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Fuchs CS et al. JAMA Oncol 2018;4:e180013

Supplement 1 to: Fuchs CS et al. JAMA Oncol 2018;4:e180013

Supplement 2 to: Fuchs CS et al. JAMA Oncol 2018;4:e180013

 

Pembrolizumab 200 mg; administer intravenously over 30 minutes in a volume of 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) sufficient to produce a pembrolizumab concentration within the range 1–10 mg/mL every 3 weeks until disease progression for up to 24 months (total dosage/3-week cycle = 200 mg)

  • Administer pembrolizumab with an administration set that contains a sterile, nonpyrogenic, low protein-binding in-line or add-on filter with pore size within the range of 0.2–5 μm

  • Pembrolizumab can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis

  • Patients who achieved a confirmed complete response after receiving at least 8 cycles of pembrolizumab could discontinue treatment after receiving 2 doses beyond the determination of complete response

 

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

 

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis is NOT indicated

See Chapter 43 for more information

 

Antimicrobial prophylaxis

Risk of fever and neutropenia is LOW

  Antimicrobial primary prophylaxis to be considered:

  • Antibacterial—not indicated

  • Antifungal—not indicated

  • Antiviral—not indicated unless patient previously had an episode of HSV

See Chapter 47 for more information

 

Patient Population Studied

Cohort 1 of the international, multicenter, open-label, single-arm, multicohort (3-cohort), phase 2 trial (KEYNOTE-059) involved 259 patients with histologically or cytologically confirmed recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma (only Siewart types II and III) incurable by locally approved therapies. Eligible patients were aged ≥18 years, had disease progression after 2 or more prior chemotherapy regimens that included a fluoropyrimidine and a platinum doublet, had human epidermal growth factor receptor 2/neu-negative disease (or human epidermal growth factor receptor 2/neu-positive disease if previously treated with trastuzumab), had Eastern Cooperative Oncology Group (ECOG) performance score status ≤1, and had life expectancy ≥3 months. Patients received pembrolizumab monotherapy infusion (200 mg over 30 minutes) on day 1 of every 3-week cycle for up to 35 cycles.

Efficacy (N = 259)

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Efficacy (N = 259)
Objective response rate 11.6%
Duration of response 8.4 months
Disease control rate 27.0%
Median progression-free survival 2.0 months
Median overall survival 5.6 months

Objective response rate was the primary efficacy end point and included patients with complete or partial response, as per RECIST version 1.1 by central review

Disease control rate included complete response, partial response, or stable disease for ≥2 months

Notes: Median duration of follow-up was 5.8 months. In total, 2.3% experienced a complete response

Therapy Monitoring

  1. Initially at the time of each dose, and eventually every 6–12 weeks, perform a total body skin examination with attention to all mucous membranes as well as a complete review of systems

  2. Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with chest x-ray, CT scan, and pulse oximetry. For toxicity ≥G2, may include nasal swab, sputum culture and sensitivity, blood culture and sensitivity, and urine culture and sensitivity

  3. Monitor patients for signs and symptoms of colitis. Encourage patients to report diarrhea immediately to any member of the healthcare team

  4. Draw AST, ALT, and bilirubin prior to each infusion and/or weekly if there are G1 LFT elevations. Note: No treatment is recommended for G1 LFT abnormalities. For toxicity ≥G2, work up for other causes of elevated LFTs, including viral hepatitis

  5. Use basic metabolic panel (Na, K, CO2, glucose) and patient history as screening tools for hypophysitis, including hypopituitarism and adrenal insufficiency. If in doubt, evaluate morning adrenocorticotropic hormone (ACTH) and cortisol levels. Consider ACTH stimulation test for indeterminate results

  6. Assess Thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation and for clinical signs and symptoms of thyroid disorders. Test for TSH and free thyroxine (FT4) every 4–6 weeks as part of routine clinical monitoring on therapy or for case detection in symptomatic patients

  7. Measure glucose at baseline and with each treatment during the first 12 weeks and every 6 weeks thereafter

  8. Obtain a serum creatinine level prior to every dose. If creatinine is found to be newly elevated, consider holding therapy while other potential causes are evaluated. Note: Routine urinalysis is not necessary other than to rule out urinary tract infections, etc

  9. Obtain a complete rheumatologic history and perform an examination of all peripheral joints for tenderness, swelling, and range of motion. Examine the spine. Consider plain x-ray/imaging to exclude metastases and evaluate joint damage (erosions), if appropriate

