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Non small cell lung cancer metastatic cARBOplatin, pemetrexed and pembrolizumab

Treatment must be initiated and supervised by specialist physicians experienced in the treatment of cancer using immunological agents. Before commencing immunotherapy treatment in any patient, clinicians should have an understanding of the immune-related adverse events (irAEs) associated with immunotherapy treatment and their management.

Check for clinical trials in this patient group. Link to Australian Clinical Trials website

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Cycle 1 to 4

Drug Dose Route Day
Pembrolizumab # 200 mg IV infusion 1
Pemetrexed 500 mg/m2 IV infusion 1
cARBOplatin 5 AUC * IV infusion 1

Cycle 5 to 35

Drug Dose Route Day
Pembrolizumab # 200 mg IV infusion 1
Pemetrexed 500 mg/m2 IV infusion 1

# Treatment with pembrolizumab must not exceed 35 doses in total or up to 24 months of treatment.

* If estimated GFR is >125 mL/min i.e. carboplatin 5 AUC dose > 750 mg, obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended.

Frequency:
21 days 
Cycles:
35 or until disease progression or unacceptable toxicity
Notes:

In the first few months after the start of immunotherapy, some patients can experience transient tumour flare (termed "pseudo progression" or an immune response). This may manifest as growth of existing lesions or the development of new lesions prior to later tumour regression. While this is rare (~5%), continuing treatment and performing a second scan 4 to 6 weeks later to confirm progression may be considered, particularly if the patient remains well.

Drug status:

Carboplatin and pemetrexed are on the PBS general schedule

Pembrolizumab is TGA registered but not PBS listed for this indication

Cost:
~ $9,580 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 to 4

Day before chemotherapy
Dexamethasone 4 mg (PO) TWICE a day with or after food
Day 1
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 4 mg (PO) TWICE a day with or after food
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes
Pemetrexed 500 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 10 minutes
cARBOplatin 5 AUC (IV infusion) in 500 mL glucose 5% over 30 to 60 minutes (if estimated GFR is >125 mL/min (i.e. 5 AUC dose >750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended)
Day 2
Dexamethasone 4 mg (PO) TWICE a day with or after food
Day 3
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone dose on day 3 may not be required and may be reduced or omitted at the clinicians discretion *

Cycle 5 to 35

Day before chemotherapy
Dexamethasone 4 mg (PO) TWICE a day with or after food
Day 1
Dexamethasone 4 mg (PO) TWICE a day with or after food
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes
Pemetrexed 500 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 10 minutes
Day 2
Dexamethasone 4 mg (PO) TWICE a day with or after food

* Link to ID 7 Prevention of chemotherapy induced nausea and vomiting. 

Frequency:
21 days 
Cycles:
35 or until disease progression or unacceptable toxicity

Cycle 1 to 4

Drug Dose Route Day
Pembrolizumab # 200 mg IV infusion 1
Pemetrexed 500 mg/m2 IV infusion 1
cARBOplatin 5 AUC * IV infusion 1

Cycle 5 to 35

Drug Dose Route Day
Pembrolizumab # 200 mg IV infusion 1
Pemetrexed 500 mg/m2 IV infusion 1

# Treatment with pembrolizumab must not exceed 35 doses in total or up to 24 months of treatment.

* If estimated GFR is >125 mL/min i.e. carboplatin 5 AUC dose > 750 mg, obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended.

Frequency:
21 days 
Cycles:
35 or until disease progression or unacceptable toxicity
Notes:

In the first few months after the start of immunotherapy, some patients can experience transient tumour flare (termed "pseudo progression" or an immune response). This may manifest as growth of existing lesions or the development of new lesions prior to later tumour regression. While this is rare (~5%), continuing treatment and performing a second scan 4 to 6 weeks later to confirm progression may be considered, particularly if the patient remains well.

