Targetable Driver Mutations Research Articles

Changing characteristics, treatment approaches and survival of patients with brain metastasis: data from six thousand and thirty-one individuals over an observation period of 30 years

BackgroundAn accurate classification of patients with brain metastases (BMs) is an important foundation to guide individualised treatment decisions and to formulate BM cohorts for modern clinical trials. MethodsSix thousand and thirty-one patients with newly diagnosed BM from different solid tumours treated between 1986 and 2020 were identified from the Vienna Brain Metastasis Registry. ResultsA rising fraction of patients presented with asymptomatic BM during the observation period (1986–1999: 20.2% vs 2010–2020: 30.6%; p < 0.001). Especially, oncogene-addicted non-small-cell lung cancer (NSCLC) and BRAF (v-Raf murine sarcoma viral oncogene homolog)-positive melanoma had a higher rate of asymptomatic BM presentation compared with wild-type tumours (p < 0.05). Significant changes of initial BM treatment approaches were observed with a decrease of neurosurgical procedures (1986–1999: 30.8% vs 2010–2020: 19.5%) and an increase of radiation treatments (1986–1999: 65.0% vs 2010–2020: 73.3%) and systemic therapies (1986–1999: 1.0% vs 2010–2020: 2.0%; p < 0.001). Median overall survival (OS) was heterogeneous between primary tumour entities but with an overall increase over the decades (median OS 1986–1999: 5 months vs 2010–2020: 7 months; p = 0.001). Survival times were longer in patients with oncogene-addicted NSCLC, BRAF-positive melanoma and hormone receptor-positive breast cancer compared with the other cancer subtypes (p > 0.05). ConclusionOur data highlight shifting trends in the symptomatic presentation and in treatment strategies of patients with BM over the last decades. Entity specific aspects and, in particular, the presence of targetable driver mutation impact the clinical presentation and prognosis. Future BM specific trials need to address the modern composition of BM cohorts and the distinct clinical course of patients with targetable driver mutations.

Whole-Brain Radiotherapy Combined With Anlotinib for Multiple Brain Metastases From Non-small Cell Lung Cancer Without Targetable Driver Mutation: A Single-Arm, Phase II Study.

Background:Existing evidence demonstrates that radiotherapy and antiangiogenic drugs have synergistic antitumour effects and may be a promising treatment option for patients with solid tumour. Thus, we performed a phase II trial to evaluate the efficacy and safety of whole-brain radiotherapy (WBRT) combined with anlotinib for multiple brain metastases (BMs) from non-small cell lung cancer (NSCLC) without targetable driver mutations.Methods:Patients with multiple BMs (⩾3) from NSCLC without targetable driver mutations who failed to respond to at least first-line chemotherapy were enrolled. Eligible patients received WBRT (30 Gy/10 f, 5 f/week) and anlotinib (12 mg/day, day 1-14 of 21 days per cycle, 2 cycles) until disease progression or treatment intolerance. The primary endpoint was intracranial objective response rate (iORR) and secondary endpoints included intracranial progression-free survival (iPFS), disease control rate (DCR), overall survival (OS), and safety.Results:Between April 2019 and March 2021, 21 patients were enrolled in the trial, of which 12 were aged ⩾60 years (57.1%), 13 were men (61.9%), 7 had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 (81.0%), 18 had adenocarcinoma (85.7%), and 11 had ⩾6 BMs (52.4%). Of the 21 evaluable patients, the iORR was 66.7% (1 complete response + 13 partial response [PR]), and 28.6% (7PR) had extracerebral lesions. The DCRs for intracerebral and extracerebral lesions were 90.5% and 81.0%, respectively. The iPFS and OS were 10.3 months (95% confidence interval [CI]: 0-24.8 months) and 13.4 months (95% CI: 0-27.9 months), respectively. The most frequently observed toxicities were loss of appetite (61.9%), hypertension (52.4%), fatigue (47.6%), diarrhoea (28.6%), vomiting (19.0%), dizziness (42.9%), and headache (33.3%). None of the patients developed grade 4 or higher grade adverse reactions.Conclusions:Anlotinib combined with WBRT is effective and well tolerated in patients with multiple BMs (⩾3) from NSCLC without targetable driver mutations. Therefore, further validation studies are required.Clinical trial registration number: ChiCTR 1900027769

Molecular Pathogenesis of Cholangiocarcinoma: Implications for Disease Classification and Therapy.

