Pembrolizumab Explained

Type:mab
Mab Type:mab
Source:zu/o
Target:PD-1
Tradename:Keytruda
Dailymedid:Pembrolizumab
Pregnancy Au:D
Pregnancy Au Comment:[1]
Routes Of Administration:Intravenous
Class:Antineoplastic agent
Atc Prefix:L01
Atc Suffix:FF02
Legal Au:S4
Legal Au Comment:[2] [3] [4] [5] [6]
Legal Ca:Rx-only
Legal Ca Comment:/Schedule D[7] [8]
Legal Uk:POM
Legal Uk Comment:[9]
Legal Us:Rx-only
Legal Eu:Rx-only
Legal Status:Rx-only
Cas Number:1374853-91-4
Drugbank:DB09037
Chemspiderid:none
Unii:DPT0O3T46P
Kegg:D10574
Chembl:3137343
Synonyms:MK-3475, lambrolizumab
C:6534
H:10004
N:1716
O:2036
S:46

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer.[10] [11] It is administered by slow intravenous injection.[12]

Common side effects include fatigue, musculoskeletal pain, decreased appetite, itchy skin (pruritus), diarrhea, nausea, rash, fever (pyrexia), cough, difficulty breathing (dyspnea), constipation, pain, and abdominal pain.[12] It is an IgG4 isotype antibody that blocks a protective mechanism of cancer cells, allowing the immune system to destroy them. It targets the programmed cell death protein 1 (PD-1) receptor of lymphocytes.

Pembrolizumab was approved for medical use in the United States in 2014.[12] It is on the World Health Organization's List of Essential Medicines.[13]

Medical uses

, pembrolizumab is used via intravenous infusion to treat inoperable or metastatic melanoma, metastatic non-small cell lung cancer (NSCLC) in certain situations, as a first-line treatment for metastatic bladder cancer in patients who cannot receive cisplatin-based chemotherapy and have high levels of PD-L1, as a second-line treatment for head and neck squamous cell carcinoma (HNSCC), after platinum-based chemotherapy, for the treatment of adult and pediatric patients with refractory classic Hodgkin's lymphoma (cHL), and recurrent locally advanced or metastatic esophageal squamous cell carcinoma.[14] [15] [16] [17] [18] [19] [20]

For non-small cell lung cancer, pembrolizumab is used in combination with chemotherapy (for all PD-L1, a PD-1 receptor ligand, levels) or by itself as a first-line treatment if the cancer expresses (≥ 1%) PD-L1 and the cancer has no mutations in EGFR or in ALK; if chemotherapy has already been administered, then pembrolizumab can be used as a second-line treatment, but if the cancer has EGFR or ALK mutations, agents targeting those mutations should be used first.[14] [21] Assessment of PD-L1 expression must be conducted with a validated and approved companion diagnostic.[14]

In 2017, the US Food and Drug Administration approved pembrolizumab for any unresectable or metastatic solid tumor with certain genetic anomalies (mismatch repair deficiency or microsatellite instability).[19] This was the first time the FDA approved a cancer drug based on tumor genetics rather than tissue type or tumor site; therefore, pembrolizumab is a so-called tissue-agnostic drug.[22]

In the European Union, pembrolizumab is indicated for:

In June 2020, the US FDA approved a new indication for pembrolizumab as the first-line treatment for people with unresectable or metastatic microsatellite instability-high (MSI‑H) or mismatch repair deficient (dMMR) colorectal cancer.[23] The approval marks the first immunotherapy approved for that population in the US as a first-line treatment and which is administered to people without also giving chemotherapy.

In March 2021, the US FDA approved pembrolizumab in combination with platinum and fluoropyrimidine-based chemotherapy to treat metastatic or locally advanced esophageal or gastroesophageal (GEJ) (tumors with epicenter 1 to 5 centimeters above the gastroesophageal junction) carcinoma in people who are not candidates for surgical resection or definitive chemoradiation.[24] Efficacy was evaluated in KEYNOTE-590 (NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 participants with metastatic or locally advanced esophageal or gastroesophageal junction carcinoma who were not candidates for surgical resection or definitive chemoradiation.

In May 2021, the US FDA approved pembrolizumab in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of people with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.[25] Approval was based on the prespecified interim analysis of the first 264 participants of the ongoing KEYNOTE-811 (NCT03615326) trial, a multicenter, randomized, double‑blind, placebo‑controlled trial in people with HER2‑positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had not previously received systemic therapy for metastatic disease.

In July 2021, the US FDA approved pembrolizumab for high-risk, early-stage, triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.[26] The FDA also granted regular approval to pembrolizumab in combination with chemotherapy for people with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score [CPS] ≥ 10) as determined by an FDA-approved test.

In November 2021, the US FDA approved pembrolizumab for the adjuvant treatment of people twelve years of age and older with stage IIB or IIC melanoma following complete resection.[27]

In November 2021, the US FDA approved pembrolizumab for the adjuvant treatment of renal cell carcinoma for people at intermediate-high or high risk of recurrence following nephrectomy.[28] Approval was based on KEYNOTE-564, a multicenter, randomized (1:1), double-blind, placebo-controlled trial in 994 patients with intermediate-high or high risk of recurrence of RCC, or M1 no evidence of disease.[29]

In March 2022, the US FDA approved pembrolizumab for the treatment of advanced endometrial cancer.[30]

In January 2023, the US FDA approved pembrolizumab for adjuvant treatment following resection and platinum-based chemotherapy for stage IB (T2a ≥ 4 cm), II, or IIIA non-small cell lung cancer.[31]

In October 2023, the US FDA approved pembrolizumab to be used with gemcitabine and cisplatin for locally advanced unresectable or metastatic biliary tract cancer.[32]

In January 2024, the US FDA approved pembrolizumab, in combination with chemoradiotherapy for the treatment of people with FIGO (International Federation of Gynecology and Obstetrics) 2014 Stage III-IVA cervical cancer.[33]

