Authors-Atul Batra, Sameer Bakhshi, Akash Kumar , Adhip Arora, Hemavathi Baskarane, Ajay Gogia ,Kaushal Kalra, Ashutosh Mishra, Suhani Suhani , Jyoti Sharma, Rajinder Parshad , Vuthaluru Seenu , Krishna Asuri, Virinder Kumar Bansal, Piyush Ranjan, Babul Bansal, Brijesh Kumar
Triple negative breast cancer (TNBC) is an aggressive subtype with limited targeted treatment options. Achieving a pathologic complete response (pCR) after neoadjuvant chemotherapy strongly predicts improved survival outcomes. The addition of immune checkpoint inhibitors (ICIs), such as pembrolizumab, to standard chemotherapy has significantly increased pCR and event-free survival rates, as shown in the KEYNOTE-522 trial. However, access to full-dose pembrolizumab remains limited in many low- and middle-income countries due to cost. Exploring low-dose pembrolizumab (LDPm) offers a promising strategy to maintain efficacy while reducing toxicity and improving affordability.
Design and Methods
This was a phase II, open-label, randomized controlled trial conducted at a single tertiary cancer center in New Delhi, India. The study enrolled patients with untreated stage II–III triple-negative breast cancer (TNBC) who had not received any prior systemic therapy. Eligible participants were randomly assigned in a 1:1 ratio to one of two treatment arms.
The experimental arm received standard neoadjuvant chemotherapy consisting of four cycles of dose-dense doxorubicin and cyclophosphamide, followed by four cycles of dose-dense paclitaxel, in combination with low-dose pembrolizumab (50 mg every six weeks for three doses). The control arm received the same neoadjuvant chemotherapy regimen without pembrolizumab.
The primary endpoint of the trial was the pathologic complete response (pCR) rate in the intention-to-treat (ITT)population. Secondary objectives included evaluating pCR among patients who underwent surgery, assessing safety profiles, and exploring other clinical and biological outcomes relevant to treatment efficacy and tolerability.
Results
A total of 157 patients were enrolled in the study, with 78 assigned to the low-dose pembrolizumab (LDPm) arm and 79 to the control arm. Among them, 152 patients successfully completed neoadjuvant therapy and underwent surgery.In the modified intention-to-treat population, the pathologic complete response (pCR) rate was 53.8% (42 of 78 patients) in the LDPm group compared with 40.5% (32 of 79 patients) in the control group. This corresponds to an absolute improvement of 13.3% (one-sided P = 0.047).
When the analysis was limited to patients who underwent surgery, the pCR rate remained higher with LDPm—56.7% versus 41.0% in the control arm, showing an absolute difference of 15.7% (one-sided P = 0.031). Regarding safety, grade 3 or higher adverse events occurred in 50% of patients in the experimental arm and 59.5% in the control arm, indicating comparable toxicity between the two groups. However, there was one treatment-related death in the pembrolizumab group, attributed to toxic epidermal necrolysis.
Baseline characteristics such as age, tumor stage, nodal status, and menopausal status were well balanced between both treatment arms, ensuring comparability of the study groups.
Conclusions
- The addition of low-dose pembrolizumab resulted in a numerically higher pCR rate (absolute ~13–16 %) compared with chemotherapy alone.
- The magnitude of the increase is in the same ballpark as what has been observed with full-dose pembrolizumab in prior trials (e.g. KEYNOTE-522 showed ~13.6 % pCR increment)
- Safety appears broadly acceptable, though serious immune-related toxicity (though rare) remains a concern.
- In resource-constrained settings where standard-dose pembrolizumab is inaccessible, a low-dose alternative might represent a pragmatic option to improve outcomes in TNBC.
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