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9113 Background: EGFR mutations are present in more than 10% of patients (pts) with NSCLC in the US. While EGFR with tyrosine kinase inhibitors (TKIs) are effective, acquired resistance is expected. Known mechanisms include acquired EGFR mutations (e.g. 718V, c797x, 724s, 721s or T790M); copy number amplifications in MET, ERBB2, and PIK3CA; gene fusion events; and histological transformation. We herein present the prevalence of resistance mutations in the largest reported cohort of EGFR mutant NSCLC. Methods: Non-small cell lung cancer (NSCLC) tumor samples were submitted to Caris Life Sciences (Phoenix, AZ) for NextGen Sequencing (NextSeq, 592 Genes) and whole exome sequencing (NovaSeq, WES). 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 > 10 mutations per MB), genomic loss of heterozygosity (gLOH) was determined by WES. Patient treatment information was obtained from insurance claims data. Results: A total of 27,848 NSCLC tumors were evaluated and 3,223 (12%) had a EGFR sensitizing mutations. We found 60 tumors with common missense resistance mutations: 790 (n = 30, 0.9%), 797 (n = 38, 1.2 %), 718 (n = 11, 0.3%), 724 (n = 7, 0.2%) and 721 (n = 4, 0.1). Table 1 describes the frequencies, PD-L1 expression and the most common co-mutations. TMB-H (> = 10) was found in 12.5% of the tumors and dMMR/MSI-H in 1.8%. The most prevalent co-alterations were TP53 54%), gLOH (28%), CTNNB1 (19%), NFKB1A (13%), APC (10%), PIK3CA (11%), SMAD4 (9%) and other 15 co-mutations in less than 7% were seen. In the 30 T790M mutants, in addition to TP53 mutations, other prevalent co-mutations were PIK3CA (14%) and CTNNB1 (17%). In 797-mutant tumors, in addition to T790M, the most prevalent co-mutations were TP53 (53%), CTNNB1 (22%), APC (16%) and PIK3CA (11%). L718 mutations co-occurred with either L858R (8/11), exon 19 (3/11) or T790M mutations (3/11). G724 mutations were found in 7 patients (0.02%) and G721 mutations in 4 patients (0.01%). Conclusions: Acquired resistance in EGFR mutant NSCLC is very heterogeneous and their frequency is still low most likely due to lack of enough sequencing of EGFR resistant tumors. While T790M and C797S mutations are well described, this report also notes a significant number of L718V mutations, primarily in osimertinib-treated pts with an original L858R. These data support the NGS evaluation of patients with resistant EGFR mutant lung cancers. [Table: see text]

9122 Background: Multiple DNA alterations in exon 14 splice sites have been identified in NSCLC and result in skipping of the juxtamembrane domain Cbl-E3 ubiquitin ligase binding region, leading to increased MET stability and oncogenesis. The effects of these alterations on transcriptome-level have not been fully characterized. We present the largest cohort study of METex14 using WTS and identify key cellular pathways associated with invasion and metastases in METex14. Methods: 17,666 NSCLC tumor samples underwent genomic profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, WTS). METex14 was captured via WTS. ssGSEA analysis was used to evaluate pathway enrichment. Wilcoxon, Fisher’s exact were used for statistical significance (p without and q values with multiple comparison correction). Results: 440 patients (2.5%) with METex14 were identified. METex14 patients were of older age, female gender, and enriched in sarcomatoid histology (Table 1). The most common alterations were point mutations (51.5%) and deletions (17.3%) at donor splice sites. Splice site alterations except point mutations at splice acceptor site translated to increased mRNA expression compared to wild-type MET (WT). MET amplification translated to higher mRNA expression compared to METex14 and WT with synergistic expression when co-altered with METex14 (q 50% (53% vs. 27.6% WT, q

2633 Background: Older patients (pts) with cancer are underrepresented in registrational clinical trials for immune checkpoint inhibitor (ICI) therapies. There may be relevant differences in the makeup of the tumor microenvironment (TME) and in genomic signatures of cancer in older pts. This analysis explores differences in the genomic makeup of common cancers and their TME in pts ≥ 80 years (yr) of age, compared to younger pts. Methods: Next-generation sequencing of DNA (592 gene panel, NextSeq or whole-exome sequencing, NovaSeq) and RNA (whole transcriptome sequencing, NovaSeq) was performed for non-small cell lung carcinoma (NSCLC; n = 19,891), melanoma (MEL n = 2,899), and renal cell carcinoma (RCC; n = 1,333) pt samples submitted to a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). PD-L1 expression was assessed by immunohistochemistry (IHC), and high tumor mutational burden (TMB-H) was defined as ≥10 mut/Mb. Pts were stratified into age subgroups of ≥80 and < 80 yr for comparison of DNA damage response (DDR) gene alterations, gene expression profiling, and TME analysis (MCP-counter; Becht, 2016). P-values were adjusted for multiple hypotheses testing (Benjamini-Hochberg) unless noted as exploratory. Results: Pts ≥80 yr accounted for 16.0%, 19.9% and 5.3% of NSCLC, MEL and RCC pts, respectively. Compared to pts < 80 yr, NSCLC and MEL pts ≥80 yr had similar DDR gene mutation rates, while BRCA1 mutations were more common in MEL pts ≥80 yr (2.1 vs 0.8%; exploratory- p < 0.05). NSCLC ≥80 yr TMEs had increased abundance of fibroblasts (1.09-fold, p < 0.01), dendritic cells (1.07-fold, p < 0.01) and macrophages (1.04-fold, p < 0.01), and MEL≥80 yr TMEs had fewer infiltrating T-lymphocytes (0.87-fold, p = 0.02). Increased expression of immune checkpoint (IC) genes PDCDL1G2 (PD-L2; 1.11-fold), HAVCR2 (TIM-3; 1.11-fold ), and CD80/86 (1.07/1.08-fold, p < 0.05) was seen in NSCLC pts ≥80 yr, while IL-6 expression was decreased (0.88-fold; p < 0.05). The largest change in IC gene expression was for IL-6 (1.24-fold, p = 0.78) in MEL, and GZMB (0.56-fold ; p = 0.17) in RCC ≥80 yr. TMB-H was less common in NSCLC (29.7 vs 36.5%, p < 0.001) and more common in MEL pts ≥80 yr (65.7 vs 49.0%, p < 0.01), and PD-L1 (IHC-SP142, ≥2+|5%) expression was less frequent in RCC pts ≥80 yr (9.1 vs 19.4%, exploratory p < 0.05). Profiling of glutamine and glucose metabolism-related genes revealed increased SLC38A5 (1.17-fold; p < 0.0001) and decreased G6PC (0.65-fold, p < 0.01) expression in NSCLC ≥80 yr. While not statistically significant, MEL and RCC pts ≥80 yr had opposite trends for SLC38A5 and G6PC expression. Conclusions: Our analysis provides new insights to immune landscape of NSCLC, MEL, and RCC pts ≥80 yr. Differential gene expression and TME composition changes in this population suggest unique, cancer-specific therapeutic opportunities, and a potential to explore biomarkers of response to ICIs.

