Search

Introduction Les fusions du gene de la neureguline 1 (NRG1) en activant les voies de signalisation d’ErbB2/ErbB3 peuvent etre responsables d’une addiction oncogenique. Les fusions NRG1 sont devenues une cible therapeutique potentielle pour de multiples types de tumeurs, y compris les adenocarcinomes (ADC) pulmonaires. L’afatinib, un inhibiteur pan-ErbB, pourrait etre une option therapeutique pour les patients atteints d’un ADC NRG1 + comme le suggerent des donnees precliniques et la publication de 7 cas cliniques ( Tableau 1 ). Methodes Nous presentons les caracteristiques clinicopathologiques et moleculaires de 4 nouveaux cas d’ADC pulmonaires NRG1 + traites par afatinib. Resultats Patient 1 : femme de 70 ans, non fumeuse, ADC non mucineux (NM) metastatique sans mutation oncogenique. Elle a recu de l’afatinib en 15e ligne et a presente une reponse partielle (RP) pendant 24 mois. Apres progression sous chimiotherapie, la fusion NRG1 a ete identifiee par NanoString (nouvelle biopsie effectuee pour comprendre l’efficacite de l’afatinib). Un rechallenge par afatinib a ete realise (meilleure reponse : RP[3 mois]). Patient 2 : femme de 66 ans, non fumeuse, ADC-NM metastatique. Une fusion CD74-NRG1 a ete identifiee par Oncomine™, et un traitement de 5e ligne par afatinib a ete debute. Elle a presente une RP, toujours en cours apres 14 mois de traitement. Patient 3 : homme de 68 ans atteint d’un ADC pulmonaire metastatique. Une fusion SDC4-NRG1 a ete identifiee par NGS et le patient a commence un traitement de 2e ligne par afatinib. Il a obtenu comme meilleure reponse une stabilite de la maladie, d’une duree de 4 mois. Patient 4 : femme de 43 ans, non fumeuse, ADC mucineux invasif metastatique. Une fusion CD74-NRG1 a ete identifiee par sequencage de l’ARN et la patiente a debute un traitement de 3e ligne par afatinib ; une RP est en cours. Conclusion Ces resultats s’ajoutent a un nombre croissant de donnees suggerant une activite de l’afatinib dans les ADC pulmonaires NRG1 + La mise en place d’une cohorte prospective avec plus de patients atteints de CBNPC NRG1 + traites par afatinib se justifie afin de mieux evaluer cette activite potentielle.

Immunotherapy has improved survival in advanced non-small cell lung cancer (NSCLC) and offers the potential for meaningful, durable responses in a subset of patients. Ongoing efforts are focused on extending these benefits to more patients.

Background: NRG1 fusions are potentially actionable driver events enriched in invasive mucinous adenocarcinomas (IMAs). Clinicopathological features and optimal treatment strategies remain unclear. Methods: A global, multicenter network of thoracic oncologists (6 countries, 13 institutions) identified NRG1 fusion-positive (NRG1+) NSCLCs. Anonymized clinical/pathologic features and clinical outcomes were collected retrospectively. Best response to systemic therapy was determined (RECIST v1.1). PFS was calculated (Kaplan-Meier). Results: 80 NRG1+ NSCLCs were identified. Median age at diagnosis was 63 years (range 29–88). Most patients were female (64%) and never smokers (58%). Median pack-year was 27 (range 1-80). Histology was adenocarcinoma in 95% with TTF1 expression in 27.5% and IMA the predominant subtype (91%). Most patients had non-metastatic disease at diagnosis (stage: I 33%, II 27%, III 18%, IV 22%). Lung was the most common site of relapse (94%) and of metastasis (86%). 12 patients received afatinib for stage IV disease. PD was the best response in 55% (n=6/11) of evaluable patients, 18% PR (n=2/11) and SD 18% (n=2/11); median PFS was 3.5 months. 19 patients received platinum-based chemotherapy (CT); most patients had SD as their best response (47%, n=8); PD 41% (n=7); PR 12% (n=2). 6 patients received bevacizumab-containing CT; SD was the best response in 60% (n=3/5) of evaluable patients; 40% PR (n=2/5). Conclusions: NRG1+ NSCLCs exhibit specific clinicopathological features, with over-representation of females, non-smokers, IMA, lung relapse and lung metastatis. Novel therapeutic approaches are needed as overall outcomes with afatinib/CT are poor.

Summary Background Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials. Methods An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG ( NCT02650401 ; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov , NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001). Findings Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred. Interpretation Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours. Funding Ignyta/F Hoffmann-La Roche.

s Background Patients with chronic viral infections including human immunodeficiency virus (HIV), hepatitis B (HBV) and hepatitis C (HCV) are at increased risk of developing malignancies. The safety and efficacy of ICI therapy in patients with both cancer and chronic viral infections is not well established as most clinical trials of ICIs excluded these patient populations. Methods We performed a retrospective analysis of patients with advanced-stage cancers and HIV, HBV, or HCV infection treated with ICI therapy at 5 MedStar Health hospitals from January 2011 to April 2018. Results We identified 50 patients including 16 HIV, 29 HBV/HCV, and 5 with concurrent HIV and either HBV or HCV. In the HIV cohort (n = 21), any grade immune-related adverse events (irAEs) were 24% with grade ≥ 3 irAEs 14%. Among 5 patients with matched pre/post-treatment results, no significant changes in HIV viral load and CD4+ T-cell counts were observed. RECIST confirmed (n = 18) overall response rate (ORR) was 28% with 2 complete responses (CR) and 3 partial responses (PR). Responders included 2 patients with low baseline CD4+ T-cell counts (40 and 77 cells/ul, respectively). In the HBV/HCV cohort (n = 34), any grade irAEs were 44% with grade ≥ 3 irAEs 29%. RECIST confirmed ORR was 21% (6 PR). Among the 6 patients with known pre/post-treatment viral titers (2 HCV and 4 HBV), there was no evidence of viral reactivation. Conclusions Our retrospective series is one of the largest case series to report clinical outcomes among HIV, HBV and HCV patients treated with ICI therapy. Toxicity and efficacy rates were similar to those observed in patients without chronic viral infections. Viral reactivation was not observed. Tumor responses occurred in HIV patients with low CD4 T-cell counts. While prospective studies are needed to validate above findings, these data support not excluding such patients from ICI–based clinical trials or treatment.

Immunotherapy has advanced the treatment of solid organ malignancies. Although generally well tolerated, treatment with immune checkpoint inhibitors can be complicated by immune-related adverse events, some of which are relatively uncommon. We report the first case of gingival linear immunoglobulin A disease related to treatment with an antiprogrammed cell death protein 1 antibody. A 73-year-old male with advanced non-small cell lung cancer achieved a durable response to nivolumab monotherapy. After 1 year of treatment, he developed gingival swelling and pain. Biopsy revealed linear immunoglobulin A disease of the gingiva which was effectively treated with systemic steroids. Ongoing vigilance for immune-mediated toxicity is paramount during and after treatment with immune checkpoint inhibitors.

Purpose: mAbs including cetuximab can induce antibody-dependent cellular cytotoxicity (ADCC) and cytokine production mediated via innate immune cells with the ability to recognize mAb-coated tumors. Preclinical modeling has shown that costimulation of natural killer (NK) cells via the Fc receptor and the IL12 receptor promotes NK-cell–mediated ADCC and production of cytokines. Patients and Methods: This phase I/II trial evaluated the combination of cetuximab with IL12 for the treatment of EGFR-expressing head and neck cancer. Treatment consisted of cetuximab 500 mg/m2 i.v. every 2 weeks with either 0.2 mcg/kg or 0.3 mcg/kg IL12 s.c. on days 2 and 5 of the 2-week cycle, beginning with cycle 2. Correlative studies from blood draws obtained prior to treatment and during therapy included measurement of ADCC, serum cytokine, and chemokine analysis, determination of NK cell FcγRIIIa polymorphisms, and an analysis of myeloid-derived suppressor cell (MDSC) frequency in peripheral blood. Results: The combination of cetuximab and IL12 was well tolerated. No clinical responses were observed, however, 48% of patients exhibited prolonged progression-free survival (PFS; average of 6.5 months). Compared with patients that did not exhibit clinical benefit, patients with PFS >100 days exhibited increased ADCC as therapy continued compared with baseline, greater production of IFNγ, IP-10, and TNFα at the beginning of cycle 8 compared with baseline values and had a predominance of monocytic MDSCs versus granulocytic MDSCs prior to therapy. Conclusions: Further investigation of IL12 as an immunomodulatory agent in combination with cetuximab in head and neck squamous cell carcinoma is warranted.

