Background: Histologic transformation of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors. However, the SCLC transformation has also been observed in non- EGFR: mutant NSCLC. In these cases, whether SCLC initially co-exists with NSCLC or originates from initial NSCLC remains to be determined. Methods: Whole exome sequencing was performed on 10 samples from 5 patients with SCLC transformation from lung adenocarcinoma (LUAD), a main subtype of NSCLC. Somatic mutations and copy number variations (CNVs) were analyzed to explore the differences between initial LUAD and transformed SCLC, as well as the origin of transformed SCLC. Results: After SCLC transformation, the mutation spectrum changed, with decreased C>T and increased C>A. Compared with initial LUAD, the CNV burden of transformed SCLC was greatly increased (39.0 vs. 61.1, Wilcoxon P=0.4). The higher the CNV burden of LUAD, the shorter the time to SCLC transformation was observed to be; and the higher the CNV burden of transformed SCLC, the shorter the overall survival (OS) after transformation. Clonal evolution analysis showed different clonal components between initial LUAD and transformed SCLC. Conclusions: The transformation of LUAD into SCLC may be promoted by CNV events rather than mutational events. CNV burden was associated with the time to SCLC transformation and with the OS of patients following SCLC transformation. Transformed SCLC did not evolve directly from the initial LUAD but branched off from LUAD before the time of initial diagnosis.

Background: Transformation to small cell lung cancer (SCLC) is a resistance mechanism of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (LADC) patients treated with EGFR tyrosine kinase inhibitors (TKIs). Here, we describe the clinical characteristics and prognosis of these patients and explore the treatment modes after transformation.Methods: EGFR‐mutant LADC patients with SCLC transformation were retrospectively included in the study. Demographic and clinical data were collected. Survival outcomes and corresponding influential factors were analyzed.Results: Twenty‐nine patients were included in the study. The median progression‐free survival (PFS) of patients who received first‐line EGFR‐TKIs was 13.1 months. The median time to SCLC transformation was 27.5 months. After transformation, the objective response rates of patients who received first‐line chemotherapy with or without EGFR‐TKIs were 43.8% and 37.5%, respectively. The median PFS of patients reveiving chemotherapy with EGFR‐TKIs was significantly longer than that of patients receiving chemotherapy without EGFR‐TKIs (5.2 vs. 3.0 months; HR, 0.19; 95% CI: 0.05–0.72; p = 0.014). However, there was no significant difference in median overall survival (OS) between patients who received chemotherapy with or without EGFR‐TKIs (14.8 vs. 13.0 months; p = 0.474). In the multivariate Cox proportional hazards regression analysis, both anti‐angiogenic treatment (HR, 0.04; 95% CI: 0.01–0.29; p = 0.001) and local radiotherapy (HR, 0.28; 95% CI: 0.08–0.97; p = 0.044) were significantly associated with better patient OS after transformation.Conclusions: Compared with chemotherapy alone, the combination of chemotherapy and EGFR‐TKIs as first‐line treatment after SCLC transformation can benefit patients in PFS but not in OS. However, anti‐angiogenic therapies and local radiotherapy can significantly prolong OS after transformation.

Background The third-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) osimertinib has become the standard treatment for patients with pretreated EGFR-mutated non-small cell lung cancer (NSCLC) who acquire the T790M resistance mutation. However, no standard treatment after osimertinib failure has been established. Objective This study was undertaken to explore the clinical resistance modality upon failure of osimertinib therapy and to assess post-progression treatments in a real-world setting. Patients and Methods Medical data were retrospectively collected in our cancer center of patients with advanced NSCLC treated between 1 March 2017 and 1 July 2018, and who developed resistance to osimertinib. Results A total of 65 patients were analyzed. Clinical resistance modality varied among patients: 15 (23.1%) with local progression, 29 (44.6%) with gradual progression, and 21 (32.3%) with dramatic progression. Most patients experienced intrathoracic progression only (40/65, 61.5%), while ten (15.4%) cases presented intracranial failure only. Upon progressive disease, 20 patients (30.8%) received subsequent chemotherapy, and showed a trend for longer median overall survival (OS) than in those receiving a non-chemotherapy regimen (25.0 vs. 11.8 months, p = 0.106). Thirty-nine patients (60.0%) continued osimertinib beyond progression with a median post-progression treatment duration of 4.1 months. No significant difference in median OS was seen between patients who continued osimertinib and those who discontinued osimertinib (18.9 vs. 15.1 months, p = 0.802). In subgroup analyses, OS was improved in patients who experienced dramatic progression and were treated with chemotherapy, but data were immature for patients with local or gradual progression. Conclusions Chemotherapy could be an effective option after osimertinib failure in unselected patients.