  10. In patients at high risk infections and in appropriately selected patients based on an infectious disease evaluation, draw screening laboratories (HIV, hepatitis A and B, and blood quantiferon for TB) to prepare patients to start infliximab

  11. Response evaluation: Every 2–4 months

Treatment Modifications

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Treatment Modifications
RECOMMENDED DOSAGEE MODIFICATIONS FOR PEMBROLIZUMAB
Adverse Event Grade/Severity Treatment Modification
Infusion reaction Clinically significant but not severe infusion reaction Interrupt the infusion in patients with clinically significant infusion reactions and consider resuming at a slower rate following resolution. If decision is made to restart, begin at ≤50% of the rate prior to the reaction and increase in 50% increments every 30 minutes if well tolerated. Infusions may be restarted at the full rate during the next cycle
G3/4 (severe infusion reaction—pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria). Not rapidly responsive to brief interruption of infusion Stop infusion and administer appropriate medical therapy (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and/or oxygen). Discontinue pembrolizumab
Colitis G1 Loperamide 4 mg as starting dose, then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. If G1 diarrhea or colitis persists >14 days, add prednisolone 0.5–1 mg/kg (non–enteric coated) or consider oral budesonide 9 mg daily if no bloody diarrhea
G2/3 diarrhea or colitis Withhold pembrolizumab. Loperamide 4 mg as starting dose, then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
G4 diarrhea or colitis Permanently discontinue pembrolizumab. Loperamide 4 mg as starting dose, then 2 mg before each meal and after each loose stool until without diarrhea for 12 hours, with maximum of 16 mg loperamide per day. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve. If symptoms do not improve over 72 hours or worsen, perform flexible sigmoidoscopy/colonoscopy to document colitis, then begin infliximab 5 mg/kg (if no perforation, sepsis, TB, hepatitis, NYHA III/IV CHF). If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider addition of tacrolimus or ATG
Pneumonitis G2 Withhold pembrolizumab. Consider pneumocystis prophylaxis depending on the clinical context and coverage with empiric antibiotics. Administer oral prednisone/prednisolone at a dose of 1–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate after 48 hours, administer 2–4 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 6 weeks when symptoms improve to G1, titrating to symptoms. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
G3/4 Permanently discontinue pembrolizumab. Consider pneumocystis prophylaxis depending on the clinical context; cover with empiric antibiotics. Administer 2–4 mg/kg intravenous (methyl)prednisolone and convert to 1–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 8 weeks when symptoms improve to G1, titrating to symptoms. If, when initially treated, improvement does not occur within 48–72 hours begin infliximab 5 mg/kg (if no perforation, sepsis, TB, hepatitis, NYHA III/IV CHF). If no response to infliximab, add MMF 500–1000 mg twice daily. Consider MMF especially if concurrent hepatic toxicity
Hepatitis G2 (AST or ALT >3–5× ULN or total bilirubin >1.5–3× ULN) Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dose of 1–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
G3/4 (AST or ALT >5× ULN or total bilirubin >3× ULN) Permanently discontinue pembrolizumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 6 weeks when symptoms improve. If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider adding tacrolimus or ATG
Hypophysitis G2/3 (moderate symptoms, ie, headache but no visual disturbance or fatigue/mood alteration but hemodynamically stable, no electrolyte disturbance) Administer analgesia as needed for headache. Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1 begin a slow corticosteroid taper over at least 4 weeks. If no improvement in 48 hours, administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve to 5 mg prednisone/prednisolone or equivalent; do not stop steroids. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
G4 (severe mass effect symptoms, ie, severe headache, any visual disturbance or severe hypoadrenalism, ie, hypotension, severe electrolyte disturbance) Permanently discontinue pembrolizumab. Administer analgesia as needed for headache. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4 weeks when symptoms improve to 5 mg prednisone/prednisolone or equivalent; do not stop steroids
Adrenal insufficiency G2 Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Serially assess adrenal function and continue steroids at replacement doses (20–40 mg hydrocortisone daily ~2/3 dose in morning upon awakening and ~1/3 at 4 PM) until recovery of adrenal function is documented. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
G3/4 Permanently discontinue pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Serially assess adrenal function and continue steroids at replacement doses (20–40 mg hydrocortisone daily ~2/3 dose in morning upon awakening and ~1/3 at 4 PM) until recovery of adrenal function is documented
Type 1 diabetes mellitus G3 hyperglycemia Withhold pembrolizumab. Admit to hospital to manage hyperglycemia. Role of corticosteroids in preventing complete loss of insulin-producing cells is unknown and use is not recommended. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
G4 hyperglycemia Permanently discontinue pembrolizumab. Admit to hospital to manage hyperglycemia. Role of corticosteroids in preventing complete loss of insulin-producing cells is unknown and use is not recommended.
Nephritis and renal dysfunction G2/3 (serum creatinine 1.5–6× ULN) Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate, administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
G4 (serum creatinine >6× ULN) Permanently discontinue pembrolizumab. Administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1
Skin G1/2 Continue pembrolizumab. Avoid skin irritants, avoid sun exposure; topical emollients recommended. Topical steroid (mild strength for G1, moderate/potent strength for G2) cream once or twice daily ± oral or topical antihistamines for itching
G3 rash or suspected SJS or TEN Withhold pembrolizumab. Avoid skin irritants, avoid sun exposure; topical emollients recommended. Administer oral or topical antihistamines for itching. Administer oral prednisone/prednisolone at a dose of 0.5–2 mg/kg or its equivalent daily for 3 days followed by a slow corticosteroid taper over at least 4 weeks when the rash improves to G1. If rash does not respond adequately, administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when the rash improves to G1. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