Cholangiocarcinomas are an aggressive group of heterogeneous malignancies that affect over 210,000 individuals globally each year. Their incidence is rising, particularly in Western countries. Traditionally, cholangiocarcinomas are classified based on anatomic location of the tumor and are treated with similar cytotoxic chemotherapy despite significant molecular and genomic differences. With the rise of genetic and molecular sequencing, several driver mutations have been identified and targeted as novel therapeutic approaches. The most common genomic alterations include changes in FGFR2, IDH1, KRAS, BRAF, HER2, and the tumor suppressor p53. In addition, increased understanding of the cellular and molecular constituents of the tumor microenvironment (TME) has created opportunities for further novel therapeutic approaches. New strategies using combination therapies targeting driver mutations and various components of the TME hold promise for improved patient outcomes. This review covers the evolving molecular and therapeutic landscape of cholangiocarcinoma.

Dual driver in non-small cell lung carcinoma – therapeutic dilemma

The presence of a targetable driver mutation in advanced non-small cell carcinoma is seen in about 40–50% of patients. The most common targetable driver identified is the mutation of the epidermal growth factor receptor gene. Conventionally, it was thought that these driver mutations of mutually exclusive. But due to the availability of a wider panel of molecular testing and highly sensitive methods of testing, there have been multiple case reports of more than one driver being identified in a single patient. Here in this series, we have described five such cases and have discussed the possible hypothesis and strategies in treatment.

Types of information that patients with lung cancer with targetable driver mutations and their caregivers learn from online forums: Results of a qualitative study.

161 Background: Patients and caregivers seek information about cancer from a variety of sources in addition to their medical team. In recent years, patients with specific lung cancer subtypes have created advocacy groups with active online forums for networking, support, and information exchange. We sought to describe the types of information that patients and caregivers learned from their peers online about lung cancer with targetable driver mutations. Methods: In this qualitative study, we enrolled patients with lung cancer with targetable driver alterations in EGFR, ALK, or ROS1 genes and their caregivers. We conducted individual, semi-structured interviews with participants from a single academic center, asking about their experiences learning about and living with lung cancer. Three reviewers used a framework analysis to code transcripts, and we synthesized the codes into themes. In this analysis, we focused on one theme that emerged from the data related to the information that participants learned from online forums. Results: Of 59 patients approached, 39 patients (mean age = 59, 56% female, median time from diagnosis 16 months) and 16 caregivers (69% male, all spouses or long-term partners) agreed to participate and completed interviews. Participants used online forums to compare their experiences with others to gain a preview of what might lie ahead. Specifically, they read about patients with long survival that were a source of hope, as well as patients’ experiences of progression and dying from cancer that made clinical estimates of prognosis more personal and vivid. Online forums provided a venue to learn about the latest research, available clinical trials, how to manage side effects, and where to find expert clinicians. Participants learned about the treatments received by patients at other centers. They were also exposed to emotionally intense stories of patients from around the world who lacked access to targeted therapy and sought advice from other forum members about how to find specialized care. Caregivers pointed out the distressing effect on patients of learning bad news about online peers as a downside of online forums, but overall found them beneficial and supported patients’ engagement with them. Conclusions: Online forums, particularly those that narrowly focus on specific diseases or treatments, provide patients and caregivers with anecdotal evidence that helps them with practical matters, such as how to manage side effects, as well as more existential issues, such as how long they can expect to live. These results suggest that clinicians should be open to and curious about the information that patients and caregivers learn from online forums in order to better understand the perspectives that patients and caregivers bring to discussions and decisions about their cancer.

MA17.01 Reduced FEV1 as Prognostic Factors in Patients With Advanced NSCLC Receiving Immune Checkpoint Inhibitors

