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Chemotherapy; Non–small cell lung cancer; RET inhibitors Quimioteràpia; Càncer de pulmó de cèl·lules no petites; Inhibidors de RET Quimioterapia; Cáncer de pulmón de células no pequeñas; Inhibidores de RET Introduction Nearly 1% to 2% of NSCLCs harbor RET fusions. Characterization of this rare population is still incomplete. Methods This retrospective multicenter study included patients with any-stage RET positive (RET+) NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing or fluorescence in situ hybridization analyses. Clinicobiological features and treatment outcomes (per investigator) with surgery, chemotherapy (CT), immune checkpoint blockers (ICBs), CT-ICB, multityrosine kinase inhibitors, and RET inhibitors (RETis) were evaluated. Results For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden was 2.5 (range: 1–4) mutations per megabase, and median programmed death-ligand 1 expression was 10% (range: 0%–55%). The most common metastatic sites were the lung (50%), bone (43%), and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of the patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent CT, 46% and 9.6 months with CT-ICB, 23% and 3.1 months with ICB, 37% and 3 months with multityrosine kinase inhibitor, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 mo [37.7–72.1] versus 16.3 mo [12.7–28.8], p < 0.0001). Conclusions Patients with RET+ NSCLC have mainly thoracic and bone disease and low tumor mutational burden and programmed death-ligand 1 expression. RETi markedly improved survival, whereas ICB may be active in selected patients. Writing assistance was provided by Mrs. Sarah Mackenzie. Dr. Marinello was the recipient for the grant for DUERTECC/EURONCO (Diplôme Universitaire Européen de Recherche Translationnelle Et Clinique en Cancérologie). Dr. Mezquita received support from the Contrato Juan Rodes 2020 (ISCIII, Ministry of Health); Ayuda de la Acción Estratégica en Salud-ISCIII FIS 2021 (PI21/01653); Ayuda SEOM-Juan Rodés 2020. Dr. Cortellini acknowledges the support from the National Institute for Health Research Imperial Biomedical Research Centre. Dr. Pinato acknowledges the support from the Wellcome Trust Strategic Fund (PS3416), Associazione Italiana per la Ricerca sul Cancro (Associazione Italiana per la Ricerca sul Cancro MFAG Grant ID 25697), National Institute for Health Research Imperial Biomedical Research Centre, Imperial Experimental Cancer Medicine Centre, and the Imperial College Tissue Bank.

Thymic tumors are epithelial tumors arising from the anterior mediastinum and constitute 0.2-1.5% of all adult malignancies but are exceptional in pediatric population. Thymic epithelial tumors (TETs) encompass a variety of histologic subtypes associated with different clinical outcomes. Due to its rarity in children, TETs' management requires a multidisciplinary approach. However, prognosis remains still poor, especially among patients with thymic carcinoma. This study presents the internationally recognized recommendations for the diagnosis and treatment of thymic tumors in children and adolescents, established by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT) group within the EU-funded project Paediatric Rare Tumours Network - European Registry (PARTNER).

9062 Background: Upfront Immune Checkpoint Blockers (ICB) alone or in combination with chemotherapy (CT) have become the backbone treatment of non-oncogene addicted aNSCLC. PD-L1 remains the only predictive biomarker, but additional biomarkers are mandatory to better discriminate the population more suitable for the combination approach (CT-ICB). We hypothesized that TLG, a parameter that measure tumor burden and metabolic activity, may help to select the optimal first-line regimen. Methods: We performed a multicentric (n = 5) retrospective study including pts treated either with ICB alone, CT-ICB or CT alone. Overall survival (OS) and progression-free survival (PFS) were estimated with Kaplan-Meier analysis. Hazard ratios (HR) were calculated using multivariate Cox proportional Hazard models adjusting for relevant covariates (neutrophil/lymphocyte ratio, ECOG PS, liver, bone metastases). TLG was calculated on PET scans as the product of metabolic tumor volume (with a threshold of 42% of SUV max) and SUV mean. Results: 250 pts with aNSCLC initiated first-line treatment (94 ICB, 102 CT-ICB and an hystorical control group of 54 CT) within 42 days from PET. Median follow up was 22 months for ICB, 16 for CT-ICB and 47 for CT. 170 pts were male (68%), 210 had non-squamous histology (84%), 110 (44%)and 38 (15%) had bone and liver metastasis, respectively. On the 194 pts with PD-L1 status available: 20%, 29% and 50% had PD-L1 < 1%, 1-49% and > 50%, respectively. No correlation was seen between PD-L1 and TLG. Presence of liver metastases (13% vs 2%) and ECOG PS > 1 (16% vs 3%) were associated with elevated TLG. PFS correlated with TLG, with longer median PFS in the lower quartile (TLG < 380) either with ICB (12.4 vs 4.7 months, HR 1.9, 95% CI1.1 – 3.35, p 0.025) and CT-ICB (17.9 vs 7.3, HR 1.9, 95% CI1.1 – 3.7, p 0.032) but not with CT (4.2 vs 3.5, p 0.986), whereas OS was correlated with TLG < 380 in all 3 groups. The risk of progression under ICB was lower in tumors with TLG < 380 (15% vs.29%, p = 0.02), but no difference was seen in other 2 groups. In PD-L1 ≥50% pts with elevated TLG, treatment with CT-ICB (n = 20) increased the PFS respect with ICB (n = 55) (10.7 vs 3.9, HR 0.54, 95% CI 0.29 – 0.99, p = 0.048).The analysis was underpowered to find a difference in OS (HR 0.49, 95% CI 0.21 - 1.12, p = 0.092). Conclusions: TLG retains a prognostic validity in aNSCLC identifying pts with an increased rate of early progression on ICB, who may benefit from CT-ICB. Further analyses are required to compare CT-ICB and ICB in PD-L1 ≥50% according to TLG. Enrollement from other centers is ongoing, an update will be presented.

