Lutetium Lu 177 Dotatate (Lutathera) and Lutetium Lu 177 Vipivotide Tetraxetan (Pluvicto)

Number: 0929

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Lutetium Lu 177 dotatate (Lutathera)

1. Criteria for Initial Approval

   Aetna considers lutetium Lu 177 dotatate (Lutathera) medically necessary for members with the following indications:

   1. Neuroendocrine tumors (NETs)

      1. Tumors of the gastrointestinal (GI) tract (carcinoid tumor) - four doses total for treatment of somatostatin receptor-positive NETs of the gastrointestinal tract when the member has locoregional advanced disease and/or distant metastases and one of the following criteria is met:

         1. Member has clinically significant tumor burden; or
         2. Member experienced disease progression on octreotide or lanreotide;

      2. Tumors of the pancreas - four doses total for treatment of somatostatin receptor-positive NETs of the pancreas when both of the following criteria are met:

         1. Member has symptomatic disease, clinically significant tumor burden, or progressive locoregional advanced disease and/or distant metastases; and
         2. Member experienced disease progression on octreotide or lanreotide;

      3. Neuroendocrine tumors (NETs) of the lung and thymus (carcinoid tumors) - four doses total for treatment of somatostatin receptor-positive NETs of the lung and thymus when one of the following criteria is met:

         1. Member has locoregional unresectable disease and has progressed on octreotide or lanreotide; or
         2. Member has distant metastatic disease, has experienced progression on octreotide or lanreotide, and meets one of the following criteria:
            
            
            1. Clinically significant tumor burden and low grade (typical carcinoid) histology; or
            2. Evidence of progression; or
            3. Intermediate grade (atypical carcinoid) histology; or
               
            4. Symptomatic disease;

      4. Well-differentiated grade 3 NETs with favorable biology - four doses total for treatment of well-differentiated grade 3 unresectable locally advanced or metastatic NETs with favorable biology (e.g., relatively low Ki-67 [less than 55%], somatostatin receptor [SSR] positive imaging) when member meets one of the following criteria:

         1. Clinically significant tumor burden; or
         2. Evidence of progression;

   2. Carcinoid Syndrome

      Four doses total for treatment of poorly controlled carcinoid syndrome when all of the following criteria are met:

      1. Member has somatostatin receptor-positive neuroendocrine tumor of the gastrointestinal tract, lung or thymus; and
      2. Member experienced progression on octreotide or lanreotide; and
      3. Lutetium Lu 177 dotatate (Lutathera) will be used in combination with either
         
         
         1. octreotide LAR or lanreotide for persistent symptoms (i.e., flushing, diarrhea) or
         2. telotristat for persistent diarrhea;
            

   3. Pheochromocytoma/paraganglioma 

      Four doses total for treatment of somatostatin receptor-positive pheochromocytoma/paraganglioma when the member meets one of the following criteria:

      1. Member has locally unresectable disease; or
      2. Member has distant metastases and will be using lutetium Lu 177 dotatate (Lutathera) in combination with octreotide or lanreotide.

   Aetna considers lutetium Lu 177 dotatate (Lutathera) experimental and investigational for all other indications.

2. Continuation of Therapy

   See Dosage and Administration information.

Lutetium Lu 177 vipivotide tetraxetan (Pluvicto)

1. Criteria for Initial Approval

   Prostate Cancer

   Aetna considers lutetium Lu 177 vipivotide tetraxetan (Pluvicto) medically necessary for treatment (up to 6 total doses) of prostate cancer when all of the following criteria are met:

   1. The member has metastatic castration-resistant prostate cancer; and
   2. The member has been treated with androgen receptor (AR) pathway inhibition (e.g., abiraterone) and taxane-based chemotherapy (e.g., docetaxel); and
   3. The disease is prostate-specific membrane antigen (PSMA)-positive.

   Aetna considers lutetium Lu 177 vipivotide tetraxetan (Pluvicto) experimental and investigational for all other indications.

2. Continuation of Therapy

   Aetna considers continuation of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) therapy (up to 6 total doses) medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.
   

