Introduction: Histologic transformation from NSCLC to SCLC is a mechanism of resistance in EGFR-mutant tumors but is also occasionally observed in nonmutated NSCLC. Methods: We performed a multicenter retrospective collection of cases presenting between 2005 and 2017. The objectives were to analyze survival data and to define epidemiologic, clinical, treatment and histomolecular characteristics at both the time of diagnosis of NSCLC and of SCLC. Results: Forty-eight EGFR-mutant NSCLC and 13 non-EGFR-mutant cases were registered. Most EGFR-mutant tumors retained the same EGFR mutation after transformation. The median time to SCLC transformation was shorter in the EGFR-mutant group than in non-EFGR mutants (16 months versus 26 months (p ¼ 0.01)). Both tumors were responsive to platinum etoposide regimens (45% partial response for the EGFR-mutant group versus 40% for non-EFGR mutants). The median overall survival rates were 28 months in the EGFR-mutant group versus 37 months in the non-EFGR-mutant group, respectively. After transformation, the median overall survival was 9 months in the non-EGFR-mutant group versus 10 months in the EGFR-mutant group. Conclusions: Transformation into SCLC seems to occur more quickly in EGFR mutated tumors; however, once the tumor is transformed its survival and response to treatment seems comparable to that of classical SCLC.

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, additive, not mandatory plasma samples were collected and analyzed at the time of revaluations. To determine changes in the risk level during follow-up, we evaluated changes in the probability of having progressive disease after two consecutive MSC tests, considering all possible combinations. Result: Overall 17 (34%) R, 17 (34%) patients with SD, 11 (22%) P and 5 (10%) not evaluable patients were identified. Considering the baseline blood samples 11 (22%) NSCLC patients were MSC H. ORR was 0% in MSC H vs 45% for other patients (p¼0.0090). Median PFS was 2.3 months for MSC H vs 10.9 months for other patients (HR¼0.38; 95%CI¼0.17-0.84; p¼0.0174). Median OS was 2.9 months for MSC H vs 22.0 months for other patients (HR¼0.18; 95%CI¼0.07-0.47; p¼0.0004). Data remained significant adjusting for age, sex, pack-years and ECOG performance status: PFS HR¼0.31 (95%CI¼0.13-0.73; p¼0.0072) and OS HR¼0.13 (95%CI¼0.04-0.39; p¼0.0003). Among the 26 patients with longitudinal evaluation of MSC risk level, all the 12 patients reaching progression during treatment showed an increase in the risk level (Sign-test p-value¼0.0039). Conversely, when considering the 14 NSCLC patients still maintaining SD or responding to ICIs at the time of the analysis, the risk level decreased for 9 (64%) of them (Sign-test p-value¼0.1655). Conclusion: These preliminary results suggest that MSC risk level at the baseline and during treatment could help to identify primary or secondary resistance in PD-L150% NSCLC patients treated with ICIs. Ongoing clinical trials are validating these results.

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