INTRODUCTION: Durvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to programmed death 1. Here we report safety and clinical activity in the NSCLC cohort of a phase I/II trial that included multiple tumor types (Study 1108; NCT01693562). METHODS: Patients with stage IIIB-IV NSCLC (squamous or nonsquamous) received durvalumab 10 mg/kg every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. Primary objectives were safety and antitumor activity. Tumoral PD-L1 expression was assessed using the VENTANA SP263 Assay. Responses were assessed by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1). Adverse events were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events (v4.03). RESULTS: Of 304 patients, 79.0% were previously treated. Confirmed objective response rate was 21.8% in patients with greater than or equal to 25% PD-L1 expression and 6.4% in those with less than 25%; 25.9% in first-line patients and 12.7% in previously treated patients; and 14.0% in squamous and 16.7% in nonsquamous disease. Median overall survival was 12.4 months and median progression-free survival was 1.7 months; both were numerically longer in the PD-L1 greater than or equal to 25% group than in the PD-L1 less than 25% group (overall survival 16.4 versus 7.6 months, respectively; progression-free survival 2.6 versus 1.4 months, respectively). Treatment-related adverse events occurred in 57.2%, were grade 3/4 in 10.2%, and led to discontinuation in 5.6%. One patient (0.3%) died of treatment-related pneumonia with underlying pneumonitis. CONCLUSIONS: Durvalumab was clinically active irrespective of histology in this mostly pretreated population, with a manageable safety profile. Response rates and survival appeared to be enhanced in patients with greater tumoral PD-L1 expression. ispartof: JOURNAL OF THORACIC ONCOLOGY vol:14 issue:10 pages:1794-1806 ispartof: location:United States status: published

e20533 Background: Nuclear protein transport is essential in guiding the organized traffic of important proteins and RNAs between the nucleus and cytoplasm of the cell. Export of proteins from the nucleus is exclusively regulated by Exportin 1(XPO1). In cancer, XPO1 is universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm, leading to their functional inactivation. XPO1 is aberrantly over expressed in NSCLC and this over expression has been linked to poor overall survival. The underlying mechanisms of XPO1 over expression are not known. Currently there are no studies evaluating the impact of XPO1 mutations on NSCLC incidence and therapy resistance. Additionally, there are no studies that examined the XPO1 related pathways in NSCLC harboring co-alterations with other driver mutations such as EGFR or ALK. Methods: Tumor samples were analyzed using next-generation sequencing (NextSeq, 592 Genes), IHC, and whole transcriptome sequencing (WTS ,NovaSeq) (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was tested by IHC using 22c3 (Dako) and TPS scores were reported (cutoff > 1%). TMB was measured by totaling somatic mutations (TMB-high cut-off ³ 10 mutations per Megabase). Gene fusions were detected by RNA sequencing using either the Archer FusionPlex panel or WTS. Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate. Statistical significance was determined using chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Results: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations. XPO1 mutant tumors were more likely to be TMB High(79% vs. 52%, p = 0.007) and less likely to have high PDL1(32% vs. 68%, p = 0.03). KRAS mutations were seen in 19%(n = 5), EGFR mutation were rare (n = 2), and no targetable fusions were seen. Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant tumors with no histology imbalance observed in mutant vs. wild-type(WT). Comparison of survival in the NSCLC group between XPO1 mutant and WT showed a negative association with a hazard ratio(HR) of 1.932 (95% CI: 1.144- 3.264 p = 0.012). Comparing the survival within the subgroup with confirmed adenocarcinoma histology (9973 XPO1 WT and 14 XPO1 mutant) showed a similar negative correlation in survival with a HR of 2.156 (95% CI: 1.027- 4.525 P = 0.037). Conclusions: Presence of XPO1 pathogenic mutations was associated with a poor survival in both the entire NSCLC cohort and the adenocarcinoma subgroup. Further studies of this negative association at the molecular level along with effect of other co-existing mutations can result in development of novel treatment strategies.

8508 Background: The dominant expression of four lineage-defining transcription factors ( ASCL1, NEUROD1, YAP1, or POU2F3) has enabled the classification of small cell lung cancer (SCLC) into four subtypes (SCLC-A/N/Y/P, respectively). Emerging evidence suggests that YAP1 expression is associated with a T-cell inflamed phenotype, and SCLC has significant intra-tumor heterogeneity mediated by MYC-driven activation of NOTCH signaling. We performed a large-scale analysis of real-world SCLC patient samples to examine the expression of clinically relevant biomarkers across SCLC subtypes. Methods: Comprehensive molecular profiling of 437 small cell lung neuroendocrine tumors (including 7.3% high-grade neuroendocrine lung carcinomas) was performed using next-generation DNA sequencing (592-gene panel), RNA sequencing (whole transcriptome), and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Tumors were stratified into 5 subgroups (SCLC-A/N/Y/P and -mixed) based on the relative expression of the four transcription factors. RNA expression of key genes and previously validated immune signatures (T-cell inflamed, NK cell, and STING pathway signatures) were evaluated across subgroups. Significance was tested by Chi-square, Fisher’s exact test, or Mann-Whitney U test. Results: Median age of the study cohort was 66 years (IQR: 59-72) and 50.6% of patients were female. The majority (67.3%) of samples were derived from metastatic sites. Stratification of tumors by expression resulted in 35.7% SCLC-A, 17.6% SCLC-N, 21.1% SCLC-Y, 6.4% SCLC-P, and 19.2% SCLC-mixed samples. Compared to tumors from metastatic sites, YAP1 expression was significantly increased (p < 0.001) in primary tumors. Amongst the 14 tumors obtained from the CNS, SCLC-N (36%, n = 5) was the most common subtype identified. dMMR/MSI-high (negative MMR protein expression/ ≥46 altered loci per tumor) was rare overall (0.5%, n = 2); TMB (median of 9-10 mut/Mb) was similar between the SCLC subtypes. SCLC-Y was associated with the highest expression of T-cell inflamed, NK cell and STING pathway signatures (p < 0.0001 each). MYC and NOTCH gene expression ( NOTCH1/2/3/4) strongly correlated with YAP1 expression. Analysis of co-mutations revealed that EGFR-sensitizing mutations (L858R and Exon 19 deletions) were recurrent (5.2%, n = 4) in SCLC-N tumors. The expression of SNF11, SSTR2, and MYC varied significantly among SCLC subtypes (p < 0.001 each), with the highest median expression of SNF11 and SSTR2 observed in SCLC-N, while MYC expression was highest in SCLC-P. Conclusions: Our analysis represents the largest real-world dataset of human SCLC tumors profiled by whole transcriptomic sequencing. The differential expression of immune genes and predictive biomarkers across SCLC subtypes may inform therapeutic vulnerabilities for rational and personalized treatment approaches in SCLC.

3091 Background: Gene fusions often represent critical therapeutic targets across cancer subtypes. Fusions within the ErbB family of receptor tyrosine kinases, including EGFR, ERBB2 ( HER2) and ERBB4 ( HER4), have been previously described and represent potentially actionable alterations. Here, we report the relative incidence and functional characterization of these rare genomic events. Methods: Tumor samples (n = 64,354; representing > 40 tumors types) submitted to Caris Life Sciences (Phoenix, AZ) were molecularly profiled by next-generation sequencing of DNA (NextSeq, 592-gene panel; or NovaSeq, whole exome) and RNA (whole transcriptome). Gene fusion partners, in/out-of-frame status, retention of ERBB kinase domain, and topology of fusion breakpoints were characterized for each ERBB fusion transcript detected. Fusion prevalence was further examined in public data sets (TCGA, MSK-IMPACT and AACR GENIE). Results: From the Caris database, a total of 64 EGFR fusion isoforms were detected in 59 tumors (incidence 0.09%); 83% were in-frame and 91% retained the EGFR kinase domain. 206 ERBB2 fusion isoforms were detected in 114 tumors (0.18%); 37% were in-frame and 34% retained the ERBB2 kinase domain. 131 ERBB4 fusion isoforms were detected in 108 tumors (0.17%); 62% were in-frame and 51% retained the kinase domain. All fusions were detected at low incidence across all tumor types. EGFR fusions were most common in high grade glioma (1.7%, n = 35), largely driven by recurrent EGFR-SEPT14 fusions (n = 20). ERBB2 fusions were most common in esophageal/gastroesophageal junction carcinoma (1.1%, n = 20), with recurrent fusion to PGAP3 observed in multiple tumor types (n = 37). ERBB4 fusions were most common in ovarian (0.7%, n = 40) and bladder (0.7%, n = 15) cancers, which often resulted from recurrent fusion with IKZF2 (n = 36). EGFR and ERBB2 fusions were generated predominantly (44-48%) from inversion events, while ERBB4 fusions arose more frequently and at similar rates (27-32%) from deletions, duplications, or translocations. Mining of public data sets corroborated the prevalence of ERBB gene fusions: the frequency of EGFR fusions was 0.63%, ERBB2 was 0.14% and ERBB4 was 0.04%. TP53 mutations frequently co-occurred with ERBB2 and ERBB4 fusions ( > 60% average across public data sets), with higher co-mutation rates ( > 70%) observed for samples in the Caris database. Conclusions: ERBB gene fusions are detectable at low frequency in various tumor types and may represent a unique genomic subset of cancer. Identification of novel ERBB gene fusions warrants further investigation to determine the potential pathogenicity and actionability of these fusions.

