Oct 18PIII CLEAR study (NCT02811861) continues to recruit; collection of primary outcome data now expected Apr 20 [6].
Dec 17The PIII CLEAR study NCT02811861 is still recruiting; date of collection of primary data unchanged [4].
Sep 16Eisai initiates the PIII CLEAR (comparison of the efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib alone in first-line treatment of subjects with Advanced Renal cell carcinoma) trial to compare the safety and efficacy of lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) versus sunitinib (Arm C), as first-line treatment of patients with advanced renal cell carcinoma (NCT02811861; Study 307). Patients will be randomised 1:1:1 to one of three treatment arms to receive either lenvatinib 18mg (orally, once daily) plus everolimus 5mg (orally, once daily) [arm A], lenvatinib 20mg (orally, once daily) plus pembrolizumab 200mg (intravenously every three weeks) [arm B], or sunitinib 50mg (orally, once daily) on a schedule of four weeks on treatment followed by two weeks off [arm C]. The primary outcome measure will be progression-free survival. The open-label, randomised trial expects to enrol approximately 735 patients in the US, Europe and Japan. Collection of primary outcome data is expected to complete Oct 19 [4].

Evidence based evaluations

LenvimaEndometrial cancer - second-line combination therapy with pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

Launched
Launched
Launched
November 2021
Nov 21MHRA approves a licence extension for use in combination with pembrolizumab for the treatment of adult patients with advanced or recurrent endometrial carcinoma who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery or radiation [12].
Nov 21Approved in the EU [11].
Oct 21Recommended for EU approval by CHMP – the additional indication is “use in combination with pembrolizumab for the treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery or radiation” [10].
Jul 21FDA approves the combination of Keytruda and Lenvima for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. The approval for this population is based on results from the pivotal Phase 3 KEYNOTE-775/Study 309 trial. Keytruda plus Lenvima was previously approved under the FDA ’s accelerated approval process, and the Real-Time Oncology Review pilot program and Project Orbis initiative, for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation based on data from the KEYNOTE-146/Study 111 trial. In accordance with accelerated approval regulations, continued approval was contingent upon verification and description of clinical benefit; these accelerated approval requirements have been fulfilled with the data from KEYNOTE-775/Study 309 [9].
Apr 21Filing of data from Study 309 accepted in the US [8].
Mar 21Filing accepted in the EU [8].
Sep 19Approved in US under the FDA’s accelerated Real-Time Oncology Review pilot program. Approval is for use in combination with pembrolizumab for second-line treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), and who are not candidates for curative surgery or radiation [4].

Category

A multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of several receptors involved in tumour proliferation.
In the UK there are about 8,600 new cases per year [1].
Endometrial cancer - second-line combination therapy with pembrolizumab
Oral

Further information

Yes

Trial or other data

Dec 20Merck and Eisai announce that the pivotal PIII KEYNOTE-775/Study 309 trial met its dual primary endpoints of OS and PFS and its secondary efficacy endpoint of objective response rate (ORR) in patients with advanced endometrial cancer following at least one prior platinum-based regimen. These positive results were observed in the mismatch repair proficient (pMMR) subgroup and the intention-to-treat (ITT) study population, which includes both patients with endometrial carcinoma that is pMMR as well as patients whose disease is microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR). Merck and Eisai will discuss these data with regulatory authorities worldwide, with the intent to submit marketing authorisation applications based on these results [7].
Dec 20PIII KEYNOTE-775 is no longer recruiting [6].
Sep 19PIII KEYNOTE-775 study is recruiting [5].
Sep 19Mid-stage data from PII KEYNOTE-146/Study 111 show the combination treatment demonstrates a 38.3% objective response rate, with a complete response rate of 10.6% and a partial response rate of 27.7% [4].
Sep 18Joint development with Merck & Co [2].
Jun 18PIII KEYNOTE-775 study starts (NCT03517449). This is a study of pembrolizumab (MK-3475, KEYTRUDA®) in combination with lenvatinib (E7080) versus treatment of physician´s choice (doxorubicin or paclitaxel) for the treatment of advanced endometrial cancer. Participants will be randomly assigned to receive either pembrolizumab and lenvatinib or treatment of physician´s choice. The primary study hypothesis is that pembrolizumab in combination with lenvatinib prolongs progression free survival (PFS) and overall survival (OS) when compared to treatment of physician´s choice. 780 adults will be recruited in the US, Canada, Australia, EU (including UK), and many more countries. Collection of primary outcome data due to complete Feb 22 [3].