3132 Background: Reversion mutations (RM) in homologous recombination pathway genes including BRCA1/2 have been identified in patients with ovarian, breast, and prostate cancers whose tumors have become refractory to platinum chemotherapy or PARP inhibition. Utilizing a multi-institutional molecular database, we report the prevalence of BRCA1/2 RM in a large cohort across various tumor types. Methods: Primary and/or metastatic tumor samples underwent DNA (underwent NextSeq, 592 genes; NovaSeq, whole-exome) and RNA (NovaSeq, whole transcriptome) sequencing (Caris Life Sciences, Phoenix, AZ). RM were identified by a board-certified molecular geneticist and called only if the patient had been treated with a PARPi or a platinum agent. Baseline clinical and outcomes data were obtained through linked insurance claims data. Results: Among 118,000 solid tumors profiled, RM were observed in 54 tumors samples. RMs were seen most commonly in ovarian cancer (OC), 1.5% (23/1500) of tumors with BRCA1/2 pathogenic mutations (mut), followed by breast cancer (BC) (2.4%, 17/700), endometrial cancer (1.0%, 4/400), pancreatic cancer (1.0%, 2/210), cholangiocarcinoma (2.5%, 2/80), prostate cancer (1.3%, 3/230), cervical cancer (1.4%, 1/70), cancer of unknown primary (1.0%, 1/100), and a neuroendocrine tumor of prostate (1 RM of 9 BRCA mut). Among all RM, we detected 17 in BRCA1 and 6 in BRCA2 in OC. In BC, we identified 7 RM in BRCA1 and 10 in BRCA2. Frameshift mut that restored the reading frame in BRCA1/2 were the most common type of RM. Molecular profiles of 14 high-grade serous ovarian cancers (HGSOC) with RM were compared to 87 control HGSOC with pathogenic BRCA1/2 mut without RM. Tumors with RM had lower ER expression (25% vs. 64%, p = 0.024) and higher KDM6A mut rate (15% vs. 0, p = 0.016). Additionally, TP53 mut rates were similar in RM and control (100% vs. 95%), seen in HGSOC. In patients with RM, 7 of the 14 (50%) TP53 mut were gain-of-function (GOF) while only 19 of 84 (23%) TP53 mut in the control group were GOF (p = 0.048). More detailed clinical data were available for 29 patients with RM (17 BRCA1 & 12 BRCA2). Among these patients, 7 had received prior platinum-based chemotherapy (carboplatin or cisplatin), 7 patients were treated with PARP inhibitors (olaparib or rucaparib), or both (n = 7). Notably, 5 patients had been treated with carboplatin (n = 2, ovarian), olaparib (n = 1, breast), or both agents (n = 2, ovarian and prostate) after the detection of RM. Conclusions: This dataset is one of the largest reporting on the prevalence of BRCA1/2 RM across various tumor types. We demonstrate that the rate of RM was low among BRCA1/2 mutated tumors; this may be because some patients may not have repeat profiling post-treatment. Repeating tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.

3120 Background: The cell-surface transferrin receptor TFR1 imports iron-bound transferrin into cells via clathrin-mediated endocytosis. Tumors require constitutive iron import to drive proliferation, and several studies establish TFR1 as a target able to facilitate intracellular delivery of cytotoxic therapeutic molecules. Our own work previously revealed association between high expression of TFRC, the gene encoding TFR1, and high risk for poor outcome in diffuse large B-cell lymphoma (DLBCL). We showed therapetuic targeting of TFR1 in DLBCL results in significant anti-tumor benefit. Systematic analysis of TFRC expression as a prognostic marker across tumor types, however, has not been investigated. Methods: Tissue samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq, or whole exome sequencing, NovaSeq), RNA (NovaSeq, whole transcriptome sequencing, WTS) and immunohistochemistry. Overall survival (OS) was calculated from date of tissue collection to last contact from insurance claims data and employed Kaplan-Meier analysis by Wilcoxon statistics, with p < 0.05 defined as significant. Results: Amongst 47 cancer types included, colorectal cancer (CRC) displayed the highest level of TFRC mRNA, followed by gastric cancer. In an all-tumor cohort (n = 93248), patients with higher TFRC expression (cutoff = median) had significantly worse OS (HR = 1.348, 95% CI [1.317-1.38], p < 0.00001). This was statistically significant in 23 individual tumor types. Drilling down further, TFRC adverse prognostic value was mainly driven by cohorts with larger number of samples in the database, including non-small cell lung cancer (n = 17309), CRC (n = 12860), breast cancer (n = 8632), ovarian carcinoma (n = 7998), uterine neoplasms (n = 6097), prostate adenocarcinoma (n = 3411), glioblastoma (n = 2821), gastric cancer (n = 1579), and others. Surprisingly, TFRC overexpression correlated with improved outcome in vulvar squamous cell carcinoma (VSCC, n = 297). TFRC was found to be most prognostic in prostate adenocarcinoma with median OS 1139 days in pts with high vs 3230 days in pts with low TFRC (HR = 2.556, 95% CI [2.213-2.951], p < 0.00001). Conclusions: Our study is the first to combine modern molecular profiling with a large cohort of clinical tissue samples to reveal a prognostic role for TFRC expression in a variety of solid tumor types. We found TFRC overexpression to be prognostic in a large proportion of histologies, though surprisingly association with improved OS in VSCC. Highest expression occured in CRC and gastric cancer, diseases with needs for new therapies. A number of TFR1-targeting therapeutics are currently at various stages of development, and warrant further investigation in disease cohorts identified from our study.

