Checkpoint Inhibitors & Advanced Cancers: A Healthcare Professional's Guide
Immune Checkpoint Inhibitors: A Novel Approach
Cancer is smart. But we are getting smarter. Researchers, after many decades of work, have now identified ways in which cancer can evade detection and bypass inactivation by our own immune system.
In the late 19th century, surgeon William Coley observed that injections of killed bacteria could lead to tumor shrinkage, linking cancer and immunology for the first time. Today, pioneers like Dr. James Allison and the "Cancer Moonshot" team at MD Anderson Cancer Center in Houston lead the way in checkpoint inhibition immunotherapy.
One way that cancer cells hide from the immune system is to take control of regulatory pathways like the "checkpoint" inhibitor pathway. Today, immune checkpoint inhibitors are a newer class of cancer agents that work with the immune system to regain control and fight these advanced malignancies. What do healthcare providers need to know about these novel agents?
Checkpoint Inhibitors: FDA Approvals
As of May 2017, there are 6 FDA-approved checkpoint inhibitors that target the different protein receptors PD-1/PD-L1 and CTLA-4.
- Yervoy (ipilimumab), first approved March 2011 from Bristol Myers Squibb; targets CTLA-4; approved for advanced, metastatic melanoma
- Keytruda (pembrolizumab), first approved Sept. 2014 from Merck; targets PD-1; approved for advanced melanoma, non-small cell lung cancer (NSCLC) including 1st line treatment in some patients, head and neck squamous cell carcinoma; Hodgkin's lymphoma; advanced urothelial (bladder) cancer; for any cancer with specific genetic features (microsatellite instability-high cancer); advanced gastric cancer
Checkpoint Inhibitors: More FDA Approvals
- Opdivo (nivolumab), first approved Dec. 2014 from Bristol-Myers Squibb; targets PD-1; approved for advanced melanoma, advanced NSCLC, advanced renal cell (kidney) cancer, Hodgkin's lymphoma; head and neck squamous cell carcinoma; urothelial (bladder) cancer; colorectal cancer; hepatocellular (liver) cancer
- Tecentriq (atezolizumab), first approved May 2016 from Genentech; targets PD-L1; approved for advanced bladder cancer, non-small cell lung cancer (NSCLC)
- Bavencio (avelumab), approved March 2017 from EMD Serono; targets PD-L1; approved for Merkel Cell Carcinoma and urothelial (bladder) cancer
- Imfinzi (durvalumab), approved May 2017; from AstraZeneca; targets PD-L1; approved for metastatic urothelial carcinoma (bladder cancer).
Releasing the Brakes
Normally, when a tumor antigen is presented, the immune system activates to target and destroy the tumor. The immune system can also "turn off" this activity to prevent healthy tissue destruction.
But remember, cancer is smart. Cancer knows how to hijack the immune system to prevent tumor destruction. Sites on certain tumor cells can attach to protein receptor sites on T-cells and deactivate them, preventing activation of the T-cell which normally would destroy the cancer.
In essence, all checkpoint inhibitors take the "brakes" off of the immune system to enable T-cell proliferation and activation to attack the cancer.
Mechanism of Action: Keytruda and Opdivo
When a tumor antigen is presented, the immune system activates to target and destroy the tumor. The immune system can also "turn off" this activity to prevent healthy tissue destruction.
However, cancer has learned how to interrupt this process. Sites on certain tumor cells can attach to PD-1 receptor sites on T-cells and deactivate them, preventing activation of the T-cell which normally would target the cancer. However, when a PD-1 immune checkpoint inhibitor such as Keytruda (pembrolizumab) or Opdivo (nivolumab) is introduced, it prevents the tumor cell from linking to and inactivating the T-cell, which boosts anti-tumor immune activity. Basically, this allows re-activation of the immune system to fight off the cancer. The checkpoint inhibitor interrupts one of cancer's main defenses against attack.
Specifically, Keytruda and Opdivo block the interaction between PD-1 (on T cells) and its ligands, PD-L1 and PD-L2 (on the tumor), thereby activating T lymphocytes, leading to T-cell proliferation and cytokine production.
