ASCO: Studies pave the way on immunotherapy clinical trials for rare, aggressive cancers

Several MD Anderson-led studies at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting focus on using immunotherapy to provide new treatment options for rare, aggressive cancers, including anaplastic thyroid cancer (ATC), glioblastoma, leptomeningeal disease (LMD) and soft-tissue sarcomas. For most of these rare diseases, survival is poor and few – if any – effective treatment options are currently available.

As these studies show, MD Anderson is leading the way in designing novel clinical trials for rare cancers and proving that it’s possible to quickly and safely enroll patients even if they have serious symptoms.  

Here are a few rare cancer studies that MD Anderson researchers are presenting at this year’s ASCO Annual Meeting, May 29-31:

Concurrent intrathecal and intravenous nivolumab for metastatic melanoma patients with leptomeningeal disease (abstract 10008)

It is thought that at least 10% of stage IV melanoma patients develop metastasis in the leptomeninges, which represent the outer lining of the brain and spinal cord; this type of metastasis is known as leptomeningeal disease. Melanoma patients with leptomeningeal disease only live an average of 12 weeks, and treatment options remain very limited.

“In the first in-human clinical trial of intrathecal immunotherapy with nivolumab, an anti-PD1 antibody,  for leptomeningeal disease, we’ve demonstrated that this is a safe and feasible approach,” says lead author Isabella Glitza Oliva, MD., Ph.D., assistant professor of Melanoma Medical Oncology.

Eighteen patients received concurrent intrathecal (IT) and intravenous (IV) nivolumab. The treatment approach was well tolerated by all patients, with no unexpected systemic or neurological toxicity. No grade 4 or 5 adverse events were attributed to IT or IV nivolumab. Because leptomeningeal disease patients often have neurological symptoms, the clinical trial was designed to allow enrollment of patients who might be excluded based on traditional criteria.

Intrathecal therapy allows the delivery of drugs directly to the cerebrospinal fluid through a special port in the skull, called an Ommaya. MD Anderson has over 20 years of experience treating LMD patients with a different type of immunotherapy, called interleukin-2 (IL-2). However, the intrathecal IL-2 approach is only available to select patients because the side effects are so severe.

“Intrathecal nivolumab has shown to be safe, and is tolerated significantly better than intrathecal IL-2,” Glitza says. Based on the positive safety data, the clinical trial is being expanded to include lung cancer leptomeningeal disease patients, and to continue to increase the dose of intrathecal nivolumab. The next step is to analyze data from blood and cerebrospinal fluid (CSF) biopsies taken at multiple points throughout each treatment cycle.

“These samples will provide a unique opportunity for us to learn more about what’s actually happening in the CSF space,” Glitza says. “There’s currently very little understanding of how leptomeningeal disease occurs.”

Neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma (abstract 11505)

There are more than 70 different types of soft-tissue sarcomas, making each one a rare disease. About half of patients with dedifferentiated liposarcoma (DDLPS) or undifferentiated pleomorphic sarcoma (UPS) will have a recurrence or their cancer will metastasize within five years. At MD Anderson, patients are usually treated with radiation and chemotherapy before surgery.

“This was the first study to introduce neoadjuvant immunotherapy for localized undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma,” says lead author Christina L. Roland, M.D., assistant professor of Surgical Oncology. Previous studies have assessed neoadjuvant immunotherapy in metastatic undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. The primary endpoint was pathological response.

The MD Anderson-led Phase II study found significant pathological response for the undifferentiated pleomorphic sarcoma cohort that received radiation plus checkpoint blockade (either nivolumab alone or ipilimumab and nivolumab). Median pathological response was 95% for the undifferentiated pleomorphic sarcoma cohort, with less than 15% residual tumor remaining for eight of nine patients, and 22.5% for the dedifferentiated liposarcomaDDLPS cohort.

“Results from the undifferentiated pleomorphic sarcoma arm were significantly better than historical controls,” Roland says. “Our next step will be to perform DNA and RNA analysis on the longitudinal biopsies to try to figure out the differences between responders and non-responders.”

Because the recurrence rate for these types of soft-tissue sarcomas is so high, better treatment for early-stage disease is needed. Historically, responses to pre-operative therapy are associated with better long-term outcomes. Long-term follow-up for this study is ongoing. 