TPS3180 Background: Oncogenic neuregulin 1 ( NRG1) gene fusions occur in ̃0.2% of solid tumors overall and in up to 31% of cases of invasive mucinous lung adenocarcinoma [Laskin et al. Ann Oncol. 2020;31(12):1693–1703; Cadranel et al. Oncologist. 2021;26(1):7–16]. NRG1 fusion proteins provide an extracellular anchor for the epidermal growth factor (EGF) domain of NRG1 to bind to ErbB3 (HER3), leading to HER3 heterodimerization and activation of downstream signaling pathways, resulting in oncogenesis. Afatinib, an irreversible pan-ErbB tyrosine kinase inhibitor, represents a potential treatment for NRG1-fusion positive ( NRG1+) tumors. This study aims to examine the safety and efficacy of afatinib in patients with NRG1+ solid tumors, for which no authorized targeted therapy exists. Methods: This prospective, decentralized, US study (NCT05107193) will include 40 evaluable patients aged ≥18 years. Participating molecular test providers across the USA will identify eligible fusions in the course of routine diagnostic assays. When a patient with an NRG1 fusion is identified, participating test providers will notify the treating physician of the study as a treatment option for the patient. Patients’ primary oncologists will then contact the trial sponsor to confirm patient eligibility. Once approved by the central Institutional Review Board, patients will receive afatinib on a single-patient protocol basis, until disease progression or treatment is no longer tolerated. The recommended dosage per SmPC is 40 mg orally QD. Patients will be screened and enrolled into the study at their existing point-of-care setting. Inclusion criteria include a histologically or cytologically confirmed diagnosis of an advanced, unresectable/metastatic, non-hematologic malignancy with an NRG1 fusion, evaluable per RECIST 1.1. Any coding gene as the NRG1 fusion partner is permitted. Fusion status will be confirmed prospectively by a contracted molecular test provider. Exclusion criteria include prior systemic anti-cancer therapy or investigational drug within 14 days or 5 half-lives (whichever is shorter) of the start of afatinib treatment; an actionable driver mutation other than NRG1 fusion for which FDA-approved targeted therapy is available; and prior treatment with an ErbB-targeted therapy. The primary endpoint of the study is confirmed objective response (OR) by independent central review per RECIST 1.1, defined as best overall response of either complete response or partial response and analysed as the proportion of patients with an OR. The key secondary endpoint is duration of response, defined as the time from the first documented OR to progression or death. Secondary endpoints include time to OR and disease control per investigator assessment. Safety will also be assessed. The study is open for recruitment. Clinical trial information: NCT05107193.

Background Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)–programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stag...

PURPOSE Genetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 ( ROS1) are oncogenic drivers in non-small-cell lung cancer (NSCLC). We report the results of an updated integrated analysis of three phase I or II clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2) of the ROS1 tyrosine kinase inhibitor, entrectinib, in ROS1 fusion–positive NSCLC. METHODS The efficacy-evaluable population included adults with locally advanced or metastatic ROS1 fusion–positive NSCLC with or without CNS metastases who received entrectinib ≥ 600 mg orally once per day. Co-primary end points were objective response rate (ORR) assessed by blinded independent central review and duration of response (DoR). Secondary end points included progression-free survival (PFS), overall survival (OS), intracranial ORR, intracranial DoR, intracranial PFS, and safety. RESULTS In total, 161 patients with a follow-up of ≥ 6 months were evaluable. The median treatment duration was 10.7 months (IQR, 6.4-17.7). The ORR was 67.1% (n = 108, 95% CI, 59.3 to 74.3), and responses were durable (12-month DoR rate, 63%, median DoR 15.7 months). The 12-month PFS rate was 55% (median PFS 15.7 months), and the 12-month OS rate was 81% (median OS not estimable). In 24 patients with measurable baseline CNS metastases by blinded independent central review, the intracranial ORR was 79.2% (n = 19; 95% CI, 57.9 to 92.9), the median intracranial PFS was 12.0 months (95% CI, 6.2 to 19.3), and the median intracranial DoR was 12.9 months (12-month rate, 55%). The safety profile in this updated analysis was similar to that reported in the primary analysis, and no new safety signals were found. CONCLUSION Entrectinib continued to demonstrate a high level of clinical benefit for patients with ROS1 fusion–positive NSCLC, including patients with CNS metastases.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor, is the preferred frontline therapy for EGFR-mutant advanced NSCLC. However, despite its high initial response rates, multiple EGFR-independent mechanisms of resistance have been reported in patients receiving osimertinib. One such mechanism is the emergence of acquired, targetable oncogenic fusion events. It has been documented in other case reports that combination therapies can be efficacious in these scenarios. In our case report, we present a patient with EGFR-mutant advanced NSCLC who developed an acquired EML4-ALK rearrangement mediating resistance to osimertinib, which was overcome by using a combination of osimertinib with the ALK tyrosine kinase inhibitor alectinib.

KRAS is the most commonly mutated oncogene in NSCLC and development of direct KRAS inhibitors has renewed interest in this molecular variant. Different KRAS mutations may represent a unique biologic context with different prognostic and therapeutic impact. We sought to characterize genomic landscapes of advanced, KRAS-mutated non–small cell lung cancer (NSCLC) in a large national cohort to help guide future therapeutic development. Molecular profiles of 17,095 NSCLC specimens were obtained using DNA next-generation sequencing of 592 genes (Caris Life Sciences) and classified on the basis of presence and subtype of KRAS mutations. Co-occurring genomic alterations, tumor mutational burden (TMB), and PD-L1 expression [22C3, tumor proportion score (TPS) score] were analyzed by KRAS mutation type. Across the cohort, 4,706 (27.5%) samples harbored a KRAS mutation. The most common subtype was G12C (40%), followed by G12V (19%) and G12D (15%). The prevalence of KRAS mutations was 37.2% among adenocarcinomas and 4.4% in squamous cell carcinomas. Rates of high TMB (≥10 mutations/Mb) and PD-L1 expression varied across KRAS mutation subtypes. KRAS G12C was the most likely to be PD-L1 positive (65.5% TPS ≥ 1%) and PD-L1 high (41.3% TPS ≥ 50%). STK11 was mutated in 8.6% of KRAS wild-type NSCLC but more frequent in KRAS-mutant NSCLC, with the highest rate in G13 (36.2%). TP53 mutations were more frequent in KRAS wild-type NSCLC (73.6%). KRAS mutation subtypes have different co-occurring mutations and a distinct genomic landscape. The clinical relevance of these differences in the context of specific therapeutic interventions warrants investigation.

