The production of antibodies is the immune system’s way of waging an attack on something threatening. Monoclonal antibodies can be designed as immunotherapies that will attach to specific proteins on cancer cells, flag them for recognition by the immune system, and thus help decimate them. They can also be engineered to “release the brakes” on the immune system so it works more effectively to find and kill cancer cells. The PD-1/PD-L1 and CTLA-4 pathways are immune checkpoints that help cancer cells evade attack. Drugs that inhibit these pathways, and thus enable the immune system to fight cancer, are called immune checkpoint inhibitors, and they are helping patients with life-threatening cancer live for years.
A number of immune checkpoint inhibitors have been approved by the FDA. These include the anti–PD-1/PD-L1 antibodies nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab, and the anti–CTLA-4 antibody ipilimumab.
Unfortunately, not all cancer patients are candidates for these impressive agents. It depends on tumor type, prior lines of treatment, and, in some cases, tumor expression of the biomarker PD-L1. It also depends on the underlying health of the patient. Certain conditions can prohibit their use.
Underlying Conditions Matter
The major underlying medical condition that almost universally disqualifies patients from checkpoint inhibitor therapy is autoimmune disease. “The presence of autoimmune diseases, such as rheumatoid arthritis or lupus, makes patients more susceptible to immune-related toxicities,” said David Ettinger, MD, the Alex Grass Professor of Oncology at Johns Hopkins Medicine, Baltimore, MD.
Some subtypes of autoimmune diseases do not, however, automatically eliminate patients from treatment. For example, the inflammatory type of scleroderma rules out the use of immunotherapies, but the less common fibrotic type does not, according to Dr Et-tinger. It’s a complicated matter, which is why Dr Ettinger, a lung cancer specialist, said he frequently consults with rheumatologists.
“We also often deal with gastroenterologists, nephrologists, endocrinologists, and emergency room doctors,” he said, “because all these specialists can see patients with immune-related complications.”
Some exclusionary conditions may be tumor specific, he added. For example, in lung cancer, underlying interstitial lung disease can cause problems. “You may be a candidate for immune therapy with this, but it’s risky, because one of the complications of immunotherapy is pneumonitis.”
Some data suggest, however, that persons with autoimmune disorders might be safely and effectively treated with checkpoint inhibitors, added Stephanie Andrews, MS, ANP-BC, a nurse practitioner and hospitalist at Moffitt Cancer Center, Tampa, FL, who described these findings at the 2017 Annual Conference of the National Comprehensive Cancer Network in a talk on toxicities related to immunotherapies.
Larger, prospective trials are needed to confirm these findings from small trials, she said. Meanwhile, “According to clinical trial data and the prescribing information for these drugs, persons with autoimmune disorders are not candidates, at least outside of a clinical trial,” she stated. Ms Andrews also emphasized that without good performance status (ECOG 0-1), patients may not be candidates. Nor are immunotherapies the best choice for patients whose disease is rapidly progressing. “We need time to train the T cells to attack. It takes a good 12 weeks for immunotherapies to take effect,” she pointed out.
Metastatic melanoma is the disease that first demonstrated the robust activity of immune checkpoint inhibitors, including ipilimumab, nivolumab, and pembrolizumab. These immunotherapies are approved in melanoma as follows:
- Ipilimumab: For metastatic melanoma, and for stage III melanoma after surgery (ie, adjuvant treatment)
- Nivolumab: For advanced/metastatic melanoma, alone or in combination with ipilimumab
- Pembrolizumab: For advanced/metastatic melanoma
According to a leading researcher in melanoma, an even bigger bang will come from combining these bucks. “Looking at all the mouse data from almost every anti–PD-1/PD-L1 agent, results are better with combinations than with single drugs alone,” said Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center, New York City.
For patients with advanced non–small cell lung cancer (NSCLC) lacking a targetable mutation (such as EGFR or ALK), platinum-based chemotherapy doublets have been the standard of care for 30 years, but this has changed with the emergence of the checkpoint inhibitors.
