Upfront Treatment Research Articles

KRAS G12 isoforms exert influence over up-front treatments: A retrospective, multicenter, Italian analysis of the impact of first-line immune checkpoint inhibitors in an NSCLC real-life population.

KRAS is commonly mutated in non-small cell lung cancer (NSCLC); however, the prognostic and predictive impact of each G12 substitution has not been fully elucidated. The approval of specific G12C inhibitors has modified the idea of KRAS "undruggability", and although the first-line standard consists of immune checkpoint inhibitors (ICIs) with or without chemotherapy, as suggested at ASCO 2022, the outcome in KRAS-mutated population is still controversial. We retrospectively described the clinical and pathological characteristics of a homogeneous G12 mutated cohort of 219 patients treated in four Italian oncologic units. We evaluated the outcome (PFS at 18 months and OS at 30 months) of those who underwent standard first-line treatment according to PD-L1 status, focusing on differences across single mutations. In the study population, 47.9% of patients harbor the KRAS G12C mutation; 20.5%, G12V; 17.4%, G12D; and 8.2%, G12A. Smoking was a common behavior of patients harboring transversions and transition mutations. PD-L1 expression does not show particular distribution in the case series, although we recorded a prevalence of PD-L1 <1% in G12V (51.4%) compared to G12A (26.7%). ICIs alone was the clinician's choice in 32.7% of patients, and the chemo-immune combination in 17.3% of patients. We described the independent prognostic role of young age (p = 0.007), female gender (p = 0.016), and an ICI-based regimen (p = 0.034) regardless of mutations. Overall, our data confirm the worst prognostic value of G12V mutation apart from treatment choice unlike the other major mutations (C, D, and A) that showed a favorable trend in PFS. KRAS G12 mutations are confirmed to have different characteristics, and the outcome is influenced by ICI first-line regimen. This study provides valuable information for further analysis in the future.

Transfusion use and effect on progression-free, overall survival, and quality of life in upfront treatment of advanced epithelial ovarian cancer: evaluation of the European Organization for Research and Treatment EORTC-55971 Cohort

BackgroundThe impact of blood transfusion on ovarian cancer survival is uncertain.ObjectiveTo investigate whether peri-operative blood transfusion negatively impacted progression-free survival, overall survival, and quality of life in patients with advanced...

Bendamustine-Rituximab in Young CLL: Relevance in the Era of Small Molecule Inhibitors.

Chemo-immunotherapies like Fludarabine-Cyclophosphamide-Rituximab (FCR) are used for treatment of chronic lymphocytic leukemia (CLL) in young and fit patients while Bendamustine-Rituximab (BR) is used in older patients. In a resource constrained setting, managing toxicities of FCR chemotherapy is challenging and this study explores the use of upfront BR treatment in young CLL patients (age < 65). Data of 61 CLL patients treated with the BR regimen between 2016 and 2020 was analysed. Overall-survival and progression-free-survival (OS and PFS) were compared between the two age groups (< / > 65years) and correlated with the fluorescent-in-situ-hybridization (FISH) data, duration of illness and time to initiation of chemotherapy. Out of 61 patients, 34 (85%) were below 65years. Five patients had del 17p and were excluded from the analysis. Forty patients had indications for treatment. Twenty-four (70.5%) of the forty patients achieved overall response; 10 developed progressive disease. The median OS and PFS was 1874days (95%CI 1617-2130days) and 1226days (95% CI 1021-1432days) respectively and were non inferior between the 2 age-groups. There were no correlations with clinical, laboratory or FISH parameters. The OS and PFS were better for patients with longer time to initiation of chemotherapy as compared to those with short duration of illness and short wait-and-watch periods (p < 0.000). Our results show that BR chemotherapy can safely and effectively be used in upfront treatment of young CLL patients and provide durable responses.

Radioresistance Mechanisms in Prostate Cancer Cell Lines Surviving Ultra-Hypo-Fractionated EBRT: Implications and Possible Clinical Applications.

