Immunotherapy is showing promise for patients with rare cancers, offering new treatment opportunities and clinical trials to those with previously limited options. At the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium, presenters discussed the use of immunotherapy in three low-incidence cancers: sarcoma,1 Merkel cell carcinoma,2 and glioblastoma.3
Sarcoma: Histologic Subtype May Matter
Priscilla Merriam, MD
Although sarcomas account for fewer than 1% of cancers in adults in the United States, approximately 50% of high-grade sarcomas develop into metastatic disease. According to Priscilla Merriam, MD, of the Dana-Farber Cancer Institute, Boston, outcomes are poor in this patient population and improved therapies are needed.
One of the largest studies of immunotherapy in sarcoma was SARC028, a multicenter, two-cohort, single-arm, open-label, phase II trial of pembrolizumab in advanced soft-tissue and bone sarcomas.4 Although the primary endpoint of overall response was not met for either cohort, noted Dr. Merriam, pembrolizumab showed activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma.
Another large study, the phase II Alliance A091401trial, randomly assigned patients with metastatic sarcoma to nivolumab with or without ipilimumab.5 As Dr. Merriam explained, the greater diversity in histologies enrolled in the Alliance trial vs the SARC028 study of pembrolizumab led to important insights about the potential role of immunotherapy. Although nivolumab monotherapy demonstrated limited benefit, the combination of nivolumab and ipilimumab showed promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to that of available chemotherapy agents.
Anticancer activity in alveolar soft part sarcoma has been reported with the combination of pembrolizumab and the antiangiogenic tyrosine kinase inhibitor axitinib. This regimen led to a response rate exceeding 50% in a recent phase II study.6 Some case reports and oral abstracts in angiosarcoma have also described a response to checkpoint inhibition.7
“Although histology-tailored approaches are likely needed, immune-tailored approaches based on the immune subtype may be even more helpful."— Priscilla Merriam, MD
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“Although histology-tailored approaches are likely needed, immune-tailored approaches based on the immune subtype may be even more helpful,” said Dr. Merriam. “Sarcomas have variable innate immunogenicity. For those that appear to be the nonresponsive or more ‘cold’ subtypes, we will need new approaches, such as combination therapies, to impact the tumor environment.”
Finally, Dr. Merriam noted that adoptive T-cell therapies with engineered T-cell receptors have also shown some activity, but they are currently limited by the requirement of a particular human leukocyte antigen status. “As a sarcoma community, we also need to learn more about the unique toxicity profile and management of patients on adoptive T-cell therapies,” she said. “This is a very important new immunotherapy approach in sarcoma with encouraging early data. We are excited to see further results from ongoing adoptive T-cell therapy trials.”
Merkel Cell Carcinoma: Drugs Approved
Although most skin cancers are diagnosed early and are treatable, for those that do advance, immunotherapy is quickly becoming first-line therapy, not only for melanoma but for more rare tumors, said Isaac Brownell, MD, PhD, Head of Cutaneous Development and Carcinogenesis Section at the National Institute of Health.
“Checkpoint inhibitors have changed the way we do cutaneous oncology, and they are now standard of care for advanced Merkel cell carcinoma, but our work is not done."— Isaac Brownell, MD, PhD
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The effectiveness of immunotherapy in skin cancer arises from the immunogenicity of these tumors. The aggregate response to antibodies targeting programmed cell death protein 1 (PD-1) across skin cancers is much higher than for other tumors. However, with the exception of melanoma, immunotherapy trials in skin cancer have been largely underpowered.
“These studies are small, but in every case, the response rates exceed 40%, which is pretty impressive compared with other types of malignancies,” according to Dr. Brownell.
Merkel cell carcinoma is a primary neuroendocrine tumor of the skin. With approximately 2,500 cases per year in the United States, it is rare but frequently lethal. It is associated with advanced age, immunosuppression, ultraviolet radiation, and fair skin; in addition, approximately 80% of these cancers have Merkel cell polyomavirus in the genome.
“Knowing that Merkel cell carcinomas were immunogenic tumors, we suspected that checkpoint inhibitors would work, but there was a lot of reluctance from drug companies who did not see this as a profitable investment,” Dr. Brownell stated. “This changed when companies realized that orphan diseases could receive U.S. Food and Drug Administration (FDA) approval with small, single-arm, uncontrolled phase II studies.”
In the past, advanced Merkel cell carcinoma was treated with chemotherapy in first-line and salvage settings. Although responses were fairly common, they were not durable, yielding a median survival of approximately 9 months. A number of small clinical trials of avelumab, pembrolizumab, and nivolumab have subsequently produced higher response rates and much more durable responses in both the first- and second-line settings. What’s more, said Dr. Brownell, responses have been seen in both virus-positive and virus-negative tumors as well as in tumors with and without programmed cell death ligand 1 expression. The FDA has now approved both avelumab and pembrolizumab for advanced Merkel cell carcinoma.