Genetic rearrangements of the tyrosine receptor kinase ROS proto-oncogene 1 (The efficacy-evaluable population included adults with locally advanced or metastaticIn total, 161 patients with a follow-up of ≥ 6 months were evaluable. The median treatment duration was 10.7 months (IQR, 6.4-17.7). The ORR was 67.1% (n = 108, 95% CI, 59.3 to 74.3), and responses were durable (12-month DoR rate, 63%, median DoR 15.7 months). The 12-month PFS rate was 55% (median PFS 15.7 months), and the 12-month OS rate was 81% (median OS not estimable). In 24 patients with measurable baseline CNS metastases by blinded independent central review, the intracranial ORR was 79.2% (n = 19; 95% CI, 57.9 to 92.9), the median intracranial PFS was 12.0 months (95% CI, 6.2 to 19.3), and the median intracranial DoR was 12.9 months (12-month rate, 55%). The safety profile in this updated analysis was similar to that reported in the primary analysis, and no new safety signals were found.Entrectinib continued to demonstrate a high level of clinical benefit for patients with

Simple Summary Small cell lung cancer is a subtype of lung cancer and one of the deadliest thoracic tumours. Historically, chemotherapy consisting of either platinum plus etoposide or anthracycline-based regimens have been associated with a high response rate and rapid development of acquired resistance, contributing to the poor overall prognosis. Only a fraction of patients with local or early disease can be cured, whilst the treatment is palliative in those with extensive disease. In recent decades, few novel drugs have been developed, which are herein described. Abstract Small cell lung cancer (SCLC) is one of the deadliest thoracic neoplasms, in part due to its fast doubling time and early metastatic spread. Historically, cytotoxic chemotherapy consisting of platinum–etoposide or anthracycline-based regimens has demonstrated a high response rate, but early chemoresistance leads to a poor prognosis in advanced SCLC. Only a fraction of patients with limited-disease can be cured by chemo-radiotherapy. Given the disappointing survival rates in advanced SCLC, new cytotoxic agents are eagerly awaited. Unfortunately, few novel chemotherapy drugs have been developed in the latest decades. This review describes the results and potential application in the clinical practice of novel chemotherapy agents for SCLC.

BackgroundLittle is known regarding the efficacy of immune checkpoint inhibitors (ICI) in patients with advanced large-cell neuroendocrine lung carcinoma (aLCNEC).Methods125 consecutive patients with aLCNEC were identified in the electronic databases of 4 participating cancer centers. The patients were divided into group A (patients who received ICI, n=41) and group B (patients who did not receive ICI, n=84). Overall survival since advanced disease diagnosis (OS DX) and OS since ICI initiation (OS ICI) were captured.ResultsWith a median follow-up of 11.8 months (mo) (IQR 7.5–17.9) and 6.0mo (IQR 3.1–10.9), 66% and 76% of patients died in groups A and B, respectively. Median OS DX was 12.4mo (95% CI 10.7 to 23.4) and 6.0mo (95% CI 4.7 to 9.4) in groups A and B, respectively (log-rank test, p=0.02). For ICI administration, HR for OS DX was 0.59 (95% CI 0.38 to 0.93, p=0.02—unadjusted), and 0.58 (95% CI 0.34 to 0.98, p=0.04—adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), presence of liver metastases and chemotherapy administration). In a propensity score matching analysis (n=74; 37 patients in each group matched for age and ECOG PS), median OS DX was 12.5 mo (95% CI 10.6 to 25.2) and 8.4 mo (95% CI 5.4 to 16.9) in matched groups A and B, respectively (log-rank test, p=0.046). OS ICI for patients receiving ICI as monotherapy (n=36) was 11.0 mo (95% CI 6.1 to 19.4).ConclusionsWith the limitations of retrospective design and small sample size, the results of this real-world cohort analysis suggest a positive impact of ICI on OS in aLCNEC.

Summary Background Oncogenic alterations in RET have been identified in multiple tumour types, including 1–2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. Methods ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0–2 (later limited to 0–1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. Findings Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50–71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50–86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. Interpretation Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. Funding Blueprint Medicines.

Small-cell lung cancer (SCLC) is a highly lethal subtype of lung cancer. Despite concerted efforts over the past several decades, there have been limited therapeutic advances. Traditional chemotherapy offers a high response rate and rapid symptomatic improvement, but its benefit is fleeting, and relapse is quick and unforgiving. Immunotherapy has delivered improved outcomes for patients with many cancers and there was compelling rationale for development in SCLC. While initial efforts with cytotoxic T-lymphocyte protein-4 inhibitors failed to improve upon chemotherapy alone, the addition of programmed death ligand-1 (PD-L1) inhibitors to first-line chemotherapy finally provided long-awaited gains in survival. Atezolizumab, when added to carboplatin and etoposide, improved both progression-free survival and overall survival. Durvalumab, when added to platinum plus etoposide, similarly improved OS. Biomarker development has stalled as PD-L1 expression and tumor mutational burden have not been useful predictive biomarkers. However, based on the significant survival improvements, both atezolizumab and durvalumab were approved by the US Food and Drug Administration to be given with first-line chemotherapy, and these regimens represent the new standards of care for SCLC.

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

Introduction A novel CD74-NRG2α fusion has recently been identified in NSCLC. We surveyed a large tumor database comprehensively profiled by whole transcriptome sequencing to investigate the incidence and distribution of NRG2 fusions among various solid tumors. Methods Tumor samples submitted for clinical molecular profiling at Caris Life Sciences (Phoenix, AZ) that underwent whole transcriptome sequencing (NovaSeq [Illumina, San Diego, CA]) were retrospectively analyzed for NRG2 fusion events. All NRG2 fusions with sufficient reads (> three junctional reads spanning ≥ seven nucleotides) were identified for manual review, characterization of fusion class, intact functional domains, EGF-like domain isoforms, breakpoints, frame retention, and co-occurring alterations by next-generation sequencing (NextSeq [Illumina, San Diego, CA], 592 genes). Results Seven inframe functional (containing the intact EGF-like domain) NRG2α fusions were identified, namely, the following: (1) NSCLC (two of 9600, 0.02%: CDH1-NRG2α [C11, N2], F11R-NRG2α [F1, N4]); (2) endometrial (two of 3060, 0.065%: CPM-NRG2α [C2, N2], OPA3-NRG2α [O1, N2]); (3) ovarian (one of 5030, 0.02%: SPON1-NRG2α [S6, N2]); (4) prostate (one of 1600, 0.063%: PLPP1-NRG2α [P1, N2]); and (5) carcinoma of unknown origin (one of 1400, 0.07%: CYSTM1-NRG2α [C2, N2]). No NRG2β fusions were identified. Both NSCLC samples contained the reciprocal NRG2 fusions (NRG2-CDH1, NRG2-F11R). Almost all inframe NRG2α fusions have no (N = 6, 85.7%) or low (N = 1, 14.3%) programmed death-ligand 1 expression. No additional known driver mutations were identified in these seven NRG2α fusion-positive tumor samples. Conclusions Similar to NRG1 fusions, NRG2α fusions are recurrent and rare ligand-fusions in NSCLC and other multiple tumor types, especially gynecologic malignancies.

