dm+d

30037111000001101

Refrigerated Storage

Keytruda Merck Sharp & Dohme Limited

Merck Sharp & Dohme Limited
Keytruda
Concentrate for solution, 25mg/mL

Contact MSD in all cases where a deviation from the recommended storage conditions has occurred. Refer to the electronic medicines compendium (eMC) at https://www.medicines.org.uk for company contact details.

22 February 2022
London MI Service

New Medicines

KeytrudaMetastatic triple-negative breast cancer - first-line with chemotherapy

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Launched
Launched
Launched
November 2021
Nov 21MHRA approves a new indication, for use in combination with chemotherapy, for the treatment of locally recurrent unresectable or metastatic triple-negative breast cancer in adults whose tumours express PD-L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease [13].
Oct 21Approved in EU [12].
Sep 21Recommended for EU approval by CHMP – the additional indication is “Keytruda, in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumours express PD-L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease” [10].
Mar 21Has been filed to EMA with positive opinion expected Nov 2021 [9].
Nov 20Approved in US for use in combination with chemotherapy for patients with locally recurrent unresectable or metastatic triple‑negative breast cancer whose tumours express PD-L1 (CPS ≥10) [8].
Jul 20Data from KN355 has been filed in the US [7].
Feb 18EU filing will be using the centralised procedure [1].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein.
Cancer Research UK: 15% of patients with breast cancer have triple negative disease
Metastatic triple-negative breast cancer - first-line with chemotherapy
Intravenous infusion

Further information

Yes

Trial or other data

Sep 21Merck announce final overall survival results from KEYNOTE-355. Pembrolizumab plus chemotherapy reduced the risk of death by 27% (HR=0.73 [95% CI, 0.55-0.95]; p=0.0093) compared to chemotherapy alone in patients whose tumours expressed PD-L1 with Combined Positive Score ≥10. There was an increase in overall survival with pembrolizumab plus chemotherapy compared to chemotherapy alone - (23.0 months [95% CI, 19.0-26.3] vs. 16.1 months [95% CI, 12.6-18.8], respectively). [11]
May 20Merck announce additional results from PIII KEYNOTE-355 study. Pembrolizumab reduced risk of disease progression/death by 35% (HR 0.65 [95% CI 0.49-0.86]; p=0.0012) and improved PFSl to median of 9.7 months vs. 5.6 months in chemotherapy group in patients whose tumours expressed PD-L1 with Combined Positive Score ≥10 [6].
Feb 20Topline positive results from PIII KEYNOTE-355 trial which met one of its dual primary endpoints, progression-free survival (PFS). First-line treatment with Keytruda with nab-paclitaxel, paclitaxel or gemcitabine/carboplatin had a statistically significant and clinically meaningful improvement in PFS vs. chemotherapy alone. The data monitoring committee recommended the trial continue without changes to evaluate overall survival (OS). [5]
Dec 19PIII KEYNOTE-355 study (NCT02819518) completes collection of primary outcome data [4].
May 18PIII KEYNOTE-355 study (NCT02819518) has finished recruiting [3].
Jul 16PIII KEYNOTE-355 study (NCT02819518) starts. The study will consist of two parts. In Part 1, the safety of pembrolizumab (MK-3475) in combination with one of three different chemotherapies will be assessed in the treatment of locally recurrent inoperable or metastatic triple negative breast cancer (TNBC), which has not been previously treated with chemotherapy. In Part 2, the safety and efficacy of pembrolizumab plus chemotherapy will be assessed compared to the safety and efficacy of placebo plus chemotherapy in the treatment of locally recurrent inoperable or metastatic TNBC, which has not been previously treated with chemotherapy. 858 adults will be recruiited from sites around the world including the US & EU (plus UK). PFS & OS are primary outcomes for part 2 of the study; these data are due to be collected by Dec 19 [2].

KeytrudaEndometrial cancer - second-line with lenvatinib

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Launched
Launched
Launched
November 2021
Nov 21Approved in EU [11].
Nov 21MHRA approves a new indication, for use in combination with lenvatinib, for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation [10].
Oct 21Keytruda, in combination with lenvatinib, is indicated for the treatment of advanced or recurrent endometrial carcinoma in adults who have disease progression on or following prior treatment with a platinum‑containing therapy in any setting and who are not candidates for curative surgery or radiation therapy” [9].
Jul 21Nearly 2 years after the US FDA granted conditional approval, the regulator has granted full approval for pembrolizumab and lenvatinib for treatment of advanced endometrial carcinoma that is not microsatellite instability-high or mismatch repair deficient, that has progressed following prior systemic therapy and is not amenable to curative surgery or radiation [7,8].
May 21Currently pre-registration in the EU, US and Japan. Data from KEYNOTE-755 has been filed (presumably for full approval in the US) [6].
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 [3].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein
In the UK there are about 8,600 new cases per year [1].
Endometrial cancer - second-line with lenvatinib
Intravenous infusion

