Importance of Biomarker Testing for RET in Non Small Cell Lung Cancer - Episode 6

The Impact of Upfront NGS Testing on Overall Outcomes


Jessica Bauman, MD: We now base our treatment choices on NGS [next-generation sequencing] testing. So it is imperative that we have this information as soon as we can when patients have new diagnoses. We know over time with different treatments that certain populations respond better and differently to some treatments versus others. For example, in non—small cell lung cancer right now, we have targeted therapy, we have immunotherapy, and we have chemotherapy.

What someone should receive of those 3 treatments, or combinations of those 3 treatments, is important for us to be able to decide right up front. And that determines their overall survival. We know that, for example, in targeted mutation populations such as EGFR and ALK, it is really bringing those targeted therapies into the frontline setting that has allowed them to have such impressive survival rates over the course of the last several years.

Knowing that mutation up front is important in terms of our decision-making process. The other part of this that is important to highlight is that not all populations respond the same to immune therapy in particular. We have found that patients who have targetable mutations, such as EGFR and ALK in particular, and this has also now been seen with RET, is they have more of a cold immunophenotype and do not respond as well to immunotherapy, and certainly to immunotherapy when used as a single agent.

For these populations, treating them up front without this knowledge and throwing immunotherapy into the mix, or treating them with upfront immunotherapy by itself, would not be the right potential treatment option for this patient population because it does not, in fact, lead to significant responses or duration of responses. And so understanding up front the biology of each individual patient and cancer is critical for decision making.

We do recommend NGS testing up front. But you also now see that we’re starting to send NGS testing at progression on a specific type of therapy. The reason we do this is because what we are seeing is specific kinds of resistance mechanisms that are happening in each individual cancer, that may be then targeted with a new treatment. We’ve seen this paradigm in patients with EGFR-mutated non—small cell lung cancer, where those people who progress on what are first- and second-generation TKIs [tyrosine kinase inhibitors] erlotinib, gefitinib, and afatinib, when they are progressing off of those, 50% or more develop a T790M mutation, which is then associated with responses to osimertinib.

We now have moved osimertinib into the frontline setting. However, now there are data of using osimertinib and then at progression, there are specific new types of resistance mechanisms that are developing that are now also in clinical trials. For patients with a RET fusion mutation, we also see the same type of resistance mechanisms starting to emerge. So unfortunately, although we are seeing excellent responses and impressive duration of responses with the new selective RET kinase inhibitors, the problem is that these cancers learn to grow around these treatments.

And when they learn to grow, they have developed a resistance mechanism of some kind. For patients with RET fusions, the most common that we've seen thus far is a solvent-front mutation. And so taking this into account in terms of future drug development and the next generation of RET inhibitors will be important.

Transcript Edited for clarity