There is a need to tailor treatments to patients who are most likely to derive the greatest benefit from them to improve patient outcomes and enhance cost-effectiveness of cancer therapies.To compare overall survival (OS) between patients with a current or former history of smoking with patients who never smoked and initiated pembrolizumab monotherapy as first-line (1L) treatment for advanced non-small lung cancer (NSCLC).This retrospective cohort study compared patients diagnosed with advanced NSCLC aged 18 or higher selected from a nationwide real-world database originating from more than 280 US cancer clinics. The study inclusion period was from January 1, 2011, to October 1, 2019.Smoking status at the time of NSCLC diagnosis.OS measured from initiation of 1L pembrolizumab monotherapy.In this retrospective cohort study, a total of 1166 patients (median [IQR] age, 72.9 [15.3] years; 581 [49.8%] men and 585 [50.2%] women) were assessed in the primary analysis, including 91 patients [7.8%] with no history of smoking (ie, never-smokers) and 1075 patients [92.2%] who currently or formerly smoked (ie, ever-smokers). Compared with ever-smokers, never-smokers were older (median age [IQR] of 78.2 [12.0] vs 72.7 [15.5] years), more likely to be female (61 [67.0%] vs 524 [48.7%]) and to have been diagnosed with nonsquamous tumor histology (70 [76.9%] vs 738 [68.7%]). After adjustment for baseline covariates, ever-smokers who initiated 1L pembrolizumab had significantly prolonged OS compared to never-smokers (median OS: 12.8 [10.9-14.6] vs 6.5 [3.3-13.8] months; hazard ratio (HR): 0.69 [95% CI, 0.50-0.95]). This trend was observed across all sensitivity analyses for the 1L pembrolizumab cohort, but not for initiators of 1L platinum chemotherapy, for which ever-smokers showed significantly shorter OS compared with never-smokers (HR, 1.2 [95% CI, 1.07-1.33]).In patients with advanced NSCLC who received 1L pembrolizumab monotherapy in routine clinical practices in the US, patients who reported a current or former history of smoking at the time of diagnosis had consistently longer OS than never-smokers. This finding suggests that in never-smoking advanced NSCLC, 1L pembrolizumab monotherapy may not be the optimal therapy selection, and genomic testing for potential genomically matched therapies should be prioritized over pembrolizumab in never-smokers.

Small cell lung cancer (SCLC) is a particularly lethal subtype of lung cancer whose treatment landscape has been relatively devoid of advance. The recent integration of immunotherapy in the first-line treatment of SCLC has improved overall survival (OS), prompting the first major paradigm shift for this disease in decades. Despite this improvement in outcomes, most patients with SCLC will relapse after initial response. Standard salvage systemic therapy for SCLC remains disappointing, with few approved agents and consistently poor outcomes. The need for novel agents to combat this disease remains pressing. Fortunately, there are several agents in various stages of development that hold potential as novel treatments for advanced SCLC. Lurbinectedin, which targets active transcription, has shown activity in platinum-sensitive and platinum-resistant SCLC as monotherapy and in combination with doxorubicin. Aurora A kinase (AAK) inhibitors showed initial activity when given with paclitaxel but in randomized studies, failed to improve outcomes over paclitaxel plus placebo. However, in the subset of patients with MYC expression, targeting AAK was effective. Similarly, agents targeting poly-ADP ribose (PARP) pair well with other DNA damaging drugs but in the subset of patients whose tumors express Schlafen-11 (SLFN-11), efficacy appeared greater. CDK 4/6 inhibition is being explored, primarily as a means to protect myeloid cells during cytotoxic chemotherapy in a strategy expected to be uniquely effective in SCLC. Ongoing trials are also studying are novel formulations of established cytotoxic agents. Delta-like protein 3 (DLL3) is an appealing therapeutic target given its selective expression on SCLC cells, but after initial exciting results, the antibody-drug conjugate (ADC) Rovalpituzumab tesirine (Rova-T) did not have a favorable efficacy to toxicity profile in randomized trials. Other agents targeting DLL3 are under study. Targeting angiogenesis has yielded modest improvements in the past but newer agents such as anlotinib are renewing interest. While the current therapeutic landscape beyond chemo-immunotherapy remains the same as it was decades ago, drug development for SCLC is rapidly moving forward and promises to deliver the needed novel agents in the very near future.

Introduction: National-level data of cancer patients’ readmissions after a ST-segment elevation myocardial infarction (STEMI) are lacking. Objectives: The primary aim of this study was to describe rates and causes of 30-day readmissions in this population. Methods: Among patients who were admitted with STEMI in the United States National Readmission Database (NRD) from October 2015-December 2017, we identified patients with the diagnosis of active breast, colorectal, lung or prostate cancer. The primary endpoint was 30-day unplanned readmission rate. Secondary endpoints included in-hospital outcomes during the index admission and causes of readmissions. A propensity score model was used to compare the outcomes of cancer and no cancer patients. Results: A total of 385,522 patients were included in the current analysis (Cancer= 5,956, No Cancer=379,566). After propensity score matching, 23,880 patients were compared (Cancer=5,949, No Cancer=17,931). Cancer patients had higher 30-day readmission (19% vs 14%, p Conclusions: About one in five cancer patients presenting with STEMI will be readmitted within 30 days. Cancer patients’ 30-day readmissions are still predominantly cardiac-related but with a higher proportion of admissions for infectious, cancer-related and bleeding and than those without cancer.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors are the preferred initial treatment for ALK rearranged non-small cell lung cancer (NSCLC). While initial responses to next-generation inhibitors are robust, acquired resistance is expected for nearly all patients. Resistance is often mediated by point mutations along the solvent front. Use of the acquired mutational profile to guide therapy is still investigational and largely based on preclinical data demonstrating sensitivity of resistant cell lines to available kinase inhibitors. Here, we describe outcomes after development of an ALK L1196Q mutation. We present a patient with stage IV ALK rearranged lung cancer received who received first line crizotinib at 250 mg twice daily, then at progression, second line alectinib at 600 mg twice daily. When radiographic evidence of progression was noted, a biopsy was performed. Next generation sequencing (NGS) identified an acquired ALK L1196Q mutation. The patient was treated with third line brigatinib, at 90 mg daily and escalating to 180 mg daily, and achieved a partial response that is still ongoing, one year later. We highlight false-negative ALK mutation results when only plasma is used, particularly in early metastatic disease. We also discuss how the use of specific ALK resistance mutations to guide therapy is clinically relevant is being investigated.