In June 2024, the US FDA approved pembrolizumab with carboplatin and paclitaxel, followed by single-agent pembrolizumab, for adults with primary advanced or recurrent endometrial carcinoma.[34]

Adverse effects

People have had severe infusion-related reactions to pembrolizumab. There have also been severe immune-related adverse effects including lung inflammation (including fatal cases) and inflammation of endocrine organs that caused inflammation of the pituitary gland, of the thyroid (causing both hypothyroidism and hyperthyroidism in different people), and pancreatitis that caused Type 1 diabetes and diabetic ketoacidosis; some people have had to go on lifelong hormone therapy as a result (e.g. insulin therapy or thyroid hormones). People have also had colon inflammation, liver inflammation, kidney inflammation due to the drug.[15] [35]

The common adverse reactions have been fatigue (24%), rash (19%), itchiness (pruritus) (17%), diarrhea (12%), nausea (11%) and joint pain (arthralgia) (10%).[15]

Other adverse effects occurring in between 1% and 10% of people taking pembrolizumab have included anemia, decreased appetite, headache, dizziness, distortion of the sense of taste, dry eye, high blood pressure, abdominal pain, constipation, dry mouth, severe skin reactions, vitiligo, various kinds of acne, dry skin, eczema, muscle pain, pain in a limb, arthritis, weakness, edema, fever, chills, myasthenia gravis, and flu-like symptoms.[15]

Mechanism of action

Pembrolizumab is a therapeutic antibody that binds to and blocks PD-1 located on lymphocytes. This receptor is generally responsible for preventing the immune system from attacking the body's own tissues; it is a so-called immune checkpoint.[36] [37] Normally, the PD-1 receptor on activated T-cells binds to the PD-L1 or PD-L2 ligands present on normal cells in the body, deactivating any potential cell-mediated immune response against these cells.[38] [39] Many cancers make proteins such as PD-L1 that also bind to the PD-1 receptor, thus shutting down the ability of the body to kill the cancer.[36] Pembrolizumab works by inhibiting lymphocytes' PD-1 receptors, blocking the ligands that would deactivate it and prevent an immune response. This allows the immune system to target and destroy cancer cells,[40] but also blocks a key mechanism preventing the immune system from attacking the body itself. This checkpoint inhibitor function of pembrolizumab thus has immune-dysfunction side effects as a result.[37]

Tumors often have mutations that cause impaired DNA mismatch repair. This in turn often results in microsatellite instability allowing the tumor to generate numerous mutant proteins that could serve as tumor antigens, triggering an immune response against the tumor. By preventing the self-checkpoint system from blocking the T-cells, pembrolizumab appears to facilitate clearance of any such tumor by the immune system.

Pharmacology

Since pembrolizumab is cleared from the circulation through non-specific catabolism, no metabolic drug interactions are expected and no studies were done on routes of elimination.[15] The systemic clearance [rate] is about 0.2 L/day and the terminal half-life is about 25 days.[15]

Chemistry and manufacturing

Pembrolizumab is an immunoglobulin G4, with a variable region against the human PD-1 receptor, a humanized mouse monoclonal [228-L-proline(H10-S>P)]γ4 heavy chain (134-218') disulfide and a humanized mouse monoclonal κ light chain dimer (226-226:229-229)-bisdisulfide.[41]

It is recombinantly manufactured in Chinese hamster ovary (CHO) cells.[42] [43]

History

Pembrolizumab was invented by scientists at Organon after which they worked with Medical Research Council Technology (which became LifeArc) starting in 2006, to humanize the antibody; Schering-Plough acquired Organon in 2007, and Merck & Co. acquired Schering-Plough two years later.[44] Inventors Gregory Carven, Hans van Eenennaam and Gradus Dulos were recognized as Inventors of the Year by the Intellectual Property Owners Education Foundation in 2016.[45]

The development program for pembrolizumab was seen as high priority at Organon, but low at Schering and later Merck. In early 2010, Merck terminated development and began preparing to out-license it.[46] Later, in 2010, scientists from Bristol Myers Squibb published a paper in The New England Journal of Medicine showing that their checkpoint inhibitor, ipilimumab (Yervoy), had shown strong promise in treating metastatic melanoma[47] and that a second Bristol Myers Squibb checkpoint inhibitor, nivolumab (Opdivo), was also promising.[46] Merck at that time had little commitment or expertise in either oncology or immunotherapy, but understood the opportunity and reacted strongly, reactivating the program and filing its IND by the end of 2010.[46] As one example, Martin Huber was one of the few senior people at Merck with strong experience in lung cancer drug development, but had been promoted to senior management and was no longer involved in product development. He stepped down from his role to lead clinical development of pembrolizumab for lung cancer.[46]

Scientists at the company argued for developing a companion diagnostic and limiting testing of the drug only to patients with biomarkers showing they were likely to respond, and received agreement from management. Some people, including shareholders and analysts, criticized this decision as it limited the potential market size for the drug, while others argued it increased the chances of proving the drug would work and would make clinical trials faster. (The trials would need fewer patients because of the likelihood of greater effect size.) Moving quickly and reducing the risk of failure was essential for catching up with Bristol-Myers Squibb, which had an approximate five year lead over Merck.[46] The phase I study started in early 2011, and Eric Rubin, who was running the melanoma trial, argued for and was able to win expansion of the trial until it reached around 1300 people. This was the largest phase I study ever run in oncology, with the patients roughly divided between melanoma and lung cancer.[46]

In 2013, Merck quietly applied for and won a breakthrough therapy designation for the drug. This regulatory pathway was new at the time and not well understood. One of its advantages is that the US FDA holds more frequent meetings with drug developers, reducing the risk of developers of making mistakes or misunderstandings arising from the differences between regulators' expectations and what the developers want to do. This was Merck's first use of the designation and the reduction in regulatory risk was one of the reasons management was willing to put company resources into development.[46]

In 2013, the United States Adopted Name (USAN) name was changed from lambrolizumab to pembrolizumab.[41] In that year clinical trial results in advanced melanoma were published in The New England Journal of Medicine.[48] This was part of the large phase I NCT01295827 trial.