The use of a higher dose per fraction to overcome the high radioresistance of prostate cancer cells has been unsuccessfully proposed. Herein, we present PC3 and DU-145, castration-resistant prostate cancer cell lines that survived a clinically used ultra-higher dose per fraction, namely, radioresistant PC3 and DU-145 cells (PC3RR and DU-145RR). Compared to PC3, PC3RR showed a higher level of aggressive behaviour, with enhanced clonogenic potential, DNA damage repair, migration ability and cancer stem cell features. Furthermore, compared to PC3, PC3RR more efficiently survived further radiation by increasing proliferation and down-regulating pro-apoptotic proteins. No significant changes of the above parameters were described in DU-145RR, suggesting that different prostate cancer cell lines that survive ultra-higher dose per fraction do not display the same grade of aggressive phenotype. Furthermore, both PC3RR and DU-145RR increased antioxidant enzymes and mesenchymal markers. Our data suggest that different molecular mechanisms could be potential targets for future treatments plans based on sequential strategies and synergistic effects of different modalities, possibly in a patient-tailored fashion. Moreover, PC3RR cells displayed an increase in specific markers involved in bone remodeling, indicating that radiotherapy selects a PC3 population capable of migrating to secondary metastatic sites. Finally, PC3RR cells showed a better sensitivity to Docetaxel as compared to native PC3 cells. This suggests that a subset of patients with castration-resistant metastatic disease could benefit from upfront Docetaxel treatment after the failure of radiotherapy.

Treatment Landscape of Relapsed/Refractory Mantle Cell Lymphoma: An Updated Review.

Mantle cell lymphoma (MCL) accounts for nearly 2-6% of all non-Hodgkin lymphoma (NHL) cases, with a steady incidence increase over the past few decades. Although many patients achieve an adequate response to the upfront treatment, the short duration of remission with rapid relapse is challenging during MCL management. In this regard, there is no consensus on the best treatment options for relapsed/refractory (R/R) disease, and the international guidelines demonstrate wide variations in the recommended approaches. The last decade has witnessed the introduction of new agents in the treatment landscape of R/R MCL. Since the introduction of Bruton's tyrosine kinase (BTK) inhibitors, the treatment algorithm and response of R/R MCL patients have dramatically changed. Nevertheless, BTK resistance is common, necessitating further investigations to develop novel agents with a more durable response. Novel agents targeting the B-cell receptor (BCR) signaling have exhibited clinical activity and a well-tolerable safety profile. However, as the responses to these novel agents are still modest in most clinical trials, combination strategies were investigated in pre-clinical and early clinical settings to determine whether the combination of novel agents would exhibit a better durable response than single agents. In this report, we provide an updated literature review that covers recent clinical data about the safety and efficacy of novel therapies for the management of R/R MCL.

Viral infections in pediatric brain tumor patients treated with targeted therapies.

Brain tumors are the most common solid malignancies and the leading cause of cancer-related mortality in children. While numerous studies report on viral infections in children with hematologic malignancies and solid organ transplantation, epidemiologic data on the incidence and outcome of viral infections in pediatric patients with brain tumors treated with targeted therapies are still lacking. We retrospectively reviewed all children with brain tumors receiving targeted therapies in a primary or recurrent setting at the Medical University of Vienna from 2006 to 2021. Demographic variables, quantitative and qualitative parameters of possible infections, and treatment outcomes were recorded. In our cohort (n=117), 36% of the patients developed at least one PCR-proven viral infection. Respiratory and gastrointestinal tract infections were most common, with 31% and 25%, respectively. Central nervous system (CNS) infections occurred in approximately 10%, with an almost equal distribution of varicella-zoster virus, John Cunningham virus (JCV), and enterovirus. Two patients tested PCR-positive for SARS-CoV-2 infection, with one virus-related death caused by a SARS-CoV-2-related acute respiratory distress syndrome. Patients receiving bevacizumab or mTOR inhibitors seem to have a greater susceptibility to viral infections. Pediatric patients with brain tumors receiving targeted therapies have a higher risk of viral infections when compared to children receiving conventional chemotherapy or the general population, and life-threatening infections can occur. Fast detection and upfront treatment are paramount to prevent life-threatening infections in immunocompromised children suffering from brain tumors receiving targeted therapies.

Impact of Time-to-Treatment on Lung SBRT Outcomes: Histology Matters!

