Non-small cell to small cell lung cancer on PD-1 inhibitors: two cases on potential histologic transformation

Abstract

IntroductionHistologic transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a well-recognized mechanism of resistance in EGFR-mutant adenocarcinoma upon treatment with TKIs, but rarely reported with programmed death1 (PD-1) inhibitors. We report two cases of potential transformation during treatment with PD-1 inhibitors.Case presentationsCase 1, a 65-year-old man was diagnosed with stage IVa lung adenocarcinoma on pleural fluid cytology. He received six cycles of carboplatin and pemetrexed, then maintained on pemetrexed. He had disease progression after nine cycles of pemetrexed and was switched to nivolumab. He progressed after five cycles of nivolumab. Core biopsy of the lung mass revealed SCLC. Case 2, a 68-year-old man was diagnosed with two primary NSCLCs and underwent resection. He had recurrence after several months and was treated with four cycles of carboplatin, paclitaxel, and pembrolizumab on clinical trial, with partial response. He was continued on pembrolizumab and had disease progression after 30 cycles. Biopsy of the new lesions showed SCLC.DiscussionHistologic transformation from NSCLC to SCLC can be explained by the presence of a common cell precursor. Proposed molecular mechanisms include loss of RB1, TP53 mutations, and MYC amplification. The distinction between transformation and mixed histology tumors is challenging, especially when pathologic material used for the initial diagnosis is limited. The possibility of a second metachronous primary lung cancer cannot be excluded in our cases.ConclusionHistologic transformation with PD-1 inhibitors could be under-recognized. Disease progression should prompt re-biopsy to uncover new histology and change in treatment. Future studies are needed to elucidate mechanisms and predictors of transformation.

Hyperprogressive Disease in Lung Cancer with Transformation of Adenocarcinoma to Small-cell Carcinoma during Pembrolizumab Therapy

“…Recent studies revealed that transformation to small-cell carcinoma is associated with inactivation of Rb1 and p53, which may derive small-cell carcinoma clones from adenocarcinoma at a very early stage, owing to divergent evolutionary processes (10). Transformation to small-cell carcinoma has already been reported in patients treated with ICI for adenocarcinomas of the lung (11, 12). The mechanisms are believed to be similar to those of patients treated with EGFR-TKIs.…”

Acquired Resistance to Immune Checkpoint Inhibitors

“…By any measure, the number of clinical cases of acquired resistance to ICIs reported in the literature is remarkably small. We identified 13 clinical reports comprising a total of 58 patients with acquired resistance to ICIs across all tumor types (Abdallah et al, 2018;Anagnostou et al, 2017;Ascierto et al, 2017;George et al, 2017;Gettinger et al, 2017;Hu et al, 2018;Iams et al, 2019;Kakavand et al, 2017;Koyama et al, 2016;Le et al, 2017;Sade-Feldman et al, 2017;Trujillo et al, 2019;Zaretsky et al, 2016) (Figure 2 and Table S1). Importantly, these reports use differing inclusion parameters for acquired resistance and represent a heterogeneous population.…”

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

“…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 series [6][7][8] and two case reports 9 10 ) and one meeting abstract (index case).…”