Checkpoint Inhibitors & Advanced Cancers: A Healthcare Professional's Guide
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on Nov 29, 2021.
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.
- In October, the 2018 Nobel Prize in Physiology or Medicine was awarded to Dr. Allison for his novel discoveries in this groundbreaking treatment.
What do healthcare providers need to know about these novel agents? 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 an established class of cancer agents that work with the immune system to regain control and fight these advanced malignancies.
Checkpoint Inhibitors: FDA Approvals
As of October 2020, there are 8 FDA-approved checkpoint inhibitors that target the different protein receptors.
- advanced, metastatic melanoma
and in combination with Opdivo (nivolumab) for the treatment of
- Advanced renal (kidney) cell carcinoma
- Microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer
- Hepatocellular (liver) carcinoma
- Non-small cell lung cancer
- Malignant pleural mesothelioma.
- Advanced Melanoma (skin cancer)
- Non-Small Cell Lung Cancer
- Head and Neck Squamous Cell Cancer
- Classical Hodgkin Lymphoma (a type of blood cancer)
- Primary Mediastinal Large B-Cell Lymphoma (PMBCL)
- Urothelial (Bladder) Carcinoma
- Microsatellite Instability-High or Mismatch Repair Deficient Cancer (cancer that affects the proper repair of DNA inside the cell).
- Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer (CRC)
- Gastric (Stomach) Cancer
- Cervical Cancer
- Hepatocellular (Liver) Carcinoma
- Merkel Cell Carcinoma (a rare type of skin cancer)
- Renal (Kidney) Cell Cancer
- Tumor Mutational Burden-High (TMB-H) Cancer (cancers that have many gene mutations)
- Cutaneous Squamous Cell Carcinoma (a type of skin cancer)
- Esophageal Cancer
- Endometrial Cancer
- Triple-Negative Breast Cancer
Checkpoint Inhibitors: More FDA Approvals
Opdivo (nivolumab) was first approved in Dec. 2014 and is from Bristol-Myers Squibb. Opdivo targets PD-1 and is approved for advanced melanoma, advanced small and non small cell lung cancer (NSCLC), advanced renal cell (kidney) cancer, classical Hodgkin's lymphoma, head and neck squamous cell carcinoma; urothelial (bladder) cancer; colorectal cancer; hepatocellular (liver) cancer; malignant pleural mesothelioma.
Tecentriq (atezolizumab), first approved in May 2016 from Genentech; targets PD-L1; approved for advanced bladder cancer, non-small cell lung cancer (NSCLC), metastatic triple negative breast cancer (ER-/PR-, HER2-) small cell lung cancer (SCLC); hepatocellular (liver) cancer; advanced melanoma.
Bavencio (avelumab) was approved in March 2017 is from EMD Serono and targets PD-L1. Bavencio is approved for Merkel Cell Carcinoma, urothelial (bladder) cancer, and renal (kidney) cell carcinoma.
Imfinzi (durvalumab) was first approved in May 2017 and is from AstraZeneca. Imfinzi targets PD-L1 and is approved to slow progression of non-small cell lung cancer (NSCLC). It's also approved for small cell lung cancer. In Feb. 2021, the advanced bladder cancer use for Imfinzi was withdrawn by the manufacturer.
Libtayo (cemiplimab-rwlc), first approved in Sept. 2018 is from Sanofi/Regneron. Libtayo targets the PD-1 cellular pathway, and is approved to treat metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC in patients who are not candidates for curative surgery or curative radiation. In Feb. 2021, it was also approved for advanced non-small cell lung cancer and advanced basal cell (skin) cancer.
GSK’s Jemperli (dostarlimab-gxly) was cleared by the FDA in April 2021. It is a PD-1 blocking antibody used to treat adults with mismatch repair-deficient (dMMR) endometrial cancer that has returned or cannot be removed by surgery. Jemperli works by binding to the PD-1 receptor and blocking interaction with the ligands PD-L1 and PD-L2. An FDA-approved test determines if the cancer is dMMR.
Releasing the Brakes
In essence, all checkpoint inhibitors take the "brakes" off of the immune system to enable T-cell proliferation and activation to attack the cancer.