The impact of reduced pulmonary function on patients with non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICI) is not fully elucidated. The aim of study is to investigate the influence of pulmonary function on the prognosis and treatment outcome in advanced NSCLC patients receiving ICI. Data were collected retrospectively from 151 patients with stage IV NSCLC who received ICI and completed spirometry before ICI therapy in Taipei Veterans General Hospital between January 2016 and December 2020. The co-primary end points were overall survival (OS) and progression-free survival (PFS) between groups divided by 80% predicted FEV1 since ICI therapy started; the secondary outcomes were objective response rate. Among 151 patients enrolled to this study, 67.5% of patients were men, 75.5% were adenocarcinoma, 24.5% had known targetable driver mutation, 33.8% received first-line ICI, and 62.8% received ICI monotherapy. The objective response rate was 24.5% and disease control rate was 54.3%. In multivariable analysis, patient with reduced FEV1 had inferior PFS (50%≤ FEV1< 80% vs. FEV1≥80%, adjusted HR= 1.67; 30%≤ FEV1< 50% vs. FEV1≥80%, adjusted HR= 1.822, FEV1< 30% vs. FEV1≥ 80%, adjusted HR= 10.39, P=0.003), and OS (50%≤ FEV1<80% vs. FEV1≥ 80%, adjusted HR= 2.10; 30%≤ FEV1< 50% vs. FEV1≥ 80%, adjusted HR= 3.43; FEV1< 30% vs. FEV1≥ 80%, adjusted HR= 14.41, P<0.001). Median PFS and OS in the preserved FEV1 group (≥80% predicted FEV1) compared to the reduced FEV1 group (<80% predicted FEV1) were 5.4 vs. 2.9 months (adjusted HR= 1.80, P=0.006) and 34.9 vs. 11.1 months (adjusted HR=2.50, P<0.001), respectively. The other independent prognostic factors of OS include stage IVA disease (adjusted HR= 0.56, P=0.032), initial liver metastasis (adjusted HR= 2.15, P=0.030), and ICI monotherapy. (adjusted HR= 1.73, P=0.042)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Reduced FEV1 is strongly associated with inferior clinical outcomes in patients with advanced NSCLC treated with ICI.

P10.07 Real-World US Treatment Patterns and Clinical Outcomes in Advanced NSCLC After Prior Platinum Chemotherapy and Immunotherapy

Immune checkpoint inhibitor (ICI) therapy and platinum-based doublet chemotherapy (PDC), combined or sequentially, are the standard of care for treatment-naive patients with metastatic non-small cell lung cancer (NSCLC) without targetable driver mutations. Upon failure of these, there is a lack of data on physicians’ treatment choices in this setting and their real-world effectiveness. This retrospective, observational study evaluated real-world treatment patterns and outcomes within US community oncology settings in this recently emerged post-ICI/PDC patient population. This study used the nationwide electronic health record (EHR)-derived de-identified Flatiron Health NSCLC database. Patients included were ≥18 years of age, diagnosed with advanced/metastatic NSCLC between January 1, 2015 and February 29, 2020. Patients were required to have had previous treatment for their advanced disease with ICI and PDC, either combined in first line (1L) or sequentially in 1L and second line (2L), and to have received treatment post-ICI/PDC. Patients were excluded if they had evidence of EGFR or ALK alterations. Patient characteristics and treatment patterns were assessed. Overall survival (OS) was estimated using Kaplan–Meier analyses and was defined as the time from the initiation of subsequent treatment following ICI and PDC until death (event) from any cause or patient censoring on the last date of activity in the Flatiron database due to lack of an event, whichever occurred first. Additional analyses by subgroups, such as histological subtype and previous ICI/PCD treatment sequence, were also conducted. Among the 2294 patients who met the study eligibility criteria, their median age was 66 years (range: 59-73), 43.0% (n=987) were female, and 93.0% (n=2134) were treated in community-based settings. Most patients (63.2%, n=1449) had received 1L PDC followed by 2L ICI, 29.6% (n=680) 1L ICI plus PDC, and 7.2% (n=165) received 1L ICI followed by 2L PDC. Of the total sample, 29.0% (n=674) of patients received regimens containing docetaxel, mainly in combination with ramucirumab (15.0%, n=344), or as monotherapy (11.0%, n=251). The median OS was 7.29 months (95% CI, 6.90-7.66) in the overall population, 6.47 months (95% CI, 5.59-7.56) with docetaxel plus ramucirumab, and 6.74 months (95% CI, 5.65-8.48) with docetaxel monotherapy. This study reports real-world treatment patterns and survival outcomes in patients with advanced/metastatic NSCLC post-ICI/PDC. These real-world results from EHRs for patients primarily treated in community settings indicate a high unmet need for new therapies that could potentially improve outcomes in patients with advanced/metastatic NSCLC post-ICI/PDC.

MA11.02 Targeting HER2 Exon 20–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor, Mobocertinib

Although pharmacologic agents targeting driver mutations in lung adenocarcinoma have led to tremendous clinical benefits for patients, human epidermal growth factor receptor 2 (HER2)-activating mutations do not have therapeutic agents and still represent an unmet clinical need. Mobocertinib is a potent tyrosine kinase inhibitor designed to target epidermal growth factor receptor (EGFR) and HER2 exon 20 insertion mutations and has reported activity in the clinic in patients with EGFR exon 20 insertionmutant non–small cell lung cancer (NSCLC).

