Managing Oligometastases With Ablative Therapy in NSCLC

Transcript:Benjamin P. Levy, MD: Let’s move on from dual checkpoint blockade to the role of locally ablative therapy in patients who receive immunotherapy. We will have some data being presented today at the World Conference on Lung Cancer looking at local ablative therapy up to 4 sites for patients who have advanced non—small cell lung cancer and were given radiation first—or surgery, it could be either one—followed by pembrolizumab every 3 weeks. The outcomes look fairly competitive. Again, this is not a randomized trial, but the PFS [progression-free survival] is 25 months. All PD-L1 expressers were allowed. But it gets to this point of tumor heterogeneity and trying to knock out everything up front with a local measure, then following it with immunotherapy. Is there room for this in our treatment paradigm, given all the complexity with chemotherapy, I/O [immuno-oncology], and dual checkpoint blockade? Is this something where we may see some traction? There’s a lot of rationale to use radiation prior to immunotherapy. It was discussed by you, Solange, in the PACIFIC trial. Is this something that may gain traction over time?

Solange Peters, MD, PhD: I think we like to individualize patient treatment if we can, right? These patients with a very small number of lesions and restricted kinds of lesions are not very often encountered. These are exceptional patients with low tumor burden and probably good performance statuses: the patients for whom you’d like to do a little bit more than just give palliative IV [intravenous] treatment. They exist, and we’re happy to have these data, but formally they don’t create a high level of evidence. It’s about trying to find an individual treatment, and you should still keep in mind that there are standards of care for these patients.

Suresh S. Ramalingam, MD: I completely agree with Solange in the sense that these patients who have oligometastatic disease are patients who have somewhat better prognoses compared with others. In a single-arm study, when you give them some intervention and show that they do better, we have still not isolated the treatment effect. The good news is that these supportive data have already led to a randomized phase III trial in the National Clinical Trials Network in the United States. There is a trial that compares patients getting systemic therapy. After they get 4 cycles of chemotherapy alone or chemotherapy plus immune checkpoint inhibition, they’re randomized to radiation of oligometastatic disease and then continued on systemic therapy versus systemic maintenance therapy. I think that trial will elegantly answer this question and help us change the standard of care.

Sanjay Popat, PhD, FRCP: I think that’s right. This is a very attractive strategy for about 20% of our patients who have oligometastatic disease, depending on how you define it. That’s the other elephant in the room, the heterogeneity that we have with definitions.

But I think these data sets that you’re talking about are attractive because they inform us about the safety of that combination. There have been some concerns about different modalities of radiation, oral surgery, and the combination of immunotherapy. But we’re not seeing any major detriments. As we’ve seen with the PACIFIC trial, combining it with traditional radical thoracic radiotherapy hasn’t been a problem in consolidation. I think we really look forward to having randomized data sets to inform us of the treatment effect.

Benjamin P. Levy, MD: A common theme in this discussion is that there are a lot of unanswered questions. Moving forward, we hope to get these answers quickly so we can make the best treatment decisions for our patients. I just want to briefly talk about local ablative therapy and EGFR-mutant lung cancer. I think the paradigm has been for many of us to start these patients who were EGFR mutated on a TKI [tyrosine kinase inhibitor], whether it be a first-generation or now third-generation TKI. If there is progression, progression can be heterogeneous. One side of that is that you can just have these local spots that grow, and the paradigm has been to radiate that spot and continue the TKI. We’ve seen some improvement in outcomes; it’s not randomized, but there was some nice work retrospectively and prospectively suggesting that radiating at the time of oligometastatic progression can lead to longer time on drug and delay in chemotherapy.

We have a set of abstracts that will be presented at the World Conference on Lung Cancer looking at that same strategy but using local ablative therapy for synchronous metastases up front in EGFR-mutant lung cancer, as either upfront or consolidation therapy and continuing the TKI. This is a similar story to the pembrolizumab data. It’s a small number of patients. Are we going to start using these other types of means, radiation or surgery, up front for these local spots and then treating with a TKI? Or is the paradigm still to give the TKI first, because osimertinib has such a profound activity in this patient population, and save your radiation for when the disease progression occurs? Any thoughts on that?

David Planchard, MD, PhD: I would say that this is something we do already in clinical practice. If you have a patient with multiple diseases and you see small metastatic disease or tumor evolution, you try to maintain the EGFR TKI and have some local treatment.

I’m quite sure that we have to treat patients with big bone metastases. It will be an EGFR TKI, and the fact is you are still using radiation to perform local surgeries and to avoid immunochemical resistance. This is something we do in clinical practice for some patients. It’s nice to see a clinical trial trying to see the magnitude of benefit we might improve in this population. But clearly, to make an addition of a different treatment in this population—despite that they are considered to be metastatic—

we should still be quite aggressive for this population. I’m quite sure that we will buy a benefit in quite a significant proportion of patients. It definitely will be so.

Transcript Edited for Clarity