Further information

Yes

Trial or other data

Mar 21The company announces lenvatinib and pembrolizumab combination in PIII KEYNOTE-775 trial demonstrates a reduction in the risk of disease progression or death by 44% (median PFS of 7.2 months vs 3.8 months for pts on chemotherapy). A statistically significant and clinically meaningful improvement in OS was observed where the combination decreased the risk of death by 38% (median OS of 18.3 months vs 11.4 months for pts on chemotherapy). [5]
Dec 20PIII KEYNOTE-775 trial meets dual primary endpoints of OS and PFS [4].
Sep 19PIII KEYNOTE-775 study is recruiting [2].
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% [3].
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 [2].

Evidence based evaluations

Keytruda Advanced renal cell carcinoma - first-line with lenvatinib

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Launched
Launched
Launched
November 2021
Nov 21MHRA approves a licence change, for use in combination with lenvatinib for the first-line treatment of advanced renal cell carcinoma in adults (already approved for use with axitinib for first-line treatment of RCC) [11].
Nov 21Approved in the EU [7]
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 lenvatinib, as first-line treatment [9].
Aug 21The FDA 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 [8].
Aug 21Approved in US [7]
May 21Currently pre-registration in the US, EU and Japan [6].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein
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 [1].
Advanced renal cell carcinoma - first-line with lenvatinib
Intravenous infusion

Further information

Yes

Trial or other data

Feb 21Merck and Eisai share data showing Keytruda-Lenvima could cut the risk of death by 34% vs. sunitinib in newly diagnosed kidney cancer [5].
Nov 20PIII CLEAR study is ongoing and completed collection of primary outcome data in August [4].
Nov 20Topline results find pembrolizumab (200mg i.v. every 3 weeks) plus lenvatinib (20mg daily) to have demonstrated statistically significant improvement in PFS, OS and ORR vs. sunitinib as 1st line treatment for in the open-label randomised PIII KEYNOTE-581/CLEAR trial (N=1050, NCT02811861). Full data will be presented at upcoming medical meeting.[3]
Aug 19PIII CLEAR study is ongoing but no longer recruiting [2].
Oct 16PIII CLEAR study to compare the efficacy and safety of lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) versus sunitinib (Arm C) as first-line treatment in participants with advanced renal cell carcinoma starts (NCT02811861). 1,069 adults will be recruited from countries including the US, Australia, EU countries and the UK. Collection of primary outcome data (progression-free survival) is due to complete Apr 20 [2].

Evidence based evaluations

Keytruda Renal cell carcinoma - adjuvant monotherapy post nephrectomy

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Launched
Launched
Launched
February 2022
Feb 22MHRA approves a new indication for Keytruda (100mg in 4ml vial) for use as monotherapy for adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions [12].
Jan 22Approved in EU [11].
Dec 21Recommended for EU approval by CHMP – the extension to the existing indication is “for the adjuvant treatment of adults with renal cell carcinoma at increased risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions” [11].
Nov 21FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma patients at intermediate-high or high risk of recurrence after nephrectomy or following nephrectomy and resection of metastatic lesions [10]
Aug 21US FDA accept sBLA for priority review with a PDUFA of 10/12/21; proposed indication is adjuvant treatment of patients with renal cell carcinoma at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions [7].
Jul 21Is pre-registration in EU with data from KEYNOTE-564 filed [9].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein.
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 [1].
Renal cell carcinoma - adjuvant monotherapy post nephrectomy
Intravenous

Further information

Yes

Trial or other data

Aug 21PIII KEYNOTE-564 RCT (n=994) found pembrolizumab linked to significantly longer disease-free survival than placebo (at 24 months, 77.3% vs. 68.1%; HR for recurrence or death, 0.68; 95% CI, 0.53 to 0.87; p=0.002) among patients with kidney cancer who were at high risk for recurrence [8].
Jun 21Results of KEYNOTE-564 presented at the American Society of Clinical Oncology meeting report that, at the two-year mark, 77.3% of patients in the pembrolizumab arm remained alive and disease-free, vs 68.1% of patients in the placebo arm. In an interview, a company representative suggested this magnitude of improvement in disease-free survival is considered clinically meaningful [6].
Apr 21MSD announced that the pivotal PIII KEYNOTE-564 trial met its primary endpoint and demonstrated a statistically significant and clinically meaningfully improvement in DFS vs placebo. The trial will continue to evaluate overall survival (OS). The safety profile of pembrolizumab was consistent with that observed in previously reported studies. Results will be presented at an upcoming medical meeting and will be submitted to regulatory authorities [5].