Dosage and Administration

Lutetium Lu 177 dotatate (Lutathera)

Lutetium Lu 177 dotatate is available as Lutathera for injection as 370 MBq/mL (10 mCi/mL) in single-dose vial for intravenous use.

Somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults: 

The recommended dose is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses. Administer pre- and concomitant medications and administer Lutathera as recommended.

Source: Advanced Accelerator Applications USA, 2020

Lutetium Lu 177 vipivotide tetraxetan (Pluvicto)

Lutetium Lu 177 vipivotide tetraxetan is available as Pluvicto for injection as 1,000 MBq/mL (27 mCi/mL) in a single-dose vial for intravenous use.

Prostate cancer:

The recommended dosage is 7.4 GBq (200 mCi) intravenously every 6 weeks for up to 6 doses, or until disease progression, or unacceptable toxicity.

Source: Advanced Accelerator Applications USA, 2022

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Lutetium Lu 177 Dotatate (Lutathera):
Other CPT codes related to the CPB:
79101	Radiopharmaceutical therapy, by intravenous administration
84307	Somatostatin
HCPCS codes covered if selection criteria are met:
A9513	Lutetium lu 177, dotatate, therapeutic, 1 millicurie
Other HCPCS codes related to the CPB:
J1930	Injection, lanreotide, 1 mg
J1932	Injection, lanreotide, (cipla), 1 mg
J2353	Injection, octreotide, depot form for intramuscular injection, 1 mg
J2354	Injection, octreotide, nondepot form for subcutaneous or intravenous injection, 25 mcg
ICD-10 codes covered if selection criteria are met:
C25.4	Malignant neoplasm of endocrine pancreas
C7A.00 - C7A.8	Malignant neuroendocrine tumors
C7B.00 – C7B.09	Secondary carcinoid tumors
C74.10	Malignant neoplasm of medulla of unspecified adrenal gland [pheochromocytoma]
D44.7	Neoplasm of uncertain behavior of aortic body and other paraganglia [paraganglioma]
E34.0	Carcinoid syndrome
Lutetium Lu 177 Vipivotide Tetraxetan (Pluvicto):
Other CPT codes related to the CPB:
96365 - 96368	Intravenous infusion
Other CPT codes related to the CPB:
79101	Radiopharmaceutical therapy, by intravenous administration
84402	Testosterone; free
84403	total
96413-96415	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
A9607	Lutetium lu 177 vipivotide tetraxetan, therapeutic, 1 millicurie
Other HCPCS codes related to the CPB:
J9171	Injection, docetaxel, 1 mg
ICD-10 codes covered if selection criteria are met:
C61	Malignant neoplasm of prostate

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Background

Lutetium Lu 177 dotatate (Lutathera)

U.S. Food and Drug Administration (FDA)-Approved Indications

• Lutathera is indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults

Compendial Uses

• Carcinoid syndrome
• Neuroendocrine tumors (NETs) of the lung and thymus (carcinoid tumors)
• Pheochromocytoma/paraganglioma
• Well-differentiated grade 3 NETs with favorable biology

Lutetium Lu 177 dotatate (Lutathera) is a radiolabeled somatostatin analog. Lutetium Lu 177 dotatate binds to somatostatin receptors with highest affinity for subtype 2 receptors (SSRT2). Upon binding to somatostatin receptor expressing cells, including malignant somatostatin receptorpositive tumors, the compound is internalized. The beta emission from Lu 177 induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells (Advanced Accelerator Applications USA, 2020).

Lutathera carries the following warnings and precautions: 

• Risk from radiation exposure: Minimize radiation exposure during and after treatment with Lutathera consistent with institutional good radiation safety practices and patient management procedures;
• Myelosuppression: Monitor blood cell counts. Withhold, reduce dose, or permanently discontinue based on severity;
• Secondary myelodysplastic syndrome (MDS) and leukemia: Median time to development: MDS is 28 months; acute leukemia is 55 months;
• Renal toxicity: Advise patients to urinate frequently during and after administration of Lutathera. Monitor serum creatinine and calculated creatinine clearance. Withhold, reduce dose, or permanently discontinue based on severity;
• Hepatotoxicity: Monitor transaminases, bilirubin and albumin;
• Neuroendocrine hormonal crisis: Monitor for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms;
• Embryo-fetal toxicity: Can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus and to use effective contraception;
• Risk of Infertility.