In September 2014, the US Food and Drug Administration approved pembrolizumab under the Fast Track Development Program.[49] It is approved for use following treatment with ipilimumab, or after treatment with ipilimumab and a BRAF inhibitor in advanced melanoma patients who carry a BRAF mutation.[50] Barone A, Hazarika M, Theoret MR, Mishra-Kalyani P, Chen H, He K, Sridhara R, Subramaniam S, Pfuma E, Wang Y, Li H, Zhao H, Zirkelbach JF, Keegan P, Pazdur R . FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma . Clinical Cancer Research . 23 . 19 . 5661–5665 . October 2017 . 28179454 . 10.1158/1078-0432.CCR-16-0664 .

, the only PD-1/PD-L1 targeting drugs on the market are pembrolizumab and nivolumab.[51]

By April 2016, Merck applied for approval to market the drug in Japan and signed an agreement with Taiho Pharmaceutical to co-promote it there.[52]

In July 2015, pembrolizumab received marketing approval in the European Union.[15] [53]

In October 2015, the US FDA approved pembrolizumab for the treatment of metastatic non-small cell lung cancer (NSCLC) in people whose tumors express PD-L1 and who have failed treatment with other chemotherapeutic agents.[54] [55] [56]

In July 2016, the US FDA accepted for priority review an application for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after a platinum-based chemotherapy.[57] They granted accelerated approval to pembrolizumab as a treatment for patients with recurrent or metastatic head and neck squamous cell carcinoma ("regardless of PD-L1 staining") following progression on a platinum-based chemotherapy, based on objective response rates (ORR) in the phase Ib KEYNOTE-012 study in August of the same year.[58] [59]

In October 2016, the US FDA approved pembrolizumab for the treatment of people with metastatic non-small cell lung cancer whose tumors express PD-L1 as determined by an FDA-approved test.[60]

In May 2017, pembrolizumab received an accelerated approval from the US FDA for use in any unresectable or metastatic solid tumor with DNA mismatch repair deficiencies or a microsatellite instability-high state (or, in the case of colon cancer, tumors that have progressed following chemotherapy).[61] This approval marked the first instance in which the FDA approved marketing of a drug based only on the presence of a genetic mutation, with no limitation on the site of the cancer or the kind of tissue in which it originated.[62] [63] [64] The approval was based on a clinical trial of 149 patients with microsatellite instability-high or mismatch repair deficient cancers who enrolled on one of five single-arm trials. Ninety patients had colorectal cancer, and 59 patients had one of 14 other cancer types. The objective response rate for all patients was 39.6%. Response rates were similar across all cancer types, including 36% in colorectal cancer and 46% across the other tumor types. Notably, there were 11 complete responses, with the remainder partial responses. Responses lasted for at least six months in 78% of responders.[63] Because the clinical trial was fairly small, Merck is obligated to conduct further post-marketing studies to ensure that the results are valid.[65] Pembrolizumab was granted orphan drug designation for small-cell lung cancer in October 2017.

In June 2018, the US FDA approved pembrolizumab for use in both advanced cervical cancer for PD-L1 positive patients[66] and for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after two or more prior lines of therapy.[67]

In August 2018, the US FDA updated the prescribing information for pembrolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.[68] On 16 August 2018, the FDA approved the Dako PD-L1 IHC 22C3 PharmDx Assay (Dako North America, Inc.) as a companion diagnostic to select patients with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible for treatment with pembrolizumab. The 22C3 assay determines PD-L1 expression by using a combined positive score (CPS) assessing PD-L1 staining in tumor and immune cells., pembrolizumab is indicated for the treatment of those with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥ 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.

In November 2018, the US FDA granted accelerated approval to pembrolizumab for those with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.[69]

In February 2019, the US FDA approved pembrolizumab for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.[70] The FDA granted the application orphan drug designation.

In June 2019, the US FDA granted accelerated approval to pembrolizumab for those with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy,[71] and the FDA approved pembrolizumab for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).[72] Pembrolizumab was approved for use in combination with platinum and fluorouracil (FU) for all patients and as a single agent for patients whose tumors express PD‑L1 (Combined Positive Score [CPS] ≥ 1) as determined by an FDA‑approved test. The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with head and neck squamous cell carcinoma for treatment with pembrolizumab as a single agent.

In July 2019, the US FDA approved pembrolizumab for patients with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥ 10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.[73] The FDA also approved a new use for the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting patients for the above indication.

In June 2020, the US FDA approved pembrolizumab as monotherapy for the treatment of adults and children with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥ 10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.[74]

In March 2021, the accelerated approval indication in the US for the treatment of people with metastatic small-cell lung cancer (SCLC) was removed.

In January 2024, the FDA approved pembrolizumab, in combination with chemoradiotherapy, for people with FIGO 2014 Stage III-IVA cervical cancer. Efficacy was evaluated in KEYNOTE-A18 (NCT04221945), a multicenter, randomized, double-blind, placebo-controlled trial enrolling 1060 participants with cervical cancer who had not previously received definitive surgery, radiation, or systemic therapy. The trial included 596 participants with FIGO 2014 Stage III-IVA disease and 462 participants with FIGO 2014 Stage IB2-IIB, node-positive disease.

In June 2024, the US FDA approved pembrolizumab with carboplatin and paclitaxel, followed by single-agent pembrolizumab, for adults with primary advanced or recurrent endometrial carcinoma.[34] Efficacy was evaluated in KEYNOTE-868/NRG-GY018 (NCT03914612), a multicenter, randomized, double-blind, placebo-controlled trial enrolling 810 participants with advanced or recurrent endometrial carcinoma.[34] [75] The trial included two separate cohorts based on mismatch repair status: 222 participants in the mismatch repair deficient cohort, and 588 participants in the mismatch repair proficient cohort.