BACKGROUND: Rearranged during transfection (RET) gene fusions are a validated target in non-small cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. PATIENTS AND METHODS: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by next-generation sequencing (NGS) or MET fluorescence in situ hybridization. RESULTS: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received a RET-selective inhibitor (selpercatinib, n=10; pralsetinib, n=7; pralsetinib followed by selpercatinib, n=1 with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval (CI), 3.6–10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small cell histologic transformation. CONCLUSIONS: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

ispartof: ANNALS OF ONCOLOGY vol:30 issue:11 pages:1686-1688 ispartof: location:England status: published

Purpose: Approved therapies for EGFR exon 20, ERBB2 mutations, and NRG1 fusions are currently lacking for non–small cell lung cancer and other cancers. Tarloxotinib is a prodrug that harnesses tumor hypoxia to generate high levels of a potent, covalent pan-HER tyrosine kinase inhibitor, tarloxotinib-effector (tarloxotinib-E), within the tumor microenvironment. This tumor-selective delivery mechanism was designed to minimize the dose-limiting toxicities that are characteristic of systemic inhibition of wild-type EGFR. Experimental Design: Novel and existing patient-derived cell lines and xenografts harboring EGFR exon 20 insertion mutations, ERBB2 mutations and amplification, and NRG1 fusions were tested in vitro and in vivo with tarloxotinib to determine its impact on cancer cell proliferation, apoptosis, and cell signaling. Results: Tarloxotinib-E inhibited cell signaling and proliferation in patient-derived cancer models in vitro by directly inhibiting phosphorylation and activation of EGFR, HER2, and HER2/HER3 heterodimers. In vivo, tarloxotinib induced tumor regression or growth inhibition in multiple murine xenograft models. Pharmacokinetic analysis confirmed markedly higher levels of tarloxotinib-E in tumor tissue than plasma or skin. Finally, a patient with lung adenocarcinoma harboring an ERBB2 exon 20 p.A775_G776insYVMA mutation demonstrated a dramatic clinical response to tarloxotinib. Conclusions: Experimental data with tarloxotinib validate the novel mechanism of action of a hypoxia-activated prodrug in cancer models by concentrating active drug in the tumor versus normal tissue, and this activity can translate into clinical activity in patients.

Background Lutathera is a 177Lutetium-labeled somatostatin analog approved for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Somatostatin receptors are expressed in small cell lung cancer (SCLC). Nivolumab, an anti-PD-1 antibody, may act synergistically with lutathera to generate antitumor immunity. We conducted a phase I study of lutathera plus nivolumab in patients with advanced NETs of the lung. Methods Patients with relapsed/refractory extensive-stage SCLC (ES-SCLC), non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed a standard 3+3 design, assessing two dose levels (dose level 1: lutathera 3.7 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks; dose level 2: lutathera 7.4 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks). Results Nine patients were enrolled (six ES-SCLC, two pulmonary atypical carcinoid, one high-grade pulmonary neuroendocrine carcinoma). No dose-limiting toxicities (DLTs) were observed at dose level 1. At dose level 2, one patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related adverse events (TRAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). The most common grade 3 TRAE was lymphopenia (n=4). Among the seven patients with measurable disease, one patient with ES-SCLC had a partial response. Two patients with pulmonary atypical carcinoid had stable disease lasting 6 months. The RP2D was dose level 2. Conclusions Lutathera plus nivolumab was well tolerated and showed signs of antitumor activity. This combination warrants further exploration. Trial registration number NCT03325816

Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer characterized by rapid growth and early spread. It is a highly lethal disease that typically is diagnosed at a late stage. Surgery plays a very small role in this cancer, and management typically involves chemotherapy, delivered with thoracic radiation in early-stage disease. Platinum-based chemotherapy is initially very effective, inducing rapid and often deep responses. These responses, though, are transient, and upon relapse, SCLC is highly refractory to therapy. Immunotherapy has shown promise in delivering meaningful, durable responses and the addition of immunotherapy to first-line chemotherapy has led to the first improvements in survival in decades. Still, the disease remains difficult to manage. Incorporating radiation therapy at specific points in patient management may improve disease control. The development of predictive biomarkers and novel targeted therapies will hopefully improve options for patients in the near future. This review focuses on the current standards of care and future directions.

BackgroundNeuregulin 1 (NRG1) fusions, which activate ErbB signaling, are rare oncogenic drivers in multiple tumor types. Afatinib is a pan-ErbB family inhibitor that may be an effective treatment for NRG1 fusion-driven tumors.Patients and MethodsThis report summarizes pertinent details, including best tumor response to treatment, for six patients with metastatic NRG1 fusion-positive tumors treated with afatinib.ResultsThe six cases include four female and two male patients who ranged in age from 34 to 69 years. Five of the cases are patients with lung cancer, including two patients with invasive mucinous adenocarcinoma and three patients with nonmucinous adenocarcinoma. The sixth case is a patient with colorectal cancer. NRG1 fusion partners for the patients with lung cancer were either CD74 or SDC4. The patient with colorectal cancer harbored a novel POMK-NRG1 fusion and a KRAS mutation. Two patients received afatinib as first- or second-line therapy, three patients received the drug as third- to fifth-line therapy, and one patient received afatinib as fifteenth-line therapy. Best response with afatinib was stable disease in two patients (duration up to 16 months when combined with local therapies) and partial response (PR) of >18 months in three patients, including one with ongoing PR after 27 months. The remaining patient had a PR of 5 months with afatinib 40 mg/day, then another 6 months after an increase to 50 mg/day.ConclusionThis report reviews previously published metastatic NRG1 fusion-positive tumors treated with afatinib and summarizes six previously unpublished cases. The latter include several with a prolonged response to treatment (>18 months), as well as the first report of efficacy in NRG1 fusion-positive colorectal cancer. This adds to the growing body of evidence suggesting that afatinib can be effective in patients with NRG1 fusion-positive tumors.Key PointsNRG1 fusions activate ErbB signaling and have been identified as oncogenic drivers in multiple solid tumor types. Afatinib is a pan-ErbB family inhibitor authorized for the treatment of advanced non-small cell lung cancer that may be effective in NRG1 fusion-driven tumors. This report summarizes six previously unpublished cases of NRG1 fusion-driven cancers treated with afatinib, including five with metastatic lung cancer and one with metastatic colorectal cancer. Several patients showed a prolonged response of >18 months with afatinib treatment. This case series adds to the evidence suggesting a potential role for afatinib in this area of unmet medical need.

Oncogenic gene fusions are hybrid genes that result from structural DNA rearrangements, leading to deregulated activity. Fusions involving the neuregulin-1 gene (NRG1) result in ErbB-mediated pathway activation and therefore present a rational candidate for targeted treatment. The most frequently reported NRG1 fusion is CD74-NRG1, which most commonly occurs in patients with invasive mucinous adenocarcinomas (IMAs) of the lung, although several other NRG1 fusion partners have been identified in patients with lung cancer, including ATP1B1, SDC4, and RBPMS. NRG1 fusions are also present in patients with other solid tumors, such as pancreatic ductal adenocarcinoma. In general, NRG1 fusions are rare across different types of cancer, with a reported incidence of1%, with the notable exception of IMA, which represents ≈2%-10% of lung adenocarcinomas and has a reported incidence of ≈10%-30% for NRG1 fusions. A substantial proportion (≈20%) of NRG1 fusion-positive non-small-cell lung cancer cases are nonmucinous adenocarcinomas. ErbB-targeted treatments, such as afatinib, a pan-ErbB tyrosine kinase inhibitor, are potential therapeutic strategies to address unmet treatment needs in patients harboring NRG1 fusions.

