Update 13th February 2025.
In my main coverage of Immunotherapy for Neuroendocrine Neoplasms (NENs), you will see a section where one NET specialists described Neuroendocrine Tumours as an “immunological desert”. What was meant by is that there’s little evidence immunotherapy is effective in the majority of Neuroendocrine Tumours (NETs). The output from this trial continues to back that view. It is important to note the nomenclature of NETs rather than NENs as almost all the immunotherapy drug approvals to date have been for Neuroendocrine Carcinomas (NECs).
As the trial abstract conclusion said, “We conclude that immune checkpoint blockade had low activity in unselected patients with grade 1 and 2 GEP-NETs“, so excluded from that statement are ‘extra-GEPNETs’ (i.e. anything outside the GEP area) and Grade 3 GEPNETs were also excluded.
But the work is ongoing with Immunotherapy (IO) and low grade NETs so it something I continue to follow. See an expert quote on these results in the next section.
This initial output from the trial is too complex for the most patients to understand but let me quote from an export commentary from X (formerly witter) on the output below.
“Another phase 1b/2 study in G1/2 NETs showing that IO doesn’t work in NETs (PLANET trial). We know that NETs are cold tumors, PD-L1 expression and TILs do not correlate with response. Overall discouraging, but I don’t think we can close the book on IO in low-intermediate grade NETs just yet. There is potential role for combination therapies! We just need to re-invent the wheel!!
Abstract
While performing a study of immune checkpoint blockade with the anti-PD-1 antibody pembrolizumab combined with the somatostatin analogue (SSA) lanreotide in patients with low- and intermediate-grade gastroenteropancreatic neuroendocrine tumors (GEP-NETs), we studied whether there were any immune correlates of response to the anti-PD-1 therapy that could guide future attempts to integrate immunotherapy into the treatment of NETs. Patients with grade 1 and 2 GEP-NETs who had progressed on a prior SSA received lanreotide 90 mg subcutaneously and pembrolizumab 200 mg intravenously every 3 weeks until progression or intolerable toxicity. Objective response rate (ORR) at any time in the study, clinical benefit rate (CBR, defined as stable disease or better), progression-free survival (PFS), and overall survival (OS) were measured. Changes in T cell subsets in peripheral blood before and during therapy were analyzed by multiparameter mass cytometry (CyTOF). Archived tissue samples were analyzed for PD-L1 expression and TIL infiltration. Twenty-two (22) patients (GI/pancreatic 14/8, median Ki67 7% [IQR 4, 10%], median 1.5 prior systemic therapies [range 1–4]) were enrolled. Among the GI-NETs, there was one partial response, the CBR was 50%, the median PFS was 8.5 months, and the median OS was 32.7 months. No responses were seen in pancreatic NETs, which had 0% CBR, a PFS of 2.7 months, and an OS of 23.9 months. Of the 16 analyzable tumors, 6 had detectable PD-L1 expression and 15 had detectable TILs. Neither TILs nor PD-L1 expression correlated with ORR or CBR. However, clinical benefit (SD or better) was associated with peripheral blood on-treatment effector memory T cell activation and progressive disease was associated with baseline peripheral blood regulatory T cell (Treg) activation. We conclude that immune checkpoint blockade had low activity in unselected patients with grade 1 and 2 GEP-NETs. Further study of strategies to reduce Treg activation or enhance effector memory activation during immunotherapy is warranted.
Citation
Original blog follows …….
Headline: Roughly 40% of patients with advanced, progressive gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with pembrolizumab (Keytruda) in combination with lanreotide (Somulatine Depot) achieved stable disease, according to results from the phase 1b/2 PLANET clinical trial presented during the 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium.
I’ve written about Pembrolizumab (Keytruda) before in my general immunotherapy coverage – click here. I did note they weren’t really having much luck with Neuroendocrine Neoplasms although I do see some success (…. but not enough) in poorly differentiated carcinomas. Well differentiated NETs remain an immunological desert. However, this poster abstract from ASCO GI conference caught my eye.
