Radioligand Therapy Significantly Improves PFS in GEP-NET Population

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Data from the phase 3 NETTER-2 trial support the frontline use of Lutetium Lu 77 dotatate well-differentiated gastroenteropancreatic neuroendocrine tumors.

“These data have clinical practice–changing implications and support the use of consideration of first-line 177Lu-Dotatate in high grade 2 and grade 3, well-differentiated GEP-NETs,” according to lead study author Simron Singh, MD, MPH.

“These data have clinical practice–changing implications and support the use of consideration of first-line 177Lu-Dotatate in high grade 2 and grade 3, well-differentiated GEP-NETs,” according to lead study author Simron Singh, MD, MPH.

Progression-free survival (PFS) significantly improved with lutetium Lu 177 dotatate (177Lu-Dotatate; Lutathera) plus octreotide compared with octreotide alone in those with advanced grade 2/3 well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs), according to data from the phase 3 NETTER-2 trial (NCT03972488) presented at the 2024 Gastrointestinal Cancers Symposium.1

177Lu-Dotatate generated a median PFS of 22.8 months (95% CI, 19.4-not evaluable [NE]) vs 8.5 months (95% CI, 7.7-13.8) with high-dose octreotide (stratified HR, 0.276; 95% CI, 0.182-0.418; P < .0001), translating to a 72% reduction in the risk of disease progression or death with 177Lu-Dotatate vs high-dose octreotide. In the 177Lu-Dotatate arm (n = 151), 47 progression events and 8 deaths occurred. In the high-dose octreotide arm (n = 75), 41 progression events and 5 deaths occurred.

“NETTER-2 is the first randomized trial to evaluate radioligand therapy in the first line for any metastatic solid-cell tumor,” lead study author Simron Singh, MD, MPH, of the Odette Cancer Centre, Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada, stated in the presentation.

Neuroendocrine neoplasms have been traditionally defined as either well-differentiated NETs or poorly-differentiated neuroendocrine carcinomas.2 The well-differentiated category is further stratified into grade 1 disease, defined as that with a Ki67 score of less than 3%, and grade 2 disease, defined as that with a Ki67 score of 3% to 20%. Well-differentiated grade 3 NETs, defined as those with a Ki67 score above 20%, are a novel disease subtype, and no randomized trials have evaluated optimal frontline treatments for patients with grades 2 and 3 GEP-NETs.1 Therefore, the standard of care for this patient population is currently undefined.

In the pivotal phase 3 NETTER-1 trial (NCT01578239), 177Lu-Dotatate plus 30 mg of octreotide long-acting repeatable (LAR; n = 116) elicited a median PFS that was not reached vs 8.4 months (95% CI, 5.8-9.1) with 60 mg of high-dose octreotide LAR (n = 113; HR, 0.21; 95% CI, 0.13-0.33; P < .001).3 These findings supported the 2018 FDA approval of 177Lu-Dotatate for patients with somatostatin receptor–positive GEP-NETs.4

NETTER-2 screened 226 patients at least 15 years of age with advanced somatostatin receptor–positive, well-differentiated, grade 2 or grade 3 GEP-NETs with Ki67 scores ranging from 10% to lower than 55%.1 Patients needed to have been diagnosed within 6 months prior to trial enrollment and could not have received prior peptide receptor radionucleotide therapy or systemic therapy.

In the randomized treatment phase, patients were randomly assigned 2:1 to receive 177Lu-Dotatate at 4 x 7.4 GBq plus 30 mg of octreotide LAR every 8 weeks or high-dose octreotide LAR at 60 mg every 4 weeks. Patients were stratified by grade (grade 2 vs grade 3) and tumor origin (pancreas vs other origin).

In the optional treatment extension phase, patients in the 177Lu-Dotatate arm who experienced progressive disease (PD) in the randomized treatment phase received retreatment with 177Lu-Dotatate at 7.4 GBq/200mCi every 8 weeks for 2 to 4 cycles. Patients in the high-dose octreotide arm received crossover treatment with 177Lu-Dotatate at 7.4 GBq/200mCi every 8 weeks for 4 cycles plus 30 mg octreotide LAR.