1330P Second-line nintedanib + docetaxel for patients with lung adenocarcinoma after first-line chemo-immunotherapy treatment: Updated efficacy and safety results from VARGADO Cohort C

Treatment strategies for patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations have changed significantly during the last decade. Immune checkpoint inhibitors (ICIs), with or without chemotherapy, have become the first-line (1L) standard of care. Limited clinical data is available to help guide treatment decisions for treatment post-progression. Nintedanib (Vargatef®) is an oral triple angiokinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR) pathways.

1368TiP EPROPA: The European program for routine testing of patients with advanced lung cancer

Lung cancer represents a successful example of precision medicine application in medical oncology, since the introduction of routine molecular testing and targeted therapies into clinical practice has significantly contributed to decrease non-small cell lung cancer (NSCLC) patients’ mortality worldwide. International guidelines recommend the routine use of next generation sequencing (NGS) as new standard approach to profile advanced lung adenocarcinoma samples, with the aim of identifying targetable driver mutations that allow patients’ access to effective targeted drugs either available in daily practice or in the context of clinical trials.

Health-Related Quality of Life and Survival in Metastasized Non-Small Cell Lung Cancer Patients with and without a Targetable Driver Mutation.

Simple SummaryNSCLC patients with a targetable driver mutation are entitled to receive targeted therapy. Targeted therapy is usually less toxic than chemotherapy and immunotherapy. However, low-grade side effects are common and often chronic, which could also negatively impact a patient’s health-related quality of life (HRQOL). HRQOL in NSCLC patients with and without a targetable driver mutation is thus likely to be different. To optimize clinical decision making for individualized treatment in patients with metastatic NSCLC, it is necessary to understand differences in HRQOL and survival outcomes between patients with and without a targetable driver mutation. In this study, we show that NSCLC patients with a targetable driver mutation have favorable HRQOL over time compared to patients without a targetable driver mutation. Furthermore, clinically relevant HRQOL declines over time were significantly associated with worse survival. HRQOL can therefore play an important role in shaping patients’ expectations of their prognosis.Background: The aim of this study is to compare long-term health-related quality of life (HRQOL) and survival in metastatic NSCLC patients with (M+) and without (M−) a targetable driver mutation. Methods: An observational study was performed within the prospective SYMPRO-lung study (NL7897). HRQOL questionnaires were completed at baseline, 15 weeks, and 6 months. Generalized estimating equations (GEE) were used to assess clinically significant declines in HRQOL (>10 points) over time. Kaplan–Meier survival curves were plotted for both progression-free survival (PFS) and overall survival (OS). Results: 81 metastatic NSCLC patients were included (M+ patients; 16 (20%)). M+ patients had a significantly better global HRQOL (mean difference 12.8, ES 0.61), physical functioning (mean difference 13.4, ES 0.63), and less appetite loss (mean difference 23.1, ES 0.73) at 15 weeks of follow-up compared to M− patients. Patients with a clinically relevant decline in HRQOL at 6 months of follow-up had a significantly shorter PFS (5 months vs. 12 months, p-value < 0.001) and OS (11 months vs. 16 months, p-value 0.002). Conclusions: M− NSCLC patients have less favorable HRQOL over time compared to M+ patients. Furthermore, clinically relevant HRQOL declines over time were significantly associated with worse survival. HRQOL can therefore play an important role in in shaping patients’ expectations of their prognosis.

Challenges of Immunotherapy in Stage IV Non-Small-Cell Lung Cancer.

Treatment for metastatic non-small-cell lung carcinoma has seen important advances in recent years with the introduction of targeted therapies and immunotherapy. Immune checkpoint inhibitors, which target the programmed death 1 receptor and programmed death ligand-1, alone or in combination with platinum-based chemotherapy, have become standard of care in the first-line setting for patients with advanced non-small-cell lung carcinoma without targetable driver mutations. However, several clinical questions have now since emerged. Physicians treating lung cancer lack guidance when treating patients who have a poor performance status, patients who are receiving corticosteroids, and those known for pre-existing autoimmune disorders. Furthermore, data are scarce on rechallenging a patient with immune checkpoint inhibitors after the occurrence of a significant immune-related adverse event. In this review, we aim to shed light on these topics.

Multidisciplinary Management of Brain Metastases from Non-Small Cell Lung Cancer in the Era of Immunotherapy.