Keytruda: Dosing, Uses and Side Effects
Keytruda (pembrolizumab) was first approved for the treatment of metastatic melanoma, followed by metastatic non-small cell lung cancer (NSCLC), and then recurrent or metastatic squamous cell head and neck carcinoma (HNSCC). For treatment of metastatic NSCLC (which can be first-line), patients are selected based on presence of positive PD-L1 expression determined via an FDA-approved companion diagnostic test. In March, 2017 Keytruda was approved to treat classical Hodgkin's lymphoma, and in May 2017 as first-line combination therapy for patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), irrespective of PD-L1 expression. Since May of 2017, it has also been approved for multiple other indications including gastric cancer and metastatic urothelial carcinoma, a type of bladder cancer.
Keytruda is given as an intravenous (IV) infusion over 30 minutes. Access the most recent dosing recommendations here. Immune-mediated reactions, such as pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis can occur. These reactions, which can be severe and life-threatening, may result in temporary or permanent discontinuation of the drug and corticosteroids administered. Other more common side effects (occurring in >20% of patients) may include rash, cough, pruritis, constipation, diarrhea, and nausea. Obtain a complete listing of Keytruda side effects here.
Opdivo: Dosing, Uses and Side Effects
Since 2014, Opdivo (nivolumab) has been approved for several different types of cancer:
- Metastatic melanoma; also in combination with Yervoy (ipilimumab) for BRAF V600 wild-type melanoma and for advanced melanoma across BRAF status
- Metastatic squamous non-small cell lung cancer (NSCLC)
- Metastatic non-squamous NSCLC
- Metastatic renal cell carcinoma
- Classical Hodgkin lymphoma
- Advanced squamous cell carcinoma of the head and neck
- Urothelial (bladder) cancer
- Colorectal cancer
- Hepatocellular (liver) cancer
Opdivo is usually given as an intravenous (IV) infusion over 60 minutes. Full dosing recommendations can be accessed on the drug monograph. Serious and possibly life-threatening immune-mediated side effects, similar to what is seen with other checkpoint inhibitors, may occur. Common side effects (>20%) included fatigue, rash, muscle pain, diarrhea, nausea/vomiting, pruritis, fever, and shortness of breath. See a full listing of Opdivo drug side effects here.
Mechanism of Action: Tecentriq
The mechanism for Tecentriq is different than with PD-1 checkpoint inhibitors. PD-L1 is a ligand on the tumor for the checkpoint PD-1 on the T-cell. The interaction between PD-L1 on the tumor and PD-1 on the T-cell leads to T-cell inactivation and blocks the anti-tumor immune response. Due to this interaction, cytotoxic T-cell activity, T-cell proliferation and cytokine production are all suppressed, and the tumor is not effectively attacked.
However, Tecentriq acts to bind to the PD-L1 site on the tumor and blocks the PD-1 interaction on the T cell, which triggers the anti-tumor immune response.
Tecentriq: Dosing, Uses and Side Effects
Tecentriq (atezolizumab) was the first FDA-approved PD-L1 inhibitor. Tecentriq is approved for locally advanced or metastatic urothelial (bladder) carcinoma, as well as advanced non-small cell lung cancer.
Tecentriq is given via IV infusion over 60 minutes every 3 weeks. Full updated dosing recommendations can be accessed in the Tecentriq drug monograph.In addition to immune-mediated side effects, the most common side effects reported in clinical trials included fatigue, decreased appetite, nausea, urinary tract infection, fever, and constipation. See a full listing of Tecentriq side effects here.
Mechanism of Action: Yervoy
Yervoy (ipilimumab), a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking monoclonal antibody, was the first FDA-approved checkpoint inhibitor. Like PD-1, CTLA-4 is another protein receptor found on T cells that acts as a negative regulator of T-cell activation.
Yervoy binds to CTLA-4 on the T cell and prevents the interaction of CTLA-4 with its ligands. This in turn leads to a T-cell mediated anti-tumor immune response.