During the follow-up phase of the trial, patients attended follow-up visits every 6 months for 3 years.

PFS served as the primary end point of this trial, with overall response rate (ORR) and quality of life (QOL) as key secondary end points.

Of the patients randomly assigned to the 177Lu-Dotatate arm, 147 were treated, and 78 were still on treatment at data cutoff. Furthermore, 29 patients received post-treatment follow-up, and 35 patients completed the study protocol. Of the patients randomly assigned to the high-dose octreotide arm, 73 were treated, and 15 were still on treatment at the data cutoff. Furthermore, 29 patients received post-treatment follow-up, and 19 patients completed the study protocol.

In the 177Lu-Dotatate arm, patients had a median age of 61 years (range, 23-88), 54% were male, and 76%, 15%, and 9% were White, Asian, and another race, respectively. Nineteen percent and 81% of patients had a baseline Karnofsky score of 70 to 80 and 90 to 100, respectively. This population had primary tumors located in the pancreas (54%), small intestine (30%), and other sites (16%), and metastatic sites included bone (25%), liver (89%), lymph nodes (67%), and peritoneum (17%). Sixty-six percent and 34% of patients had grade 2 and grade 3 NETs, respectively, at diagnosis, and the median Ki67 index was 17 (range, 10-50).

In the high-dose octreotide arm, patients had a median age of 60 years (range, 34-82), 53% were male, and 67%, 15%, and 19% were White, Asian, and another race, respectively. One percent, 13%, and 85% of patients had baseline Karnofsky scores of 60, 70 to 80, and 90 to 100, respectively. This population had primary tumors located in the pancreas (55%), small intestine (28%), and other sites (17%), and metastatic sites included bone (24%), liver (92%), lymph nodes (45%), and peritoneum (12%). Sixty-four percent and 36% of patients had grade 2 and grade 3 NETs, respectively, at diagnosis, and the median Ki67 index was 16 (range, 10-50).

The median duration of treatment exposure in the 177Lu-Dotatate arm was 71.1 weeks (range, 8.1-182.9). One percent, 7%, 5%, and 88% of patients received 1, 2, 3, and 4 treatment cycles, respectively. The median cumulative dose of 177Lu-Dotatate was 29.21 GBq (range, 7.0-31.2), and the median dose of 177Lu-Dotatate per administration was 7.34 GBq per cycle (range, 4.1-7.8). In the high-dose octreotide arm, the median duration of exposure was 40.3 weeks (range, 4.0-124.4).

The PFS benefit with 177Lu-Dotatate was observed across all prespecified patient subgroups, including age (younger than 65 years: [HR, 0.26; 95% CI, 0.16-0.45]; at least 65 years of age: [HR, 0.37; 95% CI, 0.20-0.71]), gender (female: [HR, 0.30; 95% CI, 0.16-0.55]; male: [HR, 0.32; 95% CI, 0.18-0.54]), and race (White: [HR, 0.36; 95% CI, 0.22-0.59]; Asian: [HR, 0.14; 95% CI, 0.05-0.38]). 177Lu-Dotatate elicited superior outcomes in patients with grade 2 (HR, 0.31; 95% CI, 0.18-0.53) and grade 3 (HR, 0.27; 95% CI, 0.14-0.49) disease. Patients with tumor origin in the pancreas (HR, 0.34; 95% CI, 0.20-0.56), small intestine (HR, 0.30; 95% CI, 0.13-0.74), and non-pancreas (HR, 0.23; 95% CI, 0.12-0.46) all achieved a benefit with 177Lu-Dotatate. When grade per somatostatin receptor uptake was evaluated, both patients with grade 3 disease (HR, 0.31; 95% CI, 0.10-0.89) and those with grade 4 disease (95% CI, 0.30; 95% CI, 0.19-0.47) benefitted with 177Lu-Dotatate.