<h3>Purpose/Objective(s)</h3> "Time-to-treatment" (TTT) is considered an indicator of quality care that has been postulated to affect lung cancer outcomes. The process by which an early stage medically inoperable lung cancer patient (pt) is deemed appropriate for lung stereotactic body radiation therapy (SBRT) typically involves a multi-disciplinary assessment over extended time. This study analyzed a large single institution registry to explore the impact of TTT on SBRT outcomes. <h3>Materials/Methods</h3> From an IRB-approved lung SBRT registry, we identified 1573 pts treated definitively for early-stage lung cancer between 2003 and 2020. TTT was defined as elapsed months between date of diagnosis (date of biopsy or date of PET CT in cases of radiographic diagnosis) and SBRT start date. Fine-Gray's Test was employed to evaluate the effect of TTT on local control (LC) and freedom from disease progression (FFP), and the long rank test was used for overall survival (OS). Cumulative incidence rates with death as competing event were calculated for LC and FFP. Actuarial analysis as used to calculate OS rates. <h3>Results</h3> Median follow-up was 22.9 months. Median age at SBRT start in years was 74.5 (range 35-98), median KPS was 80 (range 40-100), 52.3% of pts were female and 84.0% were white. Median tumor size and median PET SUV max were 2.2 cm (range 0.4-10.5) and 7.5 (range 0.8-56), respectively; 88.3% of pts were stage I. Of 75.7% pts with biopsies, 30.6% were adenocarcinomas (AC), 27.8% had squamous carcinoma (SqC). Median SBRT dose was 50 Gy in 5 fractions (40.5% cases). The 2-year rates of LC, FFP and OS for all pts were 6.5%, 76.3%, and 62.6%, respectively. Median TTT was 1.7 months (range 0.2-18.1). Using a cut-off of 1.5 months to compare patients receiving upfront vs delayed treatment, there was no difference in LC (p=0.5644), FFP (p=0.1976) or OS (p=0.3018) between the two groups. Of 1038 pts with histologic diagnosis, TTT was associated with OS but not LC or FFP for SqC pts (p=0.0422), and with no AC outcomes. An association of TTT with FFP for pts aged 70-79 (p=0.0302) was seen but otherwise no significant differences were noted in TTT outcomes for pts stratified by T stage, age in decades or KPS. Pt and tumor characteristics were balanced between cut-off cohorts. <h3>Conclusion</h3> Although TTT per se was not associated with altered lung SBRT outcomes in this cohort of nearly 1600 early-stage inoperable lung cancer pts, increasing TTT was found to have a negative association with OS for SqC pts on subset analysis. Previous studies have suggested impaired LC for SqC with SBRT although this was not seen in either of the TTT cut-off cohorts. Further work is warranted to determine how TTT may affect SBRT outcomes in the SqC population.

Can Spectroscopic Magnetic Resonance Imaging be Used to Delineate Recurrent Glioblastoma?