Purpose: After progression to immunotherapy, the standard of care for non-small cell lung cancer (NSCLC) was limited. Administration of the same or different immune checkpoint inhibitors (i.e., ICI rechallenge) may serve as a novel option. The present study aimed to evaluate the efficacy of ICI rechallenge for NSCLC and explore prognostic factors. Methods: In this retrospective cohort study, data of advanced or metastatic NSCLC patients rechallenged with ICI at the Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College between December 2018 and June 2021 were retrieved. Progression-free, overall survivals (PFS; OS), etc. were calculated. Subgroup analyses were conducted according to baseline characteristics, prior treatment results, etc. for prognostic factor exploration using the Cox model. Results: Forty patients were included. Median age was 59 years. Thirty-one (78%) were male. Twenty-seven (68%) were smokers. Adenocarcinoma (28 [70%]) was the major histological subtype. Median PFS of patients receiving initial ICI was 5.7 months. The most common rechallenge regimens were ICI plus chemotherapy and/or angiogenesis inhibitor (93%). Seventeen (43%) were rechallenged with another ICI. Median PFS for ICI rechallenge was 6.8 months (95% CI 5.8–7.8). OS was immature. Tendencies for longer PFS were observed in nonsmoker or patients with adenocarcinoma, response of stable/progressive disease in initial immunotherapy, or whose treatment lines prior to ICI rechallenge were one/two. However, all results of prognostic factors were nonsignificant. Conclusion: ICI rechallenge may be an option for NSCLC after progress to immunotherapy. Further studies to confirm the efficacy and investigate prognostic factors are warranted.

Small-cell lung cancer (SCLC) transformation accounts for 3–14% of resistance in EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs without transformation after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). Our study found that LUAD-BT exhibited potential transcriptomic characteristics for transformation compared with LUAD-NT. We identified several pathways that shifted during transformation, and the transformation might be promoted by epigenetic alterations (such as HDAC10, HDAC1, DNMT3A) within the tumor cells instead of within the tumor microenvironment. For druggable pathways, transformed-SCLC were proved to be less dependent on EGF signaling but more relied on FGF signaling, while VEGF-VEGFR pathway remained active, indicating potential treatments after transformation. We also found transformed-SCLC showed an immuno-exhausted status which was associated with the duration of EGFR-TKI before transformation. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation, which obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future.

MDM2 has been established as a biomarker indicating poor prognosis for individuals undergoing immune checkpoint inhibitor (ICI) treatment for different malignancies by various pancancer studies. Specifically, patients who have MDM2 amplification are vulnerable to the development of hyperprogressive disease (HPD) following anticancer immunotherapy, resulting in marked deleterious effects on survival rates. The mechanism of MDM2 involves its role as an oncogene during the development of malignancy, and MDM2 can promote both metastasis and tumor cell proliferation, which indirectly leads to disease progression. Moreover, MDM2 is vitally involved in modifying the tumor immune microenvironment (TIME) as well as in influencing immune cells, eventually facilitating immune evasion and tolerance. Encouragingly, various MDM2 inhibitors have exhibited efficacy in relieving the TIME suppression caused by MDM2. These results demonstrate the prospects for breakthroughs in combination therapy using MDM2 inhibitors and anticancer immunotherapy.