KeytrudaPersistent, recurrent or metastatic cervical cancer, PD-L1 positive - with chemotherapy ± bevacizumab

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Launched
Launched
Launched
May 2022
May 22Licensed in UK. Full new indication "KEYTRUDA, in combination with chemotherapy with or without bevacizumab, is indicated for the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD-L1 with a CPS ≥ 1" [15].
Apr 22Approved in EU for use in combination with chemotherapy, with or without bevacizumab, for the treatment of persistent, recurrent or metastatic cervical cancer in adults whose tumours express PD-L1 (Combined Positive Score [CPS] ≥1) [14].
Mar 22EU positive opinion for a new indication of use in combination with chemotherapy with or without bevacizumab, for the treatment of persistent, recurrent, or metastatic cervical cancer in adults whose tumours express PD‑L1 with a CPS ≥ 1 [13].
Nov 21Is currently pre-registration in the EU for approval of a new indication, in combination with chemotherapy, with or without bevacizumab, for the treatment of persistent, recurrent, or metastatic cervical cancer in adults [12].
Oct 21The FDA has also approved pembrolizumab first-line in combination with chemotherapy, with or without bevacizumab, for patients with peristent, recurrent or metastatic cervical cancer whose tumours express PD-L1 (CPS ≥1) [11].
Oct 21US FDA converts accelerated approval of KEYTRUDA as a single agent for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumours express PD-L1 (CPS ≥1), as determined by an FDA-approved test, to a regular approval based on confirmatory data from KEYNOTE-826 [10].
Jul 20Licence extension based on data from KN158 in previously treated tumour mutational burden-high approved in US [7].
Jun 18PIII in UK and EU [5].
Jun 18Approved in the US under accelerated approval pathway based on tumour response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials [3].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein
Around 3,200 new cases of cervical cancer are diagnosed in the UK each year; incidence rates are highest in those aged 25 to 29 [1]. Approximate 5-year survival rate of stage IVB disease is <20% [2].
Persistent, recurrent or metastatic cervical cancer, PD-L1 positive - with chemotherapy ± bevacizumab
Intravenous

Further information

Yes

Trial or other data

Sep 21PIII KEYNOTE-826 RCT (n=617; receiving chemotherapy with or without bevacizumab) reported improved progression free (10.4 vs 8.2 months; HR 0.65; 95% CI, 0.53 to 0.79; P<0.001) and overall (53.0% vs 41.7%; 0.64; 95% CI, 0.50 to 0.81; P<0.001) survival at 24 months with pembrolizumab vs placebo [9].
Oct 19PIII KEYNOTE-826 trial is recruiting [6].
Oct 18PIII KEYNOTE-826 trial of to assess the efficacy and safety of pembrolizumab plus one of four platinum-based chemotherapy versus one of four platinum-based chemotherapy plus placebo in adult women with persistent, recurrent, or metastatic cervical cancer starts (MK-3475-826; NCT03635567). 600 patients will be recruited in countries such as the US and EU (not UK). Collection of primary outcome data (PFS & OS) is due to complete Nov 22 [6].
Jun 18Recruitment to KEYNOTE-158 (NCT02628067) continues in UK and EU. Estimated study completion date 08/23 [5].
Jun 18Accelerated approval in the US is based on data from a single cohort (cohort E) of the multicentre, open-label, multi-cohort PII trial, KEYNOTE-158 (n=98; NCT02628067) evaluating predictive biomarkers in patients with multiple types of advanced (unresectable and/or metastatic) solid tumours that have progressed on standard of care therapy. Efficacy analysis showed an ORR of 14.3%, 95% CI [7.4 to 24.1] in 77 patients whose tumours expressed PD-L1, with a complete response rate of 2.6% and a partial response rate of 11.7%. Median DOR had not been reached (range: 4.1 to 18.6+ months). No responses were observed in patients whose tumours did not have PD-L1 expression. Median follow-up time was 11.7 months. Keytruda (pembrolizumab) was discontinued due to adverse reactions in 8% of patients. The most common adverse reactions were fatigue (43%), musculoskeletal pain (27%), diarrhoea (23%), pain (22%), abdominal pain (22%), and decreased appetite (21%). Adverse reactions leading to discontinuation of Keytruda occurred in 8% of patients. Serious adverse reactions occurred in 39% of patients, the most frequent of which were anaemia (7%), haemorrhage, infections (except UTI), and fistula (4.1% each). KEYNOTE-158 is ongoing with an estimated primary completion date of August 2023 [4,5].