The anti–PD-1/PD-L1 antibodies nivolumab, pembrolizumab, and atezolizumab each demonstrated improved survival over docetaxel in patients with NSCLC whose disease progressed on platinum-based doublets. One of these agents, pembrolizumab, is now also approved in untreated patients based on results from the KEYNOTE-024 trial, which demonstrated a 40% overall survival benefit among patients receiving pembrolizumab (vs chemotherapy). Nivolumab was also tested in the frontline setting but failed to meet the primary end point.
Pembrolizumab thus became “the ultimate game changer in our therapeutic landscape,” according to lung cancer expert Corey Langer, MD, of the University of Pennsylvania Abramson Cancer Center, Philadelphia, who noted that about one-third of patients with NSCLC would be eligible for this treatment.
Roy Herbst, MD, PhD, a lung cancer specialist from Yale Cancer Center, New Haven, CT, agreed. “Patients with targetable mutations should still get targeted treatment, but those who do not have these mutations should get pembrolizumab,” he said.
The FDA has approved 3 anti–PD-1/PD-L1 agents for NSCLC, with restrictions according to line of treatment and whether patients express the ligand, PD-L1, as follows:
- Pembrolizumab: In the first-line setting for patients with ≥50% expression of PD-L1, and in previously treated patients with ≥1% PD-L1 expression
- Nivolumab: In previously treated patients, with no requirement for PD-L1 expression
- Atezolizumab: In previously treated patients, with no requirement for PD-L1 expression
In kidney cancer, nivolumab is approved for advanced/metastatic disease that progresses on prior therapy.
“There are ongoing trials in the adjuvant setting of immune checkpoint inhibitors, but we don’t have those data yet. My fingers are crossed. Time will tell,” said Eric Jonasch, MD, of The University of Texas MD Anderson Cancer Center, Houston.
Urothelial (Bladder) Cancer
Four checkpoint inhibitors are approved for bladder cancer:
- Nivolumab: In previously treated, advanced disease after progression on platinum-based chemotherapy
- Atezolizumab: In previously treated, advanced disease, and as first-line therapy for patients unable to receive cisplatin
- Pembrolizumab: In previously treated, advanced disease after progression on platinum-based chemotherapy, or first-line in patients who are not eligible for cisplatin chemotherapy
- Durvalumab: In previously treated, PD-L1–positive advanced disease after progression on platinum-based chemotherapy (accelerated breakthrough approval; full approval awaited)
Squamous Cell Carcinoma of the Head and Neck
Nivolumab and pembrolizumab are approved for recurrent or advanced head and neck cancer previously treated with platinum-based chemotherapy.
Classical Hodgkin Lymphoma
The one hematologic cancer for which checkpoint inhibitors have proved effective, so far, is classical Hodgkin lymphoma. Pembrolizumab can be prescribed in patients for whom previous drugs have not worked or whose disease has progressed after 3 lines of therapy. Nivolumab can be prescribed for recurrent or metastatic disease after patients have received autologous stem cell transplantation and brentuximab vedotin.
Merkel Cell Carcinoma
One checkpoint inhibitor—avelumab—is approved for this rare but often deadly skin cancer. It can be administered as a first-line agent to patients with Merkel cell carcinoma.
MSI-H or dMMR Solid Tumors
Accelerated approval was granted to pembrolizumab for the treatment of unresectable or metastatic solid tumors that are identified as having a biomarker referred to as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This is the first time the FDA has approved a cancer treatment based on a common biomarker rather than the location in the body where the tumor originated. This indication covers patients with solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options and patients with colorectal cancer following treatment with certain chemotherapy drugs.
“This is an important first for the cancer community,” said Richard Pazdur, MD, acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence. “Until now, the FDA has approved cancer treatments based on where in the body the cancer started—for example, lung or breast cancers. We have now approved a drug based on a tumor’s biomarker without regard to the tumor’s original location.”