Drug status:

Carboplatin and pemetrexed are on the PBS general schedule

Pembrolizumab is TGA registered but not PBS listed for this indication

Cost:
~ $9,580 per cycle "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1 to 4

Day before chemotherapy
Dexamethasone 4 mg (PO) TWICE a day with or after food
Day 1
Netupitant 300 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with palonosetron)
Palonosetron 0.5 mg (PO) 60 minutes before chemotherapy (fixed dose preparation with netupitant)
Dexamethasone 4 mg (PO) TWICE a day with or after food
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes
Pemetrexed 500 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 10 minutes
cARBOplatin 5 AUC (IV infusion) in 500 mL glucose 5% over 30 to 60 minutes (if estimated GFR is >125 mL/min (i.e. 5 AUC dose >750 mg), obtaining direct measurement rather than an estimated renal function and/or dose capping is strongly recommended)
Day 2
Dexamethasone 4 mg (PO) TWICE a day with or after food
Day 3
Dexamethasone 8 mg (PO) ONCE a day (or in divided doses) with or after food. Note: dexamethasone dose on day 3 may not be required and may be reduced or omitted at the clinicians discretion *

Cycle 5 to 35

Day before chemotherapy
Dexamethasone 4 mg (PO) TWICE a day with or after food
Day 1
Dexamethasone 4 mg (PO) TWICE a day with or after food
Pembrolizumab 200 mg (IV infusion) in 50 mL sodium chloride 0.9% over 30 minutes
Pemetrexed 500 mg/m2 (IV infusion) in 100 mL sodium chloride 0.9% over 10 minutes
Day 2
Dexamethasone 4 mg (PO) TWICE a day with or after food

* Link to ID 7 Prevention of chemotherapy induced nausea and vomiting. 

Frequency:
21 days 
Cycles:
35 or until disease progression or unacceptable toxicity

Indications

  • First-line treatment of metastatic non-squamous non-small cell lung cancer, without targetable EGFR or ALK mutations
  • ECOG performance status score 0 or 1.

Precautions

If any of these conditions are present, clinical judgement should be used and individual cases discussed with an expert in the field as indicated:

  • significant autoimmune disease (e.g. myasthenia gravis, inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, autoimmune ocular disease)
  • organ transplantation
  • previous history of viral hepatitis
  • HIV/acquired immune deficiency syndrome (AIDS)
  • previous radiation to the lungs.
Venous access required

IV cannula (IVC) or central venous access device (CVAD) is required to administer this treatment.

Read more about central venous access device line selection
Hypersensitivity/infusion related reaction

High risk with carboplatin. Hypersensitivity risk increases with number of cycles of carboplatin.
Premedication

Starting 5 to 7 days prior to the first cycle of chemotherapy

Hydroxocobalamin (Vit B12) 1000 micrograms intramuscularly and repeat once every 3 cycles;

Folic acid 500 micrograms PO once daily continuously until 21 days after the last dose of pemetrexed.

Starting 1 day prior to each cycle of chemotherapy,

Dexamethasone (for skin rash prophylaxis) 4 mg PO twice daily - administer the day before, the day of and the day after chemotherapy
Emetogenicity MODERATE

Suggested default antiemetics have been added to the treatment schedule, and may be substituted to reflect institutional policy.

Carboplatin AUC > 4 is classified by MASCC/ESMO 2016 Antiemetic Guidelines 2016 and ASCO Antiemetic Guidelines 2017 as having moderate emetogenicity. 

However, a NK1 receptor antagonist and a 5HT3 receptor antagonist in combination with dexamethasone are available on the PBS for primary prophylaxis of carboplatin induced nausea and vomiting.

Note: a steroid has been included both as an antiemetic and premedication for hypersensitivity in this protocol.

Ensure that patients also have sufficient antiemetics for breakthrough emesis:

Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR

Prochlorperazine 10 mg PO or 12.5 mg IV every 6 hours when necessary.

Read more about preventing antineoplastic induced nausea and vomiting
Immune-related adverse events (irAEs)

Immune-related adverse events (irAEs) can occur early and escalate quickly in patients receiving immune checkpoint inhibitors. irAEs can also occur after discontinuation of treatment. Fatalities have been reported. 

Examples of irAEs include arthritis, colitis, endocrinopathies, Guillain-Barré syndrome, haemolytic anaemia, hepatitis, hypophysitis, myositis, nephritis, nerve paresis, autoimmune neuropathy, pancreatitis, rash, pneumonitis, uveitis, vasculitis. 

irAEs that carry a high risk of mortality include myocarditis, encephalitis, pneumonitis and hepatitis.