Evidence based evaluations

KeytrudaMSI-H/dMMR endometrial, gastric, biliary, small intestine or colorectal cancer - second-line

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Launched
Launched
Launched
May 2022
Jun 22Earlier in Mar 22, the FDA approved pembrolizumab as a single agent, for patients with advanced endometrial carcinoma that is microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and who are not candidates for curative surgery or radiation. Approval was based on KEYNOTE-158 [8].
May 22Licensed in UK. Full new licence extension "KEYTRUDA as monotherapy is indicated for the treatment of the following MSI-H or dMMR tumours in adults with: unresectable or metastatic colorectal cancer after previous fluoropyrimidine-based combination therapy; advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation; unresectable or metastatic gastric, small intestine, or biliary cancer, who have disease progression on or following at least one prior therapy" [7].
Apr 22Approved in EU as monotherapy for the treatment of microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) tumors in adults with: unresectable or metastatic colorectal cancer after previous fluoropyrimidine-based combination therapy; advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and who are not candidates for curative surgery or radiation; unresectable or metastatic gastric, small intestine or biliary cancer, who have disease progression on or following at least one prior therapy [6].
Mar 22Recommended for EU approval by CHMP “treatment of the following MSI H or dMMR tumours in adults with: unresectable or metastatic colorectal cancer after previous fluoropyrimidine based combination therapy; advanced or recurrent endometrial carcinoma, who have disease progression on or following prior treatment with a platinum containing therapy in any setting and who are not candidates for curative surgery or radiation; unresectable or metastatic gastric, small intestine, or biliary cancer, who have disease progression on or following at least one prior therapy” [6].
Nov 21Currently pre-registration in EU for an extension of indication for Keytruda as monotherapy in the treatment of unresectable or metastatic MSI-H or dMMR colorectal, endometrial, gastric, small intestine, biliary, or pancreatic cancer in adults who have received prior therapy. The proposed indication is based on the results from the KEYNOTE-164 (KN164) and KEYNOTE-158 (KN158) trials. The company has requested an extension to the clock stop to respond to the request for supplementary information adopted by the CHMP in Oct 21 [4].
Jul 21Data from KEYNOTE-158 has been filed to the FDA [3].
May 17FDA grants accelerated approval to pembrolizumab for treatment of previously treated adult and paediatric patients with advanced, metastatic or unresectable microsatellite instability-high (MSI-H) solid tumours. Continued approval for this indication will depend upon verification and description of clinical benefit in the confirmatory trials [5].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein
In 25 tumour types including gastric, ovarian, colorectal, endometrial, esophageal and renal cancer, overall MSI-H prevalence (with 95% CI) was estimated at 14% (10%–19%). MSI-H prevalence among Stage 1/2 cancers was estimated at 15% (8%–23%); Stages 3 and 4 prevalence was estimated at 9% (3%–17%) and 3% (1%–7%), respectively. Overall, dMMR prevalence across 13 tumor types was estimated at 16% (11%–22%). Endometrial cancer had the highest pooled MSI-H and dMMR prevalence [1].
MSI-H/dMMR endometrial, gastric, biliary, small intestine or colorectal cancer - second-line
Intravenous infusion

Trial or other data

May 21PII KEYNOTE-158 study is recruiting and expects to complete collection of primary outcome data in Jun 26 [2].
Feb 21PII KEYNOTE-164 study completes [2].
Dec 15PII KEYNOTE-158 study starts (NCT02628067). In this study, participants with multiple types of advanced (unresectable and/or metastatic) solid tumors who have progressed on standard of care therapy will be treated with pembrolizumab - tumours can be Microsatellite Instability (MSI)-High (MSI-H). 1,595 adults will be recruited at sites including the US and Spain. Primary outcome is objective response rate [2].
Aug 15PII KEYNOTE-164 study starts (NCT02460198). It will assess 124 participants with previously-treated locally-advanced unresectable or metastatic mismatched repair (MMR) deficient or microsatellite instability-high (MSI-H) colorectal carcinoma (CRC) treated with pembrolizumab monotherapy. There will be two cohorts in this study: Cohort A and Cohort B. For Cohort A, participants are required to have been previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan. Enrollment into Cohort A has been completed. For Cohort B, participants are required to have been previously treated with at least one line of systemic standard of care therapy: fluoropyrimidine + oxaliplatin or fluoropyrimidine + irinotecan +/ - anti-vascular endothelial growth factor (VEGF)/ epidermal growth factor regulator (EGFR) monoclonal antibody [2].

