Novel immune checkpoint blocker approved for the treatment of advanced melanoma

Keywords:

• CTLA4
• ipilimumab
• Keytruda™
• nivolumab
• PD-1
• Yervoy™

Abbreviations:

• CTLA4, cytotoxic T lymphocyte-associate protein 4
• FDA, Food and Drug Administration
• PDCD1/PD-1, programmed cell death 1

A few days ago, on September 4th, 2014, the US Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab, a monoclonal antibody formerly known as lambrolizumab that specifically targets programmed cell death 1 (PDCD1, best known as PD-1), for use in patients with advanced or unresectable melanoma who fail to respond to other therapies (source http://www.fda.gov/NewsEvents/Newsroom/PressAnnou-ncements/ucm412802.htm). Thus, pembrolizumab, which has been developed by Merck & Co. Inc. (Whitehouse Stations, NJ, US) under the trade name of Keytruda™, adds now to the growing list of immunotherapeutic agents licensed for the treatment of cancer patients.

Pembrolizumab belongs to the class of immunotherapeutics commonly referred to as “checkpoint blockers,” i.e., it mediates antineoplastic effects by preventing cancer cells and the tumor microenvironment to deliver inhibitory signals to T lymphocytes.^1-6 The first-in-class of such agents, ipilimumab, which is now commercialized by Bristol-Myers Squibb (New York, NY, US) under the trade name of Yervoy™, has been approved by the US FDA for use in individuals with unresectable or metastatic melanoma on 2011, March 25th.^7-11 Similar to pembrolizumab, ipilimumab prevents the delivery of inhibitory signals to immune effector cells, although it specifically targets another immunosuppressive receptor, namely cytotoxic T lymphocyte-associated protein 4 (CTLA4).^12-16 In a large, randomized, double-blind, double-dummy, Phase III clinical trial enrolling 676 melanoma patients (NCT00094653), the administration of ipilimumab as a standalone immunotherapeutic intervention was associated with a 4-month improvement in overall survival (OS) over the administration of a peptide vaccine targeting the melanoma-associated antigen premelanosome protein (PMEL, best known as gp100).⁷ Accordingly, ipilimumab-treated patients exhibited an overall response rate of 10.9%, while that of individuals receiving the gp100-targeting vaccine was 1.5% only. Common side effects associated with the use of ipilimumab included fatigue, diarrhea, skin rash, endocrine deficiencies, and colitis. Moreover, severe to fatal autoimmune reactions were observed in 12.9% of patients treated with ipilimumab. These side effects often, but not always, could be managed with treatment discontinuation coupled to the administration of corticosteroids.⁷

Pembrolizumab was granted accelerated approval upon the disclosure of safety and efficacy results from a clinical trial enrolling 173 participants with advanced melanoma whose disease progressed after prior treatment.¹⁷ Remarkably, 24% of the patients who received pembrolizumab at the recommended dose of 2 mg/kg experienced tumor regression, a response that lasted at least 1.4–8.5 months. A similar response rate was observed among patients treated with 10 mg/kg pembrolizumab (source http://www.fda.gov/NewsEvents/Newsroom/PressAnnou-ncements/ucm412802.htm).¹⁷ The safety of pembrolizumab had previously been established in a clinical study enrolling 411 individuals with advanced melanoma (NCT01295827).¹⁸ In this cohort, the most common side effects associated with the use of pembrolizumab were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia and diarrhea. In addition, pembrolizumab caused severe immunological side effects involving healthy organs such as the lungs, colon, hormone-producing glands and liver, in a limited fraction of the study participants.¹⁸

Another monoclonal antibody targeting PD-1 (nivolumab, commercialized by Bristol-Myers Squibb under the trade name of Opvido™) has been licensed for use in humans by Japanese regulatory agencies only a month ago.¹⁹ The safety and favorable therapeutic profile of nivolumab have been demonstrated in several, randomized clinical trials (most of which involving melanoma patients).^20-24 Last July, Bristol-Myers Squibb announced that it would seek FDA approval on nivolumab by September 30^th, 2014 (source http://www.zacks.com/stock/news/139801/BristolMyers-to-Seek-US-Approval-for-ImmunoOncology-Drug). Now, according to a recent Bloomberg report, Bristol-Myers Squibb has filed a lawsuit against Merck & Co. Inc., accusing the latter of patent infringement on the development of pembrolizumab (http://www.bloomberg.com/news/2014-09-08/uber-technologies-bristol-myers-intellectual-property.html).

