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.[52] 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.[53]
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.[54] 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[55] and that a second Bristol Myers Squibb checkpoint inhibitor, nivolumab (Opdivo), was also promising.[54] 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.[54] 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.[54]
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 participants 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.[54] 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 participants roughly divided between melanoma and lung cancer.[54]
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.[54]
In 2013, the United States Adopted Name (USAN) name was changed from lambrolizumab to pembrolizumab.[49] In that year clinical trial results in advanced melanoma were published in The New England Journal of Medicine.[56] This was part of the large phase I NCT01295827 trial.[57]
In September 2014, the US Food and Drug Administration (FDA) approved pembrolizumab under the Fast Track Development Program.[58][59] 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.[60][61]
As of 2015, the only PD-1/PD-L1 targeting drugs on the market are pembrolizumab and nivolumab.[62]
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.[63]
In July 2015, pembrolizumab received marketing approval in the European Union.[11][64][51]
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.[65][66][67][68]
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.[69] 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.[70][71]
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.[72]
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).[73] 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.[73][74][75][76] The approval was based on a clinical trial of 149 participants with microsatellite instability-high or mismatch repair deficient cancers who enrolled on one of five single-arm trials. Ninety participants had colorectal cancer, and 59 participants had one of 14 other cancer types. The objective response rate for all participants 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.[75]
In June 2018, the US FDA approved pembrolizumab for use in both advanced cervical cancer for PD-L1 positive patients[78] 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.[79]
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.[80] 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.[80] The 22C3 assay determines PD-L1 expression by using a combined positive score (CPS) assessing PD-L1 staining in tumor and immune cells.[80] As of, 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.[80]
In November 2018, the US FDA granted accelerated approval to pembrolizumab for those with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.[81]
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.[82] The FDA granted the application orphan drug designation.[82]
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,[83] and the FDA approved pembrolizumab for the first-line treatment of patients with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).[84] 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.[84] 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.[84]
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.[85] 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.[85]
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.[86]
In March 2021, the accelerated approval indication in the US for the treatment of people with metastatic small-cell lung cancer (SCLC) was removed.[17]
In January 2024, the FDA approved pembrolizumab, in combination with chemoradiotherapy, for people with FIGO 2014 Stage III-IVA cervical cancer.[36] 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.[36] The trial included 596 participants with FIGO 2014 Stage III-IVA disease and 462 participants with FIGO 2014 Stage IB2-IIB, node-positive disease.[36]
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.[37] 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.[37][87] 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.[37]
Efficacy was evaluated in KEYNOTE-905/EV-303 (NCT03924895), an open-label, randomized, multi-center, active-controlled trial in 344 participants with previously untreated muscle invasive bladder cancer who were candidates for radical cystectomy with pelvic lymph node dissection but were ineligible for or declined cisplatin-based chemotherapy.[42] Participants were randomized (1:1) to receive neoadjuvant pembrolizumab and enfortumab vedotin followed by surgery followed by adjuvant enfortumab vedotin in combination with pembrolizumab followed by pembrolizumab as a single agent or to undergo immediate surgery alone.[42]