Evidence based evaluations

KeytrudaLocally advanced non-metastatic, triple negative breast cancer - neo-adjuvant and adjuvant therapy with chemotherapy

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Launched
Launched
Launched
May 2022
May 22MHRA approves a new indication for Keytruda, use in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, for the treatment of adults with locally advanced, or early-stage triple-negative breast cancer at high risk of recurrence [17].
May 22Approved in EU for use in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery for adults with locally advanced or early-stage triple-negative breast cancer (TNBC) at high risk of recurrence [16].
Apr 22EU positive opinion granted recommending approval for this indication. The proposed new indication is ‘Keytruda, in combination with chemotherapy as neoadjuvant treatment, and then continued as monotherapy as adjuvant treatment after surgery, is indicated for the treatment of adults with locally advanced, or early stage triple negative breast cancer at high risk of recurrence’ [15].
Aug 21Currently pre-registration in EU [13].
Jul 21Approved in US for treatment of patients with high-risk, early-stage triple-negative breast cancer [12].
Mar 21The US FDA issued a Complete Response Letter rejecting application for filing after the Oncologic Drugs Advisory Committee voted 10-0 that a regulatory decision should be deferred until further data are available from KEYNOTE-522 (expected Q3 2021).[9]
Feb 21FDA’s Oncologic Drugs Advisory Committee voted against recommending pembrolizumab for this indication. Their analysis of the KEYNOTE-522 trial had not met the pre-specified threshold for statistical significance and “remained immature with 53% of targeted EFS (event-free survival) events having occurred. The OS (overall survival) endpoint was also considered immature. There were also concerns around immune-mediated adverse events. [8]
Jul 20Data from KN522 trial has been filed in the US [7].
Apr 18Will be filed in the EU using the centralised procedure [1].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein
Cancer Research UK: 15% of patients with breast cancer have triple negative disease.
Locally advanced non-metastatic, triple negative breast cancer - neo-adjuvant and adjuvant therapy with chemotherapy
Intravenous infusion

Further information

Yes

Trial or other data

Feb 22PIII KEYNOTE-522 RCT (n=1174; 4th interim analysis) found neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than NA chemotherapy alone (84.5% vs. 76.8% at 36 months; HR 0.63;95% CI,0.48-0.82;p<0.001) [14].
Jul 21MSD announces positive event free survival (EFS) data from KEYNOTE-522. After median follow up of 39 months the Keytruda regime reduced the risk of EFS events by 37% versus the chemotherapy-placebo regimen [11]
May 21PIII KEYNOTE-522 study meets dual primary endpoint [10].
Mar 20At first interim analysis if KEYNOTE-522/NCT03036488 (n=602 previously untreated stage II/III triple-negative breast cancer), significantly more patients on pembrolizumab plus neoadjuvant chemotherapy had pathological complete response vs. placebo plus neoadjuvant chemotherapy (64.8% vs. 51.2%; p<0.001) [6].
Oct 19Interim data from PIII KEYNOTE-522 showed that, in the neoadjuvant phase, addition of Keytruda to neoadjuvant chemotherapy increased response from 51% to 64.8% in pre-surgery pts and regardless of PD-L1 expression. For event-free-survival, the Keytruda regimen reduced the risk of progression in the neoadjuvant phase and recurrence in the adjuvant phase by 37% at a median of 15.5 months. The safety profiles to date of Keytruda and chemotherapy in KEYNOTE-522 were consistent with previous studies.[5]
Jul 19PIII KEYNOTE-522 study meets primary endpoint. Based on am interim analysis of the RCT (n=1,174), pembrolizumab with chemotherapy showed a statistically significant improved pathological complete response (defined as lack of signs of cancer in tissue samples) vs chemotherapy alone, regardless of PD-L1 status [4].
Nov 18PIII KEYNOTE-522 has finished recruiting and expects to complete collection of primary outcome data this month [3].
Apr 18PIII KEYNOTE-522 is still recruiting [2].
Mar 17PIII KEYNOTE-522 trial to evaluate the efficacy and safety of pembrolizumab plus chemotherapy versus placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab versus placebo as adjuvant therapy in patients with TNBC starts (NCT03036488). The trial will enrol approximately 855 patients globally including in the US & EU (and UK). Primary outcomes are pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery, and event-free survival. Collection of these data is due to complete Nov 18 [1,2].