Society and culture

Economics

Pembrolizumab was priced at per year when it launched in 2014.[76]

It was added to the Cancer Drugs Fund list of NHS England in November 2022, after a "confidential" deal with manufacturer Merck Sharp and Dohme.[77] [78] [79]

Research

In 2015, Merck reported results in thirteen cancer types; much attention was given to early results in head and neck cancer.[80] [81]

, pembrolizumab was in phase IB clinical trials for triple-negative breast cancer (TNBC), gastric cancer, urothelial cancer, and head and neck cancer (all under the "Keynote-012" trial) and in phase II trial for TNBC (the "Keynote-086" trial).[82] At ASCO, in June 2016, Merck reported that the clinical development program was directed to around 30 cancers and that it was running over 270 clinical trials (around 100 in combination with other treatments) and had four registration-enabling studies in process.[83]

Results of a phase III clinical trial in triple-negative breast cancer were reported in October 2019.[84]

Results of a phase II clinical trial in Merkel-cell carcinoma were reported in June 2016.[85]

Results of a clinical trial in people with untreatable metastases arising from various solid tumors were reported in 2017.[86]

A clinical phase III trial in combination with epacadostat, an Indoleamine 2,3-dioxygenase (IDO1) inhibitor to treat melanoma was completed in 2019.

In 2021, researchers reported the results of a five-year follow-up study.[87]

In January 2022, a combination clinical trial of pembrolizumab and NL-201, a de novo protein undergoing a phase I clinical trial in people with advanced, relapsed or refractory solid tumors.[88]

In March 2023, Merck reported the results of NRG-GY018, a phase III clinical trial in people with stage three to four or recurrent endometrial carcinoma.[89]

In 2022, mRNA-4157/V940 drug candidate, a cancer vaccine, was studied alongside pembrolizumab for treatment of skin and pancreatic cancers. mRNA-4157/V940 went on to be granted breakthrough therapy designation by the FDA.[90] [91]

