PP2A Inhibitions May Address Transformation of NSCLC to SCLC in Patients With EGFR+ Disease

Ravia Salgia, MD, PhD

Initial responses to EGFR tyrosine kinase inhibitors in patients with non–small cell lung cancer (NSCLC) are not always durable. Preclinical research has shown that resistance can occur, and in 5% to 7% of cases, the NSCLC will transform to small cell lung cancer (SCLC).

The study observed 9 patients with EGFR-positive NSCLC who were treated with either erlotinib (Tarceva), afatinib (Gilotrif), or osimertinib (Tagrisso). Results showed that the median months to SCLC transformation was 16 months (range, 4-49). From diagnosis, the median overall survival (OS) in these patients was 29 months, with the minimum being 16 months and maximum being 62 months.

Findings from the preclinical study led to the phase 1b evaluation of LB-100 with carboplatin, etoposide, and atezolizumab (Tecentriq) for the treatment of untreated extensive-stage small cell lung cancer (NCT04560972). The study will first investigate any dose-limiting toxicities with the combination and then evaluate the secondary end points of objective response rate, duration of overall response, the incidence of adverse events, progression-free-survival, and OS.

In an interview with Targeted Oncology^TM, Ravi Salgia, MD, PhD, medical oncologist, professor, and chair, Department of Medical Oncology & Therapeutics Research, and Arthur & Rosalie Kaplan chair in Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center, discussed the research leading to the first-in-human study of LB-100 combined with chemotherapy or immunotherapy to address transformation to SCLC.

TARGETED ONCOLOGY: How common is histologically transformation to SCLC?

Salgia: Non–small cell lung cancer, as we know, can happen in many different types [of the disease]–and the type for adenocarcinoma especially– and a patient can have an EGFR mutation. And for EGFR mutations, you get these targeted therapies, and they can potentially lead to small cell transformation. It's not very common, it happens in about 5% to 7% of the time in our clinical practice, after the patients receive a tyrosine kinase inhibitor.

How do you treat patients in the case of transformation to SCLC?

That's a wide-open question at this moment in time. What I will say is that it depends on how the transformation occurs. If it's a slow transformation, and it's only one side of disease that you're seeing this transformation, whereas the other side of diseases are stable, then you might consider just radiating that site or doing something else to get rid of that site that's being problematic.

But a lot of times what happens in small cell transformation, especially when there’s an EGFR mutation and a p53 alteration, and an RB alteration, then they can be quite aggressive and quite fast. There you have to think about at least chemotherapy. Now the question that arises is: Do you give chemotherapy and continue the tyrosine kinase inhibition? That's an important question. Do you give chemotherapy and immunotherapy? That's another important question. Can patients qualify for clinical trials? And that's really an important question as well.

Can you tell me about your study at City of Hope? What did you evaluate and what were the results?

What we started to study in the laboratory was, are there characteristics of small cell lung cancer, we could take advantage of where we could come back with various therapeutics. So, we started to study the metabolism in small cell lung cancer. And what we found out was this enzyme, PP2A, was very highly dysregulated.

So, we started to inhibit the PP2A with this compound called LB-100, and what we found importantly is that chemotherapy in combination with LB-100, and immunotherapy in combination with LB-100 was very synergistic. The combinations were killing off the small cell lung cancer cells in the laboratory. We did that in vitro in tissue culture dishes. We also did it as spheroids, which are 3-dimensional surfaces, and we found very dramatic results. So, we went to the mouse model, and we found the same thing. So based on that, we designed this clinical trial of using chemotherapy and immunotherapy in combination with LD-100 for patients with newly-diagnosed extensive-stage small cell lung cancer.

Based on your findings and expert knowledge, how would you instruct other oncologists to watch out for NSCLC that transforms to SCLC?

Watch out for cancer that is growing relatively fast with the tyrosine kinase inhibition. We know that patients respond beautifully when they have an EGFR mutation in non–small cell lung cancer, to tyrosine kinase inhibition. But there may come a time when you're seeing progression, and you can't explain this rapid progression. So, we always say whenever there's progression to biopsy the sample, because you have to look at it under the microscope, you can't do a liquid biopsy, because it doesn’t show the transformation. You have to look at it under the microscope. And the only way you can do that is by doing an actual biopsy. So, look out for when you do see the scans and progression, do get a tissue biopsy and do a histology evaluation, as well as molecular evaluation.

What patient characteristics are you looking for in the first-in-human study?

We're looking for patients with newly diagnosed small cell lung cancer, and those who have extensive disease, meaning that not limited disease where you have to do chemotherapy and radiation therapy, but extensive disease, meaning metastatic small cell lung cancer. So those are the types of patients we're looking for. And at the same time, clearly control brain metastasis is important as well.

What else would you like to share around this topic?

It's very important for us to realize that we need to do a lot more research for lung cancer, and especially for small cell lung cancer. So, we need to fund research for lung cancer. That's really important for us to go forward.

_REFERENCE:

_{Mambetsariev I, Arvantitis L, Fricke J, et al. Small cell lung cancer transformation following treatment in EGFR-mutated non-small cell lung cancer. J Clin Med. 2022;5;11(5):1429. doi: 10.3390/jcm11051429.}