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BackgroundCurrent front-line treatment for ES-SCLC includes chemotherapy plus a PD-L1 inhibitor. FDA has recently approved LUR for pretreated patients with SCLC. 2SMALL is a two-part phase 1/2 study assessing the safety, tolerability and efficacy of LUR in combination with ATZ as second line treatment for ES-SCLC. Here we report data from phase I part of the 2SMALL trial (data cut off 14-07-2021)Methods2SMALL phase I was an open-label, single arm, dose exploration trial. Elegible patients had confirmed ES-SCLC, who progressed to first line platinum based treatment, ECOG performance status score 0-1 and adequate organ function; prior exposure to immunotherapy was not allowed. During dose finding phase pts received increasing doses of LUR (2.5 mg/m2 - 3.2 mg/m2) on day (D) 1 plus a fixed dose of ATZ (1200 mg) every 3 weeks following a standard 3+3 dose escalation design. Study endpoints included the definition of the safety profile and the recommended dose. Additional objectives included efficacy (ORR and PFS).Results26 patients were treated, including male 14 pts (53,84%), with median age 60.6 years. Five pts received LUR 2.5 mg/m2 + ATZ 1200 mg, and 3 pts were evaluable without DLT. Out of the 21 pts who received LUR 3.2 mg/m2+ ATZ 1200 mg (6 pts with primary G-CSF), 5 pts (20.83%) developed DTLs: 2 pts G3 febrile neutropenia (9.52%) (1 pt with G4 thrombocytopenia), 2 pts G4 neutropenia lasting more than 72h (9.52%), 1 pt G4 thrombocytopenia (4.76%). Most frequent haematological adverse events ≥ grade 2 (21 pts) were neutropenia (42.86%), thrombocytopenia (28.57%), anaemia (19.05%); lymphopenia (4.76%) and febrile neutropenia (4.76%). The most common non-haematological TAEs ≥ grade 2 was asthenia 30,76%. No deaths treatment-related were reported. Objective responses were observed in 15 pts (ORR: 57.69%), including complete responses in 2 pts (7.69%), partial response in 13 pts (50%). 6 pts had stable disease (26.92%) and 3 pts progressive disease (11.54%). Disease control rate was 84.61%. With 8 pts censored for progression, median PFS was 4.93 months (range 3.37 - 7.67 months).ConclusionsThe combination of LUR plus ATZ was well tolerated, without unexpected toxicities. Transient haematological toxicity was dose limiting. The RD for further studies is LUR 3.2 mg/m2 on D1 + ATZ 1200 mg D1 with G-CSF. Preliminary anti-tumor activity is remarkable. 2SMALL trial part II is ongoing, and will provide further data regarding efficacy and safety of the regimen for second line SCLC.Trial RegistrationNCT04253145ReferencesSubbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment. Lung Cancer 2020;150:90–96.Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol 2020; 21(5):645–654.Ethics ApprovalEthics committe Hospital Universitario 12 de Octubre

First-line treatment with platinum-based chemotherapy has been the standard treatment for non-small-cell lung cancer (NSCLC) during the past decades. The development of new targeted drugs based on molecular alterations (EGFR, ALK, and ROS1) has led to important outcome benefits, but not for squamous cell carcinoma (SCC). However, the aberrant function of the EGFR pathway in SCC may be important in the development of the tumor and has been explored in preclinical and clinical studies as a potential target. Areas covered: Necitumumab is a human IgG1 anti-EGFR antibody that binds to the receptor and inhibits further pathway activation, thereby inhibiting cell differentiation, proliferation and migration. The phase III SQUIRE trial was a randomized study of gemcitabine-cisplatin plus necitumumab versus gemcitabine-cisplatin alone for first-line stage IV squamous NSCLC, showing a higher overall survival and better disease control with the addition of necitumumab. Despite the good results, the lack of robust predictive biomarkers makes the selection of the patients who will benefit the most complex. Expert opinion: Necitumumab plus cisplatin-gemcitabine is a first-line treatment option in SCC that improves overall survival and preserves the patient's quality of life with a manageable toxicity profile.

BackgroundDespite the clinical effectiveness of Immune Checkpoint Inhibitors (ICI) in lung cancer, only around 20% remain disease free at 5 years. Predictive biomarkers for ICIs are neither sensitive nor specific. Here, we used the GeoMx Digital Spatial Profiler (DSP) (NanoString, Inc.) to analyze high-plex protein in a quantitative and spatially resolved manner from single formalin-fixed paraffin embedded tissue sections toward the goal of identification of new biomarkers with better predictive value.MethodsPre-treatment samples from 56 patients with NSCLC treated with ICI were collected, represented in Yale tissue microarray 471 (YTMA471), and analyzed. A panel of 71 photocleavable oligonucleotide-labeled primary antibodies (NanoString Human IO panel) was used for protein detection. Protein expression was measured in 4 molecularly defined tissue compartments, defined by fluorescence co-localization (tumor [panCK+], leukocytes [CD45+/CD68-], macrophages [CD68+] and an aggregate stromal immune cell compartment, defined as the sum of leukocyte and macrophage expression [panCK-/CD45+/CD68+]) generating 284 variables representing potential predictive biomarkers. Promising candidates were orthogonally validated with Quantitative Immunofluorescence (QIF). Pre-treatment samples from 40 patients with NSCLC (YTMA404) that received ICI, and 174 non-ICI treated operable NSCLC patients (YTMA423) were analyzed to provide independent cohort validation. All statistical testing was performed using a two-sided significance level of α=0.05 and multiple testing correction (Benjamini-Hochberg method, FDR < 0.1).ResultsInitial biomarker discovery on 284 protein variables were generated by univariate analysis using continuous log-scaled data. High PD-L1 expression in tumor cells predicted longer survival (PFS; HR 0.67, p=0.017) and validated the training cohort. We found 4 markers associated with PFS, and 3 with OS in the stromal compartment. Of these, expression of CD66b in stromal immune cells predicted significantly shorter OS (HR 1.31, p=0.016) and shorter PFS (HR 1.24, p = 0.04). Tertile analysis using QIF on all three tissue cohorts for CD66b expression, assessed by QIF, showed that CD66b was indicative but not prognostic for survival [discovery cohort, YTMA471 (OS; HR 3.02, p=0.013, PFS; HR 2.38, p=0.023), validation cohort; YTMA404 (OS; HR 2.97, p=0.018, PFS; HR 1.85, p=0.1), non-ICI treated cohort YTMA423 (OS; HR 1.02, p>0.9, PFS; HR 0.72, p=0.4)].ConclusionsUsing the DSP technique, we have discovered that CD66b expressed in the stromal immune [panCK-/CD45+/CD68+] molecular compartment is associated with resistance to ICI therapy in NSCLC. This observation was validated by an orthogonal approach in an independent ICI treated NSCLC cohort. Since CD66b identifies neutrophils, further studies are warranted to characterize the role of neutrophils in ICI resistance.AcknowledgementsDr Moutafi is supported by a scholarship from the Hellenic Society of Medical Oncologists (HESMO)Ethics ApprovalAll tissue samples were collected and used under the approval from the Yale Human Investigation Committee protocol #9505008219 with an assurance filed with and approved by the U.S. Department of Health and Human Services