References

Attribution

Further reading

Notes and References

  1. News: Pembrolizumab (Keytruda) Use During Pregnancy . Drugs.com . 24 September 2019 . 10 January 2020 . 14 June 2020 . https://web.archive.org/web/20200614052722/https://www.drugs.com/pregnancy/pembrolizumab.html . live .
  2. Web site: Keytruda, Microsatellite instability-high cancer . https://web.archive.org/web/20221122020756/https://www.tga.gov.au/resources/prescription-medicines-registrations/keytruda-merck-sharp-dohme-australia-pty-ltd-5 . 22 November 2022 . Department of Health and Aged Care, Commonwealth of Australia .
  3. Web site: Keytruda, Oesophageal Cancer . https://web.archive.org/web/20221122020756/https://www.tga.gov.au/resources/prescription-medicines-registrations/keytruda-merck-sharp-dohme-australia-pty-ltd-15 . 22 November 2022 . Department of Health and Aged Care, Commonwealth of Australia .
  4. Web site: Keytruda (pembrolizumab) is indicated for the adjuvant treatment of adult and adolescent (12 years and older) patients with Stage IIB, IIC, or III melanoma who have undergone complete resection. . Department of Health and Aged Care, Commonwealth of Australia . 18 March 2023 . 18 March 2023 . https://web.archive.org/web/20230318044847/https://www.tga.gov.au/resources/prescription-medicines-registrations/keytruda-merck-sharp-dohme-australia-pty-ltd-23 . live .
  5. Web site: Prescription medicines: registration of new chemical entities in Australia, 2015 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 10 April 2023 . 10 April 2023 . https://web.archive.org/web/20230410065829/https://www.tga.gov.au/prescription-medicines-registration-new-chemical-entities-australia-2015 . live .
  6. Web site: Prescription medicines and biologicals: TGA annual summary 2017 . Therapeutic Goods Administration (TGA) . 21 June 2022 . 31 March 2024 . 31 March 2024 . https://web.archive.org/web/20240331021323/https://www.tga.gov.au/resources/publication/publications/prescription-medicines-and-biologicals-tga-annual-summary-2017 . live .
  7. Web site: Regulatory Decision Summary for Keytruda . . 6 February 2024 . 2 April 2024 . 2 April 2024 . https://web.archive.org/web/20240402041803/https://dhpp.hpfb-dgpsa.ca/review-documents/resource/RDS1707495404187 . live .
  8. Web site: Health Canada New Drug Authorizations: 2015 Highlights . . 4 May 2016 . 7 April 2024 . 20 February 2020 . https://web.archive.org/web/20200220215421/https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-canada-new-drug-authorizations-2015-highlights.html . live .
  9. Web site: Keytruda 50 mg powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC) . (emc) . 7 April 2020 . 30 April 2020 . 13 December 2017 . https://web.archive.org/web/20171213010050/https://www.medicines.org.uk/emc/medicine/30602 . dead .
  10. Web site: FDA approves pembrolizumab combination for the first-line treatment of cervical cancer . . 13 October 2021 . 15 October 2021 . 13 October 2021 . https://web.archive.org/web/20211013212253/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-combination-first-line-treatment-cervical-cancer . live .
  11. 11 August 2021. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. U.S. Food and Drug Administration . 28 July 2021. 28 July 2021. https://web.archive.org/web/20210728035002/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer. live.
  12. Web site: Pembrolizumab Monograph for Professionals . Drugs.com . American Society of Health-System Pharmacists . 15 July 2019 . 14 June 2020 . https://web.archive.org/web/20200614060420/https://www.drugs.com/monograph/pembrolizumab.html . live .
  13. Book: ((World Health Organization)) . The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) . 2023 . 10665/371090 . World Health Organization . World Health Organization . Geneva . WHO/MHP/HPS/EML/2023.02 . free .
  14. Web site: Keytruda- pembrolizumab injection, powder, lyophilized, for solution Keytruda- pembrolizumab injection, solution . DailyMed . 17 September 2019 . 10 January 2020 . 17 June 2020 . https://web.archive.org/web/20200617124927/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9333c79b-d487-4538-a9f0-71b91a02b287 . live .
  15. Web site: Keytruda 50 mg powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC) . (emc) . 25 November 2019 . 10 January 2020 . 13 December 2017 . https://web.archive.org/web/20171213010050/https://www.medicines.org.uk/emc/medicine/30602 . dead .
  16. Redman JM, Gibney GT, Atkins MB . Advances in immunotherapy for melanoma . BMC Medicine . 14 . 1 . 20 . February 2016 . 26850630 . 4744430 . 10.1186/s12916-016-0571-0 . free . doi .
  17. Fuereder T . Immunotherapy for head and neck squamous cell carcinoma . Memo . 9 . 2 . 66–69 . 20 June 2016 . 27429658 . 4923082 . 10.1007/s12254-016-0270-8 .
  18. Web site: Pembrolizumab (Keytruda) for classical Hodgkin lymphoma . . 14 March 2017 . 12 January 2020 . 12 January 2020 . https://web.archive.org/web/20200112174311/https://www.fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda-classical-hodgkin-lymphoma . live .
  19. Syn NL, Teng MW, Mok TS, Soo RA . De-novo and acquired resistance to immune checkpoint targeting . The Lancet. Oncology . 18 . 12 . e731–e741 . December 2017 . 29208439 . 10.1016/s1470-2045(17)30607-1 .
  20. Web site: Checkpoint Inhibitor Use Changed for Bladder Cancer . . 26 July 2018 . 12 November 2019 . 18 March 2021 . https://web.archive.org/web/20210318215318/https://www1.cancer.gov/news-events/cancer-currents-blog/2018/bladder-cancer-checkpoint-inhibitor-change . live .
  21. Vachhani P, Chen H . Spotlight on pembrolizumab in non-small cell lung cancer: the evidence to date . OncoTargets and Therapy . 9 . 5855–5866 . September 2016 . 27713639 . 5045223 . 10.2147/ott.s97746 . free . doi .
  22. Photopoulos J . 23 September 2020. The future of tissue-agnostic drugs. Nature. 585. 7826. S16–S18. 10.1038/d41586-020-02679-6. 2020Natur.585S..16P. 221884179 .
  23. FDA Approves First-Line Immunotherapy for Patients with MSI-H/dMMR Metastatic Colorectal Cancer . . 29 June 2020 . 29 June 2020 . 29 June 2020 . https://web.archive.org/web/20200629220520/https://www.fda.gov/news-events/press-announcements/fda-approves-first-line-immunotherapy-patients-msi-hdmmr-metastatic-colorectal-cancer . live .
  24. Web site: FDA approves pembrolizumab for esophageal or GEJ carcinoma . . 22 March 2021 . 22 March 2021 . 23 March 2021 . https://web.archive.org/web/20210323003758/http://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-esophageal-or-gej-carcinoma . live .