- 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.
- However, the cancer knows how to hijack the immune system to prevent its own 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.
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. It has also been approved for multiple other indications, totaling at least 18 to 19 different uses as of Nov. 2021.
- Keytruda is usually 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.
Approved: First-Line Keytruda in Lung Cancer
In 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.
- The secondary endpoint, overall survival when compared to platinum-based chemotherapy, was also met.
- The FDA approved Keytruda for first-line use in advanced NSCLC in October 2016.
- In April 2019, the FDA expanded the label for Keytruda to include monotherapy treatment in first-line treatment of NSCLC.
- Longer term study results (from the KEYNOTE-024 study) are now available for pembolizumab (Keytruda) treatment of advanced NSCLC. Data published in Sept. 2020 shows that at 5 years, the overall survival rate was twice as high for patients who received pembrolizumab (31.9%) when compared to a chemotherapy (16.3%) regimen. Pembrolizumab also reduced the risk of death by 38% versus chemotherapy (a median overall survival of 26.3 versus 13.4 months).
- In March 2021, the use for treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy was withdrawn by the manufacturer because the confirmatory Phase 3 study as a condition of accelerated approval did not meet its significanrt overall survival endpoints.
Opdivo: Dosing, Uses and Side Effects
Since 2014, Opdivo (nivolumab) has been approved for numerous different types of cancer, including:
- Metastatic melanoma; also in combination with Yervoy (ipilimumab) for BRAF V600 wild-type melanoma and for advanced melanoma across BRAF status
- Metastatic non-small cell lung cancer (NSCLC)
- Metastatic renal cell (kidney) carcinoma
- Classical Hodgkin lymphoma
- Advanced squamous cell carcinoma of the head and neck
- Urothelial (bladder) cancer
- Colorectal cancer
- Hepatocellular (liver) cancer
- Esophageal Squamous Cell Carcinoma (ESCC)
- Mesothelioma (with Yervoy)
In Dec. 2020, BMS withdrew the indication for small cell lung cancer, as confirmatory endpoints were not met in studies required after accelerated approval.
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
Tecentriq (atezolizumab) is a programmed death-ligand 1 (PD-L1) blocking antibody used to treat advanced urothelial (bladder) carcinoma and non-small cell lung cancer. In March 2019, Tecentriq was also approved to treat both metastatic triple negative breast cancer (ER-/PR-, HER2-) and small cell lung cancer. It's also been cleared for heptatocellular carcinoma and metastatic melanoma.
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 (ligand) site on the tumor and blocks the PD-1 interaction on the T cell, which allows the anti-tumor immune response to be triggered.
Tecentriq: Dosing, Uses and Side Effects
Tecentriq (atezolizumab) was the first FDA-approved PD-L1 inhibitor.
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:
- decreased appetite
- urinary tract infection
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 also used to treat kidney (renal cell) cancer, liver (hepatocellular) cancer, non-small cell lung cancer, plural mesothelioma, and a certain type of colorectal cancer, when given in combination with Opdivo (nivolumab).
Yervoy is given via an IV infusion over 90 minutes. Up-to-date dosing guidelines can be accessed via the drug monograph.
In addition to serious immune-mediated adverse events like colitis, common adverse events (>5%) associated with Yervoy may include:
- weight loss
- 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). Bavencio was 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. Bavencio binds PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1.
- 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.
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.
In May 2017, Bavencio was also FDA-approved to treat urothelial (bladder) cancer, which can now be used as first-line manitenance treatment. In May 2019, Bavencio was approved in combination with Inlyta (axitinib) for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
Common side effects with Bavencio include fatigue, muscle pain, diarrhea, nausea, infusion-related reactions, and rash, among others.
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. However, in Feb. 2021 the manufacturer withdrew the bladder cancer indication, as endpoints were not met in the accelerated approval studies.
In February 2018, the FDA approved Imfinzi to reduce the risk of progression of non-small cell lung cancer (NSCLC). In March 2020, Infinzi was cleared to treat extensive-stage small cell lung cancer (ES-SCLC).
