Although all research achievements highlighted in this report are remarkable, one area clearly stands out from the rest: cancer immunotherapy, ASCO’s Advance of the Year. In just a few short years, researchers and regulators have moved several different immunotherapy strategies from bench to bedside.
From the first astounding successes in advanced melanoma, there is now evidence that immunotherapy works against a range of cancers. Even for patients who have exhausted all traditional treatments, immunotherapy is able to halt cancer growth, often with only mild adverse effects.
Scientists first conceived the idea of manipulating the body’s immune system to attack cancer more than a century ago. However, the task proved to be fraught with challenges and setbacks. It would take a deeper understanding of both cancer biology and the immune system before safe and effective immunotherapy could be delivered to patients.
As fundamental research on cancer immunotherapy intensified, clinical trials of promising approaches followed in quick succession. Two main strategies are now being explored, both achieving major success over the past year. The first involves unleashing the body’s natural immune response to cancer, and the second helps the immune system find and destroy cancer cells.
Immune Checkpoint Inhibitors: Enhancing the Immune Response to Cancer
An overactive immune system can lead to excessive inflammation and development of autoimmune disorders. The body uses molecules known as immune checkpoints to control the strength and duration of immune responses, minimizing damage to healthy tissue. Some tumors produce these same molecules and thereby suppress the immune response to the tumor.
The first FDA-approved immune checkpoint inhibitor, ipilimumab, blocks the CTLA-4 molecule on T cells, which leads to a broad enhancement of immune responses, including attacks on cancer cells. A range of newer drugs targets a different immune checkpoint protein known as PD-1. The treatments work by preventing cancer cells from attaching to the PD-1 protein on immune cells, which leads to an increased antitumor immune response and generally fewer adverse effects.
Melanoma Immunotherapy Moves Ahead: Comparing and Combining Treatments
By the end of 2014, three life-extending checkpoint inhibitor immunotherapies were FDA approved for the treatment of advanced melanoma: ipilimumab, nivolumab, and pembrolizumab. Overall, these new drugs have surpassed the efficacy of traditional melanoma treatments. Nevertheless, advanced melanoma remains incurable, although prolonged remissions induced by these immunotherapies extend life for multiple years for certain patients. In 2015, new studies explored how these three treatments stack up against one another and how to maximize their overall benefit—as stand-alone therapies and as combination regimens.
Ipilimumab, a CTLA-4 immune checkpoint inhibitor, was the first treatment to extend the lives of patients with advanced melanoma. Yet, recent evidence suggests that nivolumab and pembrolizumab, both PD-1 checkpoint inhibitors, may be more effective than ipilimumab. For example, in a recent phase III study, the 1-year survival rates were 68% and 74% for patients treated with pembrolizumab (depending on treatment schedule), compared with 58% for those who received ipilimumab.1 In addition, pembrolizumab was associated with a lower rate of severe adverse effects, such as fatigue, diarrhea, rash, and colon inflammation (colitis).
Patients with advanced melanoma that worsens after ipilimumab or ipilimumab and a BRAF inhibitor (for patients with BRAF-mutated melanoma) gained a new treatment option in 2014.2 The FDA granted accelerated approval to the PD-1 checkpoint inhibitor nivolumab on the basis of preliminary findings from a phase III trial.3 In this clinical trial, tumors shrunk in 32% of patients treated with nivolumab and only in 11% of those who received standard chemotherapy. Longer follow-up will be needed to determine if nivolumab extends survival of patients with advanced melanoma.
The US Food and Drug Administration Accelerated Approval Program allows for earlier approval of drugs that treat serious conditions and that fill an unmet medical need on the basis of a surrogate or intermediate end point that is reasonably likely to predict clinical benefit. After receiving early approval, clinical trials must still be performed to confirm the anticipated clinical benefit of the treatment. Approval of a drug may be withdrawn or the labeled indication of the drug may be changed if trials fail to confirm clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug.
Severe adverse effects of nivolumab included increased pancreatic and liver enzymes (lipase, ALT, AST), anemia, and fatigue, whereas chemotherapy was associated with more hematologic toxicity, including lower white blood cell counts (neutropenia, thrombocytopenia) and anemia. Severe treatment-related adverse effects occurred less frequently with nivolumab than with chemotherapy.