  25. Web site: FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer . . 5 May 2021 . 5 May 2021 . 5 May 2021 . https://web.archive.org/web/20210505194245/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer . live .
  26. Web site: FDA approves pembrolizumab for high-risk early-stage triple-negative b . . 27 July 2021 . 27 July 2021 . 27 July 2021 . https://web.archive.org/web/20210727165609/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer . live .
  27. Web site: FDA approves pembrolizumab for adjuvant treatment of Stage IIB or IIC . . 3 December 2021 . 4 December 2021 . 3 December 2021 . https://web.archive.org/web/20211203231020/http://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-stage-iib-or-iic-melanoma . live .
  28. Web site: FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. 17 November 2021. U.S. Food and Drug Administration. 2 October 2023. 6 October 2023. https://web.archive.org/web/20231006165000/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma. live.
  29. Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, Hajek J, Symeonides SN, Lee JL, Sarwar N, Thiery-Vuillemin A, Gross-Goupil M, Mahave M, Haas NB, Sawrycki P, Gurney H, Chevreau C, Melichar B, Kopyltsov E, Alva A, Burke JM, Doshi G, Topart D, Oudard S, Hammers H, Kitamura H, Bedke J, Perini RF, Zhang P, Imai K, Willemann-Rogerio J, Quinn DI, Powles T . Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma . The New England Journal of Medicine . 385 . 8 . 683–694 . August 2021 . 34407342 . 10.1056/NEJMoa2106391 . free . doi .
  30. Web site: FDA approves pembrolizumab for advanced endometrial carcinoma . . 21 March 2022 . 21 March 2022 . 22 March 2022 . https://web.archive.org/web/20220322040643/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-endometrial-carcinoma . live .
  31. Web site: FDA approves pembrolizumab as adjuvant treatment for non-small cell lung cancer . . 26 January 2023 . 27 January 2023 . 26 January 2023 . https://web.archive.org/web/20230126232005/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-non-small-cell-lung-cancer . live .
  32. Web site: 1 November 2023 . FDA approves pembrolizumab with chemotherapy for biliary tract cancer . live . https://web.archive.org/web/20231112132408/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-biliary-tract-cancer . 12 November 2023 . 12 November 2023 . U.S. Food & Drug Administration (FDA) .
  33. Web site: FDA approves pembrolizumab with chemoradiotherapy for FIGO 2014 Stage . . 12 January 2024 . 9 March 2024 . 26 June 2024 . https://web.archive.org/web/20240626040842/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemoradiotherapy-figo-2014-stage-iii-iva-cervical-cancer . live .
  34. Web site: FDA approves pembrolizumab with chemotherapy for primary advanced or recurrent endometrial carcinoma . . 17 June 2024 . 18 June 2024 . 18 June 2024 . https://web.archive.org/web/20240618005213/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-primary-advanced-or-recurrent-endometrial-carcinoma . live .
  35. Linardou H, Gogas H . Toxicity management of immunotherapy for patients with metastatic melanoma . Annals of Translational Medicine . 4 . 14 . 272 . July 2016 . 27563659 . 4971373 . 10.21037/atm.2016.07.10 . free . doi .
  36. Francisco LM, Sage PT, Sharpe AH . The PD-1 pathway in tolerance and autoimmunity . Immunological Reviews . 236 . 219–242 . July 2010 . 20636820 . 2919275 . 10.1111/j.1600-065X.2010.00923.x .
  37. Buqué A, Bloy N, Aranda F, Castoldi F, Eggermont A, Cremer I, Fridman WH, Fucikova J, Galon J, Marabelle A, Spisek R, Tartour E, Zitvogel L, Kroemer G, Galluzzi L . Trial Watch: Immunomodulatory monoclonal antibodies for oncological indications . Oncoimmunology . 4 . 4 . e1008814 . April 2015 . 26137403 . 4485728 . 10.1080/2162402x.2015.1008814 .
  38. Riley JL . PD-1 signaling in primary T cells . Immunological Reviews . 229 . 1 . 114–125 . May 2009 . 19426218 . 3424066 . 10.1111/j.1600-065X.2009.00767.x .
  39. Web site: 2 February 2011. pembrolizumab. 3 December 2020. National Cancer Institute. 23 October 2020. https://web.archive.org/web/20201023222814/https://www.cancer.gov/publications/dictionaries/cancer-drug/def/pembrolizumab. live.
  40. Pardoll DM . The blockade of immune checkpoints in cancer immunotherapy . Nature Reviews. Cancer . 12 . 4 . 252–264 . March 2012 . 22437870 . 4856023 . 10.1038/nrc3239 .
  41. Web site: Statement on a Nonproprietary Name Adopted by the USAN Council . 27 November 2013 . AMA ASSN . 5 November 2016 . 26 October 2020 . https://web.archive.org/web/20201026042208/https://searchusan.ama-assn.org/usan/documentDownload?uri=%2Funstructured%2Fbinary%2Fusan%2Fpembrolizumab.pdf . live .
  42. Web site: Assessment report: Keytruda. Procedure No. EMEA/H/C/003820/0000. European Medicines Agency (EMA). 21 May 2015. 5 November 2016. 14 June 2018. https://web.archive.org/web/20180614144321/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/003820/WC500190992.pdf. live.
  43. Web site: Keytruda EPAR . European Medicines Agency (EMA) . 17 September 2018 . 30 April 2020 . 24 May 2020 . https://web.archive.org/web/20200524093721/https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda . live . Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  44. News: Unlocking Checkpoint Inhibition. Translational Scientist. 2 March 2016. 5 November 2016. 5 November 2018. https://web.archive.org/web/20181105231508/https://thetranslationalscientist.com/issues/0216/unlocking-checkpoint-inhibition/. live.
  45. Web site: Inventors of the Year. 19 December 2016. . 8 May 2017. 28 October 2020. https://web.archive.org/web/20201028090311/https://www.inventorsdigest.com/articles/inventors-of-the-year/. live.
  46. News: Shaywitz D . The Startling History Behind Merck's New Cancer Blockbuster . Forbes. 26 July 2017 . 26 July 2017. 26 July 2017 . https://web.archive.org/web/20170726174701/https://www.forbes.com/sites/davidshaywitz/2017/07/26/the-startling-history-behind-mercks-new-cancer-blockbuster/. live.
  47. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ . Improved survival with ipilimumab in patients with metastatic melanoma . The New England Journal of Medicine . 363 . 8 . 711–723 . August 2010 . 20525992 . 3549297 . 10.1056/nejmoa1003466 .
  48. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A . Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma . The New England Journal of Medicine . 369 . 2 . 134–144 . July 2013 . 23724846 . 4126516 . 10.1056/nejmoa1305133 .
