CRBPPACL(W)+PEMB

¹Dosing based on NDFP funding criteria. Refer to NDFP form for alternative pembrolizumab dosing schedule (4 mg/kg IV q6 weeks).

²Give pembrolizumab before chemotherapy when given on the same day.

*Adjust Carboplatin dose to AUC target (using Calvert formula) as outlined in Other Notes section.

REPEAT EVERY 21 DAYS

For 4 cycles, followed by neoadjuvant AC+PEMB x 4 cycles, unless disease progression or unacceptable toxicity occurs.

• Also refer to CCO Antiemetic Recommendations.

Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.

Premedications (prophylaxis for infusion reactions):

Pembrolizumab:

• Routine pre-medication is not recommended.
• May consider antipyretic and H1-receptor antagonist in patients who experienced a grade 1-2 infusion reaction.

Paclitaxel*:

To be given 30-60 minutes prior to paclitaxel infusion:

• Dexamethasone 10 mg IV, starting in cycle 1
• Diphenhydramine 25-50 mg IV/PO
• Ranitidine 50 mg IV OR Famotidine 20 mg IV

* Consider discontinuing pre-medications for paclitaxel if there was no IR in the first 2 doses.

Carboplatin:

• There is insufficient evidence that routine prophylaxis with pre-medications reduce infusion reaction (IR) rates.
• Corticosteroids and H1-receptor antagonists ± H2-receptor antagonists may reduce IR rates for some patients (e.g. gynecological patients with a PFI >12 months or a history of drug allergy who are receiving carboplatin starting from the 7th cycle) but no optimal pre-medication regimen has been established.

Other Supportive Care:

• Avoid the use of corticosteroids or immunosuppressants before starting treatment. Corticosteroids may be used as premedication (e.g. antiemetic) when given with chemotherapy.

Refer to pembrolizumab, PACLitaxel, CARBOplatin drug monograph(s) for additional details of adverse effects

Refer to pembrolizumab, PACLitaxel, CARBOplatin drug monograph(s) for additional details

• Monitor INR in patients receiving warfarin; warfarin dosage adjustment may be required.

• Monitor closely with nephrotoxic and ototoxic drugs (ie. aminoglycosides) due to additive effects.

• Monitor closely with phenytoin; phenytoin dose adjustment may be required.

• Avoid if possible, or caution with radiation; may increase the risk of radiation pneumonitis.

• Use of systemic corticosteroids or immunosuppressants should be avoided prior to starting pembrolizumab because of potential interference with efficacy. They can be used to treat immune-mediated reactions after starting the drug. 

Refer to pembrolizumab, PACLitaxel, CARBOplatin drug monograph(s) for additional details

Administration

PACLitaxel:

• In order to minimize patients’ exposure to DEHP leaching from PVC bags or sets, use polyolefin or polypropylene infusion bags and polyethylene-lined administration sets (with an in-line filter no greater than 0.22 microns).
• For weekly dosing, may be infused over 1 hour - mix in 250mL bag of Normal Saline or 5% Dextrose (not approved by manufacturer).
• Extended infusion of paclitaxel is not recommended as primary prophylaxis to reduce paclitaxel IRs.
• Excessive shaking, agitation, or vibration may induce precipitation and should be avoided
• Precipitation may rarely occur with infusions longer than 3 hours.
   

CARBOplatin:

• Mix in 100mL to 250mL bag (5% Dextrose or Normal Saline); infuse IV over 15 to 60 minutes.

• There is insufficient evidence that routine prophylaxis with extended infusion reduces IR rates. 

• Incompatible with sets, needles or syringes containing aluminum – leads to precipitation and loss of potency.

• Protect from light.

Pembrolizumab:

• Dilute in 0.9% sodium chloride or D5W to final concentration of 1 to 10 mg/mL; mix by gentle inversion.

• Administer over 30 minutes using sterile, non-pyrogenic, low protein-binding 0.2 to 5 micron in-line or add-on filter.

• Administer pembrolizumab before chemotherapy when given on the same day.

• Do not co-administer other drugs through the same infusion line.

• If a planned dose is missed, administer as soon as possible. Adjust the schedule to maintain the prescribed dosing interval.

• Unopened vials should be stored under refrigeration (2 to 8^oC). Protect from light. Do not freeze.

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Contraindications

• Patients who have a hypersensitivity to these drugs or any of thieir components, patients with a history of severe hypersensitivity reactions to platinum-containing compounds, paclitaxel or other drugs formulated in Cremophor EL (polyethoxylated castor oil)

• Patients with pre-existing, severe renal impairment

• Patients with severe myelosuppression or bleeding tumours

Warnings/ Precautions

• Patients who have received extensive prior treatment, have poor performance status and those over 65 years of age

• Patients with abnormal renal function or those who are receiving concomitant nephrotoxic drugs

• Paclitaxel contains ethanol, and is administered with agents such as antihistamines which cause drowsiness. Patients should be cautioned regarding driving and the use of machinery.

• Pembrolizumab may cause serious immune-mediated reactions affecting multiple organ systems, including GI, hepatic, renal, respiratory, endocrine and others. Use with caution and monitor closely in patients with pre-existing conditions such as colitis, hepatic impairment, respiratory or endocrine disorders, such as hypo or hyperthyroidism or diabetes mellitus.

• Avoid live vaccines. Reduced immunogenicity may occur with the use of inactivated vaccines.

Pregnancy/ Lactation

• This regimen is not recommended for use in pregnancy. Adequate contraception should be used by patients and their partners while on treatment and after the last treatment dose. Recommended methods and duration of contraception may differ depending on the treatment. Refer to the drug monograph(s) for more information.

• Breastfeeding is not recommended during this treatment and after the last treatment dose. Refer to the drug monograph(s) for recommendations after the last treatment dose (if available).

• Fertility Effects:

  • Carboplatin: Unknown

  • Paclitaxel: Documented in animal studies

  • Pembrolizumab: Unknown

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.

Recommended Clinical Monitoring

Suggested Clinical Monitoring

Ando M, Yamauchi H, Aogi K et al. Randomized phase II study of weekly paclitaxel with and without carboplatin followed by cyclophosphamide/ epirubicin/5-fluorouracil as neoadjuvant chemotherapy for stage II/IIIA breast cancer without HER2 overexpression. Breast Cancer Res Treat 2014; 145(2): 401–409.

BC Cancer Protocol Summary for NEOAdjuvant Therapy for Triple Negative Breast Cancer Using Carboplatin and Weekly PACLitaxel Followed by DOXOrubicin and Cyclophosphamide. June 14, 2021.

CADTH Reimbursement recommendation - Pembrolizumab: For the treatment of adult patients with high-risk early-stage triple negative breast cancer. September 2022.

Carboplatin, paclitaxel, and pembrolizumab drug monographs, Ontario Health (Cancer Care Ontario).

Loibl S, O’Shaughnessy J, Untch M et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018; 19(4): 497–509.

F Poggio, M Bruzzone, M Ceppi, et al. Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. Ann Oncol. 2018 Jul 1;29(7):1497-1508. doi: 10.1093/annonc/mdy127

Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810-21. DOI: 10.1056/NEJMoa1910549

Schmid P, Cortes J, Dent R, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 2022;386:556-67.
DOI: 10.1056/NEJMoa2112651

Sikov WM, Berry DA, Perou CM et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: cALGB 40603 (Alliance). J Clin Oncol 2015; 33(1): 13–21.