Proactive monitoring, patient self-monitoring and early reporting of adverse events is critical. Treatment interruptions and administration of corticosteroids and/or supportive care is required  to minimise the risk of death.

See individual irAEs listed below for more information. 

Read more about the management of immune-related adverse events (irAEs)
Skin toxicity

Immune-related skin rash has been observed in patients receiving immune checkpoint inhibitor therapy.

Monitor for rash, erythema and pruritus (unless an alternate aetiology has been identified).

Read more about the management of immune-related adverse events (irAEs)

Link to ESMO schematic of body surface area
Thyroid toxicity

Immune-related thyroid disorders are common (hypothyroidism and hyperthyroidism) and can occur at any time during immune checkpoint inhibitor therapy.

Monitor patients for changes in thyroid function and clinical signs and symptoms of thyroid disorders.

Isolated hypothyroidism may be managed with replacement therapy, without treatment interruption, and without corticosteroids.

Read more about the management of immune-related adverse events (irAEs)
Hypophysitis

Immune-related hypophysitis has been observed in patients receiving immune checkpoint inhibitor therapy.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and secondary adrenal insufficiency) and exclude other causes of hypophysitis.

Read more about the management of immune-related adverse events (irAEs)
Diabetes

Type 1 diabetes mellitus, including diabetic ketoacidosis, has been reported in patients receiving immune checkpoint inhibitor therapy.

Monitor patients for hyperglycaemia or other signs and symptoms of diabetes. Exclude other causes of diabetes.

Initiate insulin replacement as needed. Monitor blood sugar levels to ensure appropriate insulin replacement is achieved.

Read more about the management of immune-related adverse events (irAEs)
Gastrointestinal toxicity

Immune-related diarrhoea and colitis have been observed in patients receiving immune checkpoint inhibitor therapy, in some cases these adverse events have been severe.

Patients should be monitored for symptoms of increased frequency of bowel movements, change in the consistency of the stool, diarrhoea, abdominal pain, mucus in stools, haematochezia, and constitutional symptoms (fever, fatigue, weight loss). Exclude other causes of diarrhoea or colitis.

Clinical signs of peritonism should be immediately acted upon given the risk of bowel perforation.

Read more about the management of immune-related adverse events (irAEs)
Pulmonary toxicity

Immune-related pneumonitis has been observed in patients receiving immune checkpoint inhibitor therapy.

Monitor patients for signs and symptoms of pneumonitis (e.g. new or worsening cough, shortness of breath, or chest pain). If pneumonitis is suspected, evaluate with radiographic imaging (e.g. High Resolution CT) and exclude other causes of pneumonitis.

Read more about the management of immune-related adverse events (irAEs)
Hepatotoxicity

Immune-related hepatitis has been observed in patients receiving immune checkpoint inhibitor therapy.

Monitor patients for signs and symptoms of hepatitis (e.g. abnormal LFTs, jaundice, dark urine, severe nausea and vomiting, pain on the right side of the abdomen) and exclude other causes.

Read more about the management of immune-related adverse events (irAEs)
Neurological toxicity

Rare but serious immune-related neurological events including neuropathies, encephalitis, aseptic meningitis, meningeal symptoms, Guillain-Barre syndrome and myasthenia gravis-like symptoms have been observed in patients receiving immune checkpoint inhibitor therapy.

Monitor for signs and symptoms of motor or sensory neuropathies and muscle weakness.

Read more about the management of immune-related adverse events (irAEs)
Renal toxicity

Immune-related nephritis and renal dysfunction have been observed in patients receiving immune checkpoint inhibitor therapy, in some cases the adverse events have been severe.

Monitor patients for changes in renal function (e.g. elevated serum creatinine, haematuria, decrease in urine output) and exclude other causes of nephritis.

Read more about the management of immune-related adverse events (irAEs)
Rheumatological toxicity

Arthralgia and myalgia have been reported in patients receiving immune checkpoint inhibitor therapy. Although rare, polymyositis can also occur.

Monitor patients for symptoms of arthralgia and myalgia. Moderately strong analgesia and corticosteroid therapy may be required in some patients
Blood tests

FBC, EUC, LFTs, calcium, magnesium, serum cortisol, TFTs and BSL at baseline.