Brain metastases from non-small cell lung cancer often cause neurologic symptoms which lead to initial diagnosis or identification of recurrence. In other patients, they are identified on surveillance imaging or when a patient undergoing treatment develops neurological symptoms. Patients with symptomatic lesions should be started on dexamethasone and evaluated by a neurosurgeon as soon as possible. If feasible, surgery should be offered to decrease intracranial pressure, alleviate symptoms, and prevent irreversible neurological damage. Postoperative stereotactic radiosurgery (SRS) to the resection cavity and any additional brain metastases should follow within 4 weeks of surgery, as early as 2 weeks post-op. Tissue from surgery is used to confirm the diagnosis and test for targetable oncogenic driver mutations. Treatment response and surveillance for development of additional lesions is assessed with MRI of the brain 1 month after SRS and every 3 months thereafter. Patients who are not surgical candidates or who have small, asymptomatic brain metastases should proceed with SRS, the preferred treatment, or sometimes whole-brain radiation therapy (WBRT) if multifocal disease requires more extensive treatment, such as for leptomeningeal spread of disease. The number of brain metastases that warrants use of WBRT over SRS is controversial and a topic of ongoing investigation, and is discussed in this review. When possible, SRS is preferred over WBRT due to reduce morbidity and cognitive side effects. When patients are already on systemic therapy at time of brain metastases diagnosis, systemic therapy should continue, with radiation therapy occurring between cycles. Regarding systemic therapy for new diagnosis at time of brain metastases presentation, molecular testing will guide treatment choice, when available. If there is no neurosurgical intervention, biopsy of another site of disease may provide tissue for molecular testing. If there are no targetable oncogenic driver mutations, concurrent immune checkpoint blockade (ICB) and chemotherapy is preferable for patients who can tolerate it. Single-agent ICB is an alternative option for patients who cannot tolerate chemotherapy. Systemic therapy should start as soon as possible. In some patients with poor performance status, best supportive care may be the most appropriate choice. Treatment decisions should always incorporate patients' goals of care and in many cases should be discussed in a multidisciplinary setting.

Abstract 2866: Truncated glioma-associated oncogene homolog 1 (tGLI1) is an actionable therapeutic target in breast cancer brain metastases

Abstract Breast cancer is the second leading cause of brain metastases in women; patients with breast cancer brain metastasis (BCBM) survive only 6-18 months following diagnosis. Current standard of care options for BCBM include stereotactic radiosurgery, whole-brain radiotherapy, and surgical resection. Novel agents that act on targetable driver mutations (EGFR, ALK, PI3K, etc) and penetrate the blood-brain barrier have recently shown increasing promise as systemic options for patients with distant lung and melanoma metastases. Nevertheless, brain metastases represent an area of unmet clinical need for which new pathways, novel mechanisms, and innovative therapies are needed. Cancer stem cells are thought to be one of the driving forces behind not only distant metastasis, but also late-stage recurrence. The hedgehog pathway has been identified as an important mediator of breast cancer stem cells (BCSC); however, FDA-approved therapies targeting this pathway have demonstrated limited efficacy in breast cancer clinical trials. Despite advances made in understanding BCSC, it is still challenging to effectively target BCSC underscoring the need to identify and inhibit novel mediators of BCSC for treating BCBM patients. Our laboratory recently reported that truncated glioma-associated oncogene homolog 1 (tGLI1) promotes preferential metastasis to the brain in breast cancer by activating BCSC and astrocytes in the tumor microenvironment (Oncogene 39:64-78, 2020). tGLI1 is an alternatively spliced GLI1 variant that functions as a tumor-specific gain-of-function transcription factor and terminal effector of the hedgehog pathway. We found that tGLI1 knockdown abrogated BCBM, providing the rationale to therapeutically target tGLI1. Cell-based chemical screens followed by validations demonstrated that ketoconazole, an FDA-approved azole antifungal, specifically inhibits tGLI1 leading to suppression of BCSC in vitro and BCBM in vivo. Modification of KCZ side chains produced derivative compounds that retained tGLI1-selectivity in both in vitro models of BCSC and in vivo models of BCBM with increased blood-brain barrier penetrance. Mechanistic studies suggest that KCZ-dependent cell kill is, in part, mediated through downregulation of tGLI1 target genes OCT4, Nanog, and VEGFA. Based on these data, we opened a window-of-opportunity study in patients with BCBM to determine if ketoconazole penetrates the blood-brain barrier and alters tGLI1 signaling in humans (NCT03796273). Preliminary sample analysis has confirmed tGLI1 expression in collected BCBM and glioma samples. To help identify more effective tGLI1 inhibitors, we screened 63 azole compounds for tGLI1-selectivity and identified four additional compounds as potential tGLI1 inhibitors. Collectively, these data establish tGLI1 as an actionable target for BCBM. Citation Format: Daniel L. Doheny, Sherona R. Sirkisoon, Tadas Rimkus, Dongqin Zhu, Noah R. Aguayo, Marlyn Anguelov, Sara Manore, Fei Xing, Linda Metheny-Barlow, Kounosuke Watabe, Alexandra Thomas, Adrianna Henson Masters, Roy E. Strowd, Hui-Wen Lo. Truncated glioma-associated oncogene homolog 1 (tGLI1) is an actionable therapeutic target in breast cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2866.