The most common Grade 3-4 adverse reactions (≥ 4% with a higher incidence in the Lutathera arm) are lymphopenia, increased GGT, vomiting, nausea, increased AST, increased ALT, hyperglycemia and hypokalemia. 

Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

On January 26, 2018, The FDA approved lutetium Lu 177 dotatate (Lutathera) in adult patients for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This is the first time a radioactive drug, or radiopharmaceutical, has been approved for the treatment of GEP-NETs. Lutathera was approved under priority review and received Orphan Drug designation. GEP-NETs can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon and rectum. It is estimated that approximately one out of 27,000 people are diagnosed with GEP-NETs per year.

Lutetium Lu 177 dotatate is a radioactive drug that binds to a part of a cell called a somatostatin receptor, which may be present on certain tumors. After binding to the receptor, the drug enters the cell allowing radiation to cause damage to the tumor cells.

The approval of lutetium Lu 177 dotatate was supported by two studies. In the NETTER-1 trial, Strosberg et al (2017) stated patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. The study randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a pre-specified interim analysis of overall survival was conducted and is reported here. At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. The authors concluded that treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group.

The second study, ERASMUS, was based on data patients with somatostatin receptor-positive tumors, including GEP-NETS, who received lutetium Lu 177 dotatate at a single site in the Netherlands. A total of 1214 patients received lutetium Lu 177 dotatate, of which 601 (50%) were assessed per RECIST criteria. Of the 601 patients evaluated by investigators using RECIST criteria, 360 (60%) had gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Lutetium Lu 177 dotatate 7.4 GBq (200 mCi) was administered every 6 to 13 weeks for up to 4 doses concurrently with the recommended amino acid solution. The major efficacy outcome was investigator-assessed ORR. The median age in the efficacy subset was 61 years (25 to 88 years), 52% were male, 61% had a baseline Karnofsky performance status ≥ 90 (60 to 100), 60% had progressed within 12 months of treatment, and 15% had received prior chemotherapy. Fifty five percent (55%) of patients received a concomitant somatostatin analog. The median dose of lutetium Lu 177 dotatate was 29.6 GBq (800 mCi). Baseline tumor assessments were obtained in 39% of patients. The investigator assessed ORR was 16% (95% CI 13, 20) in the 360 patients with GEP-NETs. Three complete responses were observed (< 1%). Median DoR in the 58 responding patients was 35 months (95% CI: 17, 38).

177 Lu-Dotatate for the Treatment of Glioma / Neuroblastoma

In a prospective, pilot study, Nemati and associates (2021) tested the principle that 177Lu-Dotatate may be used for the treatment of patients with high-grade gliomas (HGGs) that are either inoperable or refractory to the standard conventional treatments and also examined if this approach could be a viable therapeutic plan in this dilemma.  This trial included 16 subjects experiencing HGGs that were either inoperable or refractory to the standard conventional treatments.  All subjects were checked for somatostatin receptor (SSTR) expression on the tumors.  Subjects were treated with 1 to 4 cycles of intravenous (IV) 177Lu-Dotatate.  The primary endpoint was radiological response following peptide receptor radionuclide therapy (PRRT), and the secondary endpoint was improved quality of life (QOL) using Karnofsky Performance Score (KPS) and Eastern Cooperative Oncology Group (ECOG) score.  A total of 16 subjects (10 men and 6 women) with a mean age of 55.68 ± 13.17 years (26 to 73 years) participated in the study.  Of them, 8 patients were new HGG cases, and 8 patients had recurrent tumors.  Participants' responses to treatments were complete remission (CR) in 12.5 % of (n = 2), partial remission (PR) in 31.25 % (n = 5), stable disease (SD) in 18.7 % (n = 3), and disease progression in 37.5 % (n = 6).  In total, pre-treatment and post-treatment KPS and ECOG scores did not improve (p > 0.05).  Subjects were followed-up from 1 month to 26 months (median of 3 months).  The authors concluded that these preliminary findings suggested that PRRT using 177Lu-Dotatate may be associated with positive effects in patients with HGGs (grade III to IV); however, this approach should be examined in a more homogeneous group of patients with more favorable performance status.