Evidence based evaluations

Keytruda Malignant melanoma - post-resection adjuvant therapy in high-risk stage II patients

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Launched
Launched
Launched
July 2022
Jul 22The MHRA also approves expanding the indication in advanced (unresectable or metastatic) melanoma to adolescents (previously only adults). The revised indication is monotherapy for the treatment of adults and adolescents aged 12 years and older with advanced (unresectable or metastatic) melanoma [14].
Jul 22MHRA approves a licence change for Keytruda 100mg in 4mL vial to include treatment of adolescents and in stage IIB and IIC disease. The revised indication is use as monotherapy for the adjuvant treatment of adults and adolescents aged 12 years and older with Stage IIB, IIC or III melanoma and who have undergone complete resection [13].
Jun 22Approved in the EU as monotherapy for the adjuvant treatment of adults and adolescents aged 12 years and older with stage IIB or IIC melanoma and who have undergone complete resection. Additionally, the EC approved expanding the indications in advanced (unresectable or metastatic) melanoma and stage III melanoma to include adolescent patients aged 12 years and older [12]
May 22EU positive opinion granted recommending a licence change for use as monotherapy for treatment of advanced melanoma in adults and adolescents aged 12 years of age and older (previously licensed only in adults), and for use as adjuvant treatment of Stage IIB, IIC or III melanoma in adults and children aged 12 years and older who have undergone complete resection (previously licensed only for treatment of Stage III melanoma with lymph node involvement in adults) [11].
Dec 21FDA has approved pembrolizumab for the adjuvant treatment of adult and pediatric (12 years and older) patients with stage IIB or IIC melanoma following complete resection [7]
Nov 21Currently pre-registration in EU. MSD is seeking an extension of indication to include the adjuvant treatment of adults and adolescents aged 12 years and older with Stage IIB, Stage IIC or stage III melanoma, and to include the treatment of adolescents aged 12 years and older with advanced melanoma [8].
Aug 21US FDA accept sBLA for priority review, with a PDUFA of 4/12/21 [5].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein.
In 2011, the UK age-standardised incidence of melanoma for females was 17.6 (11.7 in 2001) and for males 17.5 (10.1 in 2001) per 100,000 population [1].
Malignant melanoma - post-resection adjuvant therapy in high-risk stage II patients
Intravenous

Further information

Yes

Trial or other data

Apr 22Results of PIII KEYNOTE-716 RCT (n=976) reported in The Lancet [10].
Mar 22 MSD announces PIII KEYNOTE-716 trial met its key secondary endpoint of distant metastasis-free survival (DMFS) at a pre-specified interim analysis. Pembrolizumab demonstrated a statistically significant improvement in the endpoint of DMFS compared to placebo in these patients. In addition treatment with pembrolizumab also continued to show an improvement in recurrence-free survival (RFS) compared to placebo [9]
Sep 21First interim analysis from PIII KEYNOTE-716 show that pembrolizumab reduced the risk of disease recurrence or death by 35% (HR=0.65 [95% CI, 0.46–0.92]; p=0.00658) compared to placebo. After 14.4 months follow-up, 11.1% (n=54/487) of patients on pembrolizumab had recurrence or died compared with 16.8% (n=82/489) of patients on placebo. [6]
Aug 21PIII KEYNOTE-716 trial (n=954) trial meets primary endpoint; treatment with pembrolizumab monotherapy was associated with statistically and clinically significant improvement in recurrence-free survival vs. placebo ​[5].
Nov 20PIII KEYNOTE-716 is no longer recruiting [4].
Mar 20PIII KEYNOTE-716 study is recruiting [2].
Sep 18PIII KEYNOTE-716 study to evaluate the safety and efficacy of pembrolizumab (MK-3475) compared to placebo in participants with surgically resected high-risk Stage II melanoma starts (NCT03553836). Participants in Part 1 will receive either pembrolizumab or placebo in a double-blind design for up to 17 cycles. Participants who receive placebo or who stop treatment after receiving 17 cycles of pembrolizumab in Part 1, do not experience disease recurrence within 6 months of completing pembrolizumab in Part 1, and do not stop treatment with pembrolizumab for disease recurrence or intolerability, may be eligible to receive up to 35 additional cycles of pembrolizumab in Part 2 in an open-label design. The primary hypothesis of this study is that pembrolizumab increases recurrence-free survival (RFS) compared to placebo. 954 patients aged 12 years and older will be recruited in countries including the US, EU & UK. Collection of primary outcome is due to complete Oct 22 [2].

