�ٺ���Ƶ

As recently as 2016, when patients with advanced bladder cancer were too medically frail to take the standard-of-care chemotherapy agent cisplatin, oncologists had no effective alternatives to offer. Today, the field of immunotherapy is expanding the options for these patients—and for those with triple-negative breast cancer, recurrent Hodgkin lymphoma, melanoma, and lung cancer. In clinical trials led by Perlmutter Cancer Center physicians, a significant portion of patients with these refractory cancers were able to achieve lasting remission—providing key evidence that could swiftly change practice patterns.

First Effective Treatments for Advanced Bladder Cancer in Three Decades

By harnessing the immune system to target bladder cancer, researchers have yielded two discrete new treatment agents. Based primarily on clinical trials led by Arjun V. Balar, MD, assistant professor of medicine and director of the Genitourinary Medical Oncology Program, the FDA approved atezolizumab (Tecentriq®) and pembrolizumab (Keytruda®) as first-line treatments for these particularly frail patients with advanced bladder cancer in early 2017. These immune system–boosting agents are the first-ever FDA-approved treatments for cisplatin-ineligible bladder cancer.

In the clinical evaluation of atezolizumab, published in The Lancet in January 2017, bladder tumors shrank by at least 30 percent and new tumor growth stalled in 28 (24 percent) of 119 patients. All study participants received the medication as their initial therapy for the disease. Similarly, pembrolizumab shrank tumors by at least a third in 24 percent of patients. Of those, 6 percent saw their tumor lesions disappear. The pembrolizumab study was published in The Lancet Oncology in November 2017. All patients enrolled in the study were ineligible for cisplatin because of medical frailty.

“Responses with non-cisplatin chemotherapy, the previous standard, are short-lived and patients die within 10 months, on average,” says Dr. Balar. “Immunotherapy harnesses the immune system to generate durable responses and is better tolerated than chemotherapy. Immunotherapy is the most important advancement in bladder cancer therapy in more than 30 years, and it has charted a new path in how we will approach understanding and treating this cancer moving forward.”

A Positive for Triple-Negative Breast Cancer

Pembrolizumab has also shown promise for patients with metastatic triple-negative breast cancer (mTNBC). According to an international clinical trial led by Sylvia Adams, MD, associate professor of medicine, breast tumors shrank by more than 30 percent in 12 (23 percent) of 52 patients who received pembrolizumab as first-line therapy, and the disease stabilized in 9 additional patients (17 percent). By contrast, breast tumors shrank by more than 30 percent in just 8 (5 percent) of the 170 patients who had been previously treated with other agents; each of these 8 patients lived at least another year. In addition, the disease stabilized in 35 (21 percent) of the 170 patients. These findings were presented at the June 2017 annual meeting of the American Society of Clinical Oncology.

“The more robust response rates of first-line therapy, compared with second or later lines, suggest that immunotherapy administered earlier in the disease course is more beneficial,” says Dr. Adams.

“Although only a small subset of women responded to the drug, pembrolizumab worked extremely well in that subset and responses were durable,” Dr. Adams adds. “By causing fewer side effects and promoting longer life expectancy, pembrolizumab could help change the outcome of mTNBC.”

Achieving Remission for Relapsed Hodgkin Lymphoma

A combination of complementary immunotherapy drugs brentuximab vedotin (Adcetris®) and nivolumab (Opdivo®) destroyed most cancer cells in 64 percent of patients with recurrent Hodgkin lymphoma, according to the results of an early-phase clinical trial led by Catherine S. Diefenbach, MD, assistant professor of medicine and director of the Clinical Lymphoma Program.

All 19 patients in the study achieved some degree of remission after three months of treatment. Dr. Diefenbach initiated the trial after her research revealed that immune dysfunction in patients with Hodgkin lymphoma could indicate that some standard treatments were less likely to work. These observations led her and her colleagues to test whether drugs that spur the immune system to attack cancer cells, such as checkpoint inhibitors like nivolumab, would work well with the targeted chemotherapy agent brentuximab vedotin. The findings were presented at the December 2016 annual meeting of the American Society of Hematology.

“If further testing proves successful, such dual therapies could become an alternative curative regimen for relapsed Hodgkin lymphoma,” says Dr. Diefenbach.

Nivolumab Safer and More Effective for Advanced Melanoma

The second-generation immune checkpoint inhibitor nivolumab is proving safer and less toxic for patients whose advanced melanoma has a high risk of recurrence after initial resection and therapy.

A head-to-head comparison of nivolumab and ipilimumab, both FDA-approved medications for metastatic melanoma, was conducted with 906 patients with high-risk stage IIIb, IIIc, and IV melanoma. At 18 months, the relapse-free survival rate for nivolumab was 66 percent, compared with 53 percent for ipilimumab. Results of the international trial, led by principal investigator Jeffrey S. Weber, MD, PhD, the Laura and Isaac Perlmutter Professor of Oncology, deputy director of Perlmutter Cancer Center, and co-leader of its Melanoma Research Program, were published in November 2017 in The New England Journal of Medicine.

“Our results demonstrate that nivolumab is more effective in treating patients with stage III and IV resected melanoma, cutting the risk of relapse by a third,” says Dr. Weber. “Results like this will change how we practice medicine. Hopefully, physicians will embrace the use of nivolumab as adjuvant therapy in these high-risk patients.”

Combination Therapy Shows Promise as First-Line Treatment for Advanced Lung Cancer

Pembrolizumab, which has already been shown safe and effective as monotherapy for advanced, non-squamous non-small cell lung cancer (NSCLC), might also be an effective component in combination therapy for the disease.

Led by Leena Gandhi, MD, PhD, associate professor of medicine and director of thoracic medical oncology, researchers from the KEYNOTE-021 study demonstrated for the first time that combining an immune checkpoint inhibitor—in this case, pembrolizumab—with a platinum-doublet chemotherapy regimen might be more effective than chemotherapy alone as first-line treatment for advanced, non-squamous NSCLC. Currently, platinum-doublet chemotherapy is the standard of care for patients without a targetable gene mutation.

The study, published in November 2016 in The Lancet Oncology and presented with updated outcomes at the October 2017 World Conference on Lung Cancer in Yokohama, Japan, reported that 57 percent of patients receiving the combination therapy responded to treatment, whereas only 31 percent responded to chemotherapy alone. The results also showed that the combination therapy significantly prolonged progression-free survival, with a median of 19 months for the combination versus 9 months for the chemotherapy group. In addition, although a survival benefit was not observed upon initial data analysis, results presented at the conference showed that those treated with the combination therapy appeared to live longer than those treated with chemotherapy alone.

Previously, most studies had shown that adding any other agent to platinum-doublet chemotherapy resulted in increased side effects that outweighed additional benefits. However, in this study, researchers found the side effects were comparable in both groups.

Based on the results of this small-scale study, in May 2017, the U.S. Food and Drug Administration granted accelerated approval to this combination regimen. Dr. Gandhi is now leading a larger, confirmatory phase III trial for this therapy (KEYNOTE-189), with preliminary results to be reported in April 2018.