This a study, it’s a phase III randomised study which we have conducted in patients with platinum-sensitive advanced head and neck squamous cell carcinoma, those who are being treated with palliative intent. There’s a huge unmet need in patients who are living especially in low- and middle-income countries where access to targeted therapies and immunotherapies is a challenge. Actually, in India less than 3% of patients are actually able to access any form of immunotherapy so there was a great unmet need.
What we did at Tata Memorial Centre is that we devised a regimen that is triple-oral metronomic chemotherapy with ultra-low-dose immunotherapy and we tried to compare it with the standard of care that is currently available in these low- and middle-income countries, that is paclitaxel/carboplatin, with the sheer aim that the triple-oral metronomic chemotherapy with ultra-low-dose immunotherapy can actually provide a survival benefit as compared to paclitaxel and carboplatin.
The unmet need or the main aim of the study is to prove superiority, that is whether TMC-I, triple-oral metronomic chemotherapy with ultra-low-dose immunotherapy, is actually going to prolong survival as compared to paclitaxel/carboplatin. That was the main aim of the study.
What was the study design?
We conducted actually a phase III open-label non-inferiority cum superiority study. It was an open-label study and patients were randomised in a 1:1 fashion to two arms. So all patients who were eligible for our study protocol, that is those having platinum-sensitive advanced head and neck squamous cell carcinoma and those who were being treated with palliative intent, were randomised in a 1:1 fashion to two arms. In arm A actually patients received paclitaxel and carboplatin, where paclitaxel was dosed at 175mg/m2 and carboplatin at AUC6. Both these drugs were given once every three weeks. In arm B patients received triple-oral metronomic chemotherapy with ultra-low-dose immunotherapy where the triple-oral metronomic chemotherapy actually consists of oral methotrexate tablets given at a dose of 9mg/m2 once a week, capsule celecoxib given at 200mg twice a day, tablet erlotinib 150mg given once a day and 20mg of nivolumab given intravenously once every three weeks. So all of these drugs were scheduled once in every 21 days or once in every three-week cycle.
The primary endpoint of our study was actually to prove non-inferiority in overall survival for the TMC-I arm as compared to the paclitaxel/carboplatin arm which we took as reference. The secondary endpoints were to prove superiority in overall survival, progression free survival, objective response rate, disease control rate, safety and quality of life. This is how we designed our study.
What were the key findings?
Our study results were positive and the primary endpoint was overall survival. With a hazard ratio of 0.57 actually there was a 43% reduction in the risk of death in patients who actually received TMC-I as compared to paclitaxel/carboplatin. The median overall survival significantly improved from 6.2 months to 10.3 months. There was a doubling in the one-year overall survival from 23.2% to 46.4%. This was the key or the primary endpoint of our study.
I’ll briefly just touch upon the secondary endpoints of the study as well. There was a significant improvement in the progression free survival with a 57% reduction in the risk of progression or death. The median PFS actually improved from 2.2 months to 5.5 months in those treated with TMC-I as compared to paclitaxel/carboplatin. There was a significant improvement in the duration of response, that is around 11 months as compared to 2.2 or 2.5 months and that was a 68% longer duration of response with TMC-I.
What about response rates, that is objective response and disease control rate? With the use of TMC-I there was nearly a doubling of the objective response rates from 24% in paclitaxel/carboplatin to around 53% with TMC-I. What about disease control rate? Around 30% absolute improvement in the disease control rates with TMC-I. So the disease control rate shot up to 74% as compared to around 45-50% with paclitaxel/carboplatin.
What about safety? Safety was a very important endpoint in our trial and grade 3 or higher treatment-related adverse events were significantly fewer with TMC-I – 37% with TMC-I as compared to 47% with TMC-I and immunotherapy-related adverse events were minimal, 3.5% all-grade toxicities and 1.5% grade 3 or higher toxicities.
Lastly, quality of life. So quality of life was maintained with TMCI-I as compared to paclitaxel/carboplatin. The global health status in both the arms was similar. There was a trend towards improvement in role functioning, social functioning and certain parameters in the quality of life, but overall, looking at quality of life as a whole the quality of life was maintained with TMC-I. So these are our key secondary endpoints.
What could be the clinical significance of these results?
The positive results of our trial are definitely going to impact not only patients in India but also globally, especially in low- and middle-income countries where access to immunotherapy and targeted therapy, that is pembrolizumab as per the KEYNOTE-048 trial and cetuximab as per the EXTREME trial, both of them, the access to both of these drugs is quite limited and by quite limited I mean less than 3% do get access to immunotherapy in whatever form, whether it’s full dose or low dose. So the clinical implications are huge. There is going to be a change in the first-line management of these patients with recurrent metastatic advanced head and neck squamous cell carcinoma where normally these patients were treated with paclitaxel/carboplatin and full dose immunotherapy now will be shifted towards a more safer and effective chemotherapy regimen that is with triple-oral metronomic and ultra-low-dose immunotherapy where not only there is improvement in survival as compared to paclitaxel/carboplatin, there is also improved safety and a preserved quality of life with almost a doubling of response rates and nearly 68% longer duration of response. In short, more number of people are going to access this regimen, number one, they’re going to have a longer survival with a better quality of life and there’s going to be an improvement in access to this regimen, not only in India but globally. So this study has the potential to change the first-line treatment management in patients with advanced platinum-sensitive head and neck squamous cell carcinoma from an IV chemotherapy regimen to a completely oral chemotherapy regimen with a once every three weekly ultra-low-dose nivolumab.
