Cycle length: 21 days.
Duration of therapy: Four cycles plus maintenance atezolizumab monotherapy. |
| Drug | Dose and route | Administration | Given on days |
| Induction phase (four cycles) |
| Atezolizumab | 1200 mg IV | Dilute in 250 mL NS* and administer first dose over 60 minutes; if first infusion is tolerated, then administer subsequent doses over 30 minutes. Administer atezolizumab prior to chemotherapy on days that chemotherapy is given. | Day 1 |
| Carboplatin | AUC¶ = 5 mg/mL × min IV | Dilute in 250 mL NS* and administer over 30 minutes. | Day 1 |
| Etoposide | 100 mg/m2 IVΔ | Dilute in 500 mL NS* or D5W to final concentration of <0.4 mg/mL. Infuse over 30 to 60 minutes; if infused more rapidly, severe hypotension may occur. | Days 1, 2, and 3 |
| Maintenance phase (until disease progression) |
| Atezolizumab | 1200 mg IV | Dilute in 250 mL NS* and administer over 30 or 60 minutes depending upon infusion tolerance. | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - Atezolizumab/carboplatin/etoposide (day 1): MODERATE.
- Etoposide (days 2 and 3): LOW.
- Atezolizumab maintenance phase: MINIMAL.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
|
| Prophylaxis for infusion reactions | - Atezolizumab can cause severe to life-threatening infusion reactions and may require permanent discontinuation for grade 3 or worse infusion-related reaction.[2]
- For mild infusion reactions, premedication is recommended for subsequent infusions.[1,2]
- Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
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| Vesicant/irritant properties | - Carboplatin and etoposide are irritants.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Infection prophylaxis | - Routine primary prophylaxis with hematopoietic growth factors is not recommended (incidence of febrile neutropenia is approximately 3%).[1]
- Refer to UpToDate topics on use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation.
|
| Dose adjustment for baseline liver or renal dysfunction | - Each carboplatin dose should be calculated based upon renal function by use of the Calvert formula.¶[3]
- A lower starting dose of etoposide may be needed for patients with renal or liver impairment.[4]
- Refer to UpToDate topics on dosing of anticancer agents in adults; chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents.
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| Immune-mediated adverse events or conditions | - Anti-PD-L1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. There are only limited data on the safety and efficacy of checkpoint inhibitors such as atezolizumab in patients with an underlying autoimmune disorder.[5] Atezolizumab should be used with extreme caution in such individuals. Individual evaluation is required for use of existing immunosuppression agents.
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
|
| Severe or life-threatening infections | - Atezolizumab can cause severe and/or life-threatening infections.
- Withhold or discontinue atezolizumab for severe infections.[2]
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
|
| Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) prior to initiation of therapy.
|
| Regulatory issues | - An FDA-approved patient medication guide, which is available with the United States Prescribing Information,[6] must be dispensed with atezolizumab.
|
| Monitoring parameters: |
- CBC with differential and platelet count weekly during induction treatment.
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- Electrolytes and liver and renal function prior to each cycle of induction chemotherapy, and liver function tests every one to two cycles, and as clinically indicated, during maintenance atezolizumab.
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- Assess thyroid function tests and blood glucose every one to two cycles during treatment (both induction and maintenance) and/or as clinically indicated.
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- Monitor for infusion reactions.
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- Monitor for signs and symptoms of immune-mediated adverse events (eg, colitis, diarrhea, hepatitis, hypophysitis, adrenal insufficiency, thyroid disorders, infection, cardiovascular, pneumonitis, renal, dermatologic, neurologic, ocular toxicity, etc).
|
| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Per protocol, at the beginning of each cycle, the ANC should be ≥1500/microL and platelets ≥100,000/microL. Cycles can be delayed for up to 42 days to allow sufficient time for count recovery. Reduce carboplatin dose by 25% for any platelet count <25,000/microL or ANC <500/microL and platelets ≥50,000/microL, or for ANC <1000/microL with a temperature >38.5°C.[1] Reduce carboplatin dose by 50% for platelets <50,000/microL: with grade ≥2 bleeding, regardless of ANC. These dose reductions should be maintained for the remainder of induction therapy. Colony-stimulating factors may be used instead of dose reduction for neutropenic fever or grade 4 neutropenia.
|
| Nonhematologic toxicity | - Chemotherapy should be held for grade 3 or 4 nonhematologic toxicities and only restarted after the toxicity has resolved to patient's baseline.[1] Once recovered, a 25% dose reduction of carboplatin is recommended for grade 3 or 4 oral mucositis, nausea/vomiting (despite optimal antiemetics), neurotoxicity, or grade 3 transaminase elevation. Discontinue carboplatin for grade 4 transaminase elevation.
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| Hepatotoxicity | - No formal etoposide dosing recommendations were provided in the protocol.[1] However, accepted dose reductions per product information may be found in the literature.
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
|
| Nephrotoxicity | - While a 25% dose reduction for initial dosing of etoposide is recommended for CrCl of 15 to 50 mL/min, further dose reduction may be needed for more severe renal dysfunction; the protocol recommended a 25% dose reduction for a decline in the CrCl during treatment.[1,4]
- Alterations in renal function during therapy may require a recalculation of the carboplatin dose.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents and dosing of anticancer agents in adults.
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| Immune-mediated adverse events[1,2] | - Dose reductions of atezolizumab are not recommended; treatment is withheld or discontinued to manage toxicities.[1,2,6]
- In general, if an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes. Based on the type and severity of the reaction, withhold treatment and administer systemic glucocorticoids. Upon resolution to ≤grade 1, initiate glucocorticoid taper. Immune-mediated adverse reactions that do not resolve with systemic glucocorticoids may be managed with other systemic immunosuppressants (based on limited data). Discontinue atezolizumab permanently for any grade 4 or recurrent grade 3 immune-mediated adverse event or one that is life threatening, grade 3 pneumonitis, AST/ALT elevation >8 times ULN, total bilirubin elevation >3 times ULN in patients with no hepatic tumor involvement, AST/ALT elevation to >10 times ULN for hepatitis with hepatic tumor involvement, grade ≥2 myocarditis, grade 3 neurologic toxicity, suspected exfoliative dermatologic condition, severe (grade 3) or life-threatening (grade 4) infusion reactions, or if there is an inability to reduce glucocorticoid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating glucocorticoids.[6]
- Guidelines for managing specific toxicities, including immune-mediated adverse events, are available in the United States Prescribing Information for atezolizumab,[6] from ASCO,[2] from the MASCC,[7] from the NCCN,[8] and from the SITC.[9]
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