9089 Background: RET fusions are targetable oncogenic drivers in 1–2% of non-small cell lung cancer (NSCLC). ARROW (NCT03037385) supported the US FDA approval of pralsetinib, a highly potent oral selective RET inhibitor for RET-altered NSCLC and thyroid cancer. Here, we present updated results for a larger population of patients with RET fusion–positive NSCLC enrolled in ARROW. Methods: ARROW is a phase 1/2 open-label study conducted at 84 sites in 13 countries. Phase 2 expansion cohorts included patients with RET fusion–positive NSCLC. Initially, all treatment-naïve patients were not candidates for platinum-based therapy, a requirement removed by protocol amendment in July 2019. Primary objectives are overall response rate (ORR; blinded independent central review [BICR] per RECIST v1.1), assessed for patients with baseline measurable disease, and safety. Results: Updated analyses were completed as of Nov 6, 2020 (data cut-off), for patients who initiated pralsetinib 400 mg QD by May 22, 2020 (enrollment cut-off). Efficacy results, including analyses for treatment-naïve patients enrolled after eligibility criteria were revised to allow candidates for platinum-based therapy, are shown in the Table. Conclusions: Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy. Overall, pralsetinib was well-tolerated. These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib. Clinical trial information: NCT03037385. [Table: see text]

9087 Background: Recent data suggest inferior responses to immune checkpoint inhibitors (ICIs) in STK11-mt NSCLC. TP53 is a critical tumor suppressor gene regulating DNA repair by arresting cells in the G1 phase in response to critical double strand breaks. We hypothesized that accumulated DNA damage from mutations in the TP53 gene might increase immunogenicity and potentially enhance benefit of ICIs in STK11-mt NSCLC. Methods: A total of 16,896 NSCLC tumors submitted to Caris Life Sciences (Phoenix, AZ) for targeted NGS (DNA-Seq, 592 genes) were analyzed. A subset (N = 5034 tumors) had gene expression profiling (RNA-Seq, whole transcriptome). PD-L1 (TPS) was tested with 22c3 antibody (Dako). Exome-level neoantigen load for STK11-mt NSCLC was obtained from published TCGA Pan-immune analysis (Thorsson et al. 2018). Non-parametric tests were used for comparing differences in tumor mutational burden (TMB) and neoantigen load. Transcriptomic analysis included differential gene expression and hierarchical clustering. Tumor immune cell content was obtained from transcriptome using Microenvironment Cell Population-counter (MCP). Publicly available data from the POPLAR/OAK trials of atezolizumab in advanced NSCLC were used to model PFS and OS for STK11-mt with TP53-mt (n = 14) and without TP53-mt (n = 20). Results: Of 16,896 NSCLC samples, 12.6% had an STK11-mt with the proportions of TMB-high (≥10 Mut/Mb), PD-L1 ≥ 50% and MSI-high being 55.9%, 11.8%, and 0.72%, respectively. STK11-mt vs. STK11-wt NSCLC did not differ in median TMB (Caris:10 vs. 10 Mut/Mb; p > 0.1) or neoantigen load (TCGA: 154.5 vs. 165; p > 0.1). Median TMB (13 vs. 9 Mut/Mb; p < 0.001) and neoantigen load (263 vs. 134; p < 0.001) were higher in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt. MCP analysis showed higher CD8, NK-cell and lower myeloid dendritic cell infiltration in STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01). Expression of MYC and HIF-α were increased in the STK11-mt/ TP53-mt vs. STK11-mt/ TP53-wt (p < 0.01) along with higher expression (p < 0.01) of genes associated with both glycolysis ( HK2, LDHA, ALDOA) and glutamine metabolism ( GOT2, PPAT2). Hierarchical clustering of STK11-mt adenocarcinomas (n = 463) for STING pathway genes (CCL5, CXCL10, cGAS) identified a STING-high and a STING low cluster. The STING high cluster was significantly enriched in TP53-mt (48 vs. 32%; p < 0.01).In the OAK/POPLAR cohort, median OS (HR is 1.14, 95% CI 0.53 - 2.48); p > 0.1) and PFS (HR 1.88, 95% CI 0.89-3.97, p = 0.098) were not statistically different between STK11-mt/ TP53-mt vs. STK-mt/ TP53-wt. However, the 15-months PFS was 21% in the STK11-mt/ TP53-mt vs 0% in the STK11-mt/ TP53-wt. Conclusions: STK11-mt NSCLC with TP53-mt are associated with an immunologically active TME with metabolic reprogramming. These intrinsic properties could be exploited to improve outcomes to ICIs in combination with metabolically directed agents.

3120 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective therapies for some patients with both germline and somatic BRCA1/2 mutations (MTs) or with homologous recombination repair deficiency (HRD). We aimed to characterize molecular differences between BRCA1 and BRCA2 MTs and their prognostic and/or predictive impact on PARPi outcomes in various cancer subtypes using real world data (RWD). Methods: Tumor samples obtained from patients with 35 types of cancer were analyzed by whole exome sequencing (WES, Novaseq) at Caris Life Sciences (Phoenix, AZ). High genomic loss of heterozygosity (gLOH-H) was defined as LOH-H in ≥16% of tested loci. MSI/MMR was tested by fragment analysis, IHC, and WES. Overall survival (OS) extracted from insurance claims was calculated from start of treatment or tissue collection until last contact or death using Kaplan-Meier curves. P-values adjusted for multiple comparisons (q-value of < 0.05 was considered to be significant). Results: In total, 17,640 tumors were included, of which 776 (4.3%) had tumor-based BRCA1/2 MTs. BRCA1/2 MTs were most commonly seen in ovarian (N = 221/2187, 10.1%), breast (138/2506, 5.5%), prostate (61/1131, 5.4%), pancreatic (48/1430, 3.4%), and non-small cell lung (100/4046, 2.5%) cancers. BRCA2 MTs were more frequent than BRCA1 except in ovarian cancers. BRCA1 MTs were more common in younger pts (median age, 61 vs 65 years, p

2552 Background: Nemvaleukin alfa (nemvaleukin, ALKS 4230) is a novel engineered cytokine that selectively binds the intermediate-affinity interleukin-2 receptor to preferentially activate CD8+ T and natural killer (NK) cells with minimal expansion of regulatory T cells (Tregs),designed for use as a cancer immunotherapy. ARTISTRY-2 (NCT03861793) is an ongoing phase 1/2 study evaluating the safety, efficacy, and pharmacokinetic and pharmacodynamic (PD) responses of subcutaneous (SC) nemvaleukin in combination with pembrolizumab in patients (pts) with advanced solid tumors. Methods: In phase 1, cohort-specific doses of SC nemvaleukin are administered on an every-7-day (q7d) or every-21-day (q21d) schedule during a 6-week monotherapy lead-in period, followed by combination with pembrolizumab 200 mg q21d. We present safety, PD effects, and preliminary clinical activity outcomes as of 12/02/2020. Results: 57 pts received nemvaleukin doses ranging from 0.3 mg to 6 mg q7d or 1 mg to 10 mg q21d. The most frequent tumor types (> 5 pts) were colorectal, pancreatic, ovarian, and lung; median number of prior therapies was 4. Treatment-related adverse events (TRAEs) in > 30% pts overall were pyrexia (43.9%), chills (38.6%), injection site erythema (33.3%), injection site reaction (33.3%), and fatigue (31.6%). 3 mg q7d (n = 7) had no drug-related dose reductions, discontinuations, or deaths during the monotherapy or combination periods. 6 mg was declared the maximum tolerated dose (MTD) for q7d dosing as 2 of 8 pts experienced dose-limiting toxicities (DLTs). For 6 mg q21d (n = 7), no drug-related dose reductions, discontinuations, or deaths have occurred during the monotherapy period; combination period data are not mature. 10 mg was declared the MTD for q21d dosing as 1 of 9 pts experienced DLTs and 3 had TRAEs leading to dose reductions. Systemic exposure to nemvaleukin increased with increasing dose. Increases in NK cells and CD8+ T cells of approximately 16-fold and 3-fold, respectively, at 3 mg q7d, and approximately 8-fold and 3-fold, respectively, at 6 mg q21d were observed, with minimal change in Tregs. 46 pts had at least 1 on-treatment scan as of the data cutoff date, and 30 (65%) had stable disease (SD) on the first scan. Of the 30 pts with ≥2 scans, 13 (43%) had 2+ consecutive scans of SD. 16 of 57 pts remain on therapy. Antitumor activity data for more recent cohorts are still maturing. Based on the totality of the safety, PD effects, and antitumor activity data, 3 mg q7d was selected as the RP2D for SC nemvaleukin. Conclusions: SC nemvaleukin 3 mg q7d was generally well tolerated as monotherapy and in combination with pembrolizumab, and demonstrated robust PD effects on NK cells and CD8+ T cells with minimal expansion of Tregs. These PD effects are similar to or greater than those observed with intravenous nemvaleukin. Thus, 3 mg q7d was selected as RP2D; phase 2 expansion cohorts for combination with pembrolizumab are enrolling. Clinical trial information: NCT03861793.