In studies, common side effects included cough, fatigue, inflammation in the lungs, respiratory tract infections, difficulty breathing, and rash.
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 or ligands, leading to increased anti-tumor activity.
Combining drugs with different MOAs at different receptor sites is not a new idea in pharmacotherapy, as this is frequently done for additive or synergistic effect. The combination of Opdivo and Yervoy is well-known as a dual treatment.
Colorectal cancer, renal cell carcinoma, and metastatic melanoma are just a sampling of cancers where checkpoint inhibitors can be combined.
Studies have also reviewed immune checkpoint inhibitors in combination with more traditional chemotherapies, like platinum-based drugs. Checkpoint inhibitors are used with chemotherapy to treat many types of cancers, for example: small cell lung cancer, triple negative breast cancer, and head and neck squamous cell cancer.
Opdivo Plus Yervoy: Complementary Checkpoint Pathways
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.
In July 2018, Opdivo plus low-dose Yervoy was approved in combination for previously treated adult and pediatric patients 12 years and older with microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan.
Other approvals for the Opdivo/Yervoy combination have been cleared by the FDA, including the most recent for mesothelioma in October 2020.
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 a few of the 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) -- including an oral agent
- T-cell immunoglobulin and mucin domain (TIM-3)
- Lymphocyte activation gene 3 (LAG3)
On the Horizon: Oral 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.
Toxicology studies show it to be safe when given in a once-daily oral dosing regimen. Curis Inc., the manufacturer, is currently investigating several agents, CA-170 and CA-327 in patients with advanced solid tumors and lymphomas.
CA-170 is called a 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.
- CA-170 is a first-in-class, oral, small molecule antagonist of the immune checkpoints VISTA and PD-L1.
- CA-170 is currently undergoing investigation in a Phase 1 clinical trial in patients with advanced solid tumors and lymphoma, according to the manufacturer.
- Dosing-ranging, Phase 1 studies in mesothelioma have been ongoing ro completed. More than 90% of cancers due to mesothelioma characterized by high levels of VISTA.
Another oral agent is in early stage research. CA-327 is an oral, first-in-class antagonist of the immune checkpoints PD-L1 and T cell immunoglobulin and mucin domain 3 (TIM3).
Early studies with CI-8993, a V-domain Ig suppressor of T-cell activation (VISTA) negative checkpoint ligand are also ongoing. Pancreatic cancer, mesothelioma and prostate cancer are characterized by high levels of VISTA.
Pseudoprogression with Checkpoint Inhibitors
Checkpoint inhibitors may not appear to shrink tumors as quickly as traditional chemotherapeutic agents. In fact, at first glance, it may seem 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 seems that the tumor is growing is size upon imaging, 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.
- This phenomenon can often cause problems for physicians or surgeons who try to evaluate tumor growth or shrinkage to determine if therapy is having a positive effect. Pseudoprogression can make it seem that the tumor is growing, when actually it is not.
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:
- Cancer Vaccines
- Cytokines (interferons and interleukins)
- BCG (Bacillus Calmette-Guérin)
- Oncolytic viruses
- Chimeric antigen receptor (CAR) T-cell therapy, such as Kymriah (tisagenlecleucel), Yescarta (axicabtagene ciloleucel), and Tecartus, now all FDA-approved.
Checkpoint Inhibitors: 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.
Many trials are planned or ongoing. A clincial trial might be an option for you, so consider discussing this topic with your oncologist. Enrolling in a trial might mean you can have access to a treatment you normally would not be able to use.
To view 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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- First-Line Treatment With Merck’s KEYTRUDA® (pembrolizumab) Doubled Five-Year Survival Rate (31.9%) Versus Chemotherapy (16.3%) in Certain Patients With Metastatic Non-Small Cell Lung Cancer Whose Tumors Express PD-L1 (TPS ≥50%). Press Release. Sept 21, 2020. Accessed Nov. 29, 2021 at https://www.merck.com/news/first-line-treatment-with-mercks-keytruda-pembrolizumab-doubled-five-year-survival-rate-31-9-versus-chemotherapy-16-3-in-certain-patients-with-metastatic-non-small-cell-lung-cance/
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Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.