Small cell transformation of non-small cell lung cancer on immune checkpoint inhibitors: uncommon or under-recognized?

Abstract

BackgroundHistological transformation of oncogene-driven lung adenocarcinoma to small cell lung cancer (SCLC) following treatment with tyrosine kinase inhibitors (TKIs) is a well-described phenomenon. Whether a similar transformation may drive acquired resistance to immune checkpoint inhibitors (ICPIs) in non-SCLC (NSCLC) is uncertain. Hence, tissue biopsies are not universally recommended at progression of NSCLC on ICPIs, unlike TKIs.Case presentationWe report a case of a woman in her mid-60s with a 35 pack-years tobacco history and stage IV squamous cell lung carcinoma with no targetable genomic alterations, whose disease progressed within 4 months of first line carboplatin/gemcitabine therapy. Her treatment was switched to second line nivolumab monotherapy which resulted in sustained partial response lasting 21 months. She subsequently developed rapid, bulky progression of mediastinal disease. Biopsy showed transformation to SCLC. Comparison of genomic profiling results from the initial NSCLC diagnosis and SCLC transformation revealed near-identical tumor profiles. Her disease responded to next line carboplatin/etoposide, though lasting for only 10 months. She died 14 months after detection of neuroendocrine transformation of her NSCLC.Systematic reviewWe performed a systematic review of the literature to identify similar cases of NSCLC-to-small cell transformation on ICPIs. Nine patients, including our index case, were identified, with seven (77.8%) on nivolumab and two (22.2%) on pembrolizumab monotherapy. Median survival time since small cell transformation was 13.0 months (95% CI 2.0 to 16.0). Using our patient case as a framework, we further discuss the lack of consensus criteria to distinguish small cell transformation from de novo metachronous SCLC.ConclusionsHistological transformation to SCLC is a potential mechanism of acquired resistance to ICPIs in NSCLC. Repeat tissue biopsies should be considered at the time of progression, similar to oncogene-directed therapies. Prospective larger studies are warranted to further characterize NSCLC-to-small cell transformation on ICPIs using molecular fingerprinting with paired tumor genomic profiles, evaluation of neuroendocrine features at baseline and consideration of initial response.

Small cell transformation of non‐small cell lung cancer under immunotherapy: Case series and literature review

“…Small cell transformation of non‐small cell lung cancer (NSCLC) is commonly recognized as one of the resistance mechanisms to epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) in EGFR ‐mutant NSCLC treatment, which accounts for 3%–14% of resistant cases 4–6 . Since we reported the first case of small cell transformation as a resistant mechanism for immunotherapy in 2017, 7 similar cases of small cell transformation after immunotherapy have been reported 8–12 and we have experienced another three cases in our facility. In cancer immunotherapy, the concept of small cell transformation is becoming more prevalent as a mechanism of immunotherapy resistance.…”

Case Report: Transformation From Non-Small Cell Lung Cancer to Small Cell Lung Cancer During Anti-PD-1 Therapy: A Report of Two Cases

“…However, there are only a few published cases of histological transformation to SCLC in patients receiving PD-1 inhibitors, and retrospective studies are lacking. Sehgal and Imakita reported disease progression in a patient who received nivolumab monotherapy as second-line therapy; re-biopsy showed transformation to SCLC (12,16). lams reported that transformation to SCLC could be a mechanism of resistance to nivolumab in KRAS-mutant lung adenocarcinoma (15).…”

“…It is well known that histological transformation to SCLC is a known mechanism of resistance in 3-14% of patients with epidermal growth factor receptor (EGFR) mutations receiving EGFR tyrosine kinase inhibitors (EGFR-TKIs) (9)(10)(11). Similarly, transformation of NSCLC to SCLC in patients receiving PD-1/PD-L1 inhibitors has been reported as a mechanism of resistance to PD-1/PD-L1 inhibitors (12)(13)(14)(15). Unlike with EGFR-TKI therapy, repeat tissue biopsies are not usually performed at the time of NSCLC progression in patients treated with PD-1/PD-L1 inhibitors.…”

“…Herein, we report two cases with squamous cell carcinoma that transformed into SCLC during treatment with PD-1 inhibitors. We also provide a detailed description of the histological examination of the pre-and posttransformation tissues, hitherto absent from prior reports (12)(13)(14)(15).…”

Case Report: A Rare Case of Metachronous Multiple Primary Lung Cancers in a Patient With Successful Management by Switching From Anti-PD-1 Therapy to Anti-PD-L1 Therapy

“…Histologic transformation of non-small-cell lung cancer to SCLC has been reported to be a potential mechanism of resistance to immunotherapy ( 3 , 4 ). Therefore, it is difficult to distinguish mMPLC from intrapulmonary metastasis or treatment-induced transformation.…”