Romiani and colleagues (2021) stated that neuroblastoma (NB) is one of the most frequently diagnosed tumors in infants; it is a neuroendocrine tumor (NET) type with various characteristics and features, and with diverse outcome.  The most malignant NBs have a 5-year survival rate of only 40 % to 50 %, indicating the need for novel and improved treatment options.  177Lu-octreotate is routinely administered for treatment of NETs over-expressing SSTR.  These researchers examined the bio-distribution of 177Lu-octreotate in mice bearing aggressive human NB cell lines to evaluate the potential usefulness of 177Lu-octreotate for the treatment of NB.  BALB/c nude mice bearing CLB-BAR, CLB-GE or IMR-32 tumor xenografts (n = 5 to 7/group) were intravenously injected with 0.15 MBq, 1.5 MBq or 15 MBq 177Lu-octreotate and sacrificed 1 hour, 24 hours, 48 hours and 168 hours following administration.  The radioactivity concentration was determined for collected tissue samples, tumor-to-normal-tissue activity concentration ratios (T/N) and mean absorbed dose for each tissue were calculated.  Immunohistochemical (IHC) staining for SSTR1-5, and Ki67 were performed for tumor xenografts from the 3 cell lines.  High 177Lu concentration levels and T/N values were observed in all NB tumors, with the highest for CLB-GE tumor xenografts (72 % IA/g 24 hours post-injection [p.i.]; 1.5 MBq 177Lu-octreotate).  The mean absorbed dose to the tumor was 6.8 Gy, 54 Gy and 29 Gy for CLB-BAR, CLB-GE and IMR-32, respectively, p.i. of 15 MBq 177Lu-octreotate.  Receptor saturation was clearly observed in CLB-BAR, resulting in higher concentration levels in the tumor when lower activity levels where administered.  IHC staining demonstrated highest expression of SSTR2 in CLB-GE, followed by CLB-BAR and IMR-32.  The authors concluded that the biodistribution studies of 177Lu-octreotate in all 3 examined human NB xenograft mouse models demonstrated very high uptake in tumors compared with that in normal tissues; thus, 177Lu-octreotate could be considered a potential therapeutic option, especially in high-risk NB patients with high expression of SSTRs and with low response to present therapeutic options.

Naik and associates (2022) noted that PRRT has been one of the most successful and exciting examples of theranostics in nuclear medicine in recent decades and is now firmly embedded in many treatment algorithms for unresectable or metastatic neuroendocrine neoplasms (NENs) worldwide.  It is widely considered to be an effective treatment for well- or moderately differentiated neoplasms, which express high levels of SSTR that can be selectively targeted.  These investigators reviewed the scientific basis of PRRT in the treatment of NENs and described its discovery dating back to the early 1990s.  Early treatments using Indium-111, a gamma-emitter, showed promise in reduction in tumor size and improvement in biochemistry, but were also met with high radiation doses and myelotoxic and nephrotoxic effects.  Subsequently, stable conjugation of DOTA-peptides with beta-emitting radionuclides (e.g., yttrium-90 and lutetium-177) served as a break-through for PRRT and studies highlighted their potential in eliciting PFS and QOL benefits.  The authors concluded that PRRT has been found to be a highly effective and well-tolerated treatment for metastatic, unresectable SSTR positive NETs.  They noted that although it is currently considered a 2nd-line treatment and there are several other options for patients with disseminated disease, further prospective trial evidence is needed to determine if more widespread use earlier in the management pathway is conceivable and to examine if competing therapeutic options currently available may have complementary roles.