Small cell lung cancer (SCLC) is an exceptionally lethal subtype of lung cancer. For patients with extensive-stage (ES) disease, which is the majority of patients, platinum-doublet chemotherapy has been the standard of care for decades. Dozens of phase III trials have failed to improve survival over standard platinum plus etoposide. Recent results, however, have met with long-overdue success. This manuscript reviews the new standards of care for ES-SCLC. Two recent phase III trials have shown an improvement in overall survival with concurrent immunotherapy and chemotherapy. In IMpower 133, the addition of the anti-PD-L1 antibody atezolizumab to carboplatin plus etoposide significantly improved both progression-free survival (PFS) and overall survival (OS). This was the first trial in over 30 years to improve survival. In CASPIAN, concurrent durvalumab, another anti-PD-L1 antibody, also led to an improvement in survival. While there is clearly a need to further improve outcomes, the improvement in survival with the addition of atezolizumab or durvalumab to platinum-doublet chemotherapy is a major advance. We now have new standards of care and the potential of a more meaningful benefit for patients with advanced SCLC.

After decades of platinum-based chemotherapy for advanced small-cell lung cancer, there has finally been a therapeutic advance. The combination of a platinum chemotherapy, etoposide, and an immune checkpoint inhibitor has yielded overall survival benefits in two successive phase 3 trials. Unfortunately, these trials only included fit patients, namely those with an Eastern Cooperative Oncology Group performance status of 0-1. In the real-world setting, roughly a third of patients with advanced small-cell lung cancer has a performance status of 2, and an additional 15% have a performance status of 3 or 4, meaning that approximately half of all patients are excluded from chemoimmunotherapy trials. Poor performance status is a known negative prognostic factor, with a dismal prognosis among patients with disease that does not respond to the first cycle of chemotherapy.We review current data on immunotherapy in advanced small-cell lung cancer and discuss how we integrate the new therapeutic options into daily practice.

Author(s): Cohen, Roger B; Delord, Jean-Pierre; Doi, Toshihiko; Piha-Paul, Sarina A; Liu, Stephen V; Gilbert, Jill; Algazi, Alain P; Damian, Silvia; Hong, Ruey-Long; Le Tourneau, Christophe; Day, Daphne; Varga, Andrea; Elez, Elena; Wallmark, John; Saraf, Sanatan; Thanigaimani, Pradeep; Cheng, Jonathan; Keam, Bhumsuk | Abstract: ObjectivesTreatment options for patients with unresectable or metastatic salivary gland carcinoma (SGC) are limited. Safety and efficacy of pembrolizumab for SGC expressing programmed death ligand 1 (PD-L1) were explored.Materials and methodsA cohort of patients with advanced, PD-L1-positive SGC was enrolled in the nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors (KEYNOTE-028; NCT02054806). Key inclusion criteria included recurrent or metastatic disease, failure of prior systemic therapy, and PD-L1 expression on ≥1% of tumor or stroma cells (per a prototype immunohistochemistry assay). Patients received pembrolizumab 10 mg/kg every 2 weeks for ≥2 years or until confirmed disease progression or unacceptable toxicity. Primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator review.ResultsTwenty-six patients with PD-L1-positive SGC were enrolled and treated; median age was 57 years, 88% were men, and 74% had received prior therapy for recurrent/metastatic disease. Confirmed objective response rate after median follow-up of 20 months was 12% (95% confidence interval, 2%-30%), with 3 patients achieving partial response; there were no complete responses. Median duration of response was 4 months (range, 4 to 21 mo). Treatment-related adverse events occurred in 22 patients (85%), resulting in discontinuation in 2 patients and death in 1 (interstitial lung disease); those occurring in ≥15% of patients were diarrhea, decreased appetite, pruritus, and fatigue.ConclusionsPembrolizumab demonstrated promising antitumor activity and a manageable safety profile in patients with advanced, PD-L1-positive SGC.

Purpose Liquid biopsies represent an attractive alternative to tissue biopsies, particularly rebiopsies, in determining patient eligibility for targeted therapies. Clinical utility of urine genotyping, however, has not been explored extensively. We evaluated epidermal growth factor receptor ( EGFR) T790M detection in matched urine, plasma, and tissue and the clinical outcomes of patients with advanced non–small-cell lung cancer treated with rociletinib. Methods Tissue (n = 540), plasma (n = 482), and urine (n = 213) were collected from evaluable patients enrolled in TIGER-X, a phase I/II study. Genotyping was performed by therascreen EGFR testing in tissue, BEAMing in plasma, and a quantitative short footprint assay (Trovera) in urine, which was used to further examine discordant samples. Results Positive percent agreement with tissue T790M results was similar for urine (82%; 142 of 173) and plasma (81%; 313 of 387) genotyping. Urine and plasma together identified more patients who were T790M positive (92%) than tissue alone (83%) among matched samples (n = 177). The ability to identify mutations in plasma was strongly associated with M stage ( P < .001); rate of T790M detection for patients with M1a/M0 disease increased from 54% for plasma alone to 85% when urine and plasma were both examined. Objective response rates of patients who were T790M positive were comparable between tumor (34%), plasma (32%), and urine (37%). Conclusion Clinical response to rociletinib was comparable irrespective of whether T790M status was identified by liquid or tissue biopsy. Combined, urine and plasma identified a higher percentage of patients who were T790M positive than tumor genotyping alone and improved detection of T790M, particularly in the absence of distant metastases. These findings support the noninvasive analysis of urine and plasma before tumor rebiopsy when assessing T790M status.