<h3>Purpose/Objective(s)</h3> Local glioblastoma cell volumes strongly correlate with whole brain spectroscopic MRI (sMRI) generated relative choline to N-Acetyl-Aspartate ratio (rChoNAA) maps at initial presentation. Significantly more disease is identified when rChoNAA maps, reflective of pathologically elevated metabolism and tumor replacement of normal brain, are combined with T1 post-contrast (T1PC) MRI. Despite primary radiotherapy (RT), glioblastoma almost always recurs. However, post-RT effects confound conventional MRI in recurrent glioblastoma (rGBM) where radiation necrosis appears like rGBM on T1PC, while benign edema and RT-induced leukoencephalopathy enlarge T2/FLAIR volumes. The uncertainty about tumor volume and fear of repeat radiotherapy (re-RT) toxicity in rGBM lead to re-RT volumes that typically only use T1PC and likely underestimate gross disease. We hypothesize that rChoNAA maps may uncover a larger volume of high-risk rGBM for enhanced re-RT targeting and dose escalation. <h3>Materials/Methods</h3> Retrospective analysis of an IRB-approved prospective cohort was performed on 14 rGBM patients that underwent sMRI as part of planning for re-RT. sMRI at 3T was acquired over the whole brain at 5.6 × 5.6 × 5 mm resolution in 15 minutes. Target volumes were delineated using rChoNAA ratio over 2 (rChoNAA>2) on sMRI similar to a prior prospective trial in upfront glioblastoma. rChoNAA maps and rChoNAA>2 contours were made available to the treating radiation oncologist through export to standard contouring software, and in all treated cases rChoNAA>2 volumes were included as part of the gross tumor volume. Volumes of rChoNAA>2 were compared with conventional multiparametric sequences on a routine clinical 3T MRI neuroimaging protocol including T1PC, T2/FLAIR, diffusion-restricted regions on apparent diffusion coefficient (ADC) maps, and perfusion relative cerebral blood volume (rCBV). <h3>Results</h3> rChoNAA>2 volumes (mean 29 cc, range 7-79 cc) were significantly different from all other imaging modalities using paired t-tests (p<0.01). T1PC volumes had a mean of 11 cc (range 1-31 cc). Compared to T1PC on a per patient basis, rChoNAA>2 volumes were 262% larger (range 23% smaller – 873% larger). FLAIR hyperintense volumes (mean 112 cc, range 19-233 cc) were much larger than all other modalities, reflecting likely benign and post-RT changes. Volumes of increased perfusion relative to surrounding brain were often small (mean 6.7 cc, range 0.2-19.1 cc) and volumes of restricted diffusion were often not identified and generally tiny (mean 0.8 cc, range 0-3.7 cc). <h3>Conclusion</h3> Multiparametric MRI techniques such as T1PC, FLAIR, ADC, and rCBV are confounded by post-RT effects in rGBM and are of questionable utility in re-RT planning. Similar to upfront treatment of GBM, sMRI suggests high-risk targets in rGBM undetected by conventional MRI. Pattern of failure analyses and radiologic-pathologic correlation studies are underway to confirm the utility of sMRI in rGBM.

Effect of preoperative biliary stent on postoperative complications after pancreaticoduodenectomy for cancer: Neoadjuvant versus upfront treatment

BackgroundLimited data are available regarding the effect of preoperative biliary stent, during long-course neoadjuvant chemotherapy, on postoperative complications. The aim of the study is to analyze whether the association of neoadjuvant chemotherapy and biliary stent increases overall and infectious complications after pancreaticoduodenectomy. MethodsData for 538 consecutive pancreatic ductal adenocarcinoma patients who underwent pancreaticoduodenectomy between 2015 and 2020 were retrospectively analyzed. Four groups of patients were identified: neoadjuvant chemotherapy + biliary stent (171 patients), neoadjuvant chemotherapy–no biliary stent (65 patients), upfront surgery + biliary stent (184 patients), and upfront surgery–no biliary stent (118 patients). Median neoadjuvant chemotherapy duration was 6 months. The main outcome of the study was the occurrence of postoperative infections. ResultsNo differences among the 4 groups were observed for pancreaticoduodenectomy-specific complications (ie, POPF, DGE, PPH). Infectious complications, in particular surgical site infections, were more frequent in neoadjuvant chemotherapy + biliary stent group (P = 0.001). At multivariate analysis, biliary stent was significantly associated with postoperative infectious complications in the overall cohort (odds ratio 1.996, confidence interval 95% 1.29–3.09, P = .002) and in neoadjuvant chemotherapy patients (odds ratio 5.974, 95% confidence interval 2.52–14.13, P < .001). Biliary stent significantly increased the comprehensive complication index by 9.5% (95% confidence interval 0.04–0.64, P = 0.024) in the overall cohort and 18.9% (95% confidence interval 0.22–1.23, P = .005) in the neoadjuvant chemotherapy group. The presence of multidrug-resistant microorganisms in intraoperative bile culture was not influenced by long-course neoadjuvant chemotherapy. ConclusionIn neoadjuvant chemotherapy patients, biliary stent increased the occurrence of postoperative infectious complications and surgical site infections, while the incidence of multidrug-resistant bacteria in intraoperative bile culture was similar between groups.

Comparing Patient Satisfaction After Upfront Treatment Versus Wait-and-Scan for Small Sporadic Vestibular Schwannoma.

