This was a randomised trial that we have conducted together with colleagues in Norway, Sweden and Denmark. The purpose was to test the feasibility and tolerability and, of course, also the efficacy of increasing the dose of the thoracic radiotherapy. We know that some patients are cured after chemoradiotherapy but that’s only approximately 25-30% of patients so there is clearly a need for better treatment. Since there hasn’t been any real progress when it comes to systemic therapy for these patients we wanted to test if increasing the radiotherapy dose might increase the outcomes.
We also know that in quite many cases local relapses are the main cause of treatment failure and it’s also strongly linked to inferior survival. We hypothesised that if we increased the thoracic radiotherapy dose we could increase the local control and then also improve survival.

This study was conducted between 2014 and 2018. We have just reached the time point for the primary endpoint which is two year survival but we will continue following these patients until all patients have been followed for at least five years and that will happen in 2023. So this is just a primary analysis.

What surprised us was that it was well tolerated, the high dose radiotherapy. We do not see any differences in radiotoxicity and the frequency of oesophagitis and pneumonitis is lower than in the previous trial that we had performed and also lower than in previous trials and in line with what was observed in the CONVERT trial that many of you are familiar with.

We also saw that in almost all cases it was possible to deliver the high dose. There were some patients that received a lower dose than they were randomly allocated to receive. We are in the process of looking into those radiotherapy plans and will also do an evaluation of whether it truly was impossible to deliver the high dose.

This was a randomised phase II trial so the aim was actually to see if there was any signal of improved efficacy. We estimated that enrolling 150 patients in total would give us a good signal. The sample size calculation is based on demonstrating a 25% improvement in two year survival from 53% that we observed in a previous trial to 66%. This is with an α of 10% so this is clearly a hypothesis generating trial. But, to our surprise, we did find a highly significant difference in favour of the high dose arm for the primary endpoint of two year survival. That increased by more than 50% from 46% to 70%.

The overall survival data are not mature yet but so far we also find a highly significant difference for the median overall survival which is 23 months in the standard arm and appears to be close to 42 months in the high dose arm. We have reached the median survival in the standard arm but not yet in the high dose arm so that estimation of median overall survival time can change slightly.

What we presented was the primary analysis of the 160 patients that completed thoracic radiotherapy as planned. We are currently also running the intention to treat analysis and so far it seems that the difference is even bigger in the ITT population than in the protocol population. So we are quite intrigued and, I have to admit, also surprised with the big difference in survival. There was no statistically significant difference in progression free survival but also these data are immature and we are looking into these data to try to see if there’s a difference in relapse pattern. One can imagine that relapses occur maybe outside the radiotherapy fields in the high dose arm to a larger extent than on the control arm and maybe that can explain why there was no statistically significant difference in the PFS but, as I said, we are looking into this data and they are still not mature. Of course, we plan to do our final report in 2023.

So how do you interpret these data? It is a randomised phase II trial, on the other hand, not many trials have been conducted in this area for quite a long time. I think that at least the twice daily 60Gy schedule should be an attractive option. It takes one week longer but is still much shorter than the high dose arm in the CONVERT trial. There is not more toxicity and even if the survival benefit is a bit overestimated, which can occur in a medium-sized trial, I believe it’s still an attractive option.

How might this impact the current standard of care, and do you see a timeline on that?

Now we are conducting another trial, that is a trial where all patients receive chemoradiotherapy and the TRT schedule is 45Gy. Then they are randomised to receive one year of immunotherapy, atezolizumab, or observation. We will have a meeting of the Norwegian Lung Cancer Study Group tomorrow and discuss whether we should change the guidelines. I have also called for an investigator meeting, I suggest that we amend the protocol and allow the 60Gy TRT schedule.
What we need to see now is how this will be received when we publish the results. We are really busy now trying to finish the manuscript and hope to submit it this month. So we will have to look at the reactions. I will also discuss with colleagues internationally to hear their opinion. I think it’s a bit difficult to predict. It is a bit difficult for me to understand why the twice daily schedule of 45Gy has not been implemented universally. We know from many population-based studies that one fraction per day is still widely used in many countries. I understand it’s inconvenient but, as has been said many times, if the survival efficacy of a drug had been comparable to the apparent survival difference of the twice daily schedule many people have claimed that it would be more widely implemented. So that is one question that remains to be answered.

But, of course, we plan or hope to finish our ongoing trial next year so I will now start contacting colleagues internationally and see if there’s any interest in doing a confirmatory phase III trial. I’m not sure if that’s possible, I agree that in principle it should be done but until it has been done or until we start a confirmative trial I would at least say that the high dose schedule here is an attractive alternative.

If anybody is interested in joining a confirmatory phase III trial I would be happy to hear from them.

What is your take away message from these results?

To conclude, we found that administering twice-daily high dose thoracic radiotherapy is feasible in almost all patients. It appears to be well tolerated and it provides a significant and clinically highly relevant survival difference.