Background Before the availability of immunotherapy, chemotherapy was standard first-line therapy for non–small-cell lung cancer (NSCLC) lacking actionable gene alterations. Preclinical evidence suggests chemotherapy is immunomodulatory, supporting chemotherapy/immunotherapy combinations. Atezolizumab, anti-programmed death ligand-1 (PD-L1) antibody, blocks programmed cell death protein-1 and B7.1 interaction with PD-L1. GP28328 ( NCT01633970 ) assessed atezolizumab with chemotherapy in multiple tumours; we report results for advanced, treatment-naive NSCLC. Methods Patients received atezolizumab plus carboplatin with paclitaxel (Arm C: atezo/cb/pac), pemetrexed (Arm D: atezo/cb/pem, maintenance pemetrexed permitted), or nab-paclitaxel (Arm E: atezo/cb/nab-pac), four–six cycles, then atezolizumab maintenance. Primary end-point was safety; secondary end-points were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results Seventy-six NSCLC patients were enrolled (n = 25, 25 and 26 for Arms C, D and E, respectively). Common treatment-related grade III/IV adverse events were neutropenia (36% atezo/cb/pac, 36% atezo/cb/pem, 42% atezo/cb/nab-pac) and anaemia (16% atezo/cb/pac, 16% atezo/cb/pem, 31% atezo/cb/nab-pac). Confirmed ORRs were 36% atezo/cb/pac, 68% atezo/cb/pem (one complete response [CR]) and 46% atezo/cb/nab-pac (four CRs). Median PFS was 7.1 months, (95% confidence interval [CI]: 4.2–8.3), 8.4 months (95% CI: 4.7–11) and 5.7 months (95% CI: 4.4–14.8), respectively. Median OS was 12.9 months (95% CI: 8.8–21.3), 18.9 months (95% CI: 9.9–27.4) and 17.0 months (95% CI: 12.7–not evaluable), respectively. Conclusion Atezolizumab with chemotherapy was well tolerated with encouraging efficacy, though the analysis was limited by small numbers. NSCLC chemotherapy combination studies are ongoing. ClinicalTrials.gov identifier NCT01633970 .

Background The addition of atezolizumab to carboplatin and etoposide (CP/ET) significantly improved progression-free and overall survival for patients with extensive-stage small-cell lung cancer (ES-SCLC) in the IMpower133 study (NCT02763579). We have evaluated adverse events (AEs) and patient-reported outcomes in IMpower133 to assess the benefit–risk profile of this regimen. Patients and methods Patients received four 21-day cycles of CP/ET plus intravenous atezolizumab 1200 mg or placebo (induction phase), followed by atezolizumab or placebo (maintenance phase) until progression or loss of benefit. AEs were assessed and patient-reported outcomes were evaluated every 3 weeks during treatment using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 (QLQ-C30) and QLQ-LC13. Results Overall, 394 patients were assessable for safety in the induction phase and 318 in the maintenance phase. The frequency of AEs, grade 3–4 AEs, and serious AEs was similar between arms in both phases. Immune-related AEs were more frequent in the atezolizumab arm during both induction (28% versus 17%; leading to atezolizumab/placebo interruption 9% versus 5%, leading to withdrawal 4% versus 0%) and maintenance (26% versus 15%; leading to atezolizumab/placebo interruption, 3% versus 2%, leading to withdrawal 1% versus 1%), most commonly rash (induction 11% versus 9%, maintenance 14% versus 4%), and hypothyroidism (induction 4.0% versus 0%, maintenance 10% versus 1%). Changes in patient-reported treatment-related symptoms commonly associated with quality of life impairment were generally similar during induction and most of the maintenance phase. Patient-reported function and health-related quality of life (HRQoL) improved in both arms after initiating treatment, with more pronounced and persistent HRQoL improvements in the atezolizumab arm. Conclusions In patients with ES-SCLC, atezolizumab plus CP/ET has a comparable safety profile to placebo plus CP/ET, and the addition of atezolizumab did not adversely impact patient-reported HRQoL. These data demonstrate the positive benefit–risk profile of first-line atezolizumab plus CP/ET in ES-SCLC and further support this regimen as a new standard of care in this setting. Clinical trials number NCT02763579.

Resistance to chemotherapy remains a critical barrier to effective cancer treatment. Although cisplatin is one of the most commonly used chemotherapeutic agents in the treatment of non-small cell lung cancer (NSCLC), mechanisms of resistance to this drug are not fully understood. Here, we report a novel cisplatin-resistance mechanism involving SET Domain Containing 2 (SETD2), a histone H3 lysine 36 (H3K36) trimethyltransferase, and cAMP-responsive element-binding protein 1 (CREB1). A549 cells selected in vivo to give brain metastases exhibited cisplatin resistance and decreased expression of phosphorylated CREB1. Next-generation sequencing (NGS) analysis identified a missense mutation in SETD2 (p.T1171K), and we demonstrated that SETD2-mediated trimethylation of H3K36 (H3K36me3) and CREB1 phosphorylation are critical for cellular sensitivity to cisplatin. Moreover, we showed that suppression of SETD2 or CREB1 and ectopic expression of mutant SETD2 conferred cisplatin resistance through inhibition of H3K36me3 and ERK activation in NSCLC cells. Our results provide evidence that SETD2 and CREB1 contribute to cisplatin cytotoxicity via regulation of the ERK signaling pathway, and their inactivation may lead to cisplatin resistance.

The artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS).Patients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1.A total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose.The MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population. CLINICALTRIALS.NCT02353026.

Background: The prognosis for patients with castration-resistant prostate cancer (CRPC) remains suboptimal and targeted therapies should be explored. One potential target is the receptor for luteinizing hormone-releasing hormone (LHRH-R), which is highly expressed on prostate cancer cells. AEZS-108 (AN-152) is an LHRH-cytotoxic hybrid whose rational design covalently couples an LHRH agonist and the cytotoxic doxorubicin. AEZS-108 exploits the presence of these receptors to target delivery of the cytotoxic. We report the phase I trial of AEZS-108 in men with taxane-resistant CRPC. We also report correlative studies of a novel circulating tumor cell (CTC) capture device that will provide both enumeration of CTCs and LHRH-R expression on captured CTCs as well as results from AEZS-108 internalization studies that exploit the auto-fluorescence of doxorubicin in captured CTCs. Methods: This is a single-arm, dose-escalation phase I study in men with CRPC to confirm the dose established in a completed phase I trial in females. Eligibility criteria included adequate organ function and progression of disease despite prior therapy with an LHRH agonist and at least one taxane-based regimen. Patients were required to discontinue LHRH agonists to avoid receptor competition. Patients received AEZS-108 every 21 days until progression or unacceptable toxicity for up to 6 cycles. The primary endpoint was safety. Results: Enrollment began in November 2010 and completed in September 2011. Twelve patients were accrued onto 3 dose levels. No DLTs have been noted. At the time of submission, a decrease in PSA was noted in 5 of the 10 evaluable patients. The grade 3 or 4 toxicities were primarily hematologic. Final reports detailing toxicity, RECIST response and PSA response will be reported. All correlative studies will also be reported. Conclusions: AEZS-108 is well tolerated and has demonstrated early signs of antitumor activity in men with CRPC. We will report the recommended dose for the planned phase II study.

Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non–small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1–NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400–9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339