Serum tumor markers for the prediction of concordance between genomic profiles from liquid and tissue biopsy in patients with advanced lung adenocarcinoma.

BackgroundThe concordance between mutations detected from plasma and tissue is critical for treatment choices of patients with advanced lung adenocarcinoma.MethodsWe prospectively analyzed the association of the serum tumor markers with the concordance between blood and tissue genomic profiles from 185 patients with advanced lung adenocarcinoma. The concordance was defined according to 3 criteria. Class 1 included all targetable driver mutations in 8 genes; class 2 included class 1 mutations plus mutations in KRAS, STK11, and TP53; class 3 included class 2 mutations plus tumor mutation burden (TMB) status.ResultsCollectively, 150 out of 185 patients had mutations in both tissue and plasma samples, while one patient was mutation-negative for both, resulting a concordance of 81.6%. The concordance rate for class 1 mutations was 80%, and 65% and 69% for class 2 and class 3, respectively. Carbohydrate antigen 19-9 (CA19-9) or cytokeratin 19 (CYFRA21-1) levels higher than the normal upper limit predicted the concordance of tissue and blood results in class 1 (P=0.005, P=0.011), class 2 (P=0.011, P<0.001), and class 3 (P=0.001, P=0.014). In class 1, the cutoff values of CA19-9 were 30, 36, and 284 U/mL to reach the concordance thresholds of 90%, 95%, and 100%, respectively (P=0.032, P=0.003, P=0.043). For CYFRA21-1, the cutoff values were 6, 18, and 52 µg/L (P=0.005, P=0.051, P=0.354). In class 2, the cutoff values for CYFRA21-1 were 18, 22, and 52 µg/L (P=0.001, P=0.001, P=0.052). In class 3, the cutoff values for CA19-9 were 36, 39, and 85 U/mL (P=0.003, P=0.001, P=0.008). For CYFRA21-1, the cutoff values were 22, 52, and 52 µg/L (P=0.900, P>0.99, P>0.99). When the sum score for 4 serum tumor markers was greater than 35, both class 1, class 2, and class 3 reached a predictive threshold of 90%.ConclusionsSerum tumor markers can be used as easy and practical clinical predictors of concordance in mutation profiles between blood and tissue samples from patients with advanced lung adenocarcinoma.

Eradication of Measurable Residual Disease in AML: A Challenging Clinical Goal.

Simple SummaryRelapse is still a major problem in AML because it occurs in about 60–80% of patients, even those who have previously achieved complete remission (CR), defined by the presence of ≤5% bone marrow (BM) leukemic cells. Thus, since CR is unable to predict the relapse risk, significantly more sensitive techniques aimed at identifying AML cells in BM or peripheral blood, a parameter termed measurable residual disease (MRD), have been developed. Among them, RT-qPCR, which analyses appropriate molecular markers, and multiparameter flow cytometry (MFC), which analyses aberrantly expressed antigens, have been identified as the methods of choice for MRD detection. Nowadays, various studies that assessed MRD by these techniques have provided compelling evidence that MRD positivity (MRD+) after standard induction/consolidation chemotherapy and before allo-HSCT is predictive of a very poor clinical outcome. In addition, other studies, which showed that MRD+ clearance even at late time points of the course of the disease may improve the disease clinical outcome, have further strengthened the relevance of MRD+. Thus, a complete MRD eradication, potentially attainable through novel innovative treatments, has emerged as an un-met clinical need in AML and is expected to improve our patients’ prognosis.In non-promyelocytic (non-M3) AML measurable residual disease (MRD) detected by multi-parameter flow cytometry and molecular technologies, which are guided by Consensus-based guidelines and discover very low leukemic cell numbers far below the 5% threshold of morphological assessment, has emerged as the most relevant predictor of clinical outcome. Currently, it is well-established that MRD positivity after standard induction and consolidation chemotherapy, as well as during the period preceding an allogeneic hematopoietic stem cell transplant (allo-HSCT), portends to a significantly inferior relapse-free survival (RFS) and overall survival (OS). In addition, it has become absolutely clear that conversion from an MRD-positive to an MRD-negative state provides a favorable clinical outcome similar to that associated with early MRD negativity. Thus, the complete eradication of MRD, i.e., the clearance of the few leukemic stem cells—which, due to their chemo-radiotherapy resistance, might eventually be responsible of disease recurrence—has become an un-met clinical need in AML. Nowadays, this goal might potentially be achieved thanks to the development of novel innovative treatment strategies, including those targeting driver mutations, apoptosis, methylation patterns and leukemic proteins. The aim of this review is to analyze these strategies and to suggest any potential combination able to induce MRD negativity in the pre- and post-HSCT period.

