Ravi Salgia, MD, PhD, is chair and professor in the department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center. 

Ravi Salgia, MD, PhD

Ravi Salgia, MD, PhD, medical oncologist, professor, and the Arthur & Rosalie Kaplan chair in medical oncology & therapeutics research at City of Hope’s comprehensive cancer center, discusses how to address and treat transformation from non–small cell lung cancer (NSCLC) to small cell lung cancer (SCLC).

 is a form of resistance to EGFR tyrosine kinase inhibitors (TKIs) which can occur in as many as 5% to 7% of cases of patients with 

-positive NSCLC treated with a TKI. In a study at City of Hope, 9 patients with NSCLC who received erlotinib (Tarceva), afatinib (Gilotrif), or osimertinib (Tagrisso) who underwent this transformation had a median time to SCLC transformation of 16 months (range, 4-49) and a median overall survival of 29 months (range, 16-62).

Salgia says that in some cases, it can be a slow transformation that only affects 1 disease site; in this case, radiotherapy or another approach that targets that site should be considered.

Other cases of small-cell transformation can be faster and more aggressive forms of SCLC, which can occur in patients with an 

 mutation as well as p53 and Rb alterations. In these cases, he says physicians may consider continuing the TKI while giving chemotherapy. Alternatively, they can give chemotherapy and immunotherapy. Physicians should also determine if the patients now qualify for any clinical trials that could offer greater benefit for their condition.

 It depends on how the transformation occurs. If it's a slow transformation, and it's only 1 site of disease that you're seeing this transformation, whereas the other sites 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 you have not only an 

 mutation but 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 questions that arise: Do you give chemotherapy and continue the TKI? 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.

Videos

Ravi Salgia, MD, PhD, discusses how to address and treat transformation from non–small cell lung cancer to small cell lung cancer.

Choosing Therapy for NSCLC to SCLC Transformation in EGFR+ Disease

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, discusses the ways in which oncologists can watch out for non-small cell lung cancer (NSCLC) that transforms to small-cell lung cancer (SCLC).

According to Salgia, there are not always durable responses with EGFR tyrosine kinase inhibitors (TKI) in patients with NSCLC. Data from preclinical research has even demonstrated resistance to these inhibitors and has shown that NSCLC will transform to SCLC in 5% to 7% of cases.

To further explore the potential for this transformation, Salgia, along with other researchers at the City of Hope Medical Center, examined a novel PP2A inhibitor, 

LB-100 combined with chemotherapy or immunotherapy, as treatment for these patients.

 Further, a clinical trial (NCT04560972) observed 9 patients who had 

-positive NSCLC and were treated with either erlotinib (Tarceva), afatinib (Gilotrif), or osimertinib (Tagrisso).

In order to keep an eye on these patients, Salgia notes the importance of watching out for cancer which is growing relatively fast with TKI therapy, and reminds oncologists to perform biopsies, histology evaluations, and molecular evaluations to watch the transformation 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 

 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.

 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. The only way you can do that is by doing an actual biopsy. 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.

Ravi Salgia, MD, PhD, discusses the ways in which oncologists can watch out for non-small cell lung cancer that transforms to small-cell lung cancer.

Key Signs of SCLC Transformation in Patients With EGFR+ NSCLC 

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, discusses the results from a study of LB-100 combined with chemotherapy or immunotherapy to address transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC).

The study done at City of Hope (NCT04560972) observed a total of 9 patients with 

-positive NSCLC treated with either erlotinib (Tarceva), afatinib (Gilotrif), or osimertinib (Tagrisso) with the goal of evaluating the characteristics and metabolism of SCLC.

The primary end point was to investigate any dose-limiting toxicities with the combination and the secondary end points included objective response rate, duration of overall response, the incidence of adverse events, progression-free-survival, and OS. 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 SCLC.

 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. We started to study the metabolism in small cell lung cancer, and what we found out was this enzyme, PP2A, was very highly dysregulated.

 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 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.

Articles

Ravi Salgia, MD, PhD, discusses the results from a study of LB-100 combined with chemotherapy or immunotherapy to address transformation from non-small cell lung cancer to small cell lung cancer.

Ravi Salgia, MD, PhD | Authors

Articles

Choosing Therapy for NSCLC to SCLC Transformation in EGFR+ Disease

Key Signs of SCLC Transformation in Patients With EGFR+ NSCLC

Examining Transformation of NSCLC to SCLC in EGFR+ Disease