Yervoy: Dosing, Uses and Side Effects
Yervoy (ipilimumab) was the first approved checkpoint inhibitor in March 2011 for metastatic melanoma. In 2015, Yervoy was subsequently approved as adjuvant therapy for patients with stage III melanoma, to lower the risk that the melanoma will return following surgery.
Yervoy is given via an IV infusion over 90 minutes. Up-to-date dosing guidelines can be accessed in the drug monograph.In addition to serious immune-mediated adverse events like colitis, common adverse events (>5%) associated with Yervoy may include fatigue, diarrhea, pruritus, rash, nausea/vomiting, headache, weight loss, fever, decreased appetite and insomnia. A full listing of Yervoy side effects can be accessed here.
Approved: Bavencio (avelumab)
Bavencio (avelumab), a PD-L1 blocking antibody, was approved in March 2017 for metastatic Merkel cell carcinoma (MCC). MCC is rare form of skin cancer most common in older patients and appears as a painless pink, red, or purple bump, often on the face, head or neck area. Most patients can get the tumor removed surgically, but more than 30% will eventually develop metastatic disease (occurring throughout the body) due to a recurrence. Bavencio is the first FDA-approved treatment for metastatic MCC and is used in patients 12 years and older including those who have not received prior chemotherapy.
Approval of Bavencio was based on a study of 88 patients with metastatic MCC who had previously received chemotherapy. In 33% of patients, complete or partial shrinkage of their tumors occurred, with a response lasting for more than 6 months in 86%, and more than 12 months in 45% of patients. Common side effects include fatigue, muscle pain, diarrhea, nausea, infusion-related reactions, and rash, among others.
In May 2017, Bavencio was also FDA-approved to treat urothelial (bladder) cancer.
Approved: Imfinzi (durvalumab)
Imfinzi (durvalumab) is also an anti-PD-L1 blocker, like Tecentriq and Bavencio, and was approved in May 2017 for the treatment of patients with advanced urothelial carcinoma (bladder cancer) who have disease progression despite use of platinum-containing chemotherapy with or without surgery.
In studies, Imfinzi had an objective response rate (ORR) of 17%, regardless of PD-L1 status, with an ORR of 26.3% in patients with PD-L1 high-expressing tumors. Among 31 patients who were responders to Imfinzi treatment, 14 patients (45%) had ongoing responses of at least 6 months and 5 patients (16%) at least 12 months. Of all evaluable patients, 2.7% achieved complete response.
Synergism: Combining Checkpoint Inhibitors
The combined use of these novel therapeutic agents is charting a new treatment paradigm for metastatic melanoma and other cancers. The mechanism of action (MOA) involves dual immune checkpoint inhibition, at different receptor proteins, leading to increased anti-tumor activity.
Combining drugs with different MOAs at different receptor sites is not a new idea in pharmacotherapy, this is frequently done for additive or synergistic effect. Late-phase studies are also looking at immune checkpoint inhibitors in combination with more traditional chemotherapies, like platinum-based drugs.
Opdivo Plus Yervoy Approved: Jan 2016
Opdivo and Yervoy target different but complementary checkpoint pathways (PD-1 and CTLA-4). Yervoy blocks CTLA-4 and boosts T-cell activation and proliferation, while Opdivo repairs the T-cell immune response directed at the tumor. The combination of these agents was first approved in October 2015 for unresectable or metastatic BRAF V600 wild-type melanoma.
In January 2016, the combo was approved across all BRAF status. However, dual therapy can lead to enhanced immune-mediated side effects including pneumonitis, colitis, hepatitis, kidney dysfunction, and rash.
In November 2016, very rare but fatal heart side effects were reported with the combined use of Opdivo and Yervoy, but experts state the heart problems can be managed, as these drugs are potentially life-saving therapies otherwise.
