Despite positive outcomes with the KEYNOTE-522 regimen for triple-negative breast cancer (TNBC), its implementation faces challenges due to resource constraints in Hong Kong’s public healthcare system. Consultant Dr Thomas Kwan-Hang Lau and Resident Dr Kang Li of the Department of Clinical Oncology at Prince of Wales Hospital (PWH) shared insights and a case series on the use of Q3W and Q1W chemotherapy for the KEYNOTE-522 regimen in PWH and explored alternative neoadjuvant chemotherapy options.
Challenges in managing TNBC in HK
TNBC is among the most aggressive breast cancer subtypes, characterized by limited targeted treatment options and a high risk of early recurrence and mortality. The emergence of immunotherapy has introduced promising new treatment avenues. [Ann Oncol 2024;35:159-182; N Engl J Med 2020;382:810-821]
In the KEYNOTE-522 trial, pembrolizumab was added to neoadjuvant chemotherapy, followed by pembrolizumab as adjuvant treatment for high-risk early-stage TNBC. (Figure 1) The KEYNOTE-522 regimen significantly improved outcomes vs placebo: pathological complete response (pCR) rates increased by 13.6 percent (95 percent confidence interval [CI], 5.4–21.8; p<0.001), event-free survival (EFS) improved by 37 percent (hazard ratio [HR], 0.63; 95 percent CI, 0.43–0.93), and overall survival (OS) at 60 months rose by 4.9 percent (86.6 vs 81.7 percent; p=0.002). [N Engl J Med 2020;382:810-821; N Engl J Med 2024;391:1981-1991]
Despite these favourable outcomes, implementing the KEYNOTE-522 regimen in Hong Kong’s public healthcare system presents several resource challenges. Cost remains a major barrier to adopting novel therapies, and pembrolizumab is no exception. The regimen also requires weekly paclitaxel during the first four cycles of the neoadjuvant phase – a schedule commonly used in the US and Europe, where greater infusion capacity and staffing support its feasibility. In contrast, Hong Kong’s public healthcare system faces limitations in infusion centre availability and ongoing workforce shortages. The weekly schedule places additional strain on the already stretched resources. As a result, the KEYNOTE-522 regimen has not been widely adopted in the local public sector.
Alternative neoadjuvant chemotherapy partner of the KEYNOTE-522 regimen: Real-world clinical experience
In response to local resource constraints, a Q3W chemotherapy-based adaptation of the KEYNOTE-522 regimen has been introduced as an alternative for patients with early-stage, high-risk TNBC. [NPJ Breast Cancer 2024;10:73]
This approach aims to maintain clinical outcomes while reducing the administrative and logistical burden on the public healthcare system. The decision reflects a pragmatic effort to optimize patient care within the limitations of staffing and facility capacity. The standard weekly paclitaxel schedule requires substantial medical manpower and frequent patient visits, placing additional strain on blood collection and infusion centres – many of which already operate near capacity in public hospitals. From the patient’s perspective, weekly chemotherapy entails repeated hospital visits, blood tests, and long waiting times for outpatient clinic consultation, which may negatively impact drug compliance. In contrast, the Q3W chemotherapy schedule offers greater flexibility, easing pressure on healthcare resources while supporting better patient adherence.
Q3W chemotherapy schedule as alternative regimen option
As the alternative neoadjuvant chemotherapy schedule is supported by favourable clinical experience and operational considerations, the clinical efficacy and safety of Q3W paclitaxel have been closely monitored. Clinically, both Q1W and Q3W paclitaxel have demonstrated favourable outcomes, achieving pCR when combined with pembrolizumab in early-stage TNBC.
The Q3W schedule is typically considered for patients with stable health and no significant comorbidities. In contrast, Q1W paclitaxel is reserved for more vulnerable patients, including the elderly, those with impaired liver function, notable comorbidities, or high tumour burden.
Carboplatin dosing remains consistent across both Q3W and Q1W regimens. An area under the curve (AUC) of 5 is preferred in the neoadjuvant setting for patients with adequate performance status, while an AUC of 4 may be more appropriate for older or frail individuals.
This treatment approach supports personalized therapeutic strategies that optimize both efficacy and tolerability while also addressing the practical demands of clinical care within the constraints of the public healthcare system.
Safety and tolerability of Q3W chemotherapy regimen
Clinical experience with Q3W paclitaxel suggests it is generally well tolerated, although infusion-related reactions (IRRs) are commonly reported. These are typically mild (grade 1) and manageable with standard premedications such as hydrocortisone and chlorpheniramine. Delayed-onset IRRs, including skin rashes, may appear several days post-infusion. For persistent or recurrent reactions, desensitization protocols are implemented per departmental guidelines or referral to immunology specialists may be considered. Nab-paclitaxel, which offers a more favourable safety profile, may be used as an alternative, though it typically requires self-funding. [Front Immunol 2023;14:1175809] Importantly, it can be administered on a Q3W schedule, maintaining alignment with the adapted regimen.
Neutropenia is a common AE in the neoadjuvant setting. Rather than reducing the paclitaxel dose, which may compromise treatment efficacy, it is typically managed with granulocyte-colony stimulating factor (G-CSF) to maintain dose intensity. Hepatotoxicity has also been observed with the Q3W regimen; however, it is usually low-grade and does not necessitate dose adjustment, allowing patients to continue the planned treatment course safely and effectively.
Exploring additional strategies for TNBC management
While the Q3W paclitaxel regimen could serve as an alternative option, other treatment regimens are also being explored.
In the NEOPACT study, a regimen consisting of carboplatin (AUC 6), docetaxel (75 mg/m²), and pembrolizumab (200 mg) was administered Q3W for six cycles. Results demonstrated that Q3W docetaxel may be an effective alternative, showing favourable outcomes in both pCR and EFS. [JAMA Oncol 2024;10:227-235] However, the potential AEs must be carefully monitored. The toxicity profile of Q3W docetaxel includes IRRs, neutropenia, peripheral neuropathy and fluid retention, rendering it less appropriate for patients with pre-existing hepatic and cardiac comorbidities or overall frailty. Nevertheless, due to its efficacy, the Q3W docetaxel regimen remains a viable alternative chemotherapy option within the KEYNOTE-522 framework, particularly in selected patients who may benefit from a less frequent dosing schedule.
Another potential adaptation is 6-weekly (Q6W) pembrolizumab, which has been employed in the Memorial Sloan Kettering Cancer Center (MSKCC)- modified KEYNOTE-522 regimen. [NPJ Breast Cancer 2024;10:39] The extended Q6W dosing interval is approved in Hong Kong. It may be helpful in the adjuvant setting where pembrolizumab monotherapy is used.
Conclusions
Managing early-stage TNBC in Hong Kong’s public healthcare system, particularly with the adoption of the KEYNOTE-522 regimen, presents challenges due to practical constraints such as limited medical personnel and restricted facility capacity. Both clinical experience and existing evidence support a Q3W chemotherapy schedule combined with pembrolizumab as a feasible and effective alternative within this healthcare setting. With an individualized dosing approach and careful patient selection, this strategy can achieve favourable clinical outcomes while easing the burden on hospital resources. Additional adaptations, such as Q6W pembrolizumab, may offer further benefit in the adjuvant setting by reducing treatment frequency. A key advantage of the adapted Q3W chemotherapy schedule is its flexibility, allowing the KEYNOTE-522 regimen to be tailored to the realities of different healthcare systems while optimizing outcomes for high-risk, early-stage TNBC patients.
As real-world data continues to emerge, further clinical validation and integration of findings into local treatment guidelines will be essential to ensure sustainable, effective, and equitable cancer care within the public sector.