11036 Background: Improved understanding of the interactions between HER2 and HER3, the heterogeneity of HER-expressing disease, and mechanisms of resistance to anti-HER2 therapy has led to increasing number of treatment options to address clinical needs. Tumor types of interest, impacted by HER2/HER3 expression and pathophysiology were breast cancer, non-small cell lung cancer (NSCLC), gastric cancer, and colorectal cancer (CRC). Increasing competency in these areas is deemed critical to clinician’s ability to individualize treatment plans and improve patient outcomes. Methods: A 2-hour CME activity was broadcast live-online in September 2020 and remains on-demand through September 2021 at OMedLive.com. The educational initiative was divided into one hour addressing HER2 and HER3, testing guidelines, resistance mechanisms and emerging data elucidating recent and ongoing clinical trials across NSCLC, gastric cancer, and CRC. The second hour focused on individualizing metastatic HER2+ breast cancer, HER2-low breast cancer as an emerging subtype, and management of side effects. Knowledge and competence questions were administered pre-, immediate post-, and 2 mos. post-activity. Behavioral impact questions were also asked at follow-up. Data from these questions were analyzed to determine engagement and clinical impact. Results: To date, 448 clinicians participated in the activity. Across the seven CME test questions, improvements in knowledge and competence were observed in the clinical applications of HER2-directed agents and HER3 antibody drug conjugates (ADCs), first-line standard of care for HER2+ breast cancer, and adverse event management for HER2 ADCs. At 2-mos. follow-up, 67% reported improved behavioral impact on both clinical practice and patient experience and outcomes. Clinicians provided specific write-in examples of these changes, noting improved patient-reported outcomes, improved treatment adherence, improved competence developing treatment plans, and increased understanding of HER2/HER3 pathophysiology. Updated and expanded results will be shared. Conclusions: The activity was successful in improving clinician understanding of the relationship between HER2/HER3, pathophysiology across tumor types, and applications of emerging targeted therapies. Open-ended responses to behavioral impact questions illustrated clear improvements in clinician-reported patient experience and outcomes, clinical practice management, and knowledge of emerging HER2/HER3 therapies and their uses across multiple solid tumors.

Emerging efficacy data have led to the emergency use authorization or approval of COVID-19 vaccines in several countries worldwide. Most trials of COVID-19 vaccines excluded patients with active malignancies, and thus data on the safety, tolerability and efficacy of the vaccines in patients with cancer are currently limited. Given the risk posed by the COVID-19 pandemic, decisions regarding the use of vaccines against COVID-19 in patients participating in trials of investigational anticancer therapies need to be addressed promptly. Patients should not have to choose between enrolling on oncology clinical trials and receiving a COVID-19 vaccine. Clinical trial sponsors, investigators and treating physicians need operational guidance on COVID-19 vaccination for patients with cancer who are currently enrolled or might seek to enrol in clinical trials. Considering the high morbidity and mortality from COVID-19 in patients with cancer, the benefits of vaccination are likely to far outweigh the risks of vaccine-related adverse events. Herein, we provide operational COVID-19 vaccine guidance for patients participating in oncology clinical trials. In our perspective, continued quality oncological care requires that patients with cancer, including those involved in trials, be prioritized for COVID-19 vaccination, which should not affect trial eligibility.

Introduction Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 ( NTRK1 ) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib. Methods We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment. Results We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3–4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR. Conclusions Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.

Immune-checkpoint inhibitors have deeply changed the therapeutic landscape of advanced non-small cell lung cancer without actionable genomic alterations. Immune-checkpoint inhibitors have become standard front-line therapy, especially among patients with tumours expressing high levels of programmed death ligand-1; yet, many patients do not respond to therapy. This has led to the adoption of front-line combination therapies, administering programmed death-1 inhibitors concomitantly either with other checkpoint inhibitors, chemotherapy or both. Today’s approved standard of care includes options with chemoimmunotherapy or dual checkpoint blockade, but each combination has only been compared to chemotherapy alone and no head-to-head trials exist. In cross-trial comparisons, combinations trials appear to show numerically superior responses to single-agent checkpoint inhibitors but the question is whether they ultimately offer a survival advantage. In this manuscript, we summarize and analyse all currently available front-line immune-checkpoint inhibitor trials in non-small cell lung cancer, whether as monotherapy or in combination with chemotherapy, second immunotherapy agents or both. Should standards of care change given the current data? While we ponder this question, we illustrate current data and conclude that the answer lies in tracking the tail of the survival curves.

Background: IMpower133 (NCT02763579), a global Phase I/III, randomized, double-blind, placebo (PBO)-controlled trial, showed that the addition of atezo (anti-PD-L1) to CE for 1L ES-SCLC led to statistically and clinically significant OS and PFS improvement vs CE alone. Here we report updated OS and exploratory analyses. Methods: Pts with untreated ES-SCLC were randomized 1:1 to receive four 21-day cycles of E (100 mg/m2 IV, days 1-3) + C (AUC 5 mg/mL/min IV, day 1) with atezo (1200 mg IV, day 1) or PBO, followed by maintenance therapy with atezo or PBO until intolerable toxicity, progression or loss of clinical benefit. PD-L1 testing was not required for enrollment. Coprimary endpoints were investigator-assessed PFS (RECIST 1.1) and OS. Interim and final OS analyses were planned for ≈240 and ≈306 events, respectively. OS was significant at the interim analysis. Updated OS, exploratory biomarkers and patterns of disease progression were analyzed. Results: 201 and 202 pts were randomized to receive atezo+CE and PBO+CE, respectively. The median follow-up was 22.9 mo and 302 deaths had occurred. Median OS for the atezo and PBO arms was 12.3 and 10.3 mo, respectively (HR, 0.76 [95% CI: 0.60, 0.95]; descriptive P = 0.0154). At the 18-mo landmark, the OS rate was 13% higher with atezo+CE than with PBO+CE (Table). Exploratory analyses showed treatment benefit with atezo+CE regardless of biomarker status. 181 (90.0%) And 194 (96.0%) pts in the atezo+CE and PBO+CE arms, respectively, had RECIST-defined disease progression. Progression at existing, new or existing and new lesions was numerically lower with atezo+CE than with PBO+CE. Common sites of new lesions included the CNS, lung, lymph node and liver, with similar incidences between arms. Conclusion: Adding atezo to CE continued to provide OS improvement for 1L ES-SCLC in an all-comer population. The updated results of IMpower133 further support this regimen for untreated ES-SCLC. Landmark OSAtezo + CE, n = 201PBO + CE, n = 20212 Mo, n (%)93 (51.9)74 (39.0)18 Mo, n (%)61 (34.0)39(21.0)Median OS in biomarker subgroupsAtezo + CEPBO + CEITT (N = 403), mo12.310.3HR (95% CI)0.76 (0.61, 0.96)aITT-BEP (n = 137), mo9.98.9HR (95% CI)0.70 (0.48, 1.02)Non-BEP (n = 266), mo14.611.2HR (95% CI)0.81 (0.61, 1.08)PD-L1 expression, 1% TC or IC< 1% (n = 65), mo10.28.3HR (95% CI)0.51 (0.30, 0.89)≥ 1% (n = 72), mo9.710.6HR (95% CI)0.87 (0.51, 1.49)PD-L1 expression, 5% TC or IC< 5% (n = 108), mo9.28.9HR (95% CI)0.77 (0.51, 1.17)≥ 5% (n = 29), mo21.69.2HR (95% CI)0.60 (0.25, 1.46)Disease progression at sites, n (%)Atezo + CEPBO + CEExisting116 (57.7)131 (64.9)New86 (42.8)99 (49.0)Existing and new42 (20.9)57 (28.2)BEP, biomarker-evaluable population; ITT, intention-to-treat population.a Stratified HR. BEP included pts evaluable by PD-L1 IHC using the VENTANA SP263 assay. Citation Format: Leora Horn, Stephen V. Liu, Aaron S. Mansfield, Tony Mok, Arnaud Scherpereel, Niels Reinmuth, Marina Chiara Garassino, Javier De Castro Carpeno, Raffaele Califano, Makoto Nishio, Francisco Orlandi, Jorge Arturo Alatorre Alexander, Ticiana Leal, Ying Cheng, Jong-Seok Lee, Sivuonthanh Lam, Mark McCleland, Yu Deng, See Phan, Martin Reck. IMpower133: Updated OS and exploratory analyses of first-line (1L) atezolizumab (atezo) + carboplatin (C) + etoposide (E) in extensive-stage SCLC (ES-SCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT220.