Future Targets for Checkpoint Inhibition
Research is extremely active in the area of immune checkpoint inhibition, and immunotherapy in general, as a novel method of cancer treatment. PD-1/PD-L1 and CLTA-4 targets are only two of many sites being investigated for checkpoint inhibition. Other sites that are under active research specifically for checkpoint inhibition include:
- B and T-cell lymphocyte attenuator (BTLA)
- V-domain immunoglobulin (Ig) suppressor of T-cell activation (VISTA)
- T-cell immunoglobulin and mucin domain (TIM-3)
- Lymphocyte activation gene 3 (LAG3)
Checkpoint inhibitors may not appear to shrink tumors as quickly as traditional chemotherapeutic agents. In fact, at first glance, it may appear that the tumor size is increasing after administration of this immunotherapy. An increase in tumor size may be due to a phenomenon known as "pseudoprogression", which can occur after administration of immune checkpoint inhibitors.
In pseudoprogression, it appears that the tumor is growing is size upon radiograph, but this is due to the large number of T-lymphocytes and other cells that enter the tumor. The increase in tumor size can occur over a period of months, but then may be followed by reduction or eradication of the tumor.
Study Update: First-Line Opdivo in Lung Cancer
Lung cancer is the number one cancer killer in the U.S. But recent clinical trial results remind us that checkpoint inhibitors are not a panacea. In August 2016, Bristol-Myers Squibb announced that its breakthrough immune checkpoint inhibitor Opdivo failed to meet its primary endpoint for progression-free survival as a first-line treatment in patients with previously untreated advanced non-small cell lung cancer (NSCLC) whose tumors expressed PD-L1 at ≥ 5% (Checkmate-226).
In addition, in January 2017 the company reported it had decided not to pursue an accelerated regulatory pathway for the combination of Opdivo plus Yervoy in first-line lung cancer in the U.S. based on a review of data available.
Approved: First-Line Keytruda in Lung Cancer
Although BMS's first-line trial for PD-L1 lung cancer failed, in June 2016 Merck announced that Keytruda (pembrolizumab) had positive results as first-line monotherapy for previously untreated advanced non-small cell lung cancer (NSCLC) in patients whose tumors expressed high levels of PD-L1. From the KEYNOTE-024 study, the primary endpoint - progression-free survival was met - as well as the secondary endpoint of overall survival when compared to platinum-based chemotherapy. FDA approved Keytruda for first-line use in advanced NSCLC in October 2016.
Combined Keytruda treatment with platinum-based chemotherapy is also under research. These studies will evaluate platinum-based chemotherapy regimens in previously untreated patients with non-squamous NSCLC (KEYNOTE-189) and squamous NSCLC (KEYNOTE-407).
Study Update: Oral Dosage Forms of Checkpoint Inhibitors
Currently, all checkpoint inhibitors are monoclonal antibodies that require intravenous (IV) infusion). However, an oral checkpoint inhibitor known as CA-170 is being developed as monotherapy or in combination. Early toxicology studies show it to be safe when given in a once-daily oral dosing regimen. Curis Inc., the manufacturer, is currently in Phase 1 trials investigating CA-170 in patients with advanced solid tumors and lymphomas. Although research is in the early stages, in June 2016, Curis submitted an investigational new drug (IND) application to the FDA for CA-170. If approved, CA-170 would be the first orally available immune checkpoint inhibitor designed to selectively target and inhibit both PD-L1 and VISTA (V-domain Immunoglobulin Suppressor of T-cell Activation) checkpoint regulators of immune activation. CA-170 is called an PD-L1/VISTA antagonist. Currently, no VISTA antagonist immune checkpoint inhibitors are approved, so this would be a new immuno-oncology mechanism for checkpoint inhibitors.
What Other Immunotherapies Exist?
Checkpoint inhibitors, which are monoclonal antibodies, are only one piece of a much larger immunotherapy map that is being charted.
Researchers have developed many other types of immunotherapy agents, some still under research in clinical trials and not yet approved. Major examples include
Other Cancers Under Study
The future looks bright. The immune checkpoint inhibitors are actively being researched in multiple types of cancers in Phase II and Phase III studies. In addition to the current indications, other oncology areas where these breakthrough therapies could have a major impact, if approved, include:
To access NCI-sponsored clinical trials visit this user-friendly site at the National Cancer Institute.
Finished: Checkpoint Inhibitors & Advanced Cancers: A Healthcare Professional's Guide
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