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Study Shows Limited Antitumor Activity of Pembrolizumab in Neuroendocrine Tumors


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Neuroendocrine tumors appear resistant to single-agent immunotherapy, according to the results of the KEYNOTE-028 trial of pembrolizumab. “Pembrolizumab monotherapy showed limited antitumor activity but a manageable safety profile in patients with previously treated, advanced neuroendocrine tumors,” said Jonathan R. Strosberg, MD, of Moffitt Cancer Center, Tampa. “There were few hints of activity.... I’d say the data with single-agent checkpoint inhibitors have been relatively negative across the board [in all studies].”

Based on findings from the phase I KEYNOTE-028 trial,1 which studied pembrolizumab in heavily pretreated patients with a variety of solid tumors, the phase II basket trial, KEYNOTE-158, was designed to evaluate pembrolizumab in 10 different tumor types, including 107 patients with neuroendocrine tumors. The primary site of disease was the pancreas in 38%, the small intestine in 22%, other gastrointestinal sites in 17%, the lungs in 13%, and other sites in 10%. Two-thirds of patients had received at least 2 prior therapies, and 16% expressed the programmed cell death ligand 1 (PD-L1). The primary endpoint was overall response.

Key Study Findings

After a median follow-up of 18.6 months, the overall response rate was 3.7%, with no complete responses and 4 partial responses, including 3 responses in patients with a neuroendocrine tumor of the pancreas and 1 in a patient with a gastrointestinal neuroendocrine tumor and an unknown primary. The median duration of response was not reached, and three of the four responses were ongoing after at least 9 months, Dr. Strosberg reported at the 2019 Gastrointestinal Cancers Symposium.2


Pembrolizumab monotherapy showed limited antitumor activity but a manageable safety profile in patients with previously treated, advanced neuroendocrine tumors.
— Jonathan R. Strosberg, MD

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“There were a small number of patients with durable responses…. Some benefited dramatically, including one of my patients with a pancreatic neuroendocrine tumor whose disease had progressed on multiple lines of therapy. But we don’t have any idea how to select these patients,” Dr. Strosberg said.

All four patients with responses to pembrolizumab had no expression of PD-L1. Stable disease was the best response for 57% of patients, he said, adding that he sees “little effect” for the drug on disease stabilization.

The median overall survival was also not reached, and at 6 months, 84.6% of patients were alive. The median progression-free survival was 4.1 months, and the 6-month progression-free survival rate was 38.2%.

Treatment-related adverse events occurred in approximately three-quarters of patients, with 20.6% experiencing grade 3 or 4 toxicity. The most commonly reported adverse event was fatigue, which was mostly mild and observed in 21.5% of patients. The most common immune-related adverse event was hypothyroidism, with grade 1 or 2 hypothyroidism noted in 10% of patients.

Clinical Implications

Dr. Strosberg said the negative findings are “perhaps not surprising.” It is becoming clear that tumor mutational burden corresponds with response, and neuroendocrine tumors, at least well-differentiated ones, “are known to be on the relatively low side of the tumor mutational burden spectrum,” he indicated.

Pembrolizumab in Neuroendocrine Tumors

  • In the phase II KEYNOTE-028 trial of heavily pretreated patients with neuroendocrine tumors, single-agent pembrolizumab showed little activity.
  • The response rate was 3.7%, and the median progression-free survival was 4.1 months.
  • However, responses were durable in some patients.
  • For more on the KEYNOTE-158 trial of immunotherapy for neuroendocrine tumors, see an interview with Jonathan R. Strosberg, MD, on The ASCO Post Newsreels at www.ascopost.com/videos.

Despite what is “essentially a negative study,” Dr. Strosberg said he might use pembrolizumab “sporadically” in patients who have “exhausted all standards of care” and who therefore may have accumulated mutations. “These patients might be the sort to respond to single-agent pembrolizumab,” he suggested. In addition, Dr. Strosberg said he is more likely to use combinations of programmed cell death protein 1 and cytotoxic T-lymphocyte–associated protein 4 inhibitors, acknowledging that this approach has not yet been proven effective. He thinks the future lies in combining checkpoint inhibitors with immune sensitizers and other immunotherapies. 

DISCLOSURE: Dr. Strosberg has received honoraria from, consulted or advised for, or served on the speakers’ bureau for Ipsen, Lexicon, Novartis, and Pharmacyclics as well as has received travel expenses from Advanced Accelerator Applications.

REFERENCES

1. Mehnert JM, Rugo HS, O’Neil BH, et al: Pembrolizumab for patients with PD-L1–positive advanced carcinoid or pancreatic neuroendocrine tumors: Results from the KEYNOTE-028 study. 2017 ESMO Congress. Abstract 427O. Presented September 10, 2017.

2. Strosberg JR, Mizuno N, Doi T, et al: Pembrolizumab treatment of advanced neuroendocrine tumors: Results from the phase II KEYNOTE-158 study. 2019 Gastrointestinal Cancers Symposium. Abstract 190. Presented January 18, 2019.


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