Background: For epidermal growth factor (EGFR) mutated non-small cell lung carcinoma (NSCLC) multiple EGFR tyrosine kinase inhibitors (TKIs) are approved. ERBB2 alteration (mutation and/or amplification) has been commonly reported as a resistance mechanism to EGFR TKIs. Here we report the prevalence of ERBB2 alteration with or without EGFR mutation in NSCLC. Methods: We retrospectively analyzed ERBB2 alterations and EGFR mutations in NSCLC patients who underwent next-generation sequencing (NSG) with Caris Life Sciences. We obtained de-identified clinical information and molecular testing results from the Caris database. The objectives were to determine the prevalence and types of ERBB2 alterations with and without EGFR as a co-mutation. Results: A total of 12946 NSCLC tumors having EGFR and/or ERBB2 NGS were available, of which 50.1% were male. Among them, 12491 patients had copy number alteration (CNA) data available for ERBB2. 1551 (12%) patients had EGFR mutation, of whom 68% were female, the median age was 68 years and 89% of patients had adenocarcinoma. 186 patients had 2 or more EGFR mutations. The most common EGFR mutation was exon 19 in 47% of patients, followed by exon 21 in 33% of patients. 321 patients (2.5%) had ERBB2 alteration (mutation and/or amplification). Among them ERBB2 was mutated in 197 patients (1.5%) and amplified in 134 (1.1%) patients. The median age of ERBB2 mutated patients was 65 years. Sixty two percent were female and 84% had adenocarcinoma. None of the patients had multiple ERBB2 mutations. 70.5% of ERBB2 mutations were in exon 20, while 10.1% in exon 8. 24 patients had concurrent EGFR mutation and ERBB2 alteration (8 had ERBB2 mutation and 16 had ERBB2 amplification). Among 8 patients who had both EGFR and ERBB2 mutations, 3 had EGFR mutation in exon 19 (E746-A750del) and exon 8 ERBB2 mutation (S310F). For the remaining 5 patients, EGFR mutation was in exon 21 (L858R), while ERBB2 mutations included exon 8 (S310F) in 3 patients, exon 8 (S310Y) in 1 patient, and exon 17 (G660D) in 1 patient. Conclusion: A minority of EGFR mutated NSCLC patients had ERBB2 alterations. In ERBB2 and EGFR co-mutated patients, exon 21 mutations for EGFR and exon 8 mutations for ERBB2 were common. Forty percent of patients who had exon 8 ERBB2 mutation had EGFR as a co-mutation. Citation Format: Vijendra Singh, Yasmine Baca, Seongho Kim, Yanis Boumber, Hirva Mamdani, Edward S. Kim, Ammar Sukari, Chul Kim, Gerold Bepler, Stephen V. Liu, Alexander I. Spira, Hossein Borghai, Mikaso Nagasaka. ERBB2 alteration with or without co-existent EGFR mutation in metastatic non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5900.

TPS9638 Background: Use of checkpoint inhibitors, alone or with chemotherapy, has emerged as the preferred standard treatment for patients with advanced, driver-negative non-small cell lung cancer (NSCLC). While outcomes are superior to chemotherapy alone, only a subset of patients achieve durable response and long term survival. One potential mechanism of primary resistance to checkpoint inhibitors is the lack of tumor-infiltrating lymphocytes. Inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) increases the number of CD8+ T-cell within a tumor and has shown synergy with anti-programmed death-ligand 1 (PD-L1) antibodies. The combination of the MEK inhibitor cobimetinib and the PD-L1 antibody atezolizumab has led to limited responses in colorectal cancer, a tumor typically non-responsive to checkpoint inhibition. This phase II trial explores the combination of cobimetinib and atezolizumab in patients with PD(L)1-refractory NSCLC. Methods: This phase II study is being conducted through the Experimental Therapeutics Clinical Trials Network (ETCTN #10166). Eligible patients have advanced NSCLC with primary resistance to anti-PD(L)1 therapy (defined as progression noted within 6 months of initiating therapy) and tumor amenable to serial core biopsy. Patients will receive atezolizumab 840mg intravenously every 2 weeks and cobimetinib 60mg orally for 21 days in 28-day cycles. Two cohorts will enroll in parallel, defined by presence or absence of a KRAS mutation. Each cohort will employ a Simon two-stage design to test a null rate of 5% vs. 25% (power = 0.90, □ = 0.10). If > 1 of 9 patients in stage 1 achieve a partial response, an additional 15 patients are enrolled and if > 3 patients achieve a durable response, the combination will be worthy of further investigation. The primary endpoint is durable (> 6 months) response rate. Secondary endpoints are overall response rate, progression free survival, overall survival, duration of response and adverse events. Biopsies performed at baseline and after 3 weeks of therapy will assess the change in the density of tumoral CD8+ T-cells. Whole exome sequencing and immune cell profiling will also be performed on serial samples. Enrollment was initially limited to KRAS-mutant NSCLC. Prespecified activity goal for the first stage of accrual has been met; second stage accrual began in September 2019. Enrollment to the KRAS wild-type cohort will commence. Clinical trial information: NCT03600701 .

3113 Background: NRG1 fusions are actionable genomic alterations detected across tumor types. The NRG1 gene encode for neuregulin, which serves as a ligand for ERBB3 and ERBB4 receptors and activates downstream signaling through the MAPK and PI3K pathways. Here, we update the detection of NRG1 gene fusions across tumor types and further describe fusion characteristics. Methods: Samples submitted for clinical molecular profiling that included RNA-sequencing (Archer Dx or Caris MI transcriptome) were retrospectively analyzed for NRG1 fusion events. All NRG1 fusions with ≥ 3 junction reads were identified for manual review and for characterization of fusion class, intact functional domains, domain prediction, breakpoints, frame retention and co-occurring alterations by NGS. Results: A total of 82 NRG1 fusion events (0.2% of 44,570) were identified. Among the fusions identified, the distribution across tumor types was as follows: non-small cell lung cancer (NSCLC, 54%), breast cancer (11%), ovarian cancer (7%), pancreatic cancer (7%), cholangiocarcinoma (6%), colorectal cancer (5%), and other (10%). Forty-two unique fusion partners were identified, the most common being CD74 (23%), ATP1B1 (9%), SLC3A2 (7%), RBPMS (6%) and SDC4 (4%). Almost half (47%) of all fusion events are expected to include the transmembrane domain contributed by the NRG1 fusion partner. Lung and pancreatobilliary cancers had the highest rates of transmembrane domain retention from their fusion partners (63.6% and 54.5%, respectively). In all other tumor groups, most fusion partners lacked transmembrane domains. In 15% of cases, the chimeric transcripts are predicted to lead to increased expression of NRG1. The most commonly reported breakpoints in NRG1 occur in exon 6 and exon 2. While fusions with the NRG1 breakpoint at exon 2 retain the immunoglobulin (Ig) domain and all downstream portions (including EGF-like domain), those at exon 6 do not contain the Ig portion and result in shorter chimeric proteins. The breakpoints in all CD74:NRG1 fusions, the most common fusions in NSCLC, occur at exon 5 or 6 and cause truncation of domains upstream of the EGF-like domain. In ATP1B1:NRG1 fusions, the most common fusions in pancreatobilliary cancers, the breakpoints are at exon 1 or 2 and retain the Ig domain. Conclusions: NRG1 fusion products are diverse across tumor types, but the significance of these variations is not clear. The biological and clinical implications of retaining certain domains of NRG1 (such as the Ig domain) and of fusion partners warrants further investigation.

e21553 Background: ERBB2 alteration (mutation and/or amplification) is associated with poor survival in non-small cell lung cancer (NSCLC) and is commonly reported as a resistance mechanism to EGFR tyrosine kinase inhibitors. Several clinical trials are ongoing for the management of ERBB2-altered NSCLC. Here we report the prevalence of different ERBB2 alterations in NSCLC. Methods: We retrospectively analyzed ERBB2 alterations in NSCLC tumors that underwent next-generation sequencing (NGS) with Caris Life Sciences. De-identified pathological and molecular information was collected. ERBB2 copy number of greater than 6 was defined as amplification; mutations were classified among 7 groups based on their mechanism of action. Results: A total of 12946 NSCLC tumors with ERBB2 NGS results were available. Among them, 12492 had ERBB2 copy number alteration (CNA) data available. 321 tumors (2.5%) had ERBB2 alteration (mutation or amplification). Among them, ERBB2 was mutated in 197 tumors (1.5%) and amplified in 134 (1.1%) tumors. Type of ERBB2 mutation, respective median age and distribution among sex is in the table. 10 tumors with ERBB2 mutation (7.46%) also showed ERBB2 amplification. Six percent of tumors (8/135) with ERBB2 exon 20 insertion mutations had co-occurring ERBB2 amplification. One tumor for each extracellular domain (ECD) and transmembrane group had co-occurring ERBB2 amplification. Eight tumors with ERBB2 mutation had an overlapping EGFR L858R or exon19del mutation. Seven of these 8 tumors were from the ECD group (7/21) and all had mutations in the S310 locus. One tumor was from the transmembrane group. Conclusions: Exon 20 insertion mutation is the most commonly found ERBB2 mutation among NSCLC, a few of them had co-occurring ERBB2 amplification. One third of tumors with extracellular domain ERBB2 mutation had EGFR mutation. Tarloxitinib (NCT03805841), trastuzumab deruxtucan (NCT03505719), pyrotinib (NCT02500199), poziotinib (NCT03318939) are just a few of the novel ERBB2 inhibitors available in clinical trials. It will be critical to utilize next generation sequencing to effectively capture uncommon mutations and amplifications in ERBB2 so that patients may be offered therapy directly targeted to their genomic alterations. [Table: see text]

