The background of this study is that in lung cancer, that is non-small cell lung cancer, in the advanced setting where you can’t operate or radiate patients you give systemic therapy. For patients who do not have genetic mutations, or what we call genomic alterations, where targeted therapy can be given, in the group of patients who do not have these mutations today the standard of care is to give immune checkpoint inhibitors or immunotherapy, to say it in lay terms, with or without chemotherapy, depending on certain factors. It is a standard in the treatment paradigm.
Unfortunately, most of the immune checkpoint inhibitors today are quite expensive and a large number of patients across multiple low- and middle-income countries cannot afford it. Because of which it is not used and it significantly impacts the oncology outcomes in terms of survival, in terms of disease control, in terms of quality of life. There is a big disparity between patients who can receive it and who cannot.

So in many settings, including our setting, immune checkpoint inhibitors are easily available today but the cost is a factor that limits access. So there are some patients who can get it and who receive the standard dose but there’s a large number of patients who cannot get it. So we had looked at patients from our centre where immune checkpoint inhibitors were indicated, either in head and neck or in lung cancers or thoracic cancers and we realised that the data from 2015 to 2019 only 2.35% of patients with thoracic cancers, predominantly lung, so the number was 2.35% who could actually receive the immune checkpoint inhibitor when they needed it.

So this was the background and this is why we came to design these low-dose immune checkpoint inhibitor studies. Our group has done a number of them, including head and neck and now in lung, looking at a lower dose and a different scheduling to make it more accessible and bring down the cost of therapy. 

Could you outline the methodology?

The study is a phase III randomised study so it looks at comparing the immune checkpoint inhibitor that is pembrolizumab at a lower dose in combination with chemotherapy. The control arm is chemotherapy alone. So patients who were included in the study were advanced non-small cell lung cancer. We tested them for mutations like EGFR and ALK, these were the two main mutations that had to be negative. Only those patients who did not have these were included in the study. Then they were randomised to two different groups, one group would be the chemotherapy only group and one group would be chemotherapy with a low dose of pembrolizumab. 

The FDA approved dose that is used globally is 200mg every three weeks and it is continued up to about two years or 35 cycles in all the landmark studies of this drug, whether it is given as a single agent or in combination with chemotherapy. In our study the intervention arm looked at it in a different way, it looked at two things. One is a lower dose of 50mg instead of 200mg and the initial four doses were given every three weeks for the initial few doses. Once the four doses were done, with the maintenance chemotherapy the pembrolizumab was given at an extended interval, so longer time between the two doses, with the same low dose of 50mg every six weeks instead of the three-weekly standard scheduling. So that was the design.

The primary endpoint that is the main endpoint of the study was overall survival, so how long the patient will live with the drug. The secondary endpoints were progression free survival, response rate, quality of life, safety of the regimen. It was a multicentre study so we had it in four centres across India and we included around 380 patients in the study and randomised them to either of these arms.

What impact could these findings have?

In our setting, the group which I work with at Tata Memorial Hospital has done a lot of pioneering work on low-dose immune checkpoint inhibitors. We in head and neck cancers are now using it almost as one of the standard of care options in the clinic and we have also started using it in the curative setting like neoadjuvant therapies and we are running trials in them. In lung cancer as well we expect this to have an impact because it cuts down the cost of the total cost of therapy. If you consider it like the landmark trials for two years it works out to around 14 million Indian rupees; so if you look at this low-dose extended regimen duration it approximately cuts it down to one seventh of that cost. So this is what we expect that if the cost is less we hope that the uptake of the use of pembrolizumab will automatically increase. Because our country doesn’t include pembrolizumab or many of the immune checkpoint inhibitors into the government sponsored schemes or whatever is available for patients, it’s all out of pocket expenditure. So cutting down expenditure to one seventh will enable patients to get the drug without the financial toxicity which is a huge impact. Also, probably in the future if we are able to develop it and scale it up and the use increases in the community, this might be a signal to our governments and our healthcare system to adopt these or to include this into the insurance or the support that patients get from the state or the government to cover these schemes. 

Also it would bring about a change. So including private or corporate insurances that patients buy to fund these out of pocket expenses, I think they also will probably increase the coverage overall. Whether it is state funded versus maybe you buy an insurance type of coverage, we hope that reducing the cost might enable more coverage to a larger number of patients. Even those who don’t have either of these and are buying out of pocket, they might be able to take therapy without leading to a significant financial loss. 

One thing I want to highlight is a lot of times when people, especially in a country like India, are paying for expensive drugs they do it by selling assets. So it’s largely out of pocket expenditure for the newer drugs and targeted therapy. A lot of the government schemes do cover chemotherapy, radiation, the standard therapies, but the newer drugs are not always included. So what patients do is they sell assets which mostly is land and in a country where people are from an agricultural background that’s not a huge loss to an individual, it’s not only for the family, it may be a financial impact on generations of that family. So a lot of our patients do that, they do sell off their assets – jewellery or whatever other kinds of things they have – to pay for these drugs. So I think cutting down the cost will not only help them as an individual but also the whole family and the whole structure that ends up indirectly paying for the cost of such a dreaded and expensive disease.