177 Lu-Dotatate Plus Octreotide for the Treatment of Midgut Neuroendocrine Tumors

Strosberg and colleagues (2021) noted that the primary analysis of the phase-III NETTER-1 Trial showed significant improvement in progression-free survival (PFS) with 177Lu-Dotatate plus long-acting release (LAR) octreotide versus high-dose LAR octreotide alone in patients with advanced midgut NETs.  These investigators reported the pre-specified final analysis of overall survival (OS) and long-term safety results.  This study was randomized, open-label, phase-III clinical trial that enrolled patients from 41 sites in 8 countries across Europe and the U.S.  Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut NETs (KPS score of greater than or equal to 60) and disease progression on fixed-dose LAR octreotide.  Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous 177Lu-Dotatate 7.4 GBq (200 mCi) every 8 weeks (4 cycles) plus intramuscular LAR octreotide 30 mg (177Lu-Dotatate group) or high-dose LAR octreotide 60 mg every 4 weeks (control group).  The primary endpoint of PFS has been previously reported; these investigators reported the key secondary endpoint of OS in the intention-to-treat (ITT) population.  Final OS analysis was pre-specified to occur either after 158 deaths or 5 years after the last patient was randomized, whichever occurred first.  During long-term follow-up, adverse events (AEs) of special interest were reported in the 177Lu-Dotatate group only.  From September 6, 2012, to January 14, 2016, a total of 231 patients were enrolled and randomly assigned for treatment.  The pre-specified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76.3 months (range of 0.4 to 95.0) in the 177Lu-Dotatate group and 76.5 months (0.1 to 92.3) in the control group.  The secondary endpoint of OS was not met -- median OS was 48.0 months (95 % CI: 37.4 to 55.2) in the 177Lu-Dotatate group and 36.3 months (25.9 to 51.7) in the control group (hazard ratio [HR] 0.84 [95 % CI: 0.60 to 1.17]; 2-sided p = 0.30).  During long-term follow-up, treatment-related serious AEs (SAEs) of grade 3 or worse were recorded in 3 (3 %) of 111 patients in the 177Lu-Dotatate group, but no new treatment-related SAEs were reported after the safety analysis cut-off; 2 (2 %) of 111 patients given 177Lu-Dotatate developed MDS, 1 of whom died 33 months after randomization (this person was the only reported 177Lu-Dotatate treatment-related death).  No new cases of MDS or acute myeloid leukemia (AML) were reported during long-term follow-up.  The authors concluded that 177Lu-Dotatate treatment did not significantly improve median OS versus high-dose LAR octreotide.  Despite final OS not reaching statistical significance, the 11.7-month difference in median OS with 177Lu-Dotatate treatment versus high-dose LAR octreotide alone might be considered clinically relevant.  No new safety signals were reported during long-term follow-up.

177 Lu-Dotatate Plus Capecitabine for the Treatment of Gastro-Entero-Pancreatic Neuroendocrine Tumors

In a single-center study, Satapathy and colleagues (2021) compared the safety and effectiveness of 177Lu-Dotatate plus radio-sensitizing capecitabine and LAR octreotide as 1st-line systemic therapy in advanced well-differentiated gastro-entero-pancreatic NETs (GEP-NETs).  Data of consecutive patients of advanced inoperable or metastatic grade 1 or 2 GEP-NETs treated with 1st-line 177Lu-Dotatate plus radio-sensitizing capecitabine or LAR octreotide from September 2012 to December 2019 were collected and analyzed for response, toxicity, and survival outcomes.  A total of 76 patients (median age of 53 years; range of 14 to 81 years) with treatment-naive advanced grade 1 or 2 GEP-NETs were included; 36 patients received a median cumulative dose of 27.3 GBq of 177Lu-Dotatate intravenously at 8 to 12 weeks' intervals along with 1,250 mg/m2 oral capecitabine on days 0 to 14 of each cycle of 177Lu-Dotatate, whereas 40 patients were administered 30 mg LAR octreotide intramuscularly every 4 weeks.  Using response evaluation criteria in solid tumors, version 1.1 (RECIST 1.1), the objective response rate (ORR) was 38 % in the 177Lu-Dotatate arm compared with 15 % in the LAR octreotide arm (p = 0.025), whereas the disease control rates (DCRs) were 88 % and 67 % in 177Lu-Dotatate and LAR octreotide arms, respectively (p = 0.035).  The median durations of PFS in the 177Lu-Dotatate and LAR octreotide arms were 54 months and 16 months, respectively (p = 0.017), whereas the median OS was not reached and not significantly different across both the arms.  Of the treatment-related AEs, no major difference was observed in the occurrence of grade 3 or 4 toxicities between the 2 treatment arms.  The authors concluded that 1st-line systemic 177Lu-Dotatate plus radio-sensitizing capecitabine achieved better radiologic response and longer PFS compared with LAR octreotide in patients with advanced grade 1 or 2 GEP-NETs.  Moreover, these researchers stated that future randomized controlled trials (RCTs) are needed to determine the best treatment sequence for the treatment-naïve patients with advanced GEP-NETs.

