UNICORN Study: Osimertinib and Other Emerging Treatments for Uncommon EGFR Mutations

Transcript:

Charu Aggarwal, MD, MPH: Dr [Kaushai] Parikh, talk a little bit about the UNICORN [NCT05421936] study. Is there a role for osimertinib, erlotinib, or gefitinib in patients? Can you talk to us about it?

Kaushal Parikh, MD: The UNICORN study was just presented at ASCO [American Society of Clinical Oncology’s annual meeting] and then now has been published in JTO [Journal of Thoracic Oncology]. It's a multiinstitutional, multinational collaboration of 60 patients. If we look at the number of institutions involved in this collaboration with a total of 60 patients, who had a defined uncommon EGFR mutation and had to be treated with osimertinib in this real-world study, they did see responses for patients clubbed as either only uncommon mutations or an uncommon plus a common alteration together, which would be a L858R as well as an L861 or a S768I. This study has been informing my practice. We do see, G719 mutations or L861Q mutations that tend to respond favorably to osimertinib. I have seen that in the clinic as well.

I agree with Dr [Tarek] Mekhail about S768I. There were a couple of patients only, but these were combined mutations. These were not only an S768I. So we don't know if osimertinib is the one that's acting on S768 or G719, which is being inhibited by osimertinib leading to PRs [partial responses] in this study, about 20% of these patients had a combined mutation and not single uncommon EGFR mutation on this trial. It does build on the [John V.] Heymach-[Jacqulyne P.] Robichaux paper, which has been pinned on my board and the reference for the past couple of years when I'm looking at uncommon mutations. This study almost reinforces a lot of the things that are predicted from the structural classification, and the functional responses of TKI [tyrosine kinase inhibitor] are validated in this study… . Again, we need more such studies, we need more real-world large collaborations.

It's difficult to have a randomized study of G719 only. This is where multiinstitution collaborations are increasingly important. When we look at other first-generation TKIs, gefitinib, for example, the NEJ002 study [NCT01024413], which includes all EGFR mutations. And when we look at the responses for gefitinib vs carbo[platin]-paclitaxel in that study, looking at the subset of uncommon mutations, it wasn't much better. The responses are inferior compared to the classical EGFR mutations. I do not think these first-generation TKIs have a role because of the conformational changes that occur, which inhibit the binding of these first-generation TKIs.

Afatinib, your second generation, our prototype agent has phase 3 evidence now, with evidence on LUX-Lung 3[NCT00949650], LUX-Lung 6 [NCT01121393], and many other retrospective real-world databases showing activity and so does osimertinib. Generally, it's one of these that I would use in my practice. Again, reviewing the Robichaux paper and reviewing the UNICORN study for each of these patients as they come along.

Charu Aggarwal, MD, MPH: Such a nice overview. Are there any particular trials for these other drugs, osimertinib, gefitinib, or erlotinib that are particularly interesting for you for this patient population of EGFR uncommon mutations?

Kaushal Parikh, MD: [Yes,] it's largely based on, post hoc analyses of clinical trials or real-world data, and data sets in retrospective studies, showing efficacy or lack of lack thereof these first generation TKI's. UNICORN has again been an informing study, of course, of osimertinib. We have our own internal data set where we collect all uncommon mutations and see what they've been treated with, again showing some responsiveness with osimertinib, particularly as others mentioned for intracranial disease. As far as other ongoing studies,[the] agents [to look] at are exon 20 insertions, for example,…the Cullinan Oncology drug CLN-081. These have shown promise in this exon 20 space, which is not your exon 18 uncommon alterations. But I'm not aware if there are any specific exon 18 or exon 21 uncommon mutation studies or trials.

Charu Aggarwal, MD, MPH: I think you named quite a few of them that specifically look very interesting, especially with intracranial activity in the exon-20 space. So I think more to come on that.Personally, I'm looking forward to more data on ADCs [antibody-drug conjugates], as Dr [Martin] Dietrich mentioned earlier, because these seem to have efficacy across a broad data set of patients with "actionable genomic alterations." So I think we just have to stay tuned for more conferences, as well as more data to emerge.

Transcript edited for clarity.