WCLC Sept 2021 | The prognostic value of ctDNA in NSCLC treated with neoadjuvant chemoimmunotherapy

We have presented the results of ctDNA analysis from NADIM study. The NADIM study evaluates the efficacy of neoadjuvant immunotherapy in combination with chemotherapy in stage IIIA non-small-cell lung cancer. And it has provided outstanding results in terms of response rates and survival rates with an OS at three years in the per protocol population, almost 90% or over 90%.

So in this clinical trial as a secondary endpoint, we also wanted to evaluate different biomarkers for chemoimmunotherapy in the neoadjuvant setting, because this scheme of treatment, it seems the results are quite promising, and now there are a lot of trials trying to validate these results and probably in the near future chemoimmunotherapy will be become a standard of care treatment for these patients. But nowadays we don’t have survival data to support this finding, the only mature survival data we have is NADIM, and the sample size is small sample size, only 46 patients, and it is not a randomized trial.

So there is the CheckMate ongoing trial and one issue that need to be addressed is that we need faster endpoints for clinical trials development, so we don’t want to wait until four years OS. We need to wait for that, but it would be good if we have good survival surrogates that can inform us if what we are measuring, if the treatment we are testing or evaluating is indeed good for patients. So in this way, we evaluated several biomarkers and we’ve seen in the NADIM clinical trial that circulating tumor DNA clearance is indeed a good prognostic factor because it significantly predicts overall survival, long-term survival and indeed it predicted long-term survival better than tumor response assessed on CT scans and according to RECIST criteria with the standard procedure. We believe with this, that ctDNA clearance is indeed a good prognostic factor and can be validated as a surrogate for long-term survival in these patients.

There are some issues though that need to be clarified because the quantification of circulating tumor DNA is not a standardized procedure, so we need to standardize this procedure and maybe it will change depending on the technology we’re using, the panel we are using but we need to do this because otherwise we cannot compare or validate results from one lab to another. But one thing that we saw is that using the technology that we used and by doing several approaches we calculated the total, the sum of all allele frequencies for mutations detected. We also calculated the median and the mean, and by doing different approaches we got similar results, but still we need to standardize the procedure and to get an agreement and how we are going to measure circulating tumor DNA across different labs and using different platforms.

Another issue is that we need prognostic factor to identify patients who get real benefit from these treatments because TMB, which is a prognostic factor for immunotherapy, does not work for the combination of immunotherapy and chemotherapy and the same results we got in the NADIM clinical trials so we don’t see that TMB is a good prognostic factor, but pre-treatment level of circulating tumor DNA indeed predicted very accurately long-term survival in these patients. Pre-treatment levels or baseline levels of circulating tumor DNA have been shown to be prognostic in very different situations and especially in EGFR positive non-small-cell lung cancer patients, we have a lot of papers going in the same directions and we’ve seen the same in the clinical trials.

This is another idea, is that by measuring baseline levels of circulating tumor DNA, we can anticipate which patients are going to do well, and which not and maybe this can be used in future trials and in the future by oncologists to tailor subsequent treatment and to be more alert with some patients that you may know they are at risk of progression and death, and maybe surveillance have to be closer and so on.

I think both circulating tumor DNA analysis can serve too as a faster clinical trial endpoint in the neoadjuvant scenario and also as an important prognostic factor to assess the risk of patient of progression and death before treatment, and that might be useful for oncologists in new designs of new clinical trials. I think the NADIM clinical trial is the first trial with pre-treatment assessing the prognostic factor of pre-treatment circulating tumor DNA in the neoadjuvant setting with chemoimmunotherapy. And in addition, Dr Provencio reported the three-year survival rate with confirmed previous results which are really encouraging and really supporting in the near future the use of this treatment for these patients.