The ORR with 177Lu-Dotatate was significantly higher than that with high-dose octreotide, at 43.0% (95% CI, 35.0%-51.3%) vs 9.3% (95% CI, 3.8%-18.3%), respectively (stratified OR, 7.81; 95% CI, 3.32-18.40; P < .0001). In the 177Lu-Dotatate arm, the respective complete response (CR), partial response (PR), stable disease (SD), non-CR/non-PD, PD, and unknown response rates were 5.3%, 37.7%, 47.7%, 0%, 5.3%, and 4.0%, respectively. In this arm, the median duration of response (DOR) was 23.3 months (95% CI, 18.4-NE). “These are some of the highest responses that have been reported in neuroendocrine malignancies to date,” Singh added in the presentation.

In the high-dose octreotide arm, the respective CR, PR, SD, non-CR/non-PD, PD, and unknown response rates were 0%, 9.3%, 56.0%, 1.3%, 18.7%, and 14.7%, respectively. In this arm, the median DOR was NE (95% CI, 2.3-NE).

The time to QOL deterioration was similar between both arms. Per the European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30) subscale, the median time to deterioration of global health status was 13.2 months (95% CI, 8.8-17.2) with 177Lu-Dotatate and 8.6 months (95% CI, 5.8-14.0) with high-dose octreotide (HR, 0.856; 95% CI, 0.570-1.283; P = .2222). Moreover, in these respective arms, the median times to deterioration of diarrhea were 17.4 months (95% CI, 14.4-28.2) and 17.3 months (95% CI, 8.1-NE [HR, 0.877; 95% CI, 0.555-1.386]), the median times to deterioration of fatigue were 6.0 months (95% CI, 3.4-6.8) and 6.0 months (95% CI, 3.9-11.0 [HR, 0.998; 95% CI, 0.695-1.432]), and the median times to deterioration of pain were 10.3 months (95% CI, 6.0-13.6) and 8.6 months (95% CI, 3.9-13.7 [HR, 0.918; 95% CI, 0.623-1.351]).

All-grade adverse effects (AEs) occurred in 93% and 95% of treated patients in the 177Lu-Dotatate and high-dose octreotide arms, respectively, and all-grade treatment-related AEs (TRAEs) occurred in 69% and 59% of patients, respectively. Grade 3 or higher AEs occurred in 35% and 27% of treated patients in the 177Lu-Dotatate and high-dose octreotide arms, respectively, and grade 3 or higher TRAEs occurred in 16% and 4% of patients, respectively.

The most common all-grade AEs were nausea (177Lu-Dotatate arm, 27.2%; high-dose octreotide arm, 17.8%), diarrhea (25.9%; 34.2%), and abdominal pain (17.7%; 27.4%). The most common grade 3 or higher AEs were decreased lymphocyte counts (5.4%; 0%), increased gamma-glutamyl transferase (4.8%; 2.7%), small intestinal obstruction (3.4%; 0%), and abdominal pain (2.7%; 4.1%). Secondary hematologic malignancies arose in 1 patient in the 177Lu-Dotatate arm and no patients in the high-dose octreotide arm.

“These data have clinical practice–changing implications and support the use of consideration of first-line 177Lu-Dotatate in high grade 2 and grade 3, well-differentiated GEP-NETs,” Singh concluded.

Disclosures: Singh has disclosed employment by Sanofi (I); receiving honoraria from Advanced Accelerator Applications/Novartis and Ipsen; having consulting or advisory roles with Advanced Accelerator Applications/Novartis and Ipsen; and receiving research funding from Novartis (Inst).

References

  1. Singh S, Halperin D, Myrehaug S, et al. [177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: primary analysis of the phase 3 randomized NETTER-2 study. J Clin Oncol. 2024(suppl 3):LBA588. doi:10.1200/JCO.2024.42.3_suppl.LBA588
  2. Hofland J, Kaltsas G, de Herder WW. Advances in the diagnosis and management of well-differentiated neuroendocrine neoplasms. Endocrine Rev. 2020;41(2):371-403. doi:10.1210/endrev/bnz004
  3. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376:125-135. doi:10.1056/NEJMoa1607427
  4. FDA approves lutetium Lu 177 dotatate for treatment of GEP-NETS. FDA. January 26, 2018. Accessed January 20, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lutetium-lu-177-dotatate-treatment-gep-nets
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