e21552 Background: Lung cancer has not declined in U.S. women as much as it has in men over the past 20 years despite similar rates of smoking cessation among the genders. We explored whether differences in hormone receptor status could contribute to the reason for the observation. Methods: A total of 3,256 non-small lung cancer (NSCLC) tumor samples submitted for molecular profiling between 2013-2018 were retrospectively identified for having hormone receptor (HR) expression results. HR-positive (HR+) status was defined as ≥ 1+ and 1% nuclear staining of Estrogen Receptor alpha (SP1, Ventana) and/or Progesterone Receptor (IE2, Ventana) by immunohistochemistry. DNA sequencing by NGS included cases sequenced by the Illumina MiSeq hot spot 47 gene panel (n = 2753) and Illumina NextSeq 592 gene panel (n = 503). Tumor mutation burden (TMB) was measured by counting somatic non- synonymous missense mutations on the 592 gene panel and ≥ 10 mutations/Megabase (mut/Mb) was considered high. Fisher’s Exact, Chi- square and likelihood ratio (LR) tests were utilized for statistical analyses. Results: Hormone receptor positivity (HR+) was identified in 318 women and 186 men, 504/3256 or 15% of NSCLC. EGFR mutation subtypes observed were Exon19del (46%), L858R (28%), uncommon non-classical (17%), G719X|S768I|L861Q (5%). HR+ occurred more commonly in women compared to men (20% vs 11%, p < 0.001). HR+ NSCLC had the same age distribution as HR-negative (HR-) cancers (range: 16-94 and 18-93, respectively). Compared to patients (pts) who were HR-, pts with HR+ NSCLC were more likely to harbor activating EGFR mutations in men and women (LR 1.39, p = 0.0017), and less likely to have mutations in TP53 (LR 0.83, p = 0.0076), K-RAS (LR 0.66, p < 0.0001), or translocations in ALK (LR 0.46 p = 0.0190). No differences in the incidence of ERBB2 or BRAF mutations were identified. The median tumor mutational burden was equivalent in HR+ vs. HR- pts, both 9 mut/MB. Conclusions: The disparity in the prevalence of hormone receptors in lung cancers affecting men and women deserves further exploration. The presence of hormone receptors in NSCLC is increased in women and in tumors bearing EGFR mutations. Further elucidation of the mechanism and dual targeting of EGFR and ER in patients with HR+ NSCLC deserves exploration.

3605 Background: NTRK gene fusions lead to transcription of chimeric TRK proteins with overexpressed kinase function. Entrectinib is a potent inhibitor of TRKA/B/C. In phase 1/2 studies (ALKA, STARTRK-1, STARTRK-2; EudraCT 2012-000148-88; NCT02097810; NCT02568267), entrectinib was effective in pts with NTRK-fp solid tumors. We present updated data in a larger population with longer follow-up. Methods: In this integrated analysis of adult pts from 3 phase 1/2 trials (data cut-off 31 Oct 2018), tumors were assessed by blinded independent central review (BICR) with RECIST v1.1 (end of cycle 1; then every 8 wks). Primary endpoints were overall response rate (ORR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), efficacy in pts with/without baseline CNS disease, and safety. Results: There were 74 evaluable pts with advanced/metastatic NTRK-fp solid tumors (Table). Median duration of survival follow-up in all pts was 14.2 mo (range 0.1–29.7). BICR ORR was 63.5% (95% CI 51.5–74.4), with 5 complete responses (6.8%). Median BICR DOR was 12.9 mo (95% CI 9.3–NE); median BICR PFS was 11.2 mo (95% CI 8.0–15.7); median OS was 23.9 mo (16.0–NE). In pts with no baseline CNS disease (investigator-assessed; n=55), BICR ORR was 65.5% (95% CI 51.4–77.8) and median BICR DOR in responders was 12.9 mo (95% CI 9.3–NE). In pts with baseline CNS disease (investigator-assessed; n=19), BICR ORR was 57.9% (95% CI 33.5–79.8) and median BICR DOR in responders was 6.0 mo (95% CI 4.2–NE). Safety was in line with that previously reported; the most common ≥grade 3 treatment-related AEs were weight gain (8, 7.1%), anemia (8, 7.1%), and fatigue (7, 6.2%). Conclusions: In this updated analysis, including more pts and longer follow-up, entrectinib continued to demonstrate clinically meaningful responses in pts with NTRK-fp solid tumors, with and without baseline CNS disease. Clinical trial information: NCT02097810, NCT02568267 . [Table: see text]

1572 Background: Rn-222 is a radioactive gas found in rocks and soil. It emits alpha particles that cause dsDNA breaks and increase potential for carcinogenesis. Rn is the 2nd leading cause of LC in the US after smoking. EPA estimates >15,000 deaths/yr (9% of LC deaths) from Rn. We hypothesize that the impact of Rn exposure may be reflected in LC gene mutation (mut) profiles. Methods: Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in FFPE specimens from 159 LC patients (pts) from the Lifespan Cancer Institute in Rhode Island (2014- 2019), followed by validation in a larger cohort of 5,532 pts using Caris platform. Based on EPA Rn maps, we identified counties with high indoor Rn levels (>4 pci/L; HR), and compared gene mut patterns with those from low Rn zones (10, tumors from HR zones had significantly higher TMB when compared to LR zones (56 vs 48%, q= .0005). Conclusions: To our knowledge, this is the first attempt to elucidate the pathobiology of Rn induced LC using gene mut analyses. Our observations suggest that LC associated with higher Rn exposure may have disabled DNA repair pathways and higher TMB. Assuming uniform tobacco smoke exposure, higher Rn was not associated with EGFR mut.

9056 Background: Malignant pleural mesothelioma (MPM) is a relatively uncommon malignancy with poor prognosis and no major therapeutic breakthroughs over the past decade. Better understanding of the genomic landscape and distribution of immune biomarkers in this disease has the potential to enable development of novel therapies. Methods: We analyzed molecular profiles of 222 MPM tumors using next-generation sequencing of 592 genes utilizing Caris Life Sciences platform. Genes were grouped into pathways: DNA damage repair (DDR) ( ATM, BRCA2, BRIP1, BAP1, CHEK2, ERCC2, FANCA/D2/E/L, MLH1, MSH6, MUTYH, NBN, PMS2, RAD50/51B, WRN), cell cycle regulation including TP53 ( RB1,CCNE1, CDKN2A, CCND1, CCND3, CDKN1B), chromatin remodeling (CR) ( ARID2, ASXL1, DNMT3A, EP300, EZH2, KDM6A, KMT2C, KMT2D, NSD3, PBRM1, SMARCB1/A4, SETD2), RAS/MAPK ( KRAS, MAP2K1, NF1, NF2), and PI3K/AKT ( AKT, PIK3CA, PIK3R1/R2, PTEN, RICTOR, TSC1, TSC2, ZNF703). Tumor mutational burden (TMB), PD-L1 expression (SP142 IHC, tumor staining), and MSI/MMR were analyzed. Seventy-two cases also had whole transcriptome sequencing data. Differences in alterations were compared for age, gender, and pathways. Results: Median age of patients (pts) was 72 yr (range, 37-90), 73% were male. Gene pathway alterations were seen in 81% of cases. DDR, specifically homologous recombination (HR), was the most commonly mutated pathway (36.9%), followed by RAS (25.2%) and CR (18.9%). Genes mutated in ≥5% of cases included BAP1 (26.3%), NF2 (23.5%), TP53 (15.5%), SETD2 (10.2%). PD-L1 was high (≥50% tumor cells positive) in 11.4% (n = 24), intermediate (1-49%) in 31.4% (n = 66), and negative ( < 1%) in 57.1% (n = 120) pts. TMB was high (≥10 mutations/Mb) in 9.6% of tumors (n = 20). None of the tumors were dMMR/MSI-H. HR gene BAP1 and CR gene SETD2 mutations trended to be more prevalent in pts ≥70 yo (p = 0.02). CR trended to be more commonly mutated in females (p = 0.02). No other significant differences were found in specific gene/pathway alterations, PD-L1 expression, or TMB in the context of age and gender. Distribution of PD-L1 expression was not different among various pathways. No highly recurrent, targetable fusion isoforms were seen among the 85 identified (mean 1.1 fusions/tumor), which have not yet been characterized for pathogenicity. Conclusions: The majority of MPM tumors harbor alteration in one of the key cellular pathways. HR pathway mutations are the most common. The majority of tumors were PD-L1 negative and carry low TMB indicating low immunogenicity. No age and gender specific differences exist except for BAP1 and SETD2 mutations.

