Immune checkpoint inhibitors may prove to be effective in treating patients with two rare cancer types—leptomeningeal metastases and angiosarcoma, according to early-phase clinical trials reported at the 2020 Annual Meeting of the Society for Immunotherapy of Cancer (SITC), which was held virtually this year.
In a phase II trial of 13 patients with leptomeningeal metastases from various solid tumor types, 38% of patients responded to pembrolizumab, including complete responses in several patients and long-term (3-year) survival in one patient with cutaneous squamous cell carcinoma, Jarushka Naidoo, MBBCh, of Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, reported.1
Jarushka Naidoo, MBBCh
“Patients with leptomeningeal metastases from solid tumors have a dismal prognosis and limited treatment options. In this phase II trial, we identified an impressive 38% response rate to pembrolizumab in the CNS [central nervous system] of such patients, including deep and durable responses in selected patients with tumors typically responsive to immune checkpoint inhibitors,” Dr. Naidoo said.
Pembrolizumab for Leptomeningeal Metastases
The study, which was closed early due to poor accrual, was a single-center investigator-initiated phase II trial in which 13 patients (of 18 planned) with leptomeningeal metastases received pembrolizumab at 200 mg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was CNS response after four cycles. To look for genomic and immunologic features as biomarkers of response, the authors also assessed baseline and serial cerebrospinal fluid samples by tumor-derived DNA aneuploidy assay (t-DNA), 16-color flow cytometry, and multiplex cytokine analysis.
More than half of the 13 patients had tumors that are not traditionally responsive to checkpoint inhibitors, including 5 patients (39%) with hormone receptor–positive breast cancer and 3 patients (23%) with high-grade glioma. The remainder had traditionally responsive tumors, including 3 patients with non–small cell lung cancer (NSCLC), 1 patient with head and neck cancer, and 1 patient with cutaneous squamous carcinoma.
A total of 5 patients (38%) responded, including 2 patients who achieved durable complete responses. One patient with cutaneous squamous carcinoma is alive beyond 3 years; 1 patient with MET exon 14–positive NSCLC is alive at 9 months. One partial responder had an overall survival of 6 months, and 2 patients had stable disease in the CNS, according to Dr. Naidoo. Median progression-free survival in the CNS was 2.9 months (95% confidence interval [CI] = 1.3 months to not reported), and median overall survival was 4.9 months (95% CI = 3.7 months to not reported).
Dr. Naidoo and her team also determined that detection of tumor DNA in the cerebrospinal cord fluid may be a better way to detect leptomeningeal metastases than the currently used technique of cytology. The t-DNA assay detected 84.6% of leptomeningeal metastases, whereas cytopathology detected 46.2%.
Ipilimumab/Nivolumab for Angiosarcoma
The multicenter phase II SWOG S1609 trial found that a regimen of ipilimumab plus nivolumab was effective in 25% of patients with unresectable angiosarcoma. Responses were observed in patients with cutaneous scalp or face tumors and radiation-associated breast tumors, according to Michael Wagner, MD, of the University of Washington, Fred Hutch Cancer Research Center, and Seattle Cancer Care Alliance.2
Michael Wagner, MD
“Angiosarcomas can arise in any part of the body and account for fewer than 3% of all soft-tissue sarcomas. Long-term survival is poor for patients who develop metastases,” he said.
Mutations that are commonly seen with angiosarcoma increase hydrophobicity, which suggests greater immunogenicity. Indeed, some types demonstrate a high tumor mutational burden, comparable to other cancer types that are responsive to immune checkpoint inhibitors, he indicated.
Dr. Wagner presented results from the angiosarcoma cohort of the SWOG S1609 DART trial. This trial is conducted through the SWOG Early Therapeutics and Rare Cancers Committee and is evaluating 50 cohorts of rare cancer subtypes.
The angiosarcoma cohort’s primary sites of disease were the face or scalp (31%) and the breast (25%), with the remainder being the extremities, heart, spleen, stomach, and liver. The median number of prior therapies was two. A total of 16 patients were treated with ipilimumab (1 mg/kg every 6 weeks) plus nivolumab (240 mg every 2 weeks).
The overall response rate to ipilimumab/nivolumab was 25%, which included partial responses in three patients with cutaneous disease of the scalp or face and one patient with radiation-associated breast angiosarcoma. The 6-month progression-free survival was estimated at 38% across all patients.
KEY POINTS
- Checkpoint inhibitors may be effective in treating patients with leptomeningeal metastases and advanced angiosarcoma.
- In a phase II study, 38% of patients with leptomeningeal metastases responded to pembrolizumab, including one patient who is still alive at 3 years.
- In the DART substudy of SWOG S1609, 25% of patients with unresectable angiosarcoma responded to ipilimumab plus nivolumab; responses were seen in patients with cutaneous disease of the scalp or face and radiation-associated angiosarcoma of the breast.
Molecular tumor characterization performed in eight patients revealed at least two deleterious genomic alterations in each patient, which were unique to each individual. Responders in this cohort tended to have tumor mutational burdens considered intermediate to high, though data were available for only two responders.
In a separate analysis of DART’s thyroid cohort presented at the SITC Annual Meeting, 2 of 17 patients had confirmed partial responses, and 2 others had unconfirmed responses.3
Three-fourths of patients had adverse events of any grade, with grade 3 or 4 toxicities seen in one-fourth of patients. Immune-related adverse events occurred in two-thirds; one patient had grade 3 or 4 elevated levels of transaminases, and another had grade 3 or 4 diarrhea.
“Even though this was a very small study, the results are exciting and encouraging, especially given angiosarcoma is such a rare cancer,” Dr. Wagner commented. “The findings warrant further study of ipilimumab and nivolumab in angiosarcoma.”
DISCLOSURE: Dr. Naidoo has received honoraria from AstraZeneca/MedImmune and Bristol Myers Squibb; has served as a consultant or advisor to AstraZeneca/MedImmune, Bristol Myers Squibb, and Roche/Genentech; has received institutional research funding from AstraZeneca, Merck, and Roche/Genentech; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca/MedImmune and Bristol Myers Squibb. Dr. Wagner has served as a consultant or advisor to Adaptimmune, Deciphera, and Tempus and has received institutional research funding Adaptimmune, Athenex, Deciphera, GSK, and Incyte.
REFERENCES
1. Naidoo J, Schreck KC, Fu W, et al: Pembrolizumab for patients with leptomeningeal metastasis from solid tumors: Efficacy, safety and cerebrospinal fluid biomarkers. 2020 Society for Immunotherapy of Cancer Annual Meeting. Abstract 788.
2. Wagner MJ, Othus M, Patel SP, et al: A multicenter phase II trial (SWOG S1609, Cohort 51) of ipilimumab and nivolumab in metastatic or unresectable angiosarcoma. 2020 Society for Immunotherapy of Cancer Annual Meeting. Abstract 795.
3. Chae YK, Othus M, Patel SP, et al: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: The thyroid tumor cohort. 2020 Society for Immunotherapy of Cancer Annual Meeting. Abstract 270.