The authors stated that this study had several drawbacks.  The relatively small number of patients included in the 2 treatment arms (total of 76 subjects), non-randomized treatment allocation, and retrospective analysis limited the strength of the observations.  In addition, evaluation of health-related QOL (HR-QOL) was not performed.  Follow-up chromogranin A levels were not available in majority of the patients owing to financial constraints.  Nevertheless, given the rarity of the disease, the current study served as a proof-of-concept examining the potential benefit of 177Lu-Dotatate over somatostatin analogs as upfront therapy in advanced GEP-NETs, especially in a lower- to middle-income country.  These researchers stated that adequately powered RCTs with head-to-head comparison of 177Lu-Dotatate and LAR octreotide would aid in validating the findings of this study and determine the best therapeutic option for the treatment-naïve patients with advanced GEP-NETs.

Nicolini and associates (2021) noted that FDG-positive NETs have a poorer prognosis and exhibit shorter response duration to peptide receptor radionuclide therapy (PRRT).  In a prospective, phase-II clinical trial, these researchers examined the effectiveness and toxicity of PRRT with 177Lu-Dotatate associated with metronomic capecitabine as a radio-sensitizer agent in patients with advanced progressive FDG-positive GEP-NETs.  Patients with advanced somatostatin receptor- and FDG-positive G1-G3 GEP-NETs (Ki67 less than 55 %) were treated with a cumulative activity of 27.5 GBq of 177Lu-Dotatate divided in 5 cycles of 5.5 GBq each, every 8 weeks.  Capecitabine (1,000 to 1,500 mg daily) was administered orally in the inter-cycle period between 177Lu-Dotatate treatments.  Prior to commencing capecitabine, all patients were triaged with the dihydropyrimidine dehydrogenase (DPD) test.  Only DPD-proficient individuals were enrolled.  The primary objectives were DCR and safety.  Secondary aims included PFS and OS.  Treatment response was assessed per RECIST 1.1.  Toxicity was evaluated by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  From August 2015 to December 2016, a total of 37 subjects were consecutively enrolled -- 25 (68 %) were affected by pancreatic NETs (P-NETs), and 12 (32 %) had gastro-intestinal NETs (GI-NETs).  By grading (WHO 2010 classification), 12 patients (32 %) had G1 (Ki67 less than or equal to 2 %), 22 (59 %) had G2 (3 % less than Ki67 less than or equal to 20 %), and 3 patients (9 %) had G3 (Ki67 greater than 20 %) NETs.  Grade 3 (G3) or 4 (G4) hematological toxicity occurred in 16.2 % of patients.  Other G3 to G4 AEs were diarrhea in 5.4 % of cases and asthenia in 5.4 %.  No renal toxicity was observed for the duration of follow-up.  In 37 patients, 33 were evaluable for response.  Objective responses included PR in 10 patients (30 %) and SD in 18 patients (55 %), with a DCR of 85 %.  The median follow-up was 38 months (range of 4.6 to 51.1 months).  The median PFS was 31.4 months (17.6 to 45.4), and median OS was not reached.  The authors concluded that this study demonstrated that the combination of PRRT with 177Lu-Dotatate and metronomic capecitabine was active and well-tolerated in patients with aggressive FDG-positive G1-G3 GEP-NETs.  These data would constitute the basis for a randomized study of PPRT alone versus PRRT plus metronomic capecitabine.