Repeat FBC, EUC, LFTs and BSL prior to each cycle and serum cortisol and TFTs alternate cycles. Calcium and magnesium as clinically indicated. N.B for CTLA4 containing regimens – repeat serum cortisol and TFTs prior to each cycle containing CTLA 4 drug. Check lipase and amylase if symptomatic of pancreatitis.

In the absence of suspicion of immune related adverse events less frequent monitoring may be applicable, according to institutional guidelines. Evidence for the frequency of routine blood testing with immunotherapies varies within published studies and guidelines.

Recalculate carboplatin dose if significant change in weight and/or creatinine.

Read more about immunotherapy blood test monitoring recommendations
Hepatitis and HIV

Hepatitis screening is recommended in all patients who are to receive immune checkpoint inhibitors, however the value of hepatitis and HIV screening is unknown and many trials no longer require screening prior to commencing immune checkpoint inhibitors.

Immunotherapy is associated with inflammatory adverse reactions resulting from increased or excessive immune activity and patients are at risk of developing autoimmune hepatitis. It should be used with caution in patients who have a history of chronic hepatic infections (hepatitis B and C) and human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS).
Vaccinations

The safety of having vaccinations during treatment is unknown. Patients in the clinical trial were allowed to receive inactivated vaccines (e.g. inactivated influenza vaccine) but live vaccines (e.g. BCG, MMR, zoster and varicella vaccines) were typically not permitted.

Caution: in patients receiving combination ipilimumab and nivolumab there have been reported cases of fatal myocarditis, myositis and rhabdomyolysis shortly after administration of the influenza vaccine.  Whilst a causative relationship to the use of influenza vaccine has not been demonstrated, caution is advised.
Effects of cancer treatment on fertility

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment.

Studies to evaluate the effects of immune checkpoint inhibitor therapy on fertility have not been performed. Therefore, the effect on male and female fertility is unknown, however, immune checkpoint inhibitors can cause fetal harm when given to pregnant women. It is important that females of reproductive potential and males use effective contraception whilst on therapy and for at least 4 months post last dose of therapy.

Read more about the effect of cancer treatment on fertility
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Immune checkpoint inhibitor dose modifications 

  • Dose reduction is not recommended
  • No dose adjustment is required in the elderly, mild or moderate renal impairment or mild hepatic impairment. Immune checkpoint inhibitors have not been studied in patients with severe renal impairment or moderate to severe hepatic impairment.

Management of immune-related adverse events (irAEs)

Link to Management of immune-related adverse events (irAEs)

Chemotherapy dose modifications 

Note: All dose reductions are calculated as a percentage of the starting dose

Haematological toxicity
ANC x 109/L (pre-treatment blood test) 
1.0 to less than 1.5 Refer to local institutional guidelines; it is the view of the expert clinicians that treatment should continue if patient is clinically well. 
0.5 to less than 1.0 Delay treatment until recovery
less than 0.5 Delay treatment until recovery and consider reducing pemetrexed and carboplatin by 25% for subsequent cycles
Febrile neutropenia Delay treatment until recovery and consider reducing pemetrexed and carboplatin by 25% for subsequent cycles
Platelets x 109/L (pre-treatment blood test) 
75 to less than 100 The general recommendation is to delay, however if the patient is clinically well it may be appropriate to continue treatment; refer to treating team and/or local institutional guidelines.
50 to less than 75 Delay treatment until recovery
less than 50 Delay treatment until recovery and consider reducing pemetrexed and carboplatin by 25% for subsequent cycles
less than 50 with bleeding Delay treatment until recovery and consider reducing pemetrexed and carboplatin by 50% for subsequent cycles
Renal impairment
Creatinine clearance (mL/min)
Consider if immune-related adverse event. See Management of immune-related adverse events (irAEs)
30 to 50 Recalculate carboplatin dose using Calvert formula and reduce pemetrexed by 50%
less than 30 Withhold chemotherapy
Hepatic impairment

Consider if immune-related adverse event. See Management of immune-related adverse events (irAEs)

No dose modifications necessary
Mucositis and stomatitis
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows:
1st occurrence: No dose reduction
2nd occurrence: Reduce pemetrexed by 25%
3rd occurrence: Reduce pemetrexed by 50%
4th occurrence: Omit pemetrexed
Grade 3 or Grade 4 Delay treatment until toxicity has resolved to Grade 1 or less and reduce the dose for subsequent cycles as follows:
1st occurrence: Reduce pemetrexed by 50%
2nd occurrence: Omit pemetrexed
Diarrhoea
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or less and reduce doses for subsequent cycles as follows:
1st occurrence: No dose reduction
2nd occurrence: Reduce pemetrexed and carboplatin 25%
3rd occurrence: Reduce pemetrexed and carboplatin by 50%
4th occurrence: Omit pemetrexed and carboplatin
Grade 3 or Grade 4

Delay treatment until toxicity has resolved to Grade 1 or less and reduce doses for subsequent cycles as follows:
1st occurrence: Reduce pemetrexed and carboplatin by 50%
2nd occurrence: Omit pemetrexed and carboplatin​​

References & Disclaimer

Carboplatin
  Interaction Clinical management
Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs) Additive nephrotoxicity Avoid combination or monitor renal function closely
Ototoxic drugs (e.g. aminoglycosides, frusemide, NSAIDs) Additive ototoxicity Avoid combination or perform regular audiometric testing
Paclitaxel Administration schedule may influence the development of myelosuppression Minimise toxicity by administering paclitaxel first in regimens using the combination
Pemetrexed
  Interaction Clinical management
NSAIDs (short acting e.g. ibuprofen, long acting e.g. piroxicam)

and

Nephrotoxic drugs (e.g. aminoglycosides, amphotericin, cisplatin, contrast dye, frusemide, NSAIDs)

and

Drugs secreted by the renal tubules (e.g. probenecid, penicillins etc.)		 Increased toxicity of pemetrexed possible due to reduced clearance Avoid combination or monitor for increased pemetrexed toxicity (esp. myelosuppression, renal and gastrointestinal toxicities)

Patients with mild to moderate renal insufficiency (CrCl 45 to 79 mL/min.) should avoid short and long acting NSAIDs from 2 and 5 days respectively prior, until 2 days after, pemetrexed administration.
Pembrolizumab
No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. Since pembrolizumab is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected.
  Interaction Clinical management
Immunosuppressants (inc. corticosteroids) Reduced efficacy of both immunosuppressants and pembrolizumab possible due to pharmacodynamic interaction

It is recommended that patients requiring corticosteroids prior to treatment receive the lowest possible dose (preferably no greater than 10 mg prednisolone or equivalent steroid per day). Once started on pembrolizumab the use of corticosteroids to treat immune related adverse events (irAEs) does not appear to impact the clinical response to pembrolizumab. In patients requiring ongoing corticosteroids post management of an irAE, the dose should be as low as possible.

Monitor for signs of organ rejection in transplant recipients.
NK-1 antagonist e.g. aprepitant, fosaprepitant, netupitant
  Interaction Clinical management
Dexamethasone Increased effects/toxicity of dexamethasone due to inhibition of its metabolism via CYP3A4

Reduce dose of antiemetic dexamethasone by approximately 50% when adding a NK-1 antagonist. For protocols that already recommend a NK-1 antagonist, the dose reduction of antiemetic dexamethasone has already been taken into account.

If dexamethasone is part of the chemotherapy protocol, dose reduction as per the product information is not routinely recommended in clinical practice and no additional dexamethasone is required for antiemetic cover. 
Warfarin

Reduced anticoagulant efficacy of warfarin due to increased clearance (aprepitant induces CYP2C9). *Note interaction only applicable to aprepitant/ fosaprepitant

INR should be monitored in the 2 week period, particularly at 7 to 10 days following the administration of aprepitant/ fosaprepitant
Combined oral contraceptive Reduced contraceptive efficacy due to increased clearance. *Note interaction only applicable to aprepitant/ fosaprepitant Alternative non-hormonal methods should be used during and for 1 month after stopping aprepitant/ fosaprepitant
CYP3A4 inducers (e.g. carbamazepine, phenytoin, phenobarbitone, rifampicin, St John’s wort etc.) Reduced efficacy of NK-1 antagonist possible due to increased clearance Avoid combination or monitor for decreased antiemetic effect. Consider using an alternative antiemetic regimen
CYP3A4 inhibitors (e.g. azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased toxicity of NK-1 antagonist possible due to reduced clearance Avoid combination or monitor for increased adverse effects of NK-1 antagonist (e.g. headache, hiccups, constipation)
Drugs metabolised by CYP3A4 (e.g. etoposide, imatinib, irinotecan, midazolam, paclitaxel, vinblastine, vincristine etc.) Increased effects/toxicity of these drugs possible due to inhibition of CYP3A4 by NK-1 antagonist Avoid combination or monitor for increased toxicity especially with orally administered drugs
General
  Interaction Clinical management
Warfarin Antineoplastic agents may alter the anticoagulant effect of warfarin. Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant.
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran

Interaction with both CYP3A4 and P-gp inhibitors /inducers.

DOAC and antineoplastic levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).

Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. 

Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp  inhibitors.

Dabigatran: avoid combination with strong P‑gp inducers and inhibitors.

If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin. Monitor digoxin serum levels; adjust digoxin dosage as appropriate.
Antiepileptics Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity. Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate.
Also monitor closely for efficacy of the antineoplastic therapy.
Antiplatelet agents and NSAIDs Increased risk of bleeding due to treatment related thrombocytopenia. Avoid or minimise combination.
If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding.
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine) Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.) Avoid combination.
If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia).
For more information link to TGA Medicines Safety Update
Vaccines Diminished response to vaccines and increased risk of infection with live vaccines. Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy.
For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Day 1

Approximate treatment time: 3 hours

Immunotherapy patient assessment and general patient assessment prior to each treatment.

Any toxicity may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Prime IV line(s) with sodium chloride 0.9%.

Insert IV cannula or access port or CVC.

Pre treatment medication

Verify premedication taken or administer as prescribed.

Verify antiemetics taken or administer as prescribed.

Pembrolizumab

Administer pembrolizumab:
  • a low protein binding 0.2 micron or 5 micron in-line or add-on filter should be used
  • via IV infusion over 30 minutes
  • observe for infusion-related reactions
  • flush with 50 mL of sodium chloride 0.9%.
Mild or moderate infusion-related reaction:
  • decrease the rate of infusion and monitor closely 
  • give any further doses with close monitoring
  • premedication with paracetamol and an antihistamine should be considered for further doses.
Severe infusion reaction:
  • stop infusion immediately 
  • medical officer review
  • permanently discontinue pembrolizumab.

Pemetrexed 

  • administer pemetrexed 30 minutes prior to carboplatin
  • via IV infusion over 10 minutes
  • flush with ~100 mL of sodium chloride 0.9%.

Carboplatin 

Administer carboplatin (irritant):
  • via IV infusion over 30 to 60 minutes
  • observe for hypersensitivity reactions
  • flush with 100 mL of sodium chloride 0.9%
  • hypersensitivity risk increases with number of cycles administered.
Stop infusion at first sign of reaction:
  • if symptoms are mild and resolve when infusion is stopped, consider recommencing infusion after review by medical officer at a slower rate
  • for severe reactions seek medical assistance immediately and do not restart infusion.

Remove IV cannula and/or deaccess port or CVC.

Continue safe handling precautions until 7 days after completion of drug(s)

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Pemetrexed premedication
  • Premedications as prescribed and written instructions on how to take them:
    • folic acid
    • hydroxycobalamin (vitamin B12)
    • dexamethasone
Patient information
  • Ensure patient receives patient information sheet.

Day 1

Approximate treatment time: 2 hours

Immunotherapy patient assessment and general patient assessment prior to each treatment.

Any toxicity may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

Prime IV line(s) with sodium chloride 0.9%.

Insert IV cannula or access port or CVC.

Pre treatment medication

Verify premedication taken or administer as prescribed.

Pembrolizumab

Administer pembrolizumab:
  • a low protein binding 0.2 micron or 5 micron in-line or add-on filter should be used
  • via IV infusion over 30 minutes
  • observe for infusion-related reactions
  • flush with 50 mL of sodium chloride 0.9%.
Mild or moderate infusion-related reaction:
  • decrease the rate of infusion and monitor closely 
  • give any further doses with close monitoring
  • premedication with paracetamol and an antihistamine should be considered for further doses.
Severe infusion reaction:
  • stop infusion immediately 
  • medical officer review
  • permanently discontinue pembrolizumab.

Pemetrexed 

  • administer via IV infusion over 10 minutes
  • flush with ~100 mL of sodium chloride 0.9%.

Remove IV cannula and/or deaccess port or CVC.

Continue safe handling precautions until 7 days after completion of drug(s)

Discharge information

Antiemetics
  • Antiemetics as prescribed.
Pemetrexed premedication
  • Premedications as prescribed and written instructions on how to take them:
    • folic acid
    • hydroxycobalamin (vitamin B12)
    • dexamethasone
Patient information
  • Ensure patient receives patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

The most common side effects with this treatment are immune-related adverse events (irAEs). irAEs can escalate quickly and close monitoring of the patient is required. Symptoms should improve promptly after the introduction of immunosuppressive therapy. If this does not occur review the diagnosis and seek further specialist advice. Refer to the Management of immune related adverse events document for further information.

Immune related adverse events
Skin toxicity

Rash including full thickness, pruritus, skin blisters, ulceration and necrosis. Radiation recall can occur at site of previous radiotherapy. Symptoms include vesiculation, desquamation and ulceration of the skin.

Read more about Management of immune related adverse events
Thyroid toxicity

Thyroid toxicity is common with immune checkpoint inhibitors. Hypothyroidism is most frequent however hyperthyroidism can also occur.

Read more about Management of immune related adverse events
Other endocrinopathies

Type 1 diabetes mellitus, hypophysitis, hypopituitarism and adrenal insufficiency are infrequent but potentially serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events
Gastrointestinal toxicity

Colitis, diarrhoea or more bowel movements than usual; blood or mucous in stools; dark, tarry, sticky stools; abdominal pain or tenderness.

Read more about Management of immune related adverse events
Pulmonary toxicity

Radiographic changes, dyspnoea, new or worsening cough, hypoxia, tachycardia or chest pain.

Read more about Management of immune related adverse events.
Hepatotoxicity

Transaminase and total bilirubin elevation, jaundice, severe nausea or vomiting, pain on the right side of the abdomen, drowsiness, dark urine, bleeding or bruising more easily than normal, anorexia.

Read more about Management of immune related adverse events.
Neurological toxicity

Aseptic meningitis, myasthenia gravis, Guillain-Barre syndrome, encephalitis, meningeal symptoms and neuropathy are infrequent but serious immune-related adverse events associated with immunotherapy treatment.

Read more about Management of immune related adverse events.
Cardiotoxicity

Cardiotoxicity is a rare but serious side effect, which may manifest as asymptomatic reduction in left ventricular ejection fraction (LVEF), arrhythmia, cardiomyopathy, myocarditis, hypertension, cardiac ischaemia and congestive heart failure (CHF). 
Renal toxicity

Increase in serum creatinine, oliguria, haematuria, peripheral oedema and anorexia.

Read more about Management of immune related adverse events.
Rheumatological toxicity

Inflammatory arthritis, myositis, arthralgia, myalgia, synovitis, vasculitis, temporal arteritis. 
Ocular changes

Symptoms may include eye pain, blurred vision, blepharitis, uveitis, optic neuritis, tear duct stenosis, conjunctivitis, hyperlacrimation, watery or dry eyes and photophobia. 

Chemotherapy immediate (onset hours to days)
Nausea and vomiting

Read more about prevention of treatment induced nausea and vomiting
Taste and smell alteration

Read more about taste and smell changes

Chemotherapy early (onset days to weeks)
Neutropenia

Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. 

Read more about neutropenia
Thrombocytopenia

A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding.  

Read more about thrombocytopenia
Diarrhoea

Read more about treatment induced diarrhoea
Fatigue

Read more about fatigue
Oral mucositis

Erythematous and ulcerative lesions of the gastrointestinal tract (GIT). It commonly develops following chemotherapy, radiotherapy to the head, neck or oesophagus, and high dose chemotherapy followed by a blood and marrow transplant (BMT).

Read more about oral mucositis
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Skin rash

Antineoplastic agents can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia

Chemotherapy late (onset weeks to months)
Anaemia

Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. 

Read more about anaemia
Alopecia - partial

Hair thinning and/or patchy hair loss. Patients can also experience mild to moderate discomfort of the hair follicles, and rarely pain as the hair is falling out.

Read more about alopecia

The evidence supporting this protocol is provided by a phase III multicentre international randomised trial, Keynote-189, involving 616 patients with previously untreated advanced non-squamous non small cell lung cancer (NSCLC). Keynote 189 randomised patients 2:1 to receive 4 cycles of platinum (carboplatin AUC5 or cisplatin 75 mg/m²)/pemetrexed/pembrolizumab followed by 24 months of maintenance pembrolizumab/pemetrexed, versus 4 cycles of platinum/pemetrexed/placebo followed by 24 months of placebo/pemetrexed.r

The co-primary end points were overall survival (OS) and progression free survival (PFS), and secondary end points were response rate, the duration of response and safety.r

Addition of pembrolizumab to standard platinum/pemetrexed chemotherapy doublet in advanced non-squamous NSCLC resulted in longer overall survival and progression free survival compared to chemotherapy alone. It also resulted in high response rates. Rates of grade 3 or higher adverse events were similar between the two arms, but there was a higher rate of adverse event leading to treatment discontinuation with pembrolizumab-chemotherapy combination compared to chemotherapy alone (13.8% and 7.9% respectively).r

Efficacy

After a median follow up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-chemotherapy group compared to 49.4% (95% CI, 42.1 to 56.2) in chemotherapy alone group (HR= 0.49; CI 95% 0.38 to 0.64; p < 0.001). This improvement was seen irrespective of PD-L1 tumour proportion scores; however, the greatest relative benefit was seen in the PD-L1 > 50% subgroup.r

There was also an improvement in median PFS with pembrolizumab-chemotherapy combination compared to chemotherapy alone (median PFS 8.8 months [95% CI 7.6 to 9.2] and 4.9 months [95% CI 4.7 to 5.5] respectively, HR 0.52; 95% CI 0.43 to 0.64; p < 0.001), however this was not statistically significant for the PD-L1 < 1% subgroup. The tumour response rates were higher with pembrolizumab-chemotherapy compared to chemotherapy alone (47.6% [95% CI, 42.6 to 52.5] versus 18.9% [95% CI, 13.8 to 25.0]; p<0.001).r 

111 of 405 patients (27.4%) received cisplatin and 294 of 405 patients (72.6%) received carboplatin in the pembrolizumab-chemotherapy arm. This was similar to the control arm (28.2% and 71.8% respectively). Similar benefits in overall survival and progression free survival were seen irrespective of platinum agent used.r 

Kaplan-Meier curve of overall survivalr

© New Engl J Med 2018

Overall survival, subgroup analysisr

© New Engl J Med 2018

Kaplan-Meier curve of progression free survivalr

© New Engl J Med 2018

Progression free survival, subgroup analysisr

© New Engl J Med 2018

Toxicity

Adverse events seen in Keynote 189 are listed below. Grade 3 or higher adverse events occurred in 67.2% of patients in the pembrolizumab-chemotherapy group compared to 65.8% in the control group; and the rates were similar in the patients who received carboplatin or cisplatin. There was a higher rate of treatment discontinuation due to adverse events in the pembrolizumab-chemotherapy arm compared to the control arm (13.8% vs 7.9% respectively). Adverse events leading to death occurred in 27 of 405 patients (6.7%) in the pembrolizumab-chemotherapy arm, and 12 of 202 patients (5.9%) in the control arm.r 

No quality of life (QOL) data was collected.r

Adverse events:r

© New Engl J Med 2018

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Version 2

Date Summary of changes
23/11/2018

Protocol taken to Medical oncology Reference Committe meeting 
20/12/2018

Protocol approved and published on eviQ. Review 1 year.
17/01/2019 Carboplatin AUC ≥ 4 changed from highly to moderately emetogenic as per MASCC/ESMO and ASCO guidelines and medical oncology reference committee consensus. Dexamethasone day 4 dose removed. NK1 receptor antagonist unchanged. Treatment detail and clinical information updated to reflect the change. Version number changed to V.2
01/07/2019 Drug status updated as pemetrexed is now on the PBS general schedule.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/3510

23 Oct 2019