Small cell transformation of non-small cell lung cancer on immune checkpoint inhibitors: uncommon or
Kartik Sehgal1, Andreas Varkaris2, Hollis Viray2
1Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA ksehgal@bidmc.harvard.edu dbcosta@bidmc.harvard.edu.
Background:
Histological 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 Presentation:
We 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 Review:
We 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.
Conclusions:
Histological 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.
Insights
Histological transformation to small cell lung cancer (SCLC) can cause acquired resistance to immune checkpoint inhibitors (ICPIs) in non-small cell lung cancer (NSCLC). Repeat biopsies are recommended upon progression to identify this transformation.
Area of Science:
- Oncology
- Pulmonology
- Genetics
Background:
- Histological transformation of lung adenocarcinoma to SCLC is known with tyrosine kinase inhibitors (TKIs).
- The role of transformation in acquired resistance to immune checkpoint inhibitors (ICPIs) in non-small cell lung cancer (NSCLC) is unclear.
- Tissue biopsies are not routinely recommended at NSCLC progression on ICPIs, unlike with TKIs.
Observation:
- A patient with stage IV squamous cell lung carcinoma progressed on chemotherapy and responded to nivolumab.
- Following 21 months of response, the patient experienced rapid progression, with biopsies revealing transformation to SCLC.
- Genomic profiling showed near-identical tumor profiles between initial NSCLC and SCLC transformation.
Findings:
- A systematic review identified nine cases (including the index case) of NSCLC transforming to SCLC under ICPIs.
- Seven cases (77.8%) were on nivolumab and two (22.2%) on pembrolizumab monotherapy.
- Median survival after SCLC transformation was 13.0 months.
Implications:
- Histological transformation to SCLC is a potential mechanism of acquired resistance to ICPIs in NSCLC.
- Repeat tissue biopsies should be considered at progression, similar to oncogene-directed therapies.
- Further studies are needed to characterize this transformation using molecular fingerprinting and paired tumor genomic profiles.