9544 Background: KRAS is the most commonly mutated oncogene in NSCLC and the development of direct KRAS inhibitors has renewed interest in this molecular subtype. However, there are several different KRAS mts, representing unique biology and different prognostic and therapeutic impact. A more comprehensive understanding of the genomic landscape relative to each KRAS mt subset will help guide therapeutic development. Methods: Molecular profiles of 17,113 NSCLC specimens were obtained using next-generation sequencing of 592 genes (Caris Life Sciences) and classified based on presence and types of KRAS mt. Incidence of KRAS mts was noted across the cohort and by histology. Co-occurring genomic alterations, tumor mutational burden (TMB) and PD-L1 IHC (22C3, TPS score) were analyzed by KRAS mt type. Results: Across the entire cohort, 4706 (27%) of samples harbored a KRAS mt (Table). The most common was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mt was 37.2% among adenocarcinoma and only 4.4% in squamous. High TMB, defined by > 10 mts/Mb, varied across the different KRAS mt types, most common in G13X (68.3%) and least common in G12D (43.2%). PD-L1 expression also varied. G12C was the most likely to be PD-L1 positive, with 65.5% TPS > 1%, and the most likely to be PD-L1 high, with 41.3% TPS > 50%. STK11 was mutated in 8.6% of KRAS wild type NSCLC but more frequently noted in every KRAS subtype, with the highest rate in G13X (36.2%) and the lowest in G12D(14.2%). TP53 mts were more frequent in KRAS wild type NSCLC (73.6%), with the highest rate among KRAS mutants at 55.4% (G12other) and the lowest at 36.8% (Q61X). NF1 was noted to be mutated in 21.4% of KRAS G13X cases, while all other KRAS mts had a lower frequency of NF1 mts than KRAS wild type (11.5%). Conclusions: KRAS mts are relatively common in lung adenocarcinoma and KRAS G12C is the most common variant. The different KRAS mts have different co-occurring mutations and a different genomic landscape. KRAS G12C was associated with the highest rate of PD-L1 expression. The clinical relevance of these differences in the context of therapeutic intervention warrants investigation. [Table: see text]

9515 Background: Pralsetinib is an investigational, highly potent, selective RET kinase inhibitor targeting oncogenic RET alterations. We provide the registrational dataset for pts with RET fusion+ NSCLC with and without prior treatment from the global ARROW study. Methods: ARROW (75 sites in 11 countries; NCT03037385) consists of a phase I dose escalation to establish recommended phase II dose (400 mg once daily [QD] orally) and phase II expansion cohorts defined by tumor type and/or RET alteration. Primary objectives were overall response rate (ORR; blinded independent central review per RECIST v1.1) and safety. Efficacy analyses are shown for response-evaluable pts (REP) with RET fusion+ NSCLC who initiated 400 mg QD pralsetinib by July 11 2019 and safety for all pts (regardless of diagnosis) treated with 400 mg QD. Results: As of November 18 2019, 354 pts with advanced solid tumors had received pralsetinib at starting dose of 400 mg QD with median follow-up 8.8 months. ORR, disease control rate (DCR), and % of pts with tumor size reduction are shown in the table for pts with metastatic RET fusion+ NSCLC (n=116; 72% KIF5B; 16% CCDC6; 12% other/fusion present but type unknown) and with prior platinum treatment (n=80) or without prior systemic treatment (n=26). ORR was similar regardless of RET fusion partner, prior therapies, or central nervous system involvement. Overall there were 7 (6%) complete responses, 4 (5%) in prior platinum pts and 3 (12%) in treatment naïve pts; median time to response overall was 1.8 months and median duration of response (DOR) was not reached (95% CI, 11.3–NR). In the safety population (n=354), most treatment-related adverse events (TRAEs) were grade 1-2, and included increased aspartate aminotransferase (31%), anemia (22%), increased alanine aminotransferase (21%), constipation (21%) and hypertension (20%). 4% of pts in the safety population (all tumor types) discontinued due to TRAEs. Conclusions: Updated, registrational, centrally reviewed data demonstrate that pralsetinib has rapid, potent, and durable clinical activity in pts with advanced RET fusion+ NSCLC regardless of RET fusion genotype or prior therapies, and QD oral dosing is well-tolerated. Clinical trial information: NCT03037385 . [Table: see text]

TPS3654 Background: NRG1 fusions are oncogenic drivers across various cancers. NRG1 fusion proteins bind to HER3, leading to HER2/HER3 heterodimerization, increased downstream signaling, and tumor growth. Clinical responses to anti-HER3 antibodies or HER2 tyrosine kinase inhibitors have been reported. In contrast to these agents, MCLA-128 is a HER2/HER3 bispecific antibody that blocks both NRG1 binding and HER2/3 dimerization. Two patients with chemotherapy-resistant ATP1B1-NRG1-positive pancreatic KRAS-wild-type adenocarcinomas who received MCLA-128 through FDA-approved single-patient Investigational New Drug (IND) applications showed significant tumor shrinkage and durable tumor marker (CA-19-9) response. These data support the evaluation of MCLA-128 in NRG1 fusion-positive tumors using a basket approach. Methods: This is a global, open-label, multicenter phase 2 basket trial of MCLA-128 in patients with solid tumors harboring NRG1 gene fusions. Main eligibility criteria are locally advanced unresectable or metastatic cancers harboring an NRG1 fusion, and failure under prior standard therapy appropriate for the tumor type and disease stage. Genomic screening of tumor tissue is done at a local laboratory (with post-hoc central confirmation) or central laboratory (RNA sequencing). Three NRG1 fusion-positive tumor cohorts are being evaluated: pancreatic cancer, NSCLC, and other solid tumors. The sample size for the first two cohorts is up to 25 patients; the basket group may enroll up to 40 patients. The primary endpoint for all cohorts is investigator-assessed objective response rate (RECIST v1.1). The key secondary endpoint is duration of response. Other secondary endpoints include progression-free and overall survival. Eligible patients receive a bi-weekly dosing regimen of 750 mg of MCLA-128 (2-hour infusion), every 2 weeks, in 4-week cycles. The study is actively accruing patients in North America, Europe, and Asia. Previously presented at ESMO 2019, 685TiP, Schram et al.-Reused with permission. Clinical trial information: NCT02912949 .

Introduction Les fusions NRG1 sont des anomalies oncogeniques retrouvees dans differents types de cancers solides, en particulier les cancers du poumon non a petites cellules (CBNPC) et les cancers du pancreas KRAS sauvage. La proteine de fusion NRG1 active HER3 conduisant a l’heterodimerisation d’HER3 avec HER2 et a la promotion de la croissance tumorale. Une efficacite clinique des anticorps anti-HER3 et des inhibiteurs de tyrosine kinase d’HER2 a ete rapportee dans les tumeurs NRG1-positives. Le MCLA-128 est un anticorps bispecifique qui bloque la liaison NRG1-HER3 ainsi que la dimerisation HER2/HER3. Il a montre une activite preclinique robuste dans des modeles tumoraux NRG1- positifs. Sur la base de ces donnees, un essai basket propose d’evaluer l’efficacite du MCLA-128 chez des patients atteints de tumeurs presentant des fusions de NRG1. Methodes Il s’agit d’une etude internationale, ouverte, non controlee, multicentrique de phase II « basket » evaluant l’efficacite du MCLA-128 chez des patients ayant des cancers solides avancees avec fusion NRG1. Le critere d’eligibilite principal est cancer avance avec fusion de NRG1 en echec du traitement standard recommande. Le diagnostic moleculaire de la fusion NRG1 est effectue soit localement avec confirmation centralisee post-hoc, soit centralise. Trois cohortes de patients seront evaluees : cancer du pancreas (n = 25), CBNPC (n = 25), tout autres tumeurs solides avec fusion NRG1 (n = 40). Le critere de jugement principal pour les 3 cohortes est le taux de reponse objective selon l’investigateur (RECIST v1.1). Les criteres d’efficacite secondaires sont la duree de reponse, la survie sans progression et la survie globale. Les patients eligibles recevront le MCLA-128 a une dose fixe de 750 mg en perfusion IV de 2 heures, toutes les 2 semaines, en cycles de 4 semaines. L’etude recrute activement des patients en Amerique du Nord, Europe et Asie.

RET fusions are oncogenic drivers of various tumors, including non–small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor–naïve patients with RET fusion–positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%–38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%–17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion–positive NSCLC), and 67% (95% CI, 30%–93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion–positive NSCLCs was not reached (range, 5 to 18+ months). Significance: Although KIF5B–RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non–KIF5B–RET-containing cancers. Novel approaches to targeting KIF5B–RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed. This article is highlighted in the In This Issue feature, p. 305

© 2018, Springer-Verlag GmbH Germany, part of Springer Nature. Purpose: Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib. Methods: Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0–1.5 mg/m2/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120–360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation. Results: The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy. Conclusions: The combination of topotecan and oral tivantinib was not tolerable in this patient population.

