PracticeUpdate Oncology May 2019

EXPERT OPINION 21

Immunotherapy and TKIs in Stage III Lung Cancer Interview with Wilfried Eberhardt MD by Tyeese L. Gaines DO Dr. Gaines: What has been the traditional approach to management of stage III lung cancer? now and it’s well known both in North America and in Europe. Right now, there has been a change in the clinical practice because of a large randomized trial, the PACIFIC study, which showed that there is a significant benefit of progression-free survival, but also now of overall survival. This has been presented at the World Conference on Lung Cancer in Toronto only a few weeks ago, and since then we have had the registration for durvalumab consolidation treatment for 1 year after concurrent chemoradiotherapy in Europe. You had it a bit earlier in the US, which is usually the case, but right now we are very enthusiastic about this situation because the benefit is significant. It’s clinically significant and clinically meaningful. Dr. Gaines: And what role do you envision for TKIs in stage III lung cancer? Dr. Eberhardt: For TKI, the situation is a bit more difficult. The patient group we are talking about is probably somewhere about 10 to 12%. Those are patients who have driver mutations and who are diagnosed in stage III. But there are initiatives now that in those patients we could use either, let’s say, an induction treatment with a TKI or with a molecular targeted agent. And then do, let’s say, either surgery and in this situation the whole treatment approach would be a neoadjuvant approach, and then you could look at the pathologic response. So, if that is the case then you can decide whether you carry on with a, let’s say, consolidation or continuous treatment of the TKI, but you could also envision that you could combine this with radiation or you could combine it with chemo- therapy. Now, there are different permutations that are theoretically possible. There is an initiative now also, especially in the IASLC, that these trials would be something for the future that we would give neoadjuvant treatment and see what is the pathologic response. And maybe then go to the registrational agen- cies to have an early registration if there is a benefit in those patients. Dr. Gaines: So, what questions still remain about immunotherapy in this setting? Dr. Eberhardt: The immunotherapy in that setting is, again, the question in some patients who are operable what would we do in those situations? There is still a group of, let’s say, between 15 and 20% of the patients that has the possibility to be operable in that situation. So, do we give neoadjuvant chemoimmunotherapy? It could be one possibility. It could also be the possibility to give chemoradi- ation plus immunotherapy consolidation in that situation without surgery. But you could also have the possibility to give chemoradiation plus immunother- apy plus surgery. So, these are important trials that probably will be performed in the next years. Dr. Gaines: Beyond systemic therapy options, what additional advancements are needed to improve the outcome for patients with stage III lung cancer? Dr. Eberhardt: So for stage III, one issue is brain metastasis. They are first signals that possibly also immunotherapy has an impact upon the reduction of develop- ment of brain mets. That is one of the outcomes also of the PACIFIC study. We’re not quite sure yet, but there are signals. So, we will follow-up on these signals, which is of importance. Then, development of second cancers is an important issue in that patient population. That was also discussed here at ESMO. So again, one could think about looking at the possibility that immunotherapy could also reduce the incidence of second cancers. That’s very provocative, but it has to be looked at. So, there are quite a number of trials that in the future will be per- formed, and hopefully, we will get nice answers from them. www.practiceupdate.com/c/75488 Dr. Eberhardt: So, an approach in stage III non-small cell lung cancer, the standard of care used to be concurrent chemo- radiotherapy. That’s well implemented for more than 10 years

we’re keeping the patients at least neurologically intact. So, if they come with an incidentally discov- ered set of four small metastases, and they’re up, for example, immunotherapy, you know, we would lean towards stereotactic radiosurgery. If they come with several large lesions, and let’s say it’s causing weakness, we would probably consider surgery first, remove it, and then consider either whole-brain radiation or stereotactic boost, and then have them continue on their immunotherapy. Dr. Shah: Okay. Dr. Lim: If it’s a newly diagnosed setting, where they’ve not had any immunotherapy first and the brain mets is the first presentation of their mel- anoma. So, and then if we think out a scenario where a patient presents with new brain metas- tases as their first presentation of melanoma, in that situation, the sequence of events, should you start the stereotactic radiosurgery followed by the immunotherapy, or should you do immunother- apy first? Those are questions that are still in play right now. You know, we personally, have looked in our lab, and we think that there’s some synergism, and what we did was, in our laboratory, we actually treated animals with the different sequences. We gave some animals the immunotherapy first, followed by radiosurgery, another set of mice radiosurgery and immunotherapy at the same time, and another set of mice we gave the immu- notherapy after the radiosurgery. And we just timed it within one half-life, and what we found was that there was no difference in survival in the animals once, if you did it within one half-life.

Dr. Shah is Executive Publisher, Online Content at Elsevier.

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VOL. 3 • NO. 2 • 2019