More broadly, these findings imply that patients whose tumors stopped responding to one type of immune checkpoint inhibitor may still benefit from a different checkpoint inhibitor. In fact, some experts believe that combining immunotherapies may be the most promising strategy for patients with advanced melanoma.
An early-stage clinical trial of an immune checkpoint inhibitor combination showed encouraging results.4 Tumor shrinkage rates were nearly six-fold higher (61% v 11%) among patients with untreated advanced melanoma who received ipilimumab and nivolumab than among those who received ipilimumab and placebo.
The combination treatment controlled tumor growth longer than ipilimumab alone, but the rates of severe adverse effects, colitis, diarrhea, and elevated liver enzyme (ALT) levels were higher with the immunotherapy combination (54% v 24%). On the basis of these findings, the FDA granted accelerated approval to nivolumab in combination with ipilimumab for the treatment of patients with advanced melanoma without the BRAF V600 genetic mutation.5
Meanwhile, results from a larger phase III trial of the same immunotherapy combination were also reported in 2015.6 The trial included nearly 1,000 patients with advanced melanoma who had not previously received cancer treatment. The median time before the disease worsened was 11.5 months with ipilimumab and nivolumab, 7 months with nivolumab alone, and 3 months with ipilimumab alone.
The rates of adverse effects were consistent with prior studies and were the highest among patients who received the immunotherapy combination. Given that the combination treatment was associated with the highest rate of severe adverse effects, the researchers also sought to determine whether there would be a particular group of patients who could benefit from this treatment.
They found that patients with higher levels of the PD-L1 protein in their tumors seemed to do as well with nivolumab alone as with the combination, with a median period of 14 months before the disease became worse. In contrast, patients with low PD-L1 levels in their tumors benefited much more from the combination than from nivolumab alone. If validated, these findings would provide clinically relevant information for appropriate selection of patients who are most likely to benefit, while sparing patients in whom toxicities would not be justified.
New Treatment Paradigm For Lung Cancer
The role of immunotherapy reached beyond melanoma to include patients with lung cancer in 2015. Highly promising clinical trials explored the role of immunotherapy using agents directed toward the PD-1 or PD-L1 immune checkpoint proteins. In addition, physicians gained new insight into which patients may benefit most from these drugs.
Lung cancer is the most common malignancy worldwide and the leading cause of cancer-related death, taking 1.6 million lives each year (according to WHO 2012 estimates). Although advanced lung cancer remains incurable, targeted therapies, such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma receptor tyrosine kinase (ALK) inhibitors, may help control tumor growth. However, only a small proportion of patients with tumors that harbor specific genetic abnormalities can benefit from targeted therapies at this time.
Non–small-cell lung cancer (NSCLC) is the most common form of lung cancer, accounting for 85% of all cases. With modern platinum-based chemotherapy, the median life expectancy is only approximately 10 months. For patients whose disease worsens after initial treatment, docetaxel chemotherapy offers only a modest improvement in survival.
Moreover, the adverse effects of chemotherapy are too difficult for many patients to bear. Growing research evidence suggests that immunotherapy may be able to control advanced lung cancer longer, with fewer adverse effects.
In March 2015, the FDA approved nivolumab for the treatment of squamous NSCLC that worsens after platinum-based doublet chemotherapy.7 The approval was given on the basis of findings from a randomized clinical trial of patients with advanced, squamous NSCLC.8 The clinical trial reported that compared with standard second-line chemotherapy, nivolumab significantly improved the median overall survival (9 months v 6 months), nearly doubling the 1-year survival rate (42% v 24%).
Another randomized trial showed that nivolumab can provide a similar benefit to patients with advanced nonsquamous NSCLC, the predominant form of the disease.9 Compared with standard chemotherapy, the median survival was prolonged with nivolumab (12.2 months v 9.4 months). This clinical trial also suggested that patients who had tumors with high PD-L1 levels experienced more benefit from nivolumab.
Generally, nivolumab was easier for patients to tolerate than docetaxel, causing fewer adverse effects. No new toxicities were reported with nivolumab in the treatment of NSCLC. However, rare but serious inflammation involving the lungs (pneumonitis), colon (colitis), and kidneys (nephritis) was also reported in this trial. In October 2015, the FDA expanded the approved use of nivolumab to treat patients with nonsquamous NSCLC whose disease worsened during or after platinum-based chemotherapy.10
Perhaps even more promising than the finding that immune checkpoint inhibitors are active for patients with lung cancer are the early results showing that these responses are quite durable. For example, in one early clinical trial that included patients with advanced, squamous, or nonsquamous NSCLC, the 2- and 3-year survival rates were 42% and 27%, respectively, at the dose chosen for further development.11
Treatment with the PD-1 blocking immunotherapy pembrolizumab was associated with a median survival of 12 months in another early study of patients with advanced, previously treated NSCLC. Overall, tumors shrank in approximately one in five patients, but the rate was again much greater in those with high PD-L1 levels, of whom nearly half experienced tumor shrinkage.12 This group of patients also lived longer before the cancer worsened. No new safety concerns were reported.
In September 2015, the FDA granted accelerated approval to pembrolizumab as a treatment for patients with advanced, PD-L1-positive NSCLC that worsens after other treatments.13 Early reports from ongoing studies have suggested that nivolumab and pembrolizumab may also be effective as initial therapies for patients with advanced NSCLC.14,15
A new immune checkpoint inhibitor, atezolizumab, has also shown promising results in the treatment of advanced NSCLC. Atezolizumab unleashes the immune response to cancer by blocking the PD-L1 protein on tumor cells. In an early study, the median survival among patients who received atezolizumab was 12.6 months, compared with 9.7 months among those treated with docetaxel chemotherapy.16
As in the other studies, patients with the highest levels of PD-L1 in their tumors and immune cells benefited even more. In this group, the median survival was 15.5 months with immunotherapy, compared with 11.1 months with docetaxel. In contrast, among patients with low PD-L1 levels, atezolizumab did not extend survival compared with docetaxel.
Fewer patients experienced severe treatment-related adverse effects in the atezolizumab group compared with the docetaxel group. The most common severe adverse effects related to atezolizumab were pneumonia and increased AST levels.
In February 2015, the FDA granted atezolizumab a breakthrough therapy designation for the treatment of PD-L1–positive NSCLC that worsens after platinum chemotherapy, and a randomized phase III trial for this indication is under way (ClinicalTrials.gov identifier: NCT02486718). Other ongoing phase III clinical trials are exploring atezolizumab in combination with chemotherapy.
Breakthrough Therapy Designation
The US Food and Drug Administration (FDA) Breakthrough Therapy Designation serves to expedite the development and review of drugs for treating serious or life-threatening illnesses where preliminary clinical data suggest the drug may provide a substantial improvement in patient outcomes. The designation helps ensure patients gain faster access to promising new treatments through FDA approval.
The therapeutic mechanism of immune checkpoint inhibitors—unleashing immune response to cancer—is profoundly different from that of standard treatments for NSCLC. This may explain the longer duration of benefit some patients experience from immunotherapy compared with chemotherapy or targeted therapy. Unlike other therapies, the effects of immunotherapy can persist long after the patient stops treatment. Future research directions for lung cancer immunotherapy include evaluating combinations of PD-1 or PD-L1 inhibitors with chemotherapy, targeted therapy, and other types of immunotherapy.
Broadening The Possibilities For Checkpoint Inhibitors
The past year brought early reports suggesting that immune checkpoint inhibitors targeting PD-1 and PD-L1 are effective across a range of different cancer types, beyond melanoma and lung cancer. A particularly encouraging finding was that immunotherapy was effective against many tumors that were resistant to traditional treatments.
In the last three decades, there has been little progress in the treatment of advanced bladder cancer. Most patients with advanced bladder cancer are older (the median age of diagnosis is 73 years), and many suffer from kidney impairment. As a result, many patients forgo chemotherapy to avoid its difficult adverse effects. Outcomes are poor for patients who cannot tolerate chemotherapy or whose cancer worsens after initial chemotherapy.
Findings from an early clinical trial of patients with advanced urothelial bladder cancer bring new hope.17 The PD-L1 immune checkpoint inhibitor atezolizumab shrank tumors rapidly—within weeks of starting treatment in many study participants. Again, atezolizumab was particularly effective for patients who had high PD-L1 levels in their tumors and immune cells, with approximately half of these patients experiencing tumor shrinkage. The median duration of response was much longer than that typical for chemotherapy.
The most commonly reported treatment-related adverse effects were decreased appetite and fatigue. Severe adverse effects, such as weakness (asthenia) and hematologic abnormalities (thrombocytopenia and decreased blood phosphorus), occurred in 4% of patients. On the basis of these findings, the FDA granted atezolizumab a breakthrough therapy designation for the treatment of PD-L1–positive, advanced bladder cancer in 2014. An ongoing phase III trial seeks to compare atezolizumab with standard chemotherapy in patients with advanced bladder cancer (ClinicalTrials.gov identifier: NCT02302807).
Advanced kidney cancer is another malignancy in dire need of better treatments. The most common type of kidney cancer in adults is called renal cell carcinoma (RCC). At the time of diagnosis, nearly one third of patients with RCC already have metastatic disease, which is difficult to treat.
The last major advance in kidney cancer care occurred a decade ago, with the introduction of targeted therapies for metastatic RCC. Vascular endothelial growth factor (VEGF)–directed therapies and inhibitors of the mammalian target of rapamycin (mTOR) extended the median survival of patients with this disease from 1 year to nearly 3 years.
Yet, new drugs are needed to further extend survival when kidney cancers worsen despite VEGF- and mTOR-targeted therapies. Recent research has suggested that PD-1–directed immunotherapy may improve the outlook for at least some of these patients.
In a randomized phase II trial, nivolumab shrank tumors in approximately 20% of patients with metastatic clear cell RCC who were previously treated with a VEGF inhibitor.18 One striking result was related to the durability of these responses, which lasted more than 22 months in some patients. The median overall survival extended up to 25 months, roughly 1 year longer than is typically achieved with targeted therapies, as reported in prior clinical trials of patients with advanced RCC. Fatigue was the most common treatment-related adverse effect.
Meanwhile, larger ongoing trials are exploring additional uses of PD-1–directed therapies for metastatic RCC. In a phase III study of patients with advanced RCC who were previously treated with VEGF inhibitors, nivolumab improved outcomes compared with the mTOR inhibitor everolimus.19 The median survival was 25 months with nivolumab versus 19.6 months with everolimus. The toxicity profile of nivolumab was consistent with prior reports. However, compared with everolimus, there were fewer severe treatment-related adverse events reported.
Furthermore, although tumors shrank in 25% of patients treated with nivolumab, only 5% of those treated with everolimus experienced tumor shrinkage. Interestingly, however, everolimus delayed tumor growth for a similar length of time as nivolumab, approximately 4 months.
Another ongoing phase III trial is investigating the combination of nivolumab and ipilimumab as an initial treatment for advanced kidney cancer (ClinicalTrials.gov identifier: NCT02231749). The FDA approved nivolumab for the treatment of advanced RCC in November 2015.20
Liver cancer is the second most common cause of death resulting from cancer worldwide, claiming approximately 750,000 lives each year.21 The most common type of liver cancer is hepatocellular carcinoma (HCC). The only FDA approved treatment for advanced HCC, sorafenib, extends survival by merely 3 months.
Last year, researchers reported preliminary findings showing a promising role for nivolumab in the treatment of metastatic HCC.22 In the small study, nearly 20% of patients had marked tumor shrinkage in response to nivolumab. Tumors completely disappeared in two patients.
The responses were durable, lasting 9 months or longer in nearly all patients who responded. At 1 year, 62% of patients treated with nivolumab were still alive. This is a dramatic improvement when compared with the historical tumor response rate for sorafenib of only 2% to 3% and 1-year survival rate of 30%. Again, no new safety signals were reported. Of note, severe adverse effects of nivolumab included elevated ALT, AST, and lipase levels.
These early findings suggest that immunotherapy may be an effective treatment for some patients with advanced liver cancer. An expansion phase of this study, which seeks to recruit 400 patients, is projected to be completed in 2018 (ClinicalTrials.gov identifier: NCT01658878).
Head and Neck Cancer (HNC)
People with recurrent or metastatic HNC have a poor prognosis. With existing treatments—chemotherapy and the targeted drug cetuximab— survival ranges from 10 to 12 months, on average. Overall, few patients respond to these treatments, and adverse effects are significant.
Early findings suggest PD-1 immune checkpoint inhibitors are active in patients with HNC. In one small trial, approximately 25% of patients who received the PD-1 immune checkpoint inhibitor pembrolizumab experienced tumor shrinkage.23 In contrast, the reported response rate to cetuximab was less than 13% in prior clinical trials. Although the toxicity profile of pembrolizumab in this population was similar to that in other trials, only 10% of patients experienced severe adverse effects, such as swelling of the face and lung inflammation (pneumonitis).
Perhaps as important, these agents might be active regardless of whether HNC is associated with human papillomavirus (HPV). It is well known that a subgroup of HNCs is HPV-positive disease, and that these tumors respond better to standard treatment than those that are HPV negative. Yet, in the clinical trial discussed here,23 pembrolizumab was active across a wide range of patients, including those with HPV-positive and HPV-negative tumors.
Although these early data are encouraging, larger studies are needed to determine if pembrolizumab can prolong patient survival. Two phase III trials evaluating pembrolizumab versus standard treatment in patients with recurrent or metastatic HNC are already under way (ClinicalTrials.gov identifiers: NCT02358031 and NCT02252042).
Blood Cancer: Hodgkin Lymphoma
Hodgkin lymphoma is a cancer of the lymphatic system, and it is most common in two age groups: age 15 to 40 years (particularly young adults in their 20s) and older than age 55 years. With existing initial treatments, four of five patients survive 5 years after a Hodgkin lymphoma diagnosis. People with the disease seldom experience recurrence if a complete response is achieved with initial treatment. When Hodgkin lymphoma does come back, however, it is more difficult to treat. At that time, patients are typically offered additional chemotherapy, radiation therapy, or stem-cell transplantation.
Emerging research data suggest that immunotherapy, specifically PD-1 blockade, may play a role in the treatment of recurrent Hodgkin lymphoma. Moreover, it has been speculated that a certain genetic abnormality makes Hodgkin lymphoma particularly vulnerable to PD-1 blockade. Findings from a small clinical trial of adult patients with recurrent Hodgkin lymphoma support this hypothesis (this study was funded in part by a grant from the NIH).24
Nearly all the patients in the trial had previously received three or more treatments, including stem-cell transplantation and a targeted drug. Remarkably, the great majority (20 of 23 patients) responded to nivolumab, with cancer completely disappearing in 17%. By 6 months, only 14% of patients experienced disease progression.
The most common treatment-related adverse effects were rash and decreased platelet count (thrombocytopenia). Severe treatment-related adverse effects were rare.
Genetic Abnormality Tied To Better Response To PD-1 Immunotherapy
Tumors with a high number of genetic mutations are likely to trigger a strong immune response, because they make more proteins (antigens) that the immune system recognizes as foreign. Melanoma, bladder cancer, and lung cancer are among the cancers with the most mutations.
In some patients with other types of cancers, the tumors have large numbers of mutations as a result of a genetic abnormality called mismatch repair deficiency, which undermines the ability of a cell to repair DNA damage. Scientists have speculated that tumors with this abnormality may be susceptible to immune checkpoint blockade.
Mismatch repair deficiency occurs in approximately 15% of colorectal cancers. It is also found less frequently in other types of cancer, such as stomach, small bowel, endometrial, prostate, and ovarian cancers. The abnormality is sometimes inherited from parents, as is the case for patients with Lynch syndrome, but more often, mismatch repair deficiency develops at random during a person’s life.
Furthermore, the researchers found that pembrolizumab was active against other types of cancer with mismatch repair deficiency, such as endometrial, ampullary, duodenal, and stomach cancers. Five of seven patients responded to pembrolizumab, and the median time to disease progression was 5.4 months.
The toxicity profile of pembrolizumab was similar to that in other trial reports. Severe adverse effects, such as low serum protein levels (hypoalbuminemia), low blood cell counts (anemia and lymphopenia), and bowel obstruction, occurred in 41% of patients.
Although this study was small, it opens the possibility of a new treatment option for patients with advanced cancer who have tumors with mismatch repair deficiency. More broadly, it shows that evaluation of the tumor genome can help identify patients who benefit from immunotherapy, regardless of the type of tumor they have. It is already suspected that cancers with other DNA repair deficiencies might also be sensitive to PD-1 blockade.
Mismatch Repair Deficiency: A New Understanding of Cancer Genetics Proves Life Changing for Mike Chettle
“It’s shocking to see your name on a diagnosis like that,” said Mike Chettle, four years after he first learned that he had duodenal and colon cancer.
Mike had known that he had a family history of Lynch syndrome, an inherited condition that increases the risk for certain types of cancer, particularly colorectal. Because of this, he took precautions and underwent regular screening. In 2011, however, he developed a bleeding ulcer that turned out to be cancer.
With his diagnosis began a litany of treatments–“It was a long, long road,” said Mike. His first treatments included a complex surgery involving the colon and several organs, followed by chemotherapy.
A year later, the cancer had spread to Mike’s liver. He underwent another surgery, and it was then that doctors discovered 26 tumors throughout his abdomen. Subsequent treatment included various chemotherapy regimens, which caused Mike numerous side effects, including nausea, vomiting, neuropathy and “chemo brain.” Today, nearly four years later, he still experiences many of chemotherapy’s lingering effects.
All the treatments proved unsuccessful, however. Two years ago, Mike was told that the cancer had spread to his bones. Cancerous spots were also still present on his liver.
“It was spreading fast,” he recalled. “I was limping. I couldn’t turn my neck. I was in a lot of pain.” He had exhausted all treatment options and was at the point of considering comfort care.
The turning point came when his oncologist, Steven M. Duffy, MD, of the Bon Secours Cancer Institute Medical Oncology at St. Mary’s in Richmond, Virginia, referred Mike to Luis Diaz, MD, an attending physician at Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland. “I probably wouldn’t be alive if he hadn’t sent me there,” reflects Mike.
Dr. Diaz suggested Mike enroll in a phase II clinical trial he was conducting that studied a genetic abnormality called mismatch repair (MMR) deficiency. Dr. Diaz, together with Dung T. Le, MD, sought to determine whether this abnormality makes tumors more susceptible to treatment with a drug called pembrolizumab, an immunotherapy that targets an immune checkpoint known as the PD-1 checkpoint.
“Opening the door to this effective new therapy is a breakthrough for this subset of patients with metastatic colon cancer and other hard-to-treat cancers,” said Dr. Le.
Within two or three months of enrolling in the trial, Mike’s symptoms began to subside. “I was able to turn my neck again,” Mike said. By the time his daughter’s wedding took place a few months later, he was experiencing noticeable improvement. Mike walked her down the aisle.
The new treatment comes with minimal side effects compared to what Mike experienced with chemotherapy, and it is also more convenient. He receives a half-hour infusion every two weeks, as opposed to four- or five-hour infusions for chemo. “Half an hour treatment, and then I’m on my way home,” he said.
Mike has been on the trial for almost two years and has experienced a complete response to the treatment, meaning nearly all tumors have disappeared. “I feel like I’ve been blessed to have good doctors who led me to where I am, to be in that trial,” he said.
Dung T. Le, MD
Photo: Flynn Larsen
“It’s satisfying to see patients like Mike respond and do well,” said Dr. Le. “While he still has to come see us every couple of weeks, we hope soon that he can transition into the stage of care called surveillance, a time when we actively monitor him after treatment is no longer needed. He may only need scans every few months.”
The researchers anticipate that other patients with MMR deficiency will benefit from these findings for years to come and that the study will have broad implications for patients with a wide range of cancers going forward. “This study is really about bridging immunotherapy and genomics for the benefit of patients,” said Dr. Le, reiterating the importance of clinical trials in advancing cancer care. Mike feels that by participating in a clinical trial, he became one of the lucky ones.
Mike is pictured above with his wife. See "Genetic Abnormality Tied to Better Response to PD-1 Immunotherapy" above to learn more about the trial that saved Mike’s life, featured as one of the year’s top cancer advances.
Novel Immunotherapy Approaches Boost The Immune System
T-Cell Therapies Promising For Blood Cancers
In addition to immune checkpoint inhibitors, researchers are exploring other immunotherapy approaches, all of which are centered on T cells. A unique new immunotherapy, the antibody blinatumomab, attaches to two different proteins on white blood cells: CD19 on B cells and CD3 on T cells. By doing so, the antibody brings the cancer-killing T cells into contact with the malignant B-cell leukemia cells.
In an early-stage trial, nearly one third of patients with relapsed or treatment-resistant ALL had no evidence of cancer (complete remission) after receiving blinatumomab.26 The responses were durable, lasting more than 6 months in many patients.
The study participants had an uncommon but aggressive type of ALL known as Philadelphia chromosome–negative precursor B-cell ALL, a rapidly growing cancer in which the bone marrow makes too many immature white blood cells. On the basis of these results, in December 2014, the FDA approved blinatumomab to treat this difficult disease.27
CAR T-cell therapy: this promising new treatment involves
collecting T cells from a patient, genetically reprogramming them in the lab, and infusing them into the patient to find and attack cancer cells.
Although more research is needed to determine whether blinatumomab can improve survival compared with standard chemotherapy, it seems that immunotherapy will play a role in the treatment of ALL. Future directions include exploring use of blinatumomab earlier in the course of the disease and in combination with other therapies.
Another unique new strategy is the so-called chimeric antigen receptor (CAR) T-cell therapy. This approach involves collecting T cells from a patient, genetically reprogramming them in the laboratory, and infusing them back into the patient. The reprogrammed T cells make specific proteins that enable them to find and attack cancer cells throughout the body.
Early reports have suggested that patients with various difficult-to-treat blood cancers might benefit from CAR T-cell therapy. For example, CD19-directed CAR T cells are programmed to attack malignant B cells that have the CD19 molecule on their surface.
Although these findings are promising and support further research, the studies were small and limited to patients with hard-to-treat cancers. It is not yet clear if CAR T-cell therapy will have broader use in the future. In addition, because CAR T-cell therapy can cause considerable toxicities, such as fever (pyrexia), low blood pressure (hypotension), delirium, and neurologic adverse effects, it is administered only in specialized clinical centers at this time.
A Policy Focus: The 21st Century Cures Act
"The 21st Century Cures is the promise of the future. This initiative will provide the next generation of doctors with powerful tools that will alleviate human suffering—and fight cancer—on a scale never before known."
— Rep. Michael C. Burgess, MD (R-TX)
Cancer Vaccines: A Potential New Treatment Option For Brain Cancer
Glioblastoma is an aggressive and incurable form of brain cancer. Most patients are diagnosed when the disease is already at an advanced stage. Although surgery and chemotherapy can be effective initially, the cancer inevitably worsens over time. After a relapse, few treatment options remain, and the average survival duration is only 1.5 years.
Researchers have been exploring several new avenues for treating brain cancer, including immunotherapy strategies, such as vaccines, which deliver substances that trigger a specific immune response. Unlike prevention vaccines such as the HPV vaccine, the goal of therapeutic cancer vaccines is not to prevent cancer but to help the immune system find and attack it.
Preliminary findings from a phase II trial indicate that therapeutic cancer vaccines can improve outcomes for patients with relapsed glioblastoma.30 The rindopepimut vaccine works against glioblastoma tumors with a specific genetic mutation known as EGFRvIII, which contributes to uncontrolled growth of brain tumors. The mutation occurs in approximately one in four glioblastomas. It does not occur in healthy brain tissue.
In the study, patients with recurrent glioblastoma who received the vaccine along with the targeted drug bevacizumab developed an immune response to the cancer. Compared with patients who received bevacizumab alone, those who also received the vaccine experienced greater tumor shrinkage and a longer time before disease worsening. The median survival in the vaccine group was 12 months compared with 8.8 months in the bevacizumabalone group. The most common toxicity of rindopepimut was a mild injection site reaction.
In early 2015, the FDA granted rindopepimut breakthrough therapy designation for EGFRvIII-positive glioblastoma. A phase III trial of rindopepimut in patients newly diagnosed with this type of glioblastoma is under way (ClinicalTrials.gov identifier: NCT01480479). Meanwhile, several ongoing, early-stage clinical trials are exploring other vaccines for glioblastoma. Cancer vaccines are also being explored as treatments for a range of other cancers, including breast, lung, bladder, cervical, kidney, pancreatic, prostate, and blood cancers.
A Policy Focus: Expanding Cancer Research to Include More Older Adults
Continuing Immunotherapy Research
Altogether, the rapid succession of immunotherapy research advances heralds a new pillar of cancer treatment beyond the traditional staples of chemotherapy, radiation therapy, and surgery. Compared with chemotherapy and targeted therapy, immunotherapy has the potential to control tumor growth much longer and often with fewer adverse effects.