  49. FDA approves Keytruda for advanced melanoma . 24 December 2015 . . 4 September 2014 . https://web.archive.org/web/20151227110435/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm412802.htm . 27 December 2015 . dead .
  50. Web site: FDA Approves Anti-PD-1 Drug for Advanced Melanoma . 4 September 2014 . CancerNetwork . 7 September 2014. 10 January 2016 . https://web.archive.org/web/20160110030027/http://www.cancernetwork.com/news/fda-approves-pembrolizumab-keytruda-advanced-melanoma . live .
  51. News: Pollack A . New Class of Drugs Shows More Promise in Treating Cancer . 29 May 2015 . . 30 May 2015 . 29 May 2015 . https://web.archive.org/web/20150529233228/http://www.nytimes.com/2015/05/30/business/new-class-of-drugs-shows-more-promise-in-treating-cancer.html . live .
  52. News: Merck & Co and Taiho to co-promote cancer immunotherapy pembrolizumab in Japan . The Pharma Letter . 13 April 2016 . 10 November 2016 . 18 April 2018 . https://web.archive.org/web/20180418093036/https://www.thepharmaletter.com/article/merck-co-and-taiho-to-co-promote-cancer-immunotherapy-pembrolizumab-in-japan . live .
  53. Web site: Keytruda index page at EMA . European Medicines Agency (EMA) . 10 November 2016 . 20 June 2018 . https://web.archive.org/web/20180620054901/http://www.ema.europa.eu/ema//index.jsp?curl=pages%2Fmedicines%2Fhuman%2Fmedicines%2F003820%2Fhuman_med_001886.jsp&mid=WC0b01ac058001d124 . live .
  54. FDA approves Keytruda for advanced non-small cell lung cancer . . 2 October 2015 . https://web.archive.org/web/20151108150925/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm . 8 November 2015 . dead . 12 January 2020 .
  55. FDA Approves Keytruda (pembrolizumab) for the Treatment of Patients with Metastatic Non-Small Cell Lung Cancer Whose Tumors Express PD-L1 with Disease Progression On or After Platinum-Containing Chemotherapy . Merck . 2 October 2015 . 26 June 2024 . 26 June 2024 . https://web.archive.org/web/20240626040939/https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-the-treatment-of-patients-with-metastatic-non-small-cell-lung-cancer-whose-tumors-express-pd-l1-with-disease-progression-on-or-after-platinum-containing/ . live .
  56. Web site: Pembrolizumab injection . . 5 October 2015 . https://wayback.archive-it.org/7993/20170111231626/http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm465650.htm . 11 January 2017 . 26 June 2024.
  57. http://global.onclive.com/web-exclusives/potential-biomarkers-identified-for-pembrolizumab-in-head-and-neck-cancer Potential Biomarkers Identified for Pembrolizumab in Head and Neck Cancer. July 2016
  58. pembrolizumab (Keytruda) . . 5 August 2016 . 10 January 2020 . 16 December 2019 . https://web.archive.org/web/20191216043601/https://www.fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda . live .
  59. Web site: FDA Approves Pembrolizumab for Head and Neck Cancer . OncLive . 6 August 2016 . 5 December 2021 . 5 December 2021 . https://web.archive.org/web/20211205005434/https://www.onclive.com/view/fda-approves-pembrolizumab-for-head-and-neck-cancer . live .
  60. Web site: Pembrolizumab (Keytruda) Checkpoint Inhibitor . . 25 October 2016 . 26 June 2024 . https://wayback.archive-it.org/7993/20170111231548/http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm526430.htm . 11 January 2017 . live .
  61. FDA approves first cancer treatment for any solid tumor with a specific genetic feature . . 23 May 2017 . 10 January 2020 . 12 January 2020 . https://web.archive.org/web/20200112174949/https://www.fda.gov/news-events/press-announcements/fda-approves-first-cancer-treatment-any-solid-tumor-specific-genetic-feature . live .
  62. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication . . 23 May 2017 . 10 January 2020 . 23 April 2019 . https://web.archive.org/web/20190423133424/https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm . live .
  63. News: Bala S, Nair A, Lemery S, Marcus L, Goldberg KB, Pazdur R . FDA D.I.S.C.O.: First Tissue/Site Agnostic Approval Transcript. U.S. Food and Drug Administration. 30 May 2017. 12 January 2020. 12 January 2020. https://web.archive.org/web/20200112174119/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-first-tissuesite-agnostic-approval-transcript. live.
  64. Ledford H . Tissue-independent cancer drug gets fast-track approval from US regulator. Nature. 24 May 2017. 10.1038/nature.2017.22054. 17 June 2017. 12 November 2020. https://web.archive.org/web/20201112002855/https://www.nature.com/news/tissue-independent-cancer-drug-gets-fast-track-approval-from-us-regulator-1.22054. live.
  65. Web site: Accelerated approval notice: BLA 125514/S-14. U.S. Food and Drug Administration. 23 May 2017. 17 June 2017. 28 August 2021. https://web.archive.org/web/20210828210950/https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/125514Orig1s014ltr.pdf. live.
  66. News: FDA Approves Pembrolizumab for Advanced Cervical Cancer with Disease Progression During or After Chemotherapy. 12 June 2018. ASCO. 13 June 2018. 12 January 2020. https://web.archive.org/web/20200112181242/https://www.asco.org/practice-policy/policy-issues-statements/asco-in-action/fda-approves-pembrolizumab-advanced-cervical. dead.
  67. FDA approves pembrolizumab for treatment of relapsed or refractory PMBCL. U.S. Food and Drug Administration. 16 June 2018. 13 June 2018. 12 January 2020. https://web.archive.org/web/20200112175556/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-treatment-relapsed-or-refractory-pmbcl. live.
  68. FDA updates prescribing information for Keytruda and Tecentriq . . 16 August 2018 . 10 January 2020 . 22 December 2020 . https://web.archive.org/web/20201222065035/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-updates-prescribing-information-keytruda-and-tecentriq . live .
  69. FDA grants accelerated approval to pembrolizumab for hepatocellular carcinoma . . 9 November 2018 . 10 January 2020 . 12 January 2020 . https://web.archive.org/web/20200112175710/https://www.fda.gov/drugs/fda-grants-accelerated-approval-pembrolizumab-hepatocellular-carcinoma . live .
  70. FDA approves pembrolizumab for adjuvant treatment of melanoma . . 15 February 2019 . 10 January 2020 . 12 January 2020 . https://web.archive.org/web/20200112175731/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adjuvant-treatment-melanoma . live .
