Resistance to tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) is well established to be mediated by histological transformation to SCLC in 3%–14% of cases.1–3 Similarly, transformation of prostate adenocarcinoma to small cell carcinoma on androgen-deprivation therapy is reported to occur at an incidence of 17% and is associated with poor survival outcomes.4 5 More recently, reports have emerged regarding SCLC transformation of NSCLC as a resistance mechanism to immune checkpoint inhibitors (ICPIs). However, unlike disease progression on TKIs, repeat tissue biopsies are not universally recommended at the time of NSCLC progression on ICPIs.

In our practice, we cared for a patient who had small cell transformation of stage IV poorly differentiated squamous cell carcinoma of the lung after prolonged nivolumab monotherapy (figure 1). She was in her mid-60s with a history of 35 pack-years of smoking at the time of diagnosis of her lung cancer (metastatic to lungs, mediastinal lymph nodes and L1 vertebral body) with no targetable genomic alterations. After a short-lived response to first-line platinum-gemcitabine chemotherapy lasting less than 4 months, she had progression of her disease. She was then switched to nivolumab monotherapy, with sustained partial response for 21 months. On follow-up imaging, she was noted to have bulky mediastinal and right hilar lymphadenopathy; biopsy showed SCLC. Review of the biopsy at initial NSCLC diagnosis did not show any small cell component. Tumor genomic profiling performed at initial diagnosis and following disease progression on nivolumab showed nearly identical results (table 1). Treatment with carboplatin/etoposide led to near-complete response, however, lasting for only 10 months. Biopsy of the tumor again confirmed small cell histology. She was treated with concurrent nivolumab and radiotherapy to the chest, though ultimately elected to pursue comfort focused care and died 14 months after the detection of neuroendocrine transformation.

We performed a systematic review of the literature, in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, to identify similar published reports of NSCLC-to-small cell transformation on ICPIs (figure 2). We searched PubMed, Embase and the American Society of Clinical Oncology/International Association for the Study of Lung Cancer virtual meeting library databases on 7 December 2019, using the keywords small cell transformation/neuroendocrine transformation with or without ICPIs/anti-PD-1/pembrolizumab/nivolumab/atezolizumab/durvalumab. Two investigators (KS and AV) independently reviewed abstracts and full-text articles. Patients with advanced NSCLC who had received molecularly targeted therapies prior to small cell transformation or non-lung primary cancers were excluded. Nine patients were identified from five articles (three case series6–8 and two case reports9 10) and one meeting abstract (index case).

All patients were on treatment with ICPIs at the time of detection of SCLC, with seven (77.8%) on nivolumab and two (22.22%) on pembrolizumab monotherapy. Five (55.6%) were male; median age was 68 years (range 65–75 years). All eight (100%) patients for whom smoking history was described had history of tobacco exposure. The median number of treatments received before ICPI was 1 (range 0–3). All (100%) patients had received chemotherapy before switch to either second line or maintenance ICPI. After detection of small cell transformation, seven (77.8%) patients received carboplatin/etoposide as the next immediate line of therapy. Among eight patients for whom survival data was available, median survival since detection of small cell transformation was 13.0 months (95% CI 2.0 to 16.0 months; Stata/IC V.15.1), which was comparable to 10.9 months (95% CI 8.0 to 13.7 months) previously reported with transformed EGFR-mutant lung adenocarcinoma on TKIs.11 The full clinicopathological and tumor genomic details of these cases are summarized in table 1.

No consensus guidelines exist on how to define NSCLC-to-small cell transformation and distinguish it from new primary SCLC. Absence of neuroendocrine features on initial biopsy, protracted response to nivolumab monotherapy and the near-identical genomic profile of the two tumors favored the diagnosis of histological transformation in our patient. Proof of transformation with molecular fingerprinting was described in only two of the other eight patients (table 1). The genomic profiles of ‘transformed small cell tumors’ in three patients were completely different from the ‘original’ NSCLC tumors, which raises the question of true treatment-induced transformation versus metachronous primary SCLC. Genomic profiling was not described in the remaining four cases. Presence of mixed small cell and non-small cell histology at diagnosis, minimum duration of therapy and attainment of initial response with ICPIs are other criteria which merit further investigation. Of note, two patients in table 1 had received less than four cycles of ICPIs, while three patients did not have any on-treatment response.

The real-world frequency of histological transformation with ICPIs remains uncertain—and is likely under-recognized and under-reported due to the infrequency of tumor rebiopsy in advanced NSCLC being treated with sequential chemotherapies and/or ICPIs. Bar et al studied biopsies at the time of NSCLC progression on ICPIs at a single institution and reported a small cell transformation rate of 25% in 8 patients with NSCLC with available with preprogression and postprogression tissue biopsies (with two postprogression biopsies not showing any tumor cells).7 However, Gettinger et al did not find any clear changes in lung cancer histology (0%) on evaluation of 23 NSCLC cases (all with tumor cells) from a single institution with acquired resistance to anti-PD-1 drugs.12 Both studies are hampered by small sample sizes, which makes it prudent to study this putative phenomenon prospectively.

The underlying evolutionary genomic/epigenetic alterations responsible for this mechanism of therapeutic resistance warrant more detailed exploration. Insights from small cell transformation in EGFR-mutated lung adenocarcinoma and prostate adenocarcinoma may help direct further mechanistic investigations towards study of common cell-of-origin, drug-tolerant persister state and stromal interactions.2 3 13–15 In the meanwhile, we recommend that tissue biopsies should be considered at the time of NSCLC progression on ICPIs similar to TKIs, if safe and feasible from the patient perspective.