PEN-221 Demonstrates Clinical Benefit in Gastrointestinal NETs


The small molecule drug conjugate PEN-221 was generally well tolerated and elicited significant clinical benefit in patients with pretreated gastrointestinal neuroendocrine tumors.

Daniel M. Halperin, MD

Daniel M. Halperin, MD

The small molecule drug conjugate PEN-221 was generally well tolerated and elicited significant clinical benefit in patients with pretreated gastrointestinal (GI) neuroendocrine tumors (NETs), according to findings from a phase 2 study (NCT02936323) that were presented during the 2021 North American Neuroendocrine Tumor Society (NANETS) virtual symposium.1

Of 26 evaluable patients, 23 (88.5%) had a best response of stable disease, with a clinical benefit rate of 88.5% (95% CI, 69.8%-97.6%). Some degree of target lesion shrinkage was reported in 10 (38%) patients.

“PEN-221 exposure is proportional to body surface area and required body surface area dosing at 8.8 mg/m2 every 3 weeks,” lead study author Daniel M. Halperin, MD, an associate professor in the Department of Gastrointestinal Medical Oncology and Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in a virtual presentation of the data.1

Somatostatin receptor 2 (SSTR2) is commonly expressed in NETs, particularly gastroenteropancreatic-NETs. PEN-221 is a small peptide drug conjugate that selectively targets SSTR2 with a cleavable linker to a DM1 payload.

Preclinical data have shown that PEN-221 binds with high affinity and selectivity to SSTR2, leading to internalization with DM1 build up causing cell cycle arrest and death.

In the phase 1 portion of the study, PEN-221 was shown to be effective and well tolerated in patients with GI NETs. The phase 2 expansion portion of the study evaluated PEN-221 in 32 patients with well-differentiated GI NETs.

Eligible patients had advanced or metastatic, well-differentiated, low- or intermediate-grade, SSTR2-positive GI mid-gut NETs with radiographic disease progression within 6 months before the initiation of the study. Patients also must have received at least 1 prior therapy and an ECOG performance status (PS) of 0 or 1.

In the study, patients received a 1-hour intravenous infusion of PEN-221 every 3 weeks at the recommended phase 2 dose (RP2D).

Patients were stratified by whether they have received prior peptide receptor radionuclide therapy (PRRT).

The primary objective was ascertaining a clinical benefit rate of at least 75%. Secondary objectives included the determination of the maximum-tolerated dose (MTD) and RP2D, safety and tolerability at the RP2D, progression-free survival (PFS), overall survival, objective response rate, duration of response, and pharmacokinetics of PEN-221, DM1, and peptide from PEN-221.

Circulating pharmacodynamic biomarker changes served as an exploratory objective.

In the phase 1 portion of the study, the MTD was determined to be 18 mg. However, the maximum benefit was reported at dose levels of 8.75 mg/m2 or less, and because most toxicities were reported at dose levels of greater than 8.75 mg/m2, the study regimen was amended to be given at a dose of 8.8 mg/m2.

Regarding patient characteristics, the median age was 66 years (range, 32-81). A total of 17 men and 15 women were enrolled. Most patients had an ECOG PS of 1 (n = 21; 66%) and low- (n = 17; 53%) or intermediate-grade (n = 13; 41%) disease.

The median time from diagnosis to treatment was 49 months (range, 6-249), and the median number of prior therapies was 2 (range, 0-4).

Additional results showed that the median PFS was 9 months (95% CI, 5-16.5). Patients with PRRT-naïve disease had a median PFS of 9 months (95% CI, 5.0-16.5), whereas patients with PRRT-recurrent disease had a median PFS of 6.1 months (95% CI, 2.2-not evaluable).

Notably, biomarkers including chromogranin A, neuron-specific enolase, 5-hydroxyindoleacetic acid, and circulating tumor cells were not associated with clinical outcome.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) occurring in at least 15% of patients included nausea (n = 16; 50%), fatigue (n = 15; 46.9%), diarrhea (n = 15; 46.9%), decreased appetite (n = 15; 46.9%), peripheral neuropathy (n = 11; 34.4%), infusion reaction (n = 10; 31.3%), aspartate aminotransferase (AST) elevation (n = 9; 28.1%), alkaline phosphatase (ALP) elevation (n = 8; 25%), anemia (n = 8; 25%), alanine aminotransferase (ALT) elevation (n = 7; 21.9%), vomiting (n = 6; 18.8%), constipation (n = 6; 18.8%), abdominal pain (n = 5; 15.6%), and arthralgia (n = 5; 15.6%).

Grade 3 TRAEs included fatigue (n = 3; 9.4%), diarrhea (n = 1; 3.1%), peripheral neuropathy (n = 1; 3.1%), infusion reaction (n = 1; 3.1%), AST elevation (n = 2; 6.3%), ALP elevation (n = 2; 6.3%), ALT elevation (n = 3; 9.4%), and arthralgia (n = 1; 3.1%).

One grade 4 TRAE was reported; no grade 5 events were reported.

A randomized trial of PEN-221 in midgut NETs is in development.


  1. Halperin DM, Johnson ML, Chan JA, et al. The safety and efficacy of PEN-221 somatostatin analog (SSA)-DM1 conjugate in patients with advanced GI midgut neuroendocrine tumors: phase 2 results. Presented at: NANETS 2021; November 3-6, 2021; virtual. Abstract 120.
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