Immunotherapy-Based Combos May be Necessary in Neuroendocrine Neoplasms

Pembrolizumab (Keytruda) appeared safe as a treatment of patients with metastatic high-grade neuroendocrine neoplasms but had limited effectiveness, according to an analysis of 2 open-label phase 2 clinical trials, announced Fox Chase Cancer Center in a press release.¹ The study authors suggested that an immunotherapy-based combination strategy may be the best way forward to improve responses.

The immune checkpoint inhibitor was administered intravenously to 29 patients at a dose of 200 mg every 3 weeks, which induced an objective partial radiographic response in 1 patient (3.4%). The 1 patient had large cell esophageal neuroendocrine carcinoma (95% CI, 0.1%-17.8%), and the response was ongoing for 13 months before the patient decided to withdraw from the study.

“Immunotherapy is effective in many other aggressive malignancies and also small cell neuroendocrine carcinoma. We were hoping to see if the same can be translated to patients with aggressive types of neuroendocrine cancers, also known as G3 neuroendocrine neoplasms,” stated Namrata (Neena) Vijayvergia, MD, lead author on the study and assistant chief of the Gastrointestinal Medical Oncology Program in the Department of Hematology/Oncology at Fox Chase Cancer Center, in the press release. “Our results are mostly in line with work done by some other investigators, where single agent PD-1 inhibitors had low rates or responses.”

Six patients (20.7%) had stable disease (95% CI, 7.9%-39.7%), which resulted in an overall disease control rate of 24.1%. Disease progression was observed in 17 patients (58.6%; 95% CI, 38.9%-76.5%). At 18 weeks, the disease control rate was 10.3% in 3 patients. Five patients (17%) were unevaluable due to clinical progression prior to the first scheduled imaging.²

Across the studies, the median progression-free survival (PFS) was 8.9 weeks, and the median overall survival (OS) was 20.4 weeks. However, neither PFS nor OS were affected by patient variables (P >.05).

Pembrolizumab was well-tolerated with limited grade 3 adverse events (AEs) (n = 9), and no grade 4 AEs appeared to be related to the drug. The most common AEs were fatigue and liver function abnormalities, which is consistent with findings from prior reports.

The majority of patients were female (55%), and the median age was 56 years at baseline (range, 27-77). An ECOG performance status of 1 was noted in 62% of patients, and close to half of patients had a Ki-67 index ranging from 20% to 50% (48%), 41% had Ki-67 >50%, and 10% had an unknown Ki-67 index.

To be eligible for the studies, patients had to be at least 18 years old with metastatic or unresectable extrapulmonary high grade neuroendocrine neoplasms and have progressed on at least 1 line of prior therapy. One of the studies required that patients progress on prior platinum-based therapy.

Overall, patients had to have measurable disease, an ECOG performance status of 0 or 1, and normal organ and bone marrow function. Patients with neuroendocrine neoplasms of lung origin or Merkel cell carcinoma, diagnosis of immunodeficiency or ongoing systemic immunosuppressive therapy, active autoimmune disease, concurrent second primary cancer, or active central nervous system metastases were ineligible.

The primary end point of the studies was objective response rate among all patients, and secondary end points included PFS and OS.

Patients with metastatic high-grade neuroendocrine neoplasms have limited options after progression on a platinum-based regimen, representing an important unmet medical need requiring further research. Pembrolizumab has been proven effective in a number of other cancers, including melanoma, metastatic non–small cell lung cancer, and head and neck squamous cell carcinoma.

“This work suggests that we should not extrapolate results from other disease sites to treat rare tumors, but concerted efforts can help accomplish studies like this to get real answers and avoid use of ineffective therapy for this disease,” Vijayvergia said.¹

She added that a study has suggested the possibility of improved responses with a combination approach including 2 immune checkpoint inhibitors, but further study is needed to validate this strategy.

“We found that combination strategies targeting the immune checkpoint pathway from multiple angles may be the key here,” Vijayvergia commented.

_References

1. _{Fox Chase Researchers Examine Role of Pembrolizumab in Treating Patients With Metastatic Neuroendocrine Tumors [news release]. Philadelphia, PA: Fox Chase Cancer Center; May 11, 2020. https://bit.ly/2TuuexL. Accessed May 22, 2020.}
2. _{Vijayvergia N, Dasari A, Deng M, et al. Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials. Br J Cancer. 2020;122:1309-1314. doi:10.1038/s41416-020-0775-0}