KeytrudaHigh risk, non-muscle-invasive bladder cancer, unresponsive to BCG therapy

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched
Jan 20Approved in the US with priority review status as monotherapy for the treatment of patients with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer with carcinoma in-situ with or without papillary tumours who are ineligible for or have elected not to undergo cystectomy [2].
Dec 19Experts on the FDA’s Oncology Drugs Advisory Committee voted 9-4 in favour of pembrolizumab (Keytruda) for the treatment of high-risk non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ that’s unresponsive to standard Bacillus Calmette-Guérin (BCG) therapy. The decision was made based mainly on PII complete response rate data from the KEYNOTE-057 trial [1].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein
There are around 10,200 new bladder cancer cases in the UK every year. It is the 10th most common cancer in the UK. In non-muscle invasive (also called superficial or early) bladder cancer, the cancer cells are only in the inner lining of the bladder. Carcinoma in situ means very early, high grade cancer cells that are only in the innermost layer of the bladder lining. Early bladder cancer may be diagnosed as low, medium or high risk [3].
High risk, non-muscle-invasive bladder cancer, unresponsive to BCG therapy
Intravenous

Trial or other data

Feb 20PIII KEYNOTE-676 study is recruiting [6].
Jan 20FDA approval was based on interim data from KEYNOTE-057 in 96 patients. Patients received pembrolizumab 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC, or progressive disease. Assessment of tumour status was performed every 12 weeks for 2 years and then every 24 weeks for 3 years, and patients without disease progression could be treated for up to 24 months. The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and computed tomography urography [CTU] imaging) and duration of response. The median follow-up time was 28.0 months (range: 4.6 to 40.5 months). Pembrolizumab demonstrated a complete response rate of 41% (range: 31 to 51). Among the 39 patients who achieved a complete response, the median duration of response was 16.2 months (range: 0.0+ to 30.4+), and 46% (n=18) had a response of 12 months or longer [5].
Dec 18PIII KEYNOTE-676 study to assess the antitumour efficacy and safety of pembrolizumab in combination with BCG, compared to BCG monotherapy, in participants with HR NMIBC that is persistent or recurrent following adequate BCG induction starts (NCT03711032). The primary hypothesis is that the combination of pembrolizumab plus BCG has a superior complete response rate (CRR) as assessed by central pathology review compared to BCG in participants with carcinoma in situ (CIS). 550 adults will be recruited from countries around the world, including the US, EU & UK. Collection of these data is due to complete May 22 [6].
Feb 16PII trial to study the efficacy and safety of pembrolizumab (MK-3475) in subjects with high risk non-muscle invasive bladder cancer (NMIBC) unresponsive to Bacillus Calmette-Guerin (BCG) therapy, KEYNOTE-057 (NCT02625961; MK-3475-057) commenced. The open-label trial intends to enrol approximately 260 patients worldwide, including the US, Italy and Netherlands (not the UK) [4].

Keytruda HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma - first-line with trastuzumab plus chemotherapy

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched
May 21Approved in US for use in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, for first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma [6].
Feb 21Currently pre-registration in US [5].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein.
Gastric cancer is the second most common cause of cancer-related death in the world. It is a difficult disease to cure, mainly because most patients present with advanced disease. 50% involve the pylorus, 25% the lesser curve and 10% the cardia. 2-8% of gastric cancers are lymphomas. 95% of gastric cancers occur in those aged over 55 years. 4,923 new diagnoses of gastric cancer were made in the UK in 2008 [1].
HER2-positive advanced gastric or gastroesophageal junction adenocarcinoma - first-line with trastuzumab plus chemotherapy
Intravenous

Further information

Yes

Trial or other data

Aug 21Recruitment has finished in PIII KEYNOTE-811 [7].
Jan 21PIII KEYNOTE-811 study is recruiting [4].
Dec 19PIII KEYNOTE-811 study is recruiting [3].
Oct 18PIII KEYNOTE-811 study to compare the efficacy and safety of pembrolizumab plus trastuzumab in combination with standard of care (SOC) chemotherapy versus trastuzumab in combination with SOC chemotherapy in participants with HER2-positive gastric cancer starts (NCT03615326). The primary hypotheses of the study are that pembrolizumab plus trastuzumab in combination with chemotherapy is superior to trastuzumab plus chemotherapy in terms of 1) progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR), and 2) overall survival (OS). 732 patients will be recruited in countries including the US, EU & UK. Collection of primary outcome data (progression-free survival and overall survival) is due to complete Jun 23 [2].

