Basically, in triple-negative breast cancer in the neoadjuvant setting after the KEYNOTE-522 study, pembrolizumab has become the standard of care along with chemotherapy. The dose used in the KEYNOTE-522 study was 200mg delivered every three weeks with chemotherapy. Now, that showed an improvement in pathological complete response, event free survival and overall survival, however, in the real world less than 5% of patients in low- and middle-income countries can access this drug. That’s a big problem.

Our data also suggests that if you use a lower dose of immune checkpoint inhibitors they saturate the receptors and they mount an immune response and the effects have been seen. There have been trials conducted in India in head and neck trials, Hodgkin’s disease, and we have seen responses with doses as low as one tenth of the dose.

So with this background we planned a study where we chose patients who were triple-negative breast cancer, stage 2-3, who did not have access to the standard dose of pembrolizumab. These were randomised to receive either the chemotherapy arm which included anthracycline and taxane, four cycles of doxorubicin and cyclophosphamide followed by four cycles of taxane delivered in a dose dense fashion. The experimental arm had the same chemotherapy backbone and, along with this, a 50mg pembrolizumab flat dose was delivered every six weeks for three cycles. The primary endpoint of the study was complete pathological response which was defined as the absence of invasive as well as in situ disease in breast and axilla in the resected specimen.

We randomised 160 patients, 80 in each arm, and in the modified the intention to treat analysis we found that pathological complete responses were seen in 40.5% of patients in the control arm compared with the experimental arm this was 53.8% which means an improvement by 13.3% in absolute terms. This was statistically as well as clinically significant.

Also of note is the baseline characteristics of the patients where we had a higher risk of relapsed patients. These were T3 and T4 disease and more than 50% of patients, and 83% of patients were node positive.

We also did a subgroup analysis where we didn’t find any interaction with regards to age, tumour size, nodal involvement or HER2 status. The quality of life was maintained and we didn’t find any new safety signals with low-dose pembrolizumab. It was safe to use with a quite similar number of patients developing immune related adverse events, including hyperthyroidism and hypopituitarism.

What could be the implications of these findings?

If we look at the global perspective, in patients belonging to low- and middle-income countries who do not have access to standard dose pembrolizumab this becomes a viable option. Although we do not have long-term data on disease free survival and overall survival, a longer term is being planned for this study and would require an eventual confirmation. However, in the absence of availability of the standard dose of pembrolizumab it becomes a question whether when you have a patient in front of you with triple-negative breast cancer who cannot take standard dose pembrolizumab, I would be comfortable treating such patients with a lower dose of pembrolizumab.