9074 Background: Alectinib is one of the standard treatment options as an upfront therapy in advanced ALK-rearranged non-small-cell lung cancer. However, all patients will eventually progress to target therapy, developing resistance mechanisms. Preclinical data have demonstrated an enhanced activity combining an anti-vascular endothelial growth factor blockade to ALK tyrosine inhibitors. Hence, this study assesses the safety and efficacy of adding bevacizumab to alectinib. Methods: ALEK-B is an open-label phase II trial investigating the efficacy and safety of combined alectinib 600mg daily and bevacizumab 15mg/kg every three weeks in untreated patients with advanced ALK fusion-positive NSCLC. Every patient had confirmed molecular diagnosis by next-generation sequencing (Foundation One CDx) at baseline and progression. The primary endpoint was investigator progression-free survival (PFS). Secondary endpoints were investigator-assessed objective response rate (ORR), intracranial response (ICR), time to central nervous system (CNS) progression, and overall survival. Hence, we present the first interim analysis. Results: Between April 2020 and October 2021, 37 patients were recruited. At the data cut-off of January 31st, 2022, the median follow-up was 15.6 months (IQR 12.5), and an event of disease progression or death occurred in 1 of 36 patients (2.7%). The 12-month event-free survival rate was 97.1% (95% CI 91 to 99), and median PFS was not reached (95% IC 8.9 to NR). Of 36 evaluable patients, 35 had an objective response [ORR 97.2% (95% CI 91 to 99)], and 3 (8.3%) experienced a complete response. Five patients had brain metastases at baseline; among those with measurable disease (n = 4), the ICR was 100%, one complete response, and median duration of response of 11.4 months (IQR 13.1). The 12-month CNS event-free rate was 100%. Any grade adverse events occurred in 86.4% of patients; most common were AST/ALT increase (40.5%), diarrhea (32.4%), blood bilirubin increase (21.6%), anemia (18.9%), and peripheral edema (18.9%). Grade 1-2 hypertension and proteinuria occurred in five (13.5%) patients, and no > G3 occurred. Grade ≥3 treatment-related AEs (TRAEs) occurred in 32.4%; most frequent were AST/ALT increase (27%) and creatinine increase (5.4%). Conclusions: The combination of Alectinib and bevacizumab demonstrated to be a safe and highly effective treatment in terms of response in the first-line setting. Moreover, it seems promising for patients with brain metastases. These results warrant the design of larger confirmatory trials, ideally a randomized phase III study. Clinical trial information: NCT03779191.

