A phase- II randomised open labelled study to evaluate low dose pembrolizumab plus chemotherapy versus chemotherapy as neoadjuvant therapy for localised triple negative breast cancer(TNBC)

BACKGROUND- Pembrolizumab has been approved in a neoadjuvant setting in triple-negative breast cancer (TNBC) at a dose of 200mg per cycle in addition to standard chemotherapy. Due to its extremely high cost, majority of the patients in low-middle-income countries (LMIC) cannot afford it. Based on data obtained from phase 1 studies of pembrolizumab, lower doses cause receptor saturation equivalent to higher doses. It is hypothesized that lower doses may be used without compromising clinical efficacy.

GENERAL AIM**-** Evaluation of efficacy and safety of low-dose pembrolizumab along with neoadjuvant chemotherapy in non-metastatic TNBC in terms of pathological complete response.

PRIMARY OBJECTIVE (ENDPOINT**)**- To compare the pathological complete response with the addition of low dose pembrolizumab in addition to NACT in patients with TNBC

SECONDARY OBJECTIVES (ENDPOINT)

1. To compare the radiological response with mammograms performed at baseline and at completion of NACT

2. To compare invasive disease-free survival in the two arms

3. To estimate the cost-effectiveness of addition of low-dose pembrolizumab along with chemotherapy from an Indian perspective.

4. Quality of life assessment in both the arms.

DESIGN

Randomized open labelled study

TARGET POPULATION

Patients with non-metastatic TNBC, fulfilling the inclusion and none of the exclusion criteria. Key exclusion criteria include pre-existing autoimmune disease, pregnant and lactating females, received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor, has received a live vaccine within 30 days.

STUDY TREATMENTS

EXPERIMENTAL ARM: Will be given pembrolizumab 50mg thrice (with cycle 1,4 and 7th cycle) with dose dense AC chemotherapy (4 cycles), followed by 4 cycles of two weekly single agent paclitaxel.

CONTROL ARM**:** Will be given dose dense AC chemotherapy (4 cycles), followed by 4 cycles of two weekly single agent paclitaxel.

ASSESSMENTS

Pathological complete response rates will be documented following surgery. Quality of life assessment will be done by EORTC QLQ-30 questionnaire, and will be recorded

at baseline, after 4 cycles of NACT, and after the end of NACT.

 STATISTICAL CONSIDERATIONS

With 102 patients in each study arm, there will be at least 80% power to detect a difference of 20% in pathological complete response rates at a two-sided 0.10 significance level, using a chi-square test. (randomised 1:1 to each treatment).