The therapeutic profile of several antibodies specific for the major PD-1 ligand, i.e., CD274 (best known as PD-L1 or B7-H1),^25,26 is also being intensively investigated in both pre-clinical and clinical settings.^2,27,28 These agents include, but are not limited to, MEDI4736 (developed by Astra Zeneca, London, UK), MPDL3280A (developed by Roche, Basel, Switzerland), and MSB0010718C (developed by EMD Serono, Inc., a subsidiary of Merck and Co. Inc. based in Rockland, MA, US).^29-35 Conversely, molecules that would specifically inhibit the other main endogenous activator of PD-1, i.e., PDCD1 ligand 2 (PDCD1LG2, best known as PD-L2), have failed to reach clinical development yet.^2,28

As it stands, immune checkpoint blockers including ipilimumab, pembrolizumab and nivolumab represent a new, efficient alternative to the standard management of advanced melanoma.^9,36-42 Other immunotherapeutics employed as standalone interventions also provide clinical benefits to melanoma patients, at least in part reflecting the peculiar immunological features of melanoma cells.^43-45 At odds with several other immunotherapeutic agents, however, checkpoint blockers used as monotherapy are efficient against a wide panel of neoplasms other than melanoma, including (but not limited to)^34,46,47 hematological malignancies,⁴⁸ non-small cell lung carcinoma,^32,49-55 renal cell carcinoma,^56-60 sarcoma,⁶¹ head and neck carcinoma,^62,63 ovarian carcinoma,⁶⁴ bladder carcinoma,⁶⁵ and perhaps thymoma⁶⁶ and colorectal cancer.⁶⁷ In addition, blocking immune checkpoints may consistently ameliorate the efficacy of other (immuno)therapeutic regimens, including not only immunostimulatory cytokines^68-71 and adoptive cell transfer,^72-77 but also dendritic cell-, peptide- and DNA-based anticancer vaccines,^78-86 Toll-like receptor agonists,^87-89 irradiation,^90-96 conventional and targeted chemotherapeutics (in particular when these also exert immunostimulatory effects),^97-108 oncolytic viruses,^109-112 tumor-targeting monoclonal antibodies,^{28,33,113,114} and immunomodulatory drugs (e.g., lenalidomide).^115-117

Combinatorial regimens that simultaneously inhibit CTLA4 and PD-1 mediate superior clinical activity as compared to the blockage of either these immunosuppressive receptors, especially in immunosensitive tumors such as melanoma²³ and renal cell carcinoma.¹¹⁸ Along similar lines, combining immune checkpoint blockers with immunostimulatory monoclonal antibodies like lirilumab, which interferes with the activity of inhibitory killer-cell immunoglobulin-like receptors on natural killer cells,^119,120 or MEDI6469, which promotes the activity of tumor necrosis factor receptor superfamily, member 4 (TNFRSF4, best known as OX40),⁴² may provide improved efficacy as compared to monotherapeutic approaches. Combinatorial approaches of this type are being intensively investigated in both preclinical and clinical settings.¹²¹

As it stands, efforts should be dedicated at the identification of biomarkers that predict the therapeutic efficacy of immune checkpoint blockers.^31,122-129 This is particularly relevant not only because some immune checkpoint blockers such as ipilimumab are associated with a non-negligible rate of severe to fatal autoimmune reactions,^7,130-133 but also because all these agents are expensive (the use of pembrolizumab is expected to cost 12,500 USD per month) (source http://www.nytimes.com/2014/09/05/business/merck-wins-approval-of-novel-immune-system-drug-for-cancer.html?_r = 0).

Irrespective of these caveats, pembrolizumab adds to the therapeutic options for patients with advanced melanoma who failed to respond to other treatments. The blockade of immune checkpoints has now become a clinical reality that will benefit patients affected by several malignancies.

Funding

Authors are supported by Ligue contre le Cancer (équipe labelisée); Agence National de la Recherche (ANR); Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; AXA Chair for Longevity Research; Institut National du Cancer (INCa); Fondation Bettencourt-Schueller; Fondation de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LabEx Immuno-Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI).