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.
One small trial reported last year provided the first evidence that mismatch repair–deficient tumors are susceptible to PD-1 blockade (this study was funded in part by a grant from the NIH).25 Four of 10 patients with mismatch repair–deficient colorectal cancer responded to treatment with the immune checkpoint inhibitor pembrolizumab (the median progression-free and overall survival were not reached). In contrast, none of the eight patients with colorectal cancers that were not mismatch repair deficient experienced tumor shrinkage; the median progression-free survival was 2.2 months.
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.