KEY POINTS
- The combination of nivolumab and ipilimumab showed promising efficacy in certain sarcoma subtypes, with a manageable safety profile comparable to that of available chemotherapy agents.
- A number of small clinical trials of avelumab, pembrolizumab, and nivolumab in Merkel cell carcinoma have subsequently produced higher response rates and much more durable responses in both the first- and second-line settings than in the past.
- Researchers identified an immune-related signature correlating with clinical benefit in a large set of patients with glioblastoma treated with neoadjuvant pembrolizumab.
“Checkpoint inhibitors have changed the way we do cutaneous oncology, and they are now standard of care for advanced Merkel cell carcinoma, but our work is not done,” Dr. Brownell said. Ongoing studies are evaluating combinations and immunotherapies in both adjuvant and neoadjuvant settings, are determining predictive biomarkers, and are studying cell-based therapies for these skin cancers.
Glioblastoma: Neoadjuvant Therapy May Be Optimal Use
Patients with glioblastoma have a median survival of under 2 years and only 6 to 9 months after relapse. Although PD-1 blockade is now approved by FDA in many solid tumors, these drugs have generally been disappointing as adjuvant therapy in glioblastoma. The only anecdotal reports of clinical benefit have been in patients with DNA mismatch–repair deficiency, according to Robert M. Prins, PhD, Professor of Neurosurgery and Pharmacology at the University of California, Los Angeles, Parker Institute for Cancer Immunotherapy and Jonsson Comprehensive Cancer Center.
A significantly large number of tumor cells remain after conventional treatment with surgery, radiotherapy, and chemotherapy. “There has been a lot of interest in using the immune system to eradicate these remaining cells,” said Dr. Prins.
Studies in other solid tumors suggest the timing of checkpoint blockade therapy may dictate both the strength and persistence of antitumor immune response and therefore lead to stronger clinical benefits. “Checkpoint blockade administered prior to surgical resection may be able to enhance the function of tumor-specific T cells and let them become systemically activated and migratory,” Dr. Prins commented. “Because the tumor is widely immunosuppressive, many of us believe that resection following the generation of a systemic immune response can work together.”
Robert M. Prins, PhD
In other studies, researchers identified an interferon-gamma–related gene-expression signature correlating with clinical benefit from a large set of patients with solid tumors treated with pembrolizumab.8 Dr. Prins and colleagues then used these panels to evaluate whether pembrolizumab induced gene-expression changes; they found that unsupervised clustering delineated two groups based on the interferon signatures, and they were mostly associated with the receipt, or not, of neoadjuvant PD-1 blockade. Perhaps more important, just three of the patients in the neoadjuvant arm demonstrated enrichment for the cell-proliferation signature, whereas this occurred in the vast majority of patients in the adjuvant arm.9
Although the study was not powered to examine overall survival, the researchers also found a statistically significant difference in patients randomly assigned to the neoadjuvant vs adjuvant arm. The median overall survival doubled from 7.5 months to 13.7 months, said Dr. Prins, suggesting larger trials should be conducted in this disease.
“The benefit appears to be driven by systemic expansion of tumor-specific T cells with high interferon signaling and downregulation of the cell cycle–related signature,” said Dr. Prins, who noted coordinated T-cell responses were seen only in the neoadjuvant arm. “These results pave the way to design rational combinations that can be used to understand the influence of each immunotherapy agent on the microenvironment of the tumor.”
DISCLOSURE: Drs. Merriam and Brownell reported no conflicts of interest. Dr. Prins has received research funding from Merck.
REFERENCES
1. Merriam P: Sarcoma: Immune therapies in low-incidence cancers. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. General Session. Presented February 8, 2020.
2. Brownell I: Merkel cell and other rare skin malignancies. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. General Session. Presented February 8, 2020.
3. Prins RM: Neoadjuvant immunotherapy for glioblastoma. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. General Session. Presented February 8, 2020.
4. Tawbi HA, Burgess M, Bolejack V, et al: Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase II trial. Lancet Oncol 18:1493-1501, 2017.
5. D’Angelo SP, Mahoney MR, Van Tine BA, et al: Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): Two open-label, non-comparative, randomised, phase II trials. Lancet Oncol 19:416-426, 2018.
6. Wilky BA, Trucco MM, Subhawaong TK, et al: Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: A single-centre, single-arm, phase II trial. Lancet Oncol 20:837-848, 2019.
7. O’Sullivan Coyne G, Sharon E, Moore N, et al: Phase 2 study of atezolizumab in patients with alveolar soft part sarcoma. 2018 Connective Tissue Oncology Society Annual Meeting. Abstract 021. Presented November 14-17, 2018.
8. Ayers M, Lunceford J, Nebozhyn M, et al: IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127:2930-2940, 2017.
9. Cloughesy TF, Mochizuki AY, Orpilla JR, et al: Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat Med 25:477-486, 2019.