G4 rash or confirmed SJS or TEN Avoid skin irritants, avoid sun exposure; topical emollients recommended. Administer oral or topical antihistamines for itching. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to oral steroids 0.5–2 mg/kg prednisone/prednisolone each day or its equivalent only after a response. Taper over at least 4 weeks when the rash improves to G1. Permanently discontinue pembrolizumab
Encephalitis Confusion or altered behavior, headaches, alteration in Glasgow Coma Scale, motor or sensory deficits, speech abnormality; may or may not be febrile Initially withhold pembrolizumab, but permanently discontinue pembrolizumab if there is no doubt as to diagnosis. Exclude bacterial and ideally viral infections prior to high-dose steroids. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. If symptoms are severe, administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Consider concurrent empiric antiviral (intravenous acyclovir) and antibacterial therapy
Aseptic meningitis Headache, photophobia, neck stiffness with fever, or may be afebrile, vomiting; normal cognition/cerebral function (distinguishes from encephalitis)
Other syndromes include neurosarcoidosis, posterior reversible leukoencephalopathy syndrome (PRES), Vogt-Harada-Koyanagi syndrome, demyelination, vasculitic encephalopathy, and generalized seizures
Transverse myelitis Acute or subacute neurologic signs/symptoms of motor, sensory, autonomic origin; most have sensory level; often bilateral symptoms Initially withhold pembrolizumab, but permanently discontinue pembrolizumab if there is no doubt as to diagnosis. Administer 2 mg/kg intravenous (methyl)prednisolone or consider 1 g/day and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. Plasmapheresis may be required if steroids do not bring about improvement
Myocarditis G3 Permanently discontinue pembrolizumab. Administer 2 mg/kg intravenous (methyl)prednisolone or consider 1 g/day and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. When symptoms improve, begin a slow corticosteroid taper over at least 4–8 weeks. If no response, add MMF 500–1000 mg twice daily. If worse on MMF, consider adding tacrolimus
Peripheral neurologic toxicity Moderate: some interference with ADL, symptoms concerning to patient Withhold pembrolizumab. Initial observation reasonable or initiate prednisone/prednisolone 0.5–1 mg/kg (if progressing, eg, from mild) and/or pregabalin or duloxetine for pain. When symptoms improve, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
Severe: limits self-care and aids warranted, life-threatening, eg, respiratory problems Permanently discontinue pembrolizumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4–8 weeks when symptoms improve to G1
Guillain-Barré syndrome Progressive symmetrical muscle weakness with absent or reduced tendon reflexes—involves extremities; facial, respiratory, and bulbar and oculomotor muscles; dysregulation of autonomic nerves Permanently discontinue pembrolizumab. Use of steroids not recommended in idiopathic Guillain-Barré syndrome; however, a trial of (methyl)prednisolone 1–2 mg/kg is reasonable, converting to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. If no improvement or worsening, plasmapheresis or IVIG is indicated
Myasthenia gravis Fluctuating muscle weakness (proximal limb, trunk, ocular, eg, ptosis/diplopia or bulbar) with fatigability; respiratory muscles may also be involved Permanently discontinue pembrolizumab. Administer pyridostigmine at an initial dose of 30 mg 3 times daily. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent or 1–2 mg/kg intravenous (methyl)prednisolone, depending on the severity of symptoms. If treatment begins with intravenous drug, convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. If no improvement or worsening, plasmapheresis or IVIG may be considered. Additional immunosuppressants used in myasthenia gravis include azathioprine, cyclosporine, and mycophenolate. Avoid certain medications, e.g. ciprofloxacin, beta-blockers, that may precipitate cholinergic crisis
Other syndromes, including motor and sensory peripheral neuropathy, multifocal radicular neuropathy/plexopathy, autonomic neuropathy, phrenic nerve palsy, cranial nerve palsies (eg, facial nerve, optic nerve, hypoglossal nerve) Permanently discontinue pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent or 1–2 mg/kg intravenous (methyl)prednisolone, depending on the severity of symptoms. If treatment begins with intravenous drug, convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response
Arthralgia G1 (mild pain with inflammation, erythema, or joint swelling) Continue pembrolizumab. Administer acetaminophen (paracetamol) and ibuprofen
G2 (moderate pain with inflammation, erythema or joint swelling that limits ADLs) Withhold pembrolizumab. Administer higher doses of acetaminophen (paracetamol) and ibuprofen and use diclofenac or naproxen or etoricoxib. If inadequately controlled, consider intra-articular steroid injections for large joints or administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. If response is not adequate, administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
G3 (severe pain; irreversible joint damage; disabling; limits self-care ADLs) Withhold pembrolizumab. Administer 0.5–1 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response, followed by a taper over at least 4 weeks when symptoms improve to G1. In severe cases, infliximab or another anti-TNF-alpha drug may be required for improvement of arthritis. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
Other First occurrence of other G3 Withhold pembrolizumab. Administer oral prednisone/prednisolone at a dosage of 0.5–2 mg/kg per day or its equivalent. When symptoms improve to G1, begin a slow corticosteroid taper over at least 4 weeks. Resume pembrolizumab upon symptom control, or when prednisone/prednisolone daily dosage <10 mg
Recurrence of same G3 Permanently discontinue pembrolizumab. Administer 1–2 mg/kg intravenous (methyl)prednisolone and convert to 0.5–2 mg/kg prednisone/prednisolone orally each day or its equivalent only after a response. Taper over at least 4–8 weeks when symptoms improve to G1
Life-threatening or G4
Requirement for ≥10 mg/day prednisone or equivalent for >12 weeks Permanently discontinue pembrolizumab
Persistent G2/3 adverse reactions lasting ≥12 weeks
ADL, activities of daily living; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ATG, anti-thymocyte globulin; NYHA, New York Heart Association; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; ULN, upper limit of normal