9535 Background: Molecular characterization of metastatic lung adenocarcinomas is mandatory but might be hampered by the quantity of tissue, restricted access to molecular platforms or limited economical resources. Our aim was to develop a tool supported by the hypothesis that radiological patterns of pts could help predict the rate of positivity of the most common oncogenic drivers. Methods: We defined an algorithm based on a molecularly defined cohort of 656 pts with stage IV lung adenocarcinoma. Two radiologists centrally reviewed the baseline imaging. Clinical data were retrospectively collected. There were 135 EGFR mutations, 81 ALK fusions, 47 BRAF mutations, 141 KRAS mutations, and 146 pan-negative tumors for these 4 oncogenic drivers. Univariate correlation analyses were performed to define an algorithm predicting the molecular testing positivity based on the metastatic pattern. Subsequently, an online tool was developed. This study was approved by our institutional review board. Results: Metastatic patterns correlated with the genomic drivers when compared to the pan-negative group. In the EGFR group, pleural metastases were more frequent (32% vs. 20%; p = 0.021), whereas adrenal and node metastases less frequent (6% vs.23%; p < 0.001 and 11% vs. 23% respectively; p = 0.011). In the ALK group, there were more brain and lung metastases (respectively 42% vs. 29%; p = 0.043 and 37% vs. 24% respectively; p = 0.037). In the BRAF group, pleural and pericardial metastases were more common (47% vs. 20%; p < 0.001 and 11% vs. 3% respectively; p = 0.04) and bone metastases less common (21% vs. 42%; p = 0.011). Lymphangitis was more frequent in EGFR, ALK and BRAF groups (6%, 7% and 15% vs. 1%; p = 0,016, p = 0,009 and p < 0,001 respectively). A free online access to the algorithm is now available after registration at http//tactic-ct.fr. Physicians enter age, sex, smoking status and the sites of metastases at diagnosis (present/absent/unknown). A mutation score is calculated, reflecting the % of chance to find an oncogenic driver. On the website, contributors can also enter new cases and an artificial intelligence will refine the algorithm and expand the number of oncogenic drivers. Conclusions: Our free access tool allows establishing a hierarchy in the molecular testing based on simple clinical and radiological information. Continual learning from new cases entered in the database will increase the sensitivity of the tool. This tool might save time, tumor tissue, economical resources and accelerate access to personalized treatment.

Good bacteria help fight cancer Resident gut bacteria can affect patient responses to cancer immunotherapy (see the Perspective by Jobin). Routy et al. show that antibiotic consumption is associated with poor response to immunotherapeutic PD-1 blockade. They profiled samples from patients with lung and kidney cancers and found that nonresponding patients had low levels of the bacterium Akkermansia muciniphila . Oral supplementation of the bacteria to antibiotic-treated mice restored the response to immunotherapy. Matson et al. and Gopalakrishnan et al. studied melanoma patients receiving PD-1 blockade and found a greater abundance of “good” bacteria in the guts of responding patients. Nonresponders had an imbalance in gut flora composition, which correlated with impaired immune cell activity. Thus, maintaining healthy gut flora could help patients combat cancer. Science , this issue p. 91 , p. 104 , p. 97 ; see also p. 32

Purpose In addition to prospective trials for non–small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or next-generation sequencing. Anonymized data—clinical, pathologic, and molecular features—were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

The duration of clinical response is unpredictable in ALK-rearranged NSCLC patients treated by crizotinib but all patients invariably develop resistance. Using filter-adapted fluorescence in situ hybridization (FA-FISH) we previously reported ALK-rearrangement detection in circulating tumor cells (CTCs) from ALK-rearranged patients. Here we report the monitoring of ALK-rearranged (≥1×3’/5’, ≥1x(3’ and 5’)) and ALK-amplified (>2×3’/5’) CTCs at baseline and at an early time point under crizotinib therapy in an extended cohort of ALK-rearranged patients. The correlation between CTC subsets harboring distinct FISH patterns and clinical parameters including progression-free survival (PFS) and overall survival (OS) is presented. Forty ALK-rearranged patients were recruited. Blood samples were collected at baseline to crizotinib and at 1-3 months. Abnormal ALK-FISH patterns were examined in CTCs using immunofluorescence staining (DAPI/CD45) combined with FA-FISH after isolation by size of epithelial tumor cells (ISET) filtration. CTCs were defined into five distinct subsets according to the number of FISH ‘break-apart’ signals (3’ and 5’) or isolated red signals (3’) and/or native copies (3’/5’). All ALK-abnormal cells were validated by a cytogenetician. Clinical data was collected retrospectively. Confirming our previous data, ALK rearrangement was detected in CTCs: 32/39 patients (82%) had ≥4 ALK-rearranged CTCs per 1 ml of blood. Age >60 years and smoking status >15 pack years were associated with a higher mean number of ALK-amplified CTCs (p = 0.0423 and p = 0.0407 respectively). No statistically significant correlation was observed between the different CTC subsets with abnormal FISH patterns at baseline and PFS or OS. However we observed a statistically significant correlation (p = 0.0196) between the evolution under crizotinib of the numbers of ALK-amplified CTCs and PFS. An increase in the numbers of ALK-amplified CTCs during treatment is associated with a PFS of 6.5 months, while a decrease in this subset is associated with a PFS of 25 months. There was no corresponding correlation with OS. The evolution under crizotinib therapy of numbers of ALK-amplified CTCs is significantly correlated with PFS. Although not dominant, amplification of the ALK gene has been reported to be one mechanism of acquired resistance to crizotinib therapy in tumor biopsies. CTCs with an amplification of ALK do not express the oncogenic ALK fusion protein and are therefore not targeted by crizotinib. FISH patterns suggested these CTCs may have a high degree of ploidy and chromosomal instability which may contribute to promote the emergence of CTC subclones with a high metastatic potential. Our data suggest that number of ALK-amplified CTCs may be a predictive biomarker allowing prediction of ALK-rearranged NSCLC patients who are at risk of early resistance to crizotinib. Citation Format: Emma Pailler, Marianne Oulhen, Kirsty Ross, Fanny Billiot, Nathalie Auger, Isabelle Borger, Maud NgoCamus, Jordi Remon-Masip, David Planchard, Jean-Charles Soria, Benjamin Besse, Françoise Farace. Number of ALK-amplified circulating tumor cells predicts progression-free survival in ALK-rearranged non-small cell lung cancer patients treated by crizotinib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 856.