  71. FDA approves pembrolizumab for metastatic small cell lung cancer . . 17 June 2019 . 10 January 2020 . 6 April 2020 . https://web.archive.org/web/20200406034735/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-metastatic-small-cell-lung-cancer . live .
  72. FDA approves pembrolizumab for first-line treatment of head and neck squamous cell carcinoma . . 10 June 2019 . 10 January 2020 . 16 December 2019 . https://web.archive.org/web/20191216034123/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-first-line-treatment-head-and-neck-squamous-cell-carcinoma . live .
  73. FDA approves pembrolizumab for advanced esophageal squamous cell cancer . . 30 July 2019 . 10 January 2020 . 12 January 2020 . https://web.archive.org/web/20200112174538/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-esophageal-squamous-cell-cancer . live .
  74. Web site: 17 June 2020. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. U.S. Food and Drug Administration. 19 June 2020. 15 March 2021. https://web.archive.org/web/20210315070521/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors. live.
  75. A Phase III Randomized, Placebo-Controlled Study of Pembrolizumab (MK-3475, NSC #776864) in Addition to Paclitaxel and Carboplatin for Measurable Stage III or IVA, Stage IVB or Recurrent Endometrial Cancer . National Cancer Institute (NCI) . 13 May 2023 . ClinicalTrials.gov . NCT03914612 . 19 June 2024 . 19 June 2024 . https://web.archive.org/web/20240619060912/https://clinicaltrials.gov/study/NCT03914612 . live .
  76. Web site: Amgen slaps record-breaking $178K price on rare leukemia drug Blincyto . 18 December 2014 . 29 April 2016 . 1 April 2016 . https://web.archive.org/web/20160401035835/http://www.fiercepharmamarketing.com/story/amgen-slaps-record-breaking-178k-price-rare-leukemia-drug-blincyto/2014-12-18 . live .
  77. Web site: NHS strikes deal for potentially life-saving breast cancer drug . . 8 November 2022 . 20 June 2024 . 20 June 2024 . https://web.archive.org/web/20240620045536/https://www.england.nhs.uk/2022/11/nhs-strikes-deal-for-potentially-life-saving-breast-cancer-drug/ . live .
  78. News: Roberts . Michelle . NHS reaches deal for life-saving breast-cancer drug . 11 November 2022 . . 7 November 2022 . 11 November 2022 . https://web.archive.org/web/20221111154405/https://www.bbc.co.uk/news/health-63540179 . live .
  79. News: Roberts . Lizzie . NHS to treat aggressive form of breast cancer with potentially life-saving drug . . 8 November 2022 . 20 June 2024 . 20 June 2024 . https://web.archive.org/web/20240620053810/https://www.telegraph.co.uk/news/2022/11/08/nhs-treat-aggressive-form-breast-cancer-potentially-life-saving/ . live .
  80. News: Timmerman L . ASCO Wrapup: Immunotherapy Shines, Hope For Brain Tumors, & The Great Cancer Drug Price Debate. Forbes. 2 June 2015. 8 September 2017. 8 November 2020. https://web.archive.org/web/20201108175009/https://www.forbes.com/sites/luketimmerman/2015/06/02/asco-wrapup-immunotherapy-shines-hope-for-brain-tumors-the-great-cancer-drug-price-debate/. live.
  81. News: Adams KT . Cancer Immunotherapies--and Their Cost--Take Center Stage at ASCO's 2015 Annual Meeting. Managed Care Magazine Online. 24 July 2015. 5 November 2016. 13 December 2017. https://web.archive.org/web/20171213082823/https://www.managedcaremag.com/archives/2015/7/cancer-immunotherapies-and-their-cost-take-center-stage-ascos-2015-annual-meeting. live.
  82. News: Jenkins K . Keytruda Impresses in Triple-Negative Breast Cancer. MedPage Today. 5 May 2016. 14 May 2016. 19 December 2016. https://web.archive.org/web/20161219163114/http://www.medpagetoday.com/hematologyoncology/breastcancer/57727. live.
  83. News: Merck & Co updates Keytruda findings at ASCO. The Pharma Letter. 10 June 2016. 5 November 2016. 5 November 2016. https://web.archive.org/web/20161105161614/http://www.thepharmaletter.com/article/merck-co-updates-keytruda-findings-at-asco. live.
  84. Schmid P, Cortés J, Dent R, Pusztai L, McArthur HL, Kuemmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Jia L, Karantza V, Zhao J, Aktan G, O'Shaughnessy J . KEYNOTE-522: phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC) . Annals of Oncology . 30 . 5 . v853–v854 . 2019 . 10.1093/annonc/mdz394.003 . free . doi .
  85. Nghiem PT, Bhatia S, Lipson EJ, Kudchadkar RR, Miller NJ, Annamalai L, Berry S, Chartash EK, Daud A, Fling SP, Friedlander PA, Kluger HM, Kohrt HE, Lundgren L, Margolin K, Mitchell A, Olencki T, Pardoll DM, Reddy SA, Shantha EM, Sharfman WH, Sharon E, Shemanski LR, Shinohara MM, Sunshine JC, Taube JM, Thompson JA, Townson SM, Yearley JH, Topalian SL, Cheever MA . PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma . The New England Journal of Medicine . 374 . 26 . 2542–2552 . June 2016 . 27093365 . 4927341 . 10.1056/NEJMoa1603702 .
  86. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA . Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade . Science . 357 . 6349 . 409–413 . July 2017 . 28596308 . 5576142 . 10.1126/science.aan6733 . 2017Sci...357..409L .
  87. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leal TA, Riess JW, Jensen E, Zhao B, Pietanza MC, Brahmer JR . Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50 . Journal of Clinical Oncology . 39 . 21 . 2339–2349 . July 2021 . 33872070 . 8280089 . 10.1200/JCO.21.00174 . free . doi .
  88. Neoleukin Therapeutics Announces Clinical Collaboration with Merck to Evaluate NL-201 in Combination with Keytruda (pembrolizumab) . 10 January 2022 . Neoleukin Therapeutics . 10 January 2022 . https://web.archive.org/web/20220110134343/http://investor.neoleukin.com/news-releases/news-release-details/neoleukin-therapeutics-announces-clinical-collaboration-merck . dead .
  89. Eskander RN, Sill MW, Beffa L, Moore RG, Hope JM, Musa FB, Mannel R, Shahin MS, Cantuaria GH, Girda E, Mathews C, Kavecansky J, Leath Iii CA, Gien LT, Hinchcliff EM, Lele SB, Landrum LM, Backes F, O'Cearbhaill RE, Al Baghdadi T, Hill EK, Thaker PH, John VS, Welch S, Fader AN, Powell MA, Aghajanian C . Pembrolizumab plus Chemotherapy in Advanced Endometrial Cancer . The New England Journal of Medicine . 2159–2170 . March 2023 . 388 . 23 . 36972022 . 10.1056/NEJMoa2302312 . 10351614 . 257765751 .
  90. Precision medicine meets cancer vaccines . . 29 . 6 . 1287 . June 2023 . 37328586 . 10.1038/s41591-023-02432-2. 259184146 . free . doi .
  91. Bafaloukos D, Gazouli I, Koutserimpas C, Samonis G . Evolution and Progress of mRNA Vaccines in the Treatment of Melanoma: Future Prospects . . 11 . 3 . March 2023 . 636 . 36992220 . 10057252 . 10.3390/vaccines11030636 . free . doi .