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Researchers Describe Rare Phenomenon in Lung Cancer

Bennett, Christina MS

doi: 10.1097/01.COT.0000527178.80279.c2
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MADRID—Researchers reported the clinical features and outcomes from a small group of patients whose lung cancer underwent a rare transformation, and they described the treatment strategies that seemed to have the highest clinical activity. The findings were reported at the ESMO 2017 Congress (Abstract 1531PD).

The transformation the researchers investigated is when a subtype of non-small cell lung cancer (NSCLC) harboring the EGFR mutation develops resistance to EGFR tyrosine kinase inhibitors (TKIs) and returns as small cell lung cancer (SCLC). The subtype of NSCLC in which this rare event occurs is EGFR-mutant lung adenocarcinoma.

“[The transformation] is something that has been described in the literature for the past 8-10 years as happening rarely,” said senior author Lecia Sequist, MD, MPH, of Massachusetts General Hospital Cancer Center, Boston. “Most people have heard of it, but it is such a rare event that sometimes people haven't seen a case of it or they only have one case in their practice.”

Evidence of this transformation suggests that NSCLC and SCLC, commonly seen as different diseases with distinct biological and genetic characteristics, may be more alike than they seem; they may arise from a common cell type (Lancet Oncol 2015;16(4): e165-e172).

“We thought it would be helpful to at least describe what kind of course these patients generally can expect and what the experience has been as far as response or lack of response to different drugs,” said Sequist.

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Research Review

To describe the clinical features and outcomes of these patients, Sequist and colleagues retrospectively reviewed the records for every patient who had EGFR-mutant SCLC that had been treated at Mass General Hospital. From the time they saw the first patient in 2006 to the present, the patients seen with this rare event totaled 16.

Of the 16 patients, six were male and 10 female; median age was 53 years. Initial histology was lung adenocarcinoma for 15 patients and de novo SCLC for one patient. The 15 lung adenocarcinoma patients received an EGFR TKI before transformation; all but one were still on a TKI when SCLC was found. Also, patients initially diagnosed with EGFR-mutant lung adenocarcinoma retained the EGFR founder mutation after transformation.

“We found that the median amount of time from the initial diagnosis of lung cancer until this transformation happens was about 30 months, so 2.5 years. That was a little bit of a surprise to me. These are patients who are doing well for the most part with their advanced lung cancer,” noted Sequist. The median overall survival from the time of initial diagnosis was 38 months (95% CI: 22.1-44.1).

“One of the misconceptions that is being addressed by this data is that patients tend to do awful once this happens and, unfortunately, that can be the case, but what we found when we looked at this group of patients was that some of them actually live for quite a long time after this transformation happens,” stated Sequist. From the time of SCLC transformation, the median overall survival was 8.8 months (95% CI: 4.9-14.7). “There were definitely people who lived longer than a year, and so it is worth trying to treat because people can get some mileage out of treatment.”

The study researchers also noted which therapies seemed to have clinical activity when this rare event occurs.

“Traditionally, in the little literature that exists, the main treatment proposed has been platinum chemotherapy plus etoposide because that's a standard regimen for the more traditional small cell lung cancer,” Sequist said. She noted the platinum chemotherapy plus etoposide regimen is still an appropriate option and the study researchers saw good responses for patients on that regimen. Platinum chemotherapy plus etoposide was the most common regimen used directly after SCLC diagnosis.

“In addition, we also saw that the taxane family of chemotherapy had a really good response. That is possibly not something that people would automatically think of,” Sequist explained. Taxanes were used for eight patients in nine individual treatment lines and typically reserved for third- or fourth-line use after transformation. The clinical response rate was high (responses seen in four of nine lines).

“Granted, this is a small group of patients, so we don't want to be overly conclusive, but there doesn't seem to be any sign of activity with immune checkpoint inhibitors in these EGFR patients,” Sequist said. The study showed no responses among the five patients treated with checkpoint inhibitors. She explained that this lack of response is consistent with what happens in EGFR patients whose cancer has not transformed to SCLC.

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Future Studies

“One of the take-home points is that these patients are still more like EGFR patients even though under the microscope their cancer may have this small cell appearance,” Sequist noted. The study authors encouraged further investigation to determine optimal treatment strategies.

The study is retrospective and includes a small sample so results are not definitive, but the study findings do add to an area of research that has little information, Sequist said. Another limitation is the experiences are that of a single institution.

“Because of the interest that was drummed at ESMO, a number of our colleagues from around the world have reached out to us,” Sequist stated. “I think we're going to be able to put together a much larger cohort as a result of ESMO, so we're extremely excited about that, but again, this will be a descriptive study to learn what's happened in the past to other patients.

“I think what we need to do moving forward is start allowing these patients to go on to clinical trials. A lot of clinical trials currently exclude this group of patients because they don't fall neatly into one camp,” Sequist said. For example, she explained, the EGFR trials exclude these patients because of the SCLC histology, and the SCLC trials exclude these patients because of their history of lung adenocarcinoma. “They unfortunately get excluded from trials. I would hope that future trials would be more inclusive of this group.”

Christina Bennett is a contributing writer.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
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