Driver mutations to predict for poorer outcomes in non-small cell lung cancer patients treated with concurrent chemoradiation and consolidation durvalumab.

8528 Background: The use of durvalumab after chemoradiation in locally advanced non-small cell lung cancer (NSCLC) patients significantly improves overall survival. However, it is unclear whether this benefit applies to all genetic subtypes of lung cancer. We hypothesize that patients with driver mutation NSCLC may derive less benefit from consolidation durvalumab. Methods: Using the Genomic Marker-Guided Therapy Initiative (GEMINI) database at MD Anderson, we identified 134 patients who were treated with chemoradiation followed by durvalumab for NSCLC. We segregated patients with driver mutations to targetable (EGFR, ALK translocation, ROS1 fusion, MET exon 14 skipping, RET fusion, and/or BRAF) (N = 24) and those driven by canonical KRAS mutations (N = 26). The rest (N = 84) had none of these mutations. We gathered demographic, treatment, and outcome data and compared progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method. We used multivariate regression analysis to account for demographic and treatment variables. Results: For our cohort, median age at diagnosis was 64.8, 52% were female (n = 70), and median follow up was 1.5 years. 86% of patients have a history of smoking (n = 115). 21% had squamous cell histology (n = 28). 2 patients had stage IIA disease, 6 had stage IIB, 48 had stage IIIA, 56 had stage IIIB, 13 had stage IIIC, and 9 had stage IV. 73 patients had progression after durvalumab and 37 patients died. Patients with driver mutations had significantly worse median PFS compared to those without driver mutations (8.9 mo vs 26.6 mo; HR 2.62 p &lt; 0.001). Patients with KRAS mutations had particularly poor PFS (Median 7.9 mo, HR 3.34, p &lt; 0.001), while patients with targetable driver mutations trended to worse PFS (Median 14.5 mo, HR 1.96, p = 0.056). The median OS for the cohort was 4.8 yrs with no significant differences based on driver mutation status. On multivariate analysis, only driver mutation status was associated with PFS, but not OS. For patients with first progression, we found the targetable driver group to have significantly improved time to second objective progression (PFS2) compared to the KRAS (HR 0.28, p = 0.011) or non-mutated group (HR 0.38, p = 0.025). All patients in the targetable driver group received targeted therapy after first progression. Conclusions: Our results suggest that patients with driver mutations have worse PFS compared to patients without these mutations after chemoradiation. However, patients with targetable oncogene driver mutations have significantly improved prognosis after initial progression compared to the other groups, likely due to targeted therapy, suggesting that these therapies, including novel approaches towards KRAS mutants, should be further explored in this setting.

Genomic profiling of KRAS wide-type pancreatic ductal adenocarcinomas identifies targetable genetic alterations.