Evidence based evaluations

LenvimaEndometrial cancer - first-line combination therapy with pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

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

Category

A multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of several receptors involved in tumour proliferation.
In the UK there are about 8,600 new cases per year [1].
Endometrial cancer - first-line combination therapy with pembrolizumab
Oral

Further information

Yes

Evidence based evaluations

Kisplyx Advanced renal cell carcinoma in adults - first-line in combination with everolimus

Information

Kisplyx
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

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

Category

A multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of several receptors involved in tumour proliferation.
Renal cell carcinoma comprises more than 90% of all malignancies of the kidney and is thought to affect 338,000 people worldwide [1].
Advanced renal cell carcinoma in adults - first-line in combination with everolimus
Oral

Evidence based evaluations

SMC

LenvimaMalignant melanoma - first-line in combination with pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

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

Category

Multi-targeted kinase inhibitor, which inhibits VEGFR1-3, FGFR1-4 & RET tyrosine kinases
There are around 16,000 new melanoma skin cancer cases in the UK every year, that is 44 every day (2014-2016). Incidence rates for melanoma skin cancer are projected to rise by 7% in the UK between 2014 and 2035, to 32 cases per 100,000 people by 2035 [1].
Malignant melanoma - first-line in combination with pembrolizumab
Oral

LenvimaMetastatic colorectal cancer - second-line with pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

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

Category

A multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of several receptors involved in tumour proliferation.
Colorectal cancer, or bowel cancer, is the fourth most common cancer in the UK and the second biggest cancer killer. Nearly 43,000 people are diagnosed with bowel cancer every year in the UK. Around 268,000 people living in the UK have been diagnosed with bowel cancer. More than 16,500 people die from bowel cancer in the UK every year [1].
Metastatic colorectal cancer - second-line with pembrolizumab
Oral

LenvimaSquamous cell PD-L1-positive head and neck (or upper airways tract) cancers - first-line in combination with pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

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

Category

Multi-targeted kinase inhibitor, which inhibits VEGFR1-3, FGFR1-4 & RET tyrosine kinases
Head and neck SCC is the sixth most common cancer worldwide, predominantly associated with tobacco use. There are marked regional variations in the incidence of head and neck cancers, with rates ranging from 8 per 100,000 in the Thames and Oxford regions to 13-15 per 100,000 in Wales and in the North Western region [1].
Squamous cell PD-L1-positive head and neck (or upper airways tract) cancers - first-line in combination with pembrolizumab
Oral

Further information

Yes

Evidence based evaluations

LenvimaMetastatic non-small cell lung cancer (NSCLC) - second-line with pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

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

Category

Multi-targeted kinase inhibitor, which inhibits VEGFR1-3, FGFR1-4 & RET tyrosine kinases
In 2016, approximately 32,500 people were diagnosed with NSCLC in England, and 85-90% are non-small cell lung cancers (NSCLC) [1].
Metastatic non-small cell lung cancer (NSCLC) - second-line with pembrolizumab
Oral

Evidence based evaluations

LenvimaMetastatic non-squamous non-small cell lung cancer (NSCLC) - first-line with pemetrexed + platinum chemotherapy + pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

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

Category

Multi-targeted kinase inhibitor, which inhibits VEGFR1-3, FGFR1-4 and RET tyrosine kinases
In 2016, approximately 32,500 people were diagnosed with NSCLC in England, and 85-90% are non-small cell lung cancers (NSCLC) [1].
Metastatic non-squamous non-small cell lung cancer (NSCLC) - first-line with pemetrexed + platinum chemotherapy + pembrolizumab
Oral

LenvimaIncurable/non-metastatic hepatocellular carcinoma (HCC) - first-line in combination with pembrolizumab and TACE

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

Multi-targeted kinase inhibitor, which inhibits VEGFR1-3, FGFR1-4 & RET tyrosine kinases
There are around 5,900 new liver cancer cases in the UK every year, that is 16 every day (2014-2016). Incidence rates for liver cancer are projected to rise by 38% in the UK between 2014 and 2035, to 15 cases per 100,000 people by 2035. In males, most liver cancer cases are liver cell carcinomas, and most liver cell carcinomas are hepatocellular carcinomas. The proportion of liver cell carcinomas is higher in males (61.1%) than females (31.8%) [1].
Incurable/non-metastatic hepatocellular carcinoma (HCC) - first-line in combination with pembrolizumab and TACE
Oral

LenvimaPDL1-positive non-small cell lung cancer (NSCLC) - first-line with pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Aug 21After the external Data Monitoring Committee recommended the PIII LEAP-007 study be stopped, development has been discontinued [5].