It seems reasonable that harnessing a patient’s own immune system to fight cancer would be universally effective. In many studies thus far, however, only a minority of patients have benefited from immunotherapy approaches. With initial immunotherapies proving effective for some patients, researchers are now exploring ways to improve outcomes for more patients. These include combining different immunotherapies, using immunotherapy in combination with other traditional treatments, and starting immunotherapy earlier in the course of the disease.
Researchers are also studying ways to reliably predict response to immunotherapy, so patients can be spared the adverse effects and costs of treatments that may not help them. In addition, longer follow-up of patients who have received immunotherapies in clinical trials will help assess the true clinical benefit of these approaches.
- Robert C, Schachter J, Long GV, et al; KEYNOTE-006 investigators: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521-2532, 2015
- US Food and Drug Administration: FDA approves Opdivo for advanced melanoma. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427716.htm
- Weber JS, D’Angelo SP, Minor D, et al: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375-384, 2015
- Postow MA, Chesney J, Pavlick AC, et al: Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372:2006-2017, 2015
- US Food and Drug Administration: Nivolumab in combination with ipilimumab. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm465274.htm
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23-34, 2015
- US Food and Drug Administration: FDA expands approved use of Opdivo to treat lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436534.htm
- Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med 373:123-135, 2015
- Paz-Ares L, Horn L, Borghael H, et al: Phase III, randomized trial (CheckMate 057) of nivolumab versus docetaxel in advanced non-squamous non-small cell lung cancer. J Clin Oncol 33, 2015 (suppl; abstr LBA109)
- US Food and Drug Administration: FDA expands approved use of Opdivo in advanced lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm466413.htm
- Gettinger SN, Horn L, Gandhi L, et al: Overall Survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non–small-cell lung cancer. J Clin Oncol 33:2004-2012, 2015
- Garon EB, Rizvi NA, Hui R, et al; KEYNOTE-001 Investigators: Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015
- US Food and Drug Administration: FDA approves Keytruda for advanced non-small cell lung cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm465444.htm
- Rizvi N, Garon E, Patnaik A, et al: Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 32:507s, 2014 (suppl; abstr 800)
- Gettinger S, Shepherd F, Antonia S, et al: First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status. J Clin Oncol 32:512s, 2014 (suppl; abstr 8024)
- Vansteenkiste J, Fehrenbacher L, Spira AI, et al: Atezolizumab monotherapy vs docetaxel in 2L/3L non-small cell lung cancer: Primary analyses for efficacy, safety and predictive biomarkers from a randomized phase II study (POPLAR). Presented at the European Cancer Congress, Vienna, Austria, September 25-29, 2015 (abstr 14LBA)
- Powles T, Eder JP, Fine GD, et al: MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515:558-562, 2014
- Motzer RJ, Rini BI, McDermott DF, et al: Nivolumab for metastatic renal cell carcinoma: Results of a randomized phase II trial. J Clin Oncol 33:1430-1437, 2015
- Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investigators: Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803-1813, 2015
- US Food and Drug Administration: FDA approves Opdivo to treat advanced form of kidney cancer. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473971.htm
- GLOBOCAN 2012: Estimated cancer incidence, mortaliy, and prevalence worldwide in 2012. http://globocan.iarc.fr/Default.aspx
- El-Khoueiry AB, Melero I, Crocenzi TS, et al: Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040. J Clin Oncol 33, 2015 (suppl; abstr LBA101)
- Seiwert TY, Haddad RI, Gupta S, et al: Antitumor activity and safety of pembrolizumab in patients (pts) with advanced squamous cell carcinoma of the head and neck (SCCHN): Preliminary results from KEYNOTE-012 expansion cohort. J Clin Oncol 33, 2015 (suppl; abstr LBA6008)
- Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372:311-319, 2015
- Le DT, Uram JN, Wang H, et al: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509-2520, 2015
- Topp MS, Gökbuget N, Stein AS, et al: Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: A multicentre, single-arm, phase 2 study. Lancet Oncol 16:57-66, 2015
- US Food and Drug Administration: FDA approves Blincyto to treat a rare form of acute lymphoblastic leukemia. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm425549.htm
- Maude SL, Frey N, Shaw PA, et al: Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371:1507-1517, 2014
- Kochenderfer JN, Dudley ME, Kassim SH, et al: Chemotherapyrefractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 33:540-549, 2015
- Reardon DA, Schuster J, Tran DD, et al: ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. J Clin Oncol 33, 2015 (suppl; abstr 2009)