“Bringing in novel treatment agents early in the neoadjuvant setting will help us learn how these agents alter the tumor and the risk of recurrence, and might provide patients with longer disease-free survival,” says senior author Neeta Somaiah, M.D., associate professor of Sarcoma Medical Oncology. “MD Anderson is leading the way to show that neoadjuvant studies are feasible in individual sarcoma subtypes. These studies will become key to understanding mechanisms of response/resistance of these novel agents and identifying subtypes we should study in larger trials after this.”

Atezolizumab combinations with targeted therapy for anaplastic thyroid carcinoma (abstract 6514)

Anaplastic thyroid cancer (ATC) is a rare form of thyroid cancer with poor survival. The disease affects about 1,000 people each year in the U.S. Unlike other thyroid cancers, most ATCs are not operable, and survival is typically less than six months from diagnosis. MD Anderson researchers found the combination of anti-PDL1 immunotherapy and targeted therapy resulted in median overall survival of 18.23 months.  

The Phase II study, led by Maria E. Cabanillas, M.D., professor of Endocrine Neoplasia and Hormonal Disorders, enrolled 47 ATC patients, representing the largest single-institution clinical trial ever reported for ATC patients.

“It usually takes global recruitment to enroll an anaplastic thyroid cancer clinical trial of this size,” Cabanillas says. “The reason that we were successful in enrolling for this trial is that we designed the study to reflect the reality of anaplastic thyroid cancer patients who usually cannot swallow pills.”

Because many anaplastic thyroid cancer patients can’t swallow due to the size of the tumors in their necks, the researchers used an IV immunotherapy and permitted alternate delivery for oral chemotherapy. They also allowed patients with lower functional status to enroll in the trial, which isn’t usually permitted in cancer trials.

Patients were assigned a cohort with different targeted therapies based on the tumor mutations. If a patient could not enroll in any of the cohorts, they were assigned to cytotoxic chemotherapy. All patients received the immunotherapy atezolizumab, a PD-L1 inhibitor. The primary objective was overall survival of patients on targeted therapy plus atezolizumab (38 patients).

Median overall survival for the targeted therapy cohorts was 18 months, exceeding the estimated historical control of five months. In cohort 1, which contained 19 patients with BRAF mutations treated with vemurafenib and cobimetinib, median overall survival had not been reached; 70% of patients in cohort 1 were alive at two years.

Additionally, nine patients from cohort 1 and one from cohort 2 were able to undergo surgery to remove the primary or residual tumor. Surgery is rarely used for anaplastic thyroid tumor patients because the tumor invades the trachea, esophagus and/or carotid artery.

Autologous CMV-specific T cells in glioblastoma patients to reveal a lack of immune effector function (abstract 2515)

Glioblastoma is the most aggressive brain tumor in adults. The median survival after diagnosis is less than two years. This MD Anderson-led study demonstrated that adoptive infusion of CMV-specific T cells is safe and provided important insights for future adoptive T cell immunotherapy clinical trials in glioblastoma. The results were also published in Clinical Cancer Research in April.

The researchers collaborated with MD Anderson’s Adoptive Cell Therapy Research Platform to develop a GMP-compliant strategy to rapidly generate CMV-specific T cells obtained from each patient through leukapheresis. Patients received dose-dense temozolomide, a chemotherapy for glioblastoma, prior to up to four cycles of the autologous infusion. Patients in the dose-expansion cohort received treatment in a “window of opportunity” before surgery, allowing the researchers to analyze the resected tumor tissue for treatment response within the tumor microenvironment.

The clinical trial screened 65 patients for CMV. Twenty patients who were seropositive for CMV completed at least one cycle. No dose-limiting toxicities were observed. One patient had a complete radiographic response and two had partial responses; however, the two highest responders also had MGMT methylated tumors, which are known to respond better to temozolomide. Although circulating CMV+ CD8+ T cells increased with each infusion cycle, immune response was suppressed and had limited effect on the tumor.

“Our findings indicate that additional immune modulation will be required to obtain efficacious anti-tumor responses in adoptive T cell trials in glioblastoma,” says lead author Shiao-Pei Weathers, M.D., assistant professor of Neuro-Oncology. “Furthermore, this study highlights the need for patient selection in future trials targeting CMV in glioblastoma.”