Evidence based evaluations

Keytruda Non-small cell lung cancer (NSCLC) - stage IB-IIIA following surgical resection with or without standard adjuvant therapy

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Phase III Clinical Trials
Pre-registration (Filed)
Pre-registration (Filed)
Aug 22Also filed in the EU [9].
Jun 22US FDA accepts sBLA for adjuvant therapy of stage IB, II or IIIA non-small cell lung cancer following complete surgical resection, with a PDUFA date of 29/1/23[8].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein
UK incidence of lung cancer in 2016 was 47,388. 85-90% of cases are NSCLC [1].
Non-small cell lung cancer (NSCLC) - stage IB-IIIA following surgical resection with or without standard adjuvant therapy
Bladder instillation

Further information

Yes

Trial or other data

Sep 22Interim analysis of KEYNOTE-091 published in The Lancet Oncology. After median follow up of 35.6 months (n=1177), pembrolizumab significantly improved DFS vs. placebo (53.6 vs 42 months; HR 0.76[95% CI 0.63 to 0.91], p=0.0014) and was not associated with new safety signals [8].
May 22Merck presents data from KEYNOTE-091. Keytruda offered event-free survival advantages across the adjuvant chemotherapies used and in patients with different lymph node involvement. The drug also helped regardless of the size of the primary tumour. In 231 patients with a high number of lymph nodes involved, classified as pN stage 2, the risks of tumour recurrence or death were the same with or without Keytruda. And for 167 patients who did not receive adjuvant chemotherapy, the risk favoured those who did not get pembrolizumab. The same thing happened to a group of 135 patients who got carboplatin and paclitaxel as their adjuvant chemo. Patients who had Keytruda on top of that doublet chemo appeared to perform worse than those who got the chemo alone. Altogether, the trial randomized 1,177 patients. Data favoured Keytruda across three different types of surgery, by tumor size both above 4 cm and at or below 4 cm, and by the number of chemo cycles, plus several other chemo doublet regimens. Detailed analyses of those subgroups will be presented at the 2022 American Society of Clinical Oncology (ASCO) annual meeting [7].
Mar 22In KEYNOTE-091 study, adjuvant treatment with pembrolizumab, following surgical resection, improved DFS (median 53.6 months vs. 42.0 months for placebo; HR 0.76 [95% CI 0.63-0.91]; p=0.0014), regardless of PD-L1 expression [6].
Jan 22Merck announce interim results from KEYNOTE-091 study. Pembrolizumab significantly improves disease-free survival (DFS) vs. placebo after surgery to remove NSCLC tumours, regardless of level of PD-L1 expression. However in PD-L1 ≥50% expressers, DFS did not meet statistical significance per the pre-specified statistical plan [5].
Aug 21No update available on progress of PIII PEARLS study [4].
Jul 20PIII PEARLS study is no longer recruiting [3].
Jul 19PIII PEARLS or KEYNOTE-091 study is recruiting [2].
Nov 15PIII PEARLS or KEYNOTE-091 study to evaluate the efficacy of pembrolizumab in patients with early-stage NSCLC who have undergone resection with or without standard adjuvant therapy starts (MK-3475-091; NCT02504372). The primary endpoint is disease free survival for up to 100 months. 1,080 patients will be recruited in the EU, UK and other countries. Collection of primary outcome data is due to complete Aug 21 [2].

Evidence based evaluations

Keytruda Advanced hepatocellular carcinoma (HCC) - first-line with lenvatinib

Information

Keytruda
Licence extension / variation
Merck Sharp & Dohme (MSD)
Merck & Co (name used in US for MSD)

Development and Regulatory status

Discontinued
Discontinued
Discontinued
Aug 22Development discontinued [11].
Jul 20In a Complete Response Letter, the FDA did not consider the applications provided evidence that this regimen represents a meaningful advantage over available therapies. The companies plan to conduct a PIII trial (LEAP-002) to provide further evidence [7].
Jul 20Not approved in US [6].
May 20Data from PIb KEYNOTE-524 have been filed in the US [4].
Jul 19Granted breakthrough therapy status in US [3].

Category

Humanised monoclonal IgG4 antibody against the programmed death-1 (PD-1) protein.
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 with lenvatinib
Intravenous infusion

Trial or other data

Aug 22PIII LEAP-002 trial fails to meet dual primary endpoints of OS and PFS [10].
Dec 21Recruitment has finished in PIII LEAP-002 [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) [5].
Apr 20PIII LEAP-002 trial is no longer recruiting; collection of primary outcome data now expected to finish May 22 [8].
Dec 19PIII LEAP-002 trial is recruiting [2].
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].