David R. Spigel, MD

Insights From the ESMO Congress 2019: Immunotherapies in Lung Cancer

Question

What are some of the most encouraging new targets in lung cancer?

Answer

I wish we had some new targets, but in the last year or so I think we’ve been so focused on making sure we’re addressing kind of the main targets, which include the oncogenic drivers such as EGFR, ALK, and ROS.

I guess if we were going to classify new targets, that would probably be things like RET, and then TRK (in 0.1% of lung cancer). And of course I left out some more traditional targets like MET EXON 14, BRAF, and HER2. We are looking at newer things that are research-based like FGFR and KRAS. Those are old targets, but new in the sense that we’re now collecting patients for active clinical trials. It is all included in broad comprehensive genomic sequencing, and that’s the advantage of broad testing: we can look for new markers and more standard markers and markers used [on a] research basis for enrolling patients in trials.

One of the things I’ll mention is if we flip things a little bit on the immune side, obviously PD-L1 continues to be an important necessary marker for selecting care. Probably after ESMO, tumor mutational burden, or TMB, seems to be less relevant.

Question

In your view, is immunotherapy-induced hyperprogressive disease a real phenomenon? If so, do you think testing for serologic biomarkers would be necessary before the administration of immunotherapies?

Answer

This concept of hyperprogressive disease is a bit controversial. Ultimately the premise is that patients responding to immune therapy we may lose that response and progress at a faster rate than if had they not been exposed to immune therapy. There’s a bit of a debate about this. There’s the perspective that there is no such thing as hyperprogressive disease, this is simply lung cancer that is progressing after another line of therapy.

I am still on the fence and kind of lean against this phenomenon. I’m not seeing it in practice. I am following the literature and there were certainly a few papers at ESMO, some coming from my European colleagues who are doing a lot of important work in this area. I think it remains to be an area that needs to be further explored. Right now I don’t know how to identify those patients if they exist clinically or necessarily what we should do differently for those patients. At ESMO, a couple of papers suggested that [one] could measure and predict who these patients would be, but I’m not sure what the conclusion would be: that we not treat them with immunotherapy or we should watch them in a different way or be more prepared for when they progress? So, it’s an emerging area, but I’d say right now there’s not anything ready for primetime in terms of testing for hyperprogression or how it will affect the care for those patients.

Question

Should tumor-tissue assays and circulating cell-free DNA assays always be coupled, for an orthogonal approach in the detection of oncologic driver mutations in lung cancer? Why or why not?

Answer

It is important to search for potential oncogenic driving mutations to help decide what care patients should receive in the first-line setting. So upfront testing is essential. How you do that I think depends on your institution and the speed of turnaround time and of course, accessibility. Traditionally, tissue has been the best way to comprehensively profile patients, but it also is the way that takes the longest. Blood-based testing is emerging as a quicker way, and perhaps efficient or comprehensive way, to at least identify the most relevant markers upfront.

At ESMO, we saw results from 2 important trials, the B-F1RST and B-FAST studies, which for me are more proof-of-concept trials. You could draw blood on patients and identify in the B-F1RST example tumor mutational burden and those patients who received upfront checkpoint inhibitor therapy, in this case atezolizumab, did very well, if they had high TMB based on blood testing.

Likewise, in the B-FAST study, [those who had an] ALK rearrangement [were] identified, [and] received, in this case alectinib. They did every bit as well as patients who had gotten alectinib chosen for them using more traditional tissue testing. I think blood and tissue are both available now. My guess is we’re moving toward blood-based testing being a more universal approach for speed, efficiency, and availability. But I think tissue is not going away anytime soon. It still offers us a broader, more comprehensive platform to look for new markers for both research and for clinical care.

Question

Research suggested that surgery may influence the immunologic status of a patient. If true, how would this affect the use of immune checkpoint inhibitors in the neoadjuvant vs the adjuvant setting for early-stage NSCLC?

Answer

Yes, I think that’s a really exciting area. I think right now we don’t know enough about what surgery does to affect local immunity and if it’s a transient phenomenon. This has been described for I think over 2 decades now. There was some literature in this area in breast cancer originally that [reported that] breast cancer surgery creates a local cytokine storm that [generates] more protumor growth factors. Now we’re studying immunotherapy preoperatively and how to improve outcomes at and following surgery.

There are a lot of questions about how immunotherapy is going to affect local regional care and specifically, surgical resection, and then how this impacts the local inflammatory environment. Will it have short-term ramifications for patients or potential long-term effects? For me, I know that these are really important areas for research because there’s no question that immunotherapy is moving into earlier treatment settings.

Question

What are some limitations of emerging “chemotherapy-sparing options,” if any?

Answer

I think in lung cancer, there is this drive to get away from chemotherapy. We certainly have examples in non-small cell lung cancer, where first-line therapy in many patients now could be just immunotherapy alone without chemotherapy. And I think there are potential limitations. Chemotherapy has had a role for decades in the treatment of cancers — specifically in lung cancer. If I use lung cancer as an example, in some of the comparative studies of immunotherapy vs chemotherapy or even chemoimmuno[therapy] versus chemo, there has been a suggestion of a crossover effect early on in the first 2 to 3 months, in which the chemotherapy-alone arm seemed to outperform immunotherapy, suggesting that you might need chemotherapy to bridge you through the first several weeks.

Maybe that’s because it takes time for an immune response to be realized. I think we don’t know. And if we eliminate chemotherapy altogether, I do have some concerns that there will be subsets of patients who don’t get the opportunity to benefit entirely from immunotherapy because the disease burden is too high upfront. If they had chemotherapy upfront, perhaps for a shorter duration than traditionally, maybe that would bridge them in their care long enough to achieve benefits from immunotherapy. In my view, I don’t think chemotherapy’s going away. I think we’re just trying to figure out how to combine or use immunotherapy in sequence with more standard therapies, at least for the foreseeable future.

Question

Are there biological differences in immune landscapes across patients of other ethnicities that could skew findings that are thought to be applicable to people of all backgrounds?

Answer

Well, that’s a great question. I mean, I think the simple answer is: we don’t know. I think our literature is full of examples of how ethnicity can play a role in how patients respond to therapies — not just talking about things like disparities and access, and population-based differences in screening. I think if you’re talking about interventional studies, we’ve known historically for chemotherapy, ethnicity plays a role in how patients respond both in terms of efficacy and toxicity. And could this be true too with immunotherapy? I think it could be, but I don’t think we’ve seen any examples of this yet. Unfortunately, for most of the pivotal registration trials, there’s not been much variation. The ethnic variation has been limited and the population sizes within studies have been too small to notice differences.