Background/aim African Americans (AA) have the highest incidence and mortality of any racial/ethnic group in the US for most cancer types. Heterogeneity in the molecular biology of cancer, as a contributing factor to this disparity, is poorly understood. To address this gap in knowledge, we explored the molecular landscape of colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and high-grade glioma (HGG) from 271 AA and 636 Caucasian (CC) cases. Materials and methods DNA from formalin-fixed paraffin-embedded tumors was sequenced using next-generation sequencing. Additionally, we evaluated protein expression using immunohistochemistry. The Exome Aggregation Consortium Database was evaluated for known ethnicity associations. Results Considering only pathogenic or presumed pathogenic mutations, as determined by the American College of Medical Genetics and Genomics guidelines, and using Bonferroni and Benjamini-Hochberg corrections for multiple comparisons, we found that CRC tumors from AA patients harbored significantly more mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) than those from CC patients. CRC tumors in AA patients also appeared to harbor more mutations of mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1), MPL proto-oncogene (MPL), thrombo-poietin receptor, and neurofibromin 1 (NF1) than those from CC patients. In contrast, CRCs from AA patients were likely to carry fewer mutations of ataxia-telangiectasia mutated (ATM), as well as of proto-oncogene B-Raf (BRAF), including the V600E variant, than those from CC patients. Rates of immunohistochemical positivity for epidermal growth factor receptor (EGFR) and DNA topoisomerase 2-alpha (TOP2A) tended to be higher in CRCs from AA patients than in CC patients. In NSCLC adenocarcinoma, BRAF variants appeared to be more frequent in the AA than in the CC cohort, whereas in squamous cell lung carcinoma, programmed death-ligand 1 (PD-L1) expression tended to be lower in the AA than in CC group. Moreover, HGG tumors from AA patients showed a trend toward harboring more mutations of protein tyrosine phosphatase non-receptor 11 (PTPN11), than HGG tumors from the CC cohort. In contrast, mutations of phosphatase and tensin homolog (PTEN) and tumor protein 53 (TP53) appeared to be higher in HGG tumors in CC patients than in their AA counterparts. Conclusion Our data revealed significant differences and trends in molecular signatures of the three cancer types in AA and CC cohorts. These findings imply that there may be differences in carcinogenesis between AA and CC patients and that race may be a factor that should be considered regarding cancer incidence and outcome.

Introduction Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin. Methods Patients eligible for the phase Ib portion had advanced tumors that would be appropriate for doxorubicin therapy and those in the phase II portion had relapsed or refractory SCLC. All patients had an ECOG performance status, 0–1 and adequate organ function, including a cardiac ejection fraction ≥50%. Patients who received a lifetime cumulative doxorubicin dose of >150 mg/m2 or who had symptomatic brain metastases were excluded. Patients received ganetespib on Days 1 and 8 and doxorubicin 50 mg/m2 on day 1 in 21-day cycles. Results Eleven patients were enrolled including nine in the phase Ib dose escalation and two in the phase II expansion. The study was terminated by the sponsor. The dose recommended for future study is ganetespib 150 mg/m2 in combination with doxorubicin at a dose of 50 mg/m2. The most common adverse events of the combination were grade 1/2 diarrhea, nausea, fatigue, and transaminitis. No dose limiting toxicities were observed. Response rate was 25% and median duration of response was 137 days. Conclusion Ganetespib plus doxorubicin was a well-tolerated combination and there remains potential for the clinical development of Hsp90 inhibitors in SCLC. Clinical Trial Registration https://ClinicalTrials.gov/ct2/show/NCT02261805, identifier NCT02261805.

Background Neuregulin-1 gene (NRG1) fusions function as oncogenic drivers across various solid tumors, most notably in invasive mucinous adenocarcinoma (IMA) of the lung, and represent a rational potential target for treatment. NRG1 is a growth factor, which binds to ErbB3 or ErbB4 inducing the formation of ErbB3 or 4-containing homo- or heterodimers and activating downstream ErbB-family signaling pathways. Therefore, the ErbB-family blocker afatinib may be a potential treatment option for patients with solid tumors harboring NRG1 fusions. Methods We report a case series of all known patients with NRG1 fusion-positive solid tumors who were treated with afatinib; afatinib therapy is ongoing for some patients. Results To date, 18 patients with NRG1 fusion-positive solid tumors have been treated with afatinib (Table). These include 12 cases of non-small cell lung cancer (NSCLC; 7 of which were reported as IMA), 5 cases of gastrointestinal (GI) cancer (primarily pancreatic ductal adenocarcinoma [PDAC]) and 1 case of ovarian cancer. Various NRG1 fusion partners were identified, most commonly CD74 in patients with NSCLC (n = 7; 58%) and ATP1B1 in patients with gastrointestinal cancer (n = 3; 60%). Best response with afatinib among patients with NSCLC was partial response (PR) lasting 24 months (10 months among those specifically with IMA of the lung). Patients with PDAC experienced PR of 3 and 5.5 months' duration, and one patient has an ongoing PR after 7 months. One patient with cholangiocarcinoma had a PR lasting 8 months; another patient with ovarian cancer had stable disease (SD) of unknown duration.Table63OTableTumor typeNRG1 fusion partnerBest response, physician assessedDuration of response, mosRefsNSCLCIMACD74PR101CD74PR6.52CD74PD*3CD74SD33SDC4PD3CD74PD3CD74PR-4ADCSLC3A2PR121SDC4PR125-PR246CD74PR14+4, 6SDC4SD46GIPDACATP1B1PR37ATP1B1PR5.58APPPR7+6, 8CholangiocarcinomaATP1B1PR85Colorectal (KRASm +ve)POMKSD49OvarianCLUSD-10*PD on an anti-ErbB3 mAb prior to afatinib. -, not reported; ADC, adenocarcinoma; PD, progressive disease.1Gay. JTO 2017, 2Cheema. JTO 2017, 3Drilon. Cancer Discov 2018, 4Duruisseaux. WCLC 2019, 5Jones. Ann Oncol 2017, 6Laskin. JSMO 2019, 7Heining. Cancer Discov 2018, 8Jones. Clin Cancer Res 2019, 9Weinberg. ESMO GI 2019, 10Murumagi. AACR 2019. Conclusions Afatinib is a potential treatment option for some patients with solid tumors harboring NRG1 fusions. The efficacy and safety of afatinib will be evaluated in ongoing/planned prospective non-randomized clinical trials of targeted drugs in patients with advanced cancer with potentially actionable genomic variants (NCT02925234 and NCT02693535). Editorial acknowledgement Greg Plosker of GeoMed, an Ashfield company, part of UDG Healthcare plc. Legal entity responsible for the study The authors. Funding Boehringer Ingelheim. Disclosure Y. Goto: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Taiho Pharmaceutical; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (self): Ono Pharmaceutical; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Shionogi Pharma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Glaxo Smith Kline; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Kyorin. J. Cadranel: Advisory / Consultancy, Research grant / Funding (institution), Non-remunerated activity/ies: AZ; Advisory / Consultancy, Non-remunerated activity/ies: BI; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Lilly; Advisory / Consultancy, Non-remunerated activity/ies: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis. B.A. Weinberg: Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen; Travel / Accommodation / Expenses: Caris Life Sciences; Travel / Accommodation / Expenses: Boehringer Ingelheim. M. Duruisseaux: Honoraria (self): Roche; Honoraria (self): Takeda; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): AbbVie; Honoraria (self): Boerhinger ingelheim. S.V. Liu: Advisory / Consultancy: Apollomics; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: G1 Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Heron; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Inivata; Advisory / Consultancy: Janssen; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Regeneron; Advisory / Consultancy: Taiho (DSMB); Advisory / Consultancy: Takeda/Ariad; Advisory / Consultancy: Tempus; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Blueprint; Research grant / Funding (institution): Clovis; Research grant / Funding (institution): Corvus; Research grant / Funding (institution): Esanex; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): Molecular Partners; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Rain Therapeutics; Research grant / Funding (institution): Threshold. K. Tolba: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self): Foundation One. R.C. Doebele: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Rain Therapeutics; Honoraria (self): Guardant; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Trovagene; Advisory / Consultancy, Licensing / Royalties, Licenses are licensing fees from patents or biological materials : Ariad; Advisory / Consultancy: Takeda; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials : Ignyta; Advisory / Consultancy, Research grant / Funding (self), Licenses are licensing fees from patents or biological materials: Loxo; Research grant / Funding (self): Mirati; Licensing / Royalties, Licensing fees from patents or biological materials : Abbott Molecular; Licensing / Royalties, Licensing fees from patents or biological materials : GVKbio; Licensing / Royalties, Licensing fees from patents or biological materials: Chugai; Licensing / Royalties, Licensing fees from patents or biological materials : Genentech; Licensing / Royalties, Licensing fees from patents or biological materials: Foundation Medicine; Licensing / Royalties, Licensing fees from patents or biological materials: Black Diamond. R.F. Schlenk: Research grant / Funding (self): Boehringer Ingelheim. J.J. Laskin: Honoraria (self), Research grant / Funding (self): Roche Canada; Honoraria (self): BI Canada; Honoraria (self): AstraZeneca Canada; Research grant / Funding (self): Pfizer Canada. P.K. Cheema: Honoraria (self), Advisory / Consultancy: Astrazeneca; Honoraria (self), Advisory / Consultancy: BI; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Takeda; Honoraria (self), Advisory / Consultancy: genomic Health; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck. M.R. Jones: Full / Part-time employment: Qiagen. L.A. Muscarella: Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): Boehringer Ingelheim. A. Cseh: Full / Part-time employment: Boehringer Ingelheim. F. Solca: Full / Part-time employment: Boehringer Ingelheim. D.J. Renouf: Honoraria (self): Celgene; Honoraria (self): Tahio; Honoraria (self): Bayer; Honoraria (self): Ipsen; Honoraria (self): Servier. All other authors have declared no conflicts of interest.