Notes on general supportive care:

  • Steroid taper in most cases will proceed over a minimum of 1 month, but if symptoms improve rapidly a 2-week taper can be considered. If steroids are administered for more than 4 weeks, consider PCP prophylaxis (cotrimoxazole 480 mg twice daily M/W/F or inhaled pentamidine if cotrimoxazole allergy), regular random blood glucose, vitamin D level, and starting calcium/vitamin D supplementation as per guidelines

Notes on pregnancy and breastfeeding:

  • Pembrolizumab can cause fetal harm. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Females of reproductive potential should use highly effective contraception during treatment and for 4 months after the last dose of pembrolizumab

  • It is not known whether pembrolizumab is excreted in human milk. Therefore, it is recommended that women discontinue nursing during treatment with and for 4 months after the final dose of pembrolizumab

 

Adverse Events (N = 259)

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Adverse Events (N = 259)
Grade (%) Grade 1/2 Grade 3 Grade 4/5
Fatigue 17 2 0
Pruritus 9 0 0
Rash 8 <1 0
Hypothyroidism 7 <1 0
Decreased appetite 7 0 0
Anemia 4 3 0
Nausea 6 <1 0
Diarrhea 5 1 0
Arthralgia 5 <1 0

According to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0

Notes: Treatment-related toxicities that occurred in ≥5% are included in the table. In total, 60.2% of patients experienced at least 1 treatment-related toxicity of any grade and 17.8% of patients experienced at least 1 ≥G3 treatment-related toxicity. Treatment discontinuation owing to treatment-related adverse events was reported for 0.8%. Deaths considered by the investigator to have been related to treatment were reported for 0.8% (1 death as a result of acute kidney injury and 1 as a result of pleural effusion)

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