Recent advances in cancer research have led to enormous progress against many cancer types. From 1991 to 2015, we witnessed a 26 percent reduction in the U.S. cancer death rate, representing over 2 million lives saved. Deaths from several common cancers, including breast, lung, prostate, and colorectal cancers, have declined in recent years, which is attributed to smoking cessation, advances in early detection, and treatment improvements.
Progress against many other cancers, however, has been much slower. Death rates for some types of cancer, such as esophageal cancer, have increased in certain populations, and pancreatic cancer is projected to become the second leading cause of cancer-related mortality in the United States by 2030.
To address these areas of unmet clinical need, several presentations at the AACR Annual Meeting 2019 focused on clinical trials in patients with rare or hard-to-treat tumor types.
Combinatorial virotherapy-radiotherapy treatment for vulnerable patients with esophageal cancer
Esophageal cancer was estimated to affect around 17,000 people in 2018, representing 1 percent of all new cancer cases. The disease has a relatively poor prognosis, as the five-year relative survival rate is just over 19 percent.
Common treatment options for patients with esophageal cancer include surgery and chemoradiotherapy, which are fairly invasive. Certain patients, such as the elderly or those with health complications, are unable to receive such treatments.
To investigate treatment options for vulnerable patients with esophageal cancer, a phase I clinical trial evaluated the safety and preliminary efficacy of the experimental oncolytic adenovirus telomelysin (OBP-301) in combination with radiotherapy.
Cancer cells often overexpress the enzyme telomerase, which facilitates their replication and proliferation, explained study presenter Toshiyoshi Fujiwara, MD, PhD, professor and chairman in the department of Gastroenterological Surgery at the Okayama University Graduate School of Medicine, in an AACR press release. Because the genetically modified virus OBP-301 selectively replicates in telomerase-positive cells, viral infection is enriched in cancerous cells and causes their subsequent lysis, he explained. Treatment with the modified virus can also disrupt pathways that control DNA repair, so Fujiwara and colleagues hypothesized that infected tumor cells may be more sensitive to ionizing radiation.
In this open-label, dose-escalation trial, the investigators enrolled 13 patients with esophageal cancer who could not receive standard surgery or chemotherapy; the median patient age was 80 years. Patients received three intratumoral injections of OBP-301 via endoscope over several weeks with concurrent radiation therapy.
The objective response rate was 85 percent, including eight complete responses (CR) and three partial responses (PR). All patients developed transient and self-limiting lymphopenia (a reduction of circulating lymphocytes, which can accompany some immunotherapy treatments), and no dose-limiting toxicities were observed.
“Not only was our combinatorial therapy safe, but it induced the complete eradication of esophageal tumors in most patients,” said Fujiwara in the press release. “These preliminary results indicate that there may be less invasive treatment options available for esophageal cancer patients who are unable to receive standard therapies for their disease.”
Immune checkpoint blockade combination for patients with high-grade neuroendocrine carcinoma
Neuroendocrine tumors (NETs) are a rare type of cancer stemming from aberrant neuroendocrine cells. Because these cells are present throughout the body, NETs can develop anywhere, but are most common in the digestive tract, pancreas, rectum, lung, or appendix. Because patients often do not develop symptoms until late-stage disease, NETs can be difficult to diagnose. Patients with high-grade neuroendocrine carcinoma have few treatment options other than chemotherapy regimens, which can be aggressive.
While the use of immune checkpoint blockade has proven effective in patients with a variety of common tumor types, few studies have evaluated this type of treatment in patients with rare cancers. The aim of the Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) trial is to evaluate the combinatorial efficacy of ipilimumab and nivolumab (anti-CTLA-4 and anti-PD-1, respectively) in patients with rare tumor types. Results from a subgroup analysis of 32 patients with neuroendocrine tumors, excluding pancreatic neuroendocrine cancers, was presented at this year’s meeting by Sandip Patel, MD, associate professor of medicine at the University of California San Diego School of Medicine in La Jolla.
The overall response rate of patients with high-grade carcinoma was 44 percent, with one patient achieving an unconfirmed CR and seven patients achieving PR; no patients with low-grade disease had a CR or PR. In an AACR press release, Patel hypothesized that high-grade neuroendocrine carcinomas may have a higher tumor mutational burden, which can confer a better response to immune checkpoint inhibitors.
The six-month progression-free survival was 31 percent, and the median overall survival was around 11 months. Common toxicities included fatigue and nausea, and a common immune-related adverse event was grade 3-4 abnormal liver function.
“Rare tumor types, as an aggregate, represent nearly a quarter of all cancers,” said Patel in the press release. “Our study highlights the feasibility of performing clinical trials among patients with rare cancers, and hopefully will help dispel the belief that clinical trials are not feasible for this patient population.”
This study was covered by The Associated Press and was published in outlets around the U.S., including The New York Times and The Washington Post.
Maintenance therapy provides clinical responses for subgroup of patients with pancreatic cancer
Pancreatic cancer remains a challenging disease to treat, with an estimated five-year survival rate of less than 9 percent. However, those with mutations in BRCA or PALB2 genes, representing roughly 7 percent of patients with pancreatic cancer, are more likely to have durable responses when treated with platinum-based chemotherapies. Long-term treatment with chemotherapy can result in cumulative toxicities, representing a new challenge for these patients.
Maintenance treatment with the PARP inhibitor rucaparib has been approved for patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer who are sensitive to platinum-based chemotherapy. Compared with chemotherapy, treatment with PARP inhibitors is more tolerable and can provide patients with a better quality of life. Because no maintenance therapies have been approved for patients with pancreatic cancer, a phase II clinical trial is evaluating rucaparib in this setting for patients with platinum-sensitive pancreatic tumors.
An interim analysis of this ongoing trial was presented by Kim Reiss Binder, MD, assistant professor of medicine in the Division of Hematology Oncology at The Hospital of The University of Pennsylvania at this year’s meeting. As of Dec. 31, 2018, 19 of the 24 enrolled patients were evaluable for analysis. All patients had advanced BRCA- or PALB2-mutated pancreatic cancer that did not progress on prior platinum-based chemotherapy.
The median progression-free survival was 278 days following the initiation of rucaparib treatment. One patient had a CR, and seven patients had a PR, resulting in an overall response rate of 41 percent. The disease control rate, which is defined as the sum of PR, CR, and stable disease, was 90 percent for at least eight weeks. Eight patients remained on maintenance treatment with rucaparib for at least six months, while two patients remained on maintenance treatment with rucaparib for over a year.
“Although this is very preliminary data, the fact that we’re seeing sustained clinical responses in some of these patients is very exciting,” noted Reiss Binder in an AACR press release. “Other than the recent tissue-agnostic approval of pembrolizumab for patients with microsatellite instability-high tumors, there really is no other targeted therapy that has shown promise for patients with pancreatic cancer.”
Reiss Binder also noted that this study highlights the importance of genetic testing for germline and somatic mutations in pancreatic cancer patients, as the presence of certain mutations may guide treatment strategies.
The Philadelphia Inquirer covered the study.
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