We have used Inivata's enhanced tagged-amplicon deep sequencing (TAm-Seq™) platform to harness the power of circulating tumor DNA (ctDNA) to accurately identify low level mutations in multiple cancers, monitor the progression of disease and track patient response to therapy. We have developed an improved TAm-Seq platform, which enables detection of point mutations and indels in ctDNA with high levels of sensitivity and specificity. Our standardised TAm-Seq platform has a rapid turnaround time and is performed on plasma obtained from blood collected in a single 9mL standard EDTA tube. The TAm-Seq assay is able to analyze regions of interest (either hotspots or entire coding regions) in 35 distinct genes in the human genome with such sensitivity as to detect mutations at an allele frequency less than 1% with unpublished data demonstrating sensitivity as low as 0.1%. We performed longitudinal analyses on a series of case studies in different types of cancer to determine molecular profiles and monitor treatment response. Patient A is a stage IV NSCLC patient with bone metastases. The patient was unresponsive to initial treatment, with a suspected T790M EGFR mutation. Patient B is a BRAF V600E-positive cerebral anaplastic xanthoastrocytoma patient with first-line treatment of surgery and radiotherapy, presenting at relapse with rare multiple extra-cranial (lymph node and bone) metastases. An initial cohort of non-small cell lung cancer (NSCLC) patients, including the Patient A case study, had blood drawn at 2 time points (Day 1 and Day 21) which were analysed using TAm-Seq demonstrating clinical response correlation to reduction in mutant alleles between pre- and post-treatment. In addition to this, Patient A was confirmed by TAm-Seq as having the suspected T790M EGFR mutation at a 0.57% frequency. As tumor biopsy tissue was unavailable for testing resistant mutations in this instance, the detection of the T790M mutation by TAm-Seq enabled the patient to become eligible to receive AZD9291 off-label by special permission. The patient went on to show a complete metabolic response on PET scan. Patient B, previously presenting with a BRAF V600E mutant xanthoastrocytoma, was initiated off-label vemurafenib with ctDNA analysis detecting mutation frequency at 3.45% prior to treatment and 2.16% following 2 weeks of treatment. Follow-up samples have been collected at multiple time points for patient A and B with testing in progress. Additional case studies are in progress and all data will be presented. This work demonstrates the potential utility of using ctDNA to identify resistance mutations and monitor treatment response of a tumor when a conventional biopsy is unobtainable. It highlights the importance of high sensitivity mutation detection and analyzing multiple genomic regions, as such a high proportion of ctDNA mutations in our data were present at an allele frequency of Citation Format: Sarah K. Smalley, Davina Gale, Andrew RJ Lawson, Jordi Remon-Masip, Esperanza Perez, Michelle Pugh, Karen Howarth, Mehdi Touat, Jean-Charles Soria, Antoine Hollebecque, Benjamin Besse, Tim Forshew, Vincent Plagnol, Ludovic Lacroix, Nitzan Rosenfeld. Assessing the clinical applications of ctDNA in patients with advanced stage metastatic cancer using our enhanced TAm-Seq platform. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B7.