4121 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and the 5-year survival of PDAC patients is below 10%. The oncogenic KRASmutations account for about 90% of PDAC cases. Unfortunately, there is no FDA-approved targeted therapy for KRAS mutations. Therefore, the genomic profiling of KRAS wide-type PDACs can provide invaluable sights to the etiology of these patients and offer them the opportunity of precision therapy trials. Methods: To characterize actionable targets in 521 Chinese PDAC patients, deep sequencing of a 831-gene panel (OncoPanscan, Genetronhealth) was applied to assess somatic mutations of their tumor tissues including SNV, insertions/deletions, CNV and re-arrangements, as well as possible pathogenic germline variants of paired genomic DNA sample. Results: There were 89% (463/521) of patients in our PDAC cohort harbored KRAS mutations. Among the remaining 58 patients in KRAS wild-type subgroup, 33% (19/58) carried activating mutations in the RTK/Ras/MAPK pathway. Targetable BRAF mutations were seen in five (9%) patients: V600E (1/5), G464V (1/5), N486_P490del (2/5) and BRAF fusion (1/5). The frequency of BRAF mutations was 9% (5/58) in KRAS wild-type PDACs but only 0.4% (2/463) in KRAS-mutated PDACs (P &lt; 0.001). We found one classic EGFR activing mutation (L747_A750delinsP) and one MAP2K1 activating mutation (F53_Q58delinsL), which can be targeted by EGFR-TKIs and MEK inhibitor trametinib, respectively. An oncogenic ERBB3 mutation (V104L) was seen in one patient, who was eligible for HER2-targeted therapy clinical trials. We also found STK11/TSC2 inactivating mutations and a dominant-negative mutation of PTEN (R130Q) which could be targeted by mTOR inhibitor everolimus and AKT inhibitor capivasertib, respectively. Additionally, we observed a patient with high level amplification of MET and another patient with the NCOA4-RET fusion gene which can be targeted by MET inhibitor carbozantinib. Interestingly, we also identified two patients with inactivating mutations in ELF3 (one frameshift and one in splicing-site), which is a driver gene of ampullary carcinoma. Lastly, two patients carried deleterious germline mutations in BRCA1 and PALB2, which may be targeted with PARP inhibitors. Overall, at least 29% (17/58) KRAS wide-type patients harbored potentially actionable genomic alterations to currently used anticancer drugs. Conclusions: The mutational landscape of our PDAC cohort provided compelling evidence that targetable driver mutations accounted for a significant portion of KRAS wide-type tumors. Our findings demonstrated that genomic profiling of PDAC patients can enable physicians to optimize their clinical management and enroll them into genomically matched clinical trials.

An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer

Background: Before the approval of first-line immune checkpoint inhibitors, platinum doublets were the standard of care in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. Pemetrexed-platinum combinations are preferred in non-squamous NSCLC. However, there has been no direct comparison to paclitaxel-carboplatin. Methods: This open-label randomized trial was designed to compare pemetrexed-carboplatin with (weekly) paclitaxel-carboplatin in treatment-naïve advanced/metastatic non-squamous NSCLC without driver mutations. Patients received either pemetrexed 500 mg/m² and carboplatin AUC 5 every 3 weeks, or paclitaxel 80 mg/m² on day 1, day 8, and day 15 with carboplatin AUC 5 every 4 weeks for 4 cycles. Patients in both arms were allowed to receive pemetrexed maintenance. Results: A total of 180 patients were enrolled. The study was terminated early; however, at the time of analysis 75.8% of the required events had occurred. Finally, 164 patients were evaluable, 83 in the pemetrexed arm and 81 in the paclitaxel arm. After a median follow-up of 17 months, progression-free survival (PFS) rates at 6 months were not different in the two treatment arms (47.45 vs. 48.64%, p = 0.88). The median PFS values were 5.67 months (95% CI 3.73–7.3) and 5.03 months (95% CI 2.63–7.43) in each arm, respectively (HR 1.13, 95% CI 0.81–1.59, p = 0.44). The median overall survival was also not different: 14.83 months (95% CI 9.5–18.73) and 11.3 (95% CI 8.3–19.7; HR 1.19, 95% CI 0.8–1.78, p = 0.37). All grade toxicities were similar except for alopecia and peripheral neuropathy, which were higher in the paclitaxel arm. Conclusion: Pemetrexed-carboplatin is not superior to (weekly) paclitaxel-carboplatin as the first-line regimen in advanced non-squamous NSCLC in terms of PFS.

Recent advances in preclinical models for lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) represents a major subtype of non-small cell lung cancer with limited treatment options. Previous studies have elucidated the complex genetic landscape of LUSC and revealed multiple altered genes and pathways. However, in stark contrast to lung adenocarcinoma, few targetable driver mutations have been established so far and targeted therapies for LUSC remain unsuccessful. Immunotherapy has revolutionized LUSC treatment and is currently approved as the new standard of care. To gain a better understanding of the LUSC biology, improved modeling systems are urgently needed. Preclinical models, particularly those mimicking human disease with an intact tumor immune microenvironment, are an invaluable tool to study cancer development and evaluate new therapeutic targets. Here, we discuss recent advances in LUSC preclinical models, with a focus on genetically engineered mouse models (GEMMs) and organoids, in the context of evolving precision medicine and immunotherapy.