“Pembrolizumab has antitumor activity in a subset of GEP-NETs patients,” wrote the investigators. “We hypothesized that the lanreotide, by its antitumor effects and reduction of serotonin, a modulator of immunity, would synergize with pembrolizumab in low/intermediate grade GEP-NETs,” wrote the author led by Michael Morse, MD, of Duke Cancer Center.
In the PLANET study (NCT03043664), 22 patients with GEP-NETs who received a median of 2 prior systemic therapies (range 1-9) were treated with 90 mg of lanreotide and 200 mg of pembrolizumab every 3 weeks until disease progression or intolerable toxicity. A median of 6 doses of pembrolizumab (range, 2-15) and 7 doses of lanreotide (range, 2-15) were administered.
Median age at the time of enrollment was 60.9 years (range, 51.1-82.0). Twelve of the patients were male, and 10 were female. To be eligible for the study, participants were required to have a diagnosis of non-resectable, recurrent, or metastatic well- or moderately-differentiated GEP-NETs with disease progression in the last 12 months, received prior somatostatin analogue therapy, a minimum of 1 measurable lesion based on RECIST 1.1 criteria, an ECOG performance status of 0 or 1, adequate organ function, and a tumor mitotic rate of ≤20/10 hpf and/or Ki67 index ≤20%.
Fourteen patients (63.6%) had tumors located within the gastrointestinal tract, of whom 8 patients (36.4%) had their primary tumor site located in the pancreas. The median time since diagnosis for all patients was 5.3 years, with 6 patients having received prior locoregional therapy and 3 patients receiving prior external beam therapy. Of the 12 tumors that were analyzed, 4 had detectable PD-L1 expression and 11 had tumor infiltrating lymphocytes.
PD-L1 expression on a tumour’s cell is one of the mechanisms of immune evasion, since this inhibits functional activity of cytotoxic lymphocytes which will then not attack tumour cells. Tumor-infiltrating lymphocytes are white blood cells that have left the bloodstream and migrated towards a tumour.
The primary end point of the study was overall response rate (ORR), measured according to RECIST 1.1 criteria. Thirty-nine percent of patients showed stable disease (SD) and 52% of patients had progressive disease (PD). ORR, as measured by irRECIST to better assess the effect of immunotherapeutic agents, was 43% SD, 48% PD, with 9% of patients not evaluable.
Secondary end points were progression-free survival (PFS) and overall survival (OS). The median PFS was 5.4 months (95% CI, 1.7-8.3) and median OS at a median follow-up of 15 months was not reached.
Regarding safety, 6 of the 22 patients (27.3%) experienced treatment-related serious adverse events (AEs) including abdominal pain, pneumonitis, colitis, and hyperglycemia, which were all related to treatment with pembrolizumab. The most common treatment-related AE was hypothyroidism (23%), with other notable treatment-related AEs including colitis (9%), hyperglycemia (14%), and pneumonitis (5%). Three patients (13.6%) discontinued treatment due to AEs. No new safety signals were identified in the study. Investigators noted that peripheral blood immune analyses were pending and would be reported subsequently.
Reference:
Morse M, Halperin DM, Uronis HE, et al. Phase Ib/II study of pembrolizumab with lanreotide depot for advanced, progressive gastroenteropancreatic neuroendocrine tumors (PLANET). Presented at: 2021 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium. January 15–17, 2021; virtual. Abstract 369.
Please note that the results have been appended to the Clinical Trial doc referenced above. The trial is showing as active but not recruiting and that’s most likely because they are assessing whether they can proceed to the next phase. I will keep this blog live to bring you details when they are published.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided in the clinical trials document. It’s very important to check the trial inclusion and exclusion criteria before making any contact. If you need questions, the articles here is very useful Questions to Ask About Clinical Trials | Cancer.Net
The inclusion of any trial within this blog should not be taken as a recommendation by Ronny Allan.
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