Category

Multi-targeted kinase inhibitor, which inhibits VEGFR1-3, FGFR1-4 and RET tyrosine kinases
In 2016, approximately 32,500 people were diagnosed with NSCLC in England, and 85-90% are non-small cell lung cancers (NSCLC). Approximately 70% of NSCLC are of non-squamous histology [1].
PDL1-positive non-small cell lung cancer (NSCLC) - first-line with pembrolizumab
Oral

Lenvima Locally advanced or metastatic urothelial cancer - first-line in combination with pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Nov 21Development discontinued after an external Data Monitoring Committee recommendation to stop the PIII LEAP-011 study [4].

Category

Multi-targeted kinase inhibitor, which inhibits VEGFR1-3, FGFR1-4 & RET tyrosine kinases
Cancer arising from the transitional cells of the mucosal urothelium may present as a non-invasive, papillary tumour protruding from the mucosal surface, or as a solid, non-papillary tumour that invades the bladder wall and has a high propensity for metastasis. The overall incidence of bladder cancer in the UK is 11.4 per 100,000 population [1].
Locally advanced or metastatic urothelial cancer - first-line in combination with pembrolizumab
Oral

LenvimaAdvanced hepatocellular carcinoma (HCC) - first-line in combination with pembrolizumab

Information

Lenvima
Licence extension / variation
Eisai
Eisai

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Aug 22Development discontinued [10].
Jul 20FDA issues a Complete Response Letter (CRL) to Eisai and Merck, for the regulatory applications seeking accelerated approval for combination treatment with lenvatinib and pembrolizumab, for the use as a first-line treatment of patients with advanced, unresectable hepatocellular carcinoma. Since the applications for KEYNOTE-524/Study 116 no longer meet the criteria for accelerated approval, both companies plan to work with the FDA to take appropriate next steps, which include conducting a well-controlled clinical trial that demonstrates substantial evidence of effectiveness and the clinical benefit of the combination [8].
May 20Data from PIb KEYNOTE-524 have been filed in the US [4].
Jul 19Granted breakthrough therapy status in US [3].

Category

Multi-targeted kinase inhibitor, which inhibits VEGFR1-3, FGFR1-4 & RET tyrosine kinases
There are around 5,900 new liver cancer cases in the UK every year, that is 16 every day (2014-2016). Incidence rates for liver cancer are projected to rise by 38% in the UK between 2014 and 2035, to 15 cases per 100,000 people by 2035. In males, most liver cancer cases are liver cell carcinomas, and most liver cell carcinomas are hepatocellular carcinomas. The proportion of liver cell carcinomas is higher in males (61.1%) than females (31.8%) [1].
Advanced hepatocellular carcinoma (HCC) - first-line in combination with pembrolizumab
Oral

Further information

Yes

Trial or other data

Aug 22PIII LEAP-002 trial fails to meet dual primary endpoints of OS and PFS [11].
Apr 21PIII LEAP-002 trial is on course to complete collection of primary outcome data in May 22 [9].
May 20Results from the PIb KEYNOTE-524 study announced. This is an open-label, single-arm trial evaluating KEYTRUDA plus LENVIMA in 100 patients with unresectable HCC with no prior systemic therapy. Patients were treated with KEYTRUDA 200 mg intravenously every three weeks in combination with LENVIMA 8 or 12 mg (based on baseline body weight ?60 kilograms or =60 kilograms, respectively) orally once daily. The primary endpoints are ORR and duration of response (DOR) by modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST v1.1 per independent imaging review (IIR). In final analysis, lenvatinib in combination with pembrolizumab demonstrated an overall response rate (ORR) of 36% (n = 36) (95% CI: 26.6-46.2), with a complete response rate of 1% (n = 1) and a partial response rate of 35% (n = 35), and a median duration of response (DOR) of 12.6 months (95% CI: 6.9-not estimable [NE]), using RECIST v1.1 criteria per IIR. As assessed using mRECIST criteria per IIR, lenvatinib in combination with pembrolizumab demonstrated an ORR of 46% (n = 46) (95% CI: 36.0-56.3), with a complete response rate of 11% (n = 11) and a partial response rate of 35% (n = 35), and a median DOR of 8.6 months (95% CI: 6.9-NE) [6].
Dec 19PIII LEAP-002 trial is recruiting [4].
Dec 18PIII LEAP-002 trial to evaluate the safety and efficacy of lenvatinib in combination with pembrolizumab versus lenvatinib in combination with placebo, as first-line therapy, for the treatment of advanced hepatocellular carcinoma starts (MK7902-002; NCT03713593). Evaluation of the progression-free survival and overall survival are the primary endpoints of the trial. The randomised, double blind trial intends to enrol approximately 750 patients in the US, Australia, Chile, China, Colombia, France, Germany, Italy, Ireland, Japan, South Korea, Mexico, New Zealand, Poland, Russia, Spain, Taiwan, Turkey and the United Kingdom. Collection of primary outcome data is due to complete Jul 22 [2].

Evidence based evaluations