Lutetium Lu 177 vipivotide tetraxetan (Pluvicto)

U.S. Food and Drug Administration (FDA)-Approved Indications

• Pluvicto is indicated for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy.

Lutetium Lu 177 vipivotide tetraxetan is available as Pluvicto (Advanced Accelerator Applications USA, Inc.) and is a radioligand therapeutic agent. The active component of lutetium Lu 177 vipivotide tetraxetan is the radionuclide lutetium-177 which is connected to a component that binds to prostate-specific membrane antigen (PSMA). PSMA is a transmembrane protein that is expressed in prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Lutetium Lu 177 vipivotide tetraxetan binding to PSMA-expressing cells results in the delivery of radiation to PSMA-expressing and surrounding cells causing DNA damage and eventual cell death (Advanced Accelerator Applications USA, 2022).

Per the prescribing information, lutetium Lu 177 vipivotide tetraxetan (Pluvicto) carries the following warnings and precautions:

• Risk from radiation exposure. Pluvicto adds to a patient's overall long-term cumulative radiation exposure with an increased risk of cancer.
• Myelosuppression. Pluvicto can result in severe and life-threatening myelosuppression, including anemia, thrombocytopenia, leukopenia, and neutropenia. Grade 3 or 4 decreased hemoglobin (15%), decreased platelets (9%), decreased leukocytes (7%), and decreased neutrophils (4.5%) was noted in patients receiving Pluvicto in the VISION study.
• Renal toxicity. Pluvicto can induce severe renal toxicity. Grade 3 or 4 acute kidney injury (3%) and increased creatinine (0.9%) was noted in patient receiving Pluvicto in the VISION study.
• Embryo-fetal toxicity. The safety and efficacy of Pluvicto has not been determined in females. Pluvicto can cause fetal harm based on its mechanism of action. Male patients with female partners should be advised to use effective contraception during treatment with Pluvicto and for 14 weeks after the last dose.
• Infertility. Pluvicto can induce infertility in males. The recommended cumulative dose of 44.4 GBq of Pluvicto may result in temporary or permanent infertility due to absorption of radiation in the testes.

Per the prescribing information, lutetium Lu 177 vipivotide tetraxetan (Pluvicto) carries the following adverse reactions:

• The most common adverse reactions (≥ 20%) include fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation.
• The most common laboratory abnormalities (≥ 30%) include: decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium.

On March 23, 2022, the U.S. Food and Drug Administration (FDA) approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. The FDA granted priority review and breakthrough designation for Pluvictio and the FDA approval was based on supporting data from the VISION study.

In the VISION study, an international, randomized (2:1), multicenter, open-label, pivotal phase 3 trial, Sartor and colleagues (2021)  evaluated the safety and efficacy of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in patients with metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens and who had prostate-specific membrane antigen (PSMA) gallium-68 (68Ga)-labeled PSMA-11 positron-emission tomographic-computed tomographic scans. Patient randomization occurred in a 2:1 ratio for patients receiving Pluvicto (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard of care (n=551) or standard of care alone (n=280). Protocol-permitted standard of care prohibited the use of chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The primary endpoints were imaging-based progression-free survival and overall survival and were powered for hazard ratios of 0.67 and 0.73, respectively. Notable secondary endpoints included objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were noted as occurring no more than 30 days after the last dose and before subsequent anticancer treatment. The median follow-up was 20.9 months. Pluvicto plus standard care significantly extended, as compared with standard of care alone, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; p<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; p<0.001). Pluvicto was significantly favorable for all key secondary endpoints. The occurrence of ≥ grade 3 adverse events was greater with Pluvicto than without  (52.7% vs. 38.0%), however, quality of life not adversely impacted. The investigators concluded that Pluvicto extended imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer.

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