Management of small vestibular schwannoma (VS) remains controversial, as patients are typically candidates for all three management options including microsurgery, stereotactic radiosurgery, or wait-and-scan. This study compares patient satisfaction across treatment modalities in patients with small VS. Cross-sectional study. Survey distributed to members of the Acoustic Neuroma Association and Mayo Clinic patients. Patients with small (<1 cm in any location) sporadic VS who completed at least one survey regarding treatment history and patient satisfaction were included. Among 346 patients with small VS, 106 (31%) underwent microsurgery, 78 (23%) radiosurgery, 152 (44%) wait-and-scan, and 10 (3%) multimodal treatment. Collectively, 307 (89%) patients indicated "Yes, I am happy with my treatment type and in hindsight I would not change anything," and 39 (11%) indicated "No, in hindsight I would have chosen a different treatment type." Satisfaction differed significantly by treatment group with 85, 86, 96, and 40% of patients in the microsurgery, radiosurgery, wait-and-scan, and multimodal groups reporting that they were satisfied with treatment, respectively ( p < 0.001). Satisfaction also differed significantly among those undergoing upfront treatment with microsurgery or radiosurgery (81%), initial wait-and-scan followed by treatment (88%), and wait-and-scan only groups (96%; p = 0.001). Specifically, the wait-and-scan only group demonstrated greater satisfaction compared with the other two treatment strategies ( p < 0.05 for both). Patient satisfaction with the management of small VS is generally high. Management with wait-and-scan, even if treatment is eventually pursued, may offer higher patient satisfaction compared with upfront treatment.

The Use and Short-term Outcomes of Active Surveillance in Men With National Comprehensive Cancer Network Favorable Intermediate-risk Prostate Cancer: The Initial Michigan Urological Surgery Improvement Collaborative Experience.

National Comprehensive Cancer Network favorable intermediate-risk prostate cancer is a heterogeneous disease with varied oncologic and survival outcomes. We describe the Michigan Urological Surgery Improvement Collaborative's experience with the use of active surveillance and the short-term oncologic outcomes for men with favorable intermediate-risk prostate cancer.Materials and Methods:We reviewed the Michigan Urological Surgery Improvement Collaborative registry for men diagnosed with favorable intermediate-risk prostate cancer from 2012-2020. The proportion of men with favorable intermediate-risk prostate cancer managed with active surveillance was calculated by year of diagnosis. For men selecting active surveillance, the Kaplan-Meier method was used to estimate treatment-free survival. To assess for the oncologic safety of active surveillance, we compared the proportion of patients with adverse pathology and biochemical recurrence-free survival between men undergoing delayed radical prostatectomy after a period of active surveillance with men undergoing immediate radical prostatectomy. Of the 4,275 men with favorable intermediate-risk prostate cancer, 1,321 (31%) were managed with active surveillance, increasing from 13% in 2012 to 45% in 2020. The 5-year treatment-free probability for men with favorable intermediate-risk prostate cancer on active surveillance was 73% for Gleason Grade Group 1 and 57% for Grade Group 2 disease. More men undergoing a delayed radical prostatectomy had adverse pathology (46%) compared with immediate radical prostatectomy (32%, P < .001), yet short-term biochemical recurrence was similar between groups (log-rank test, P = .131). The use of active surveillance for men with favorable intermediate-risk prostate cancer has increased markedly. Over half of men with favorable intermediate-risk prostate cancer on active surveillance remained free of treatment 5 years after diagnosis. Most men on active surveillance will not lose their window of cure and have similar short-term oncologic outcomes as men undergoing up-front treatment. Active surveillance is an oncologically safe option for appropriately selected men with favorable intermediate-risk prostate cancer.

HL-507 First-Line Brentuximab Vedotin Plus Chemotherapy Improves Overall Survival in Patients With Stage III/IV Classical Hodgkin Lymphoma: An Updated Analysis of ECHELON-1

Overall survival (OS) benefit from upfront treatment with new over existing approaches has never been shown in first-line (1L) classical Hodgkin lymphoma (cHL). With newer therapies for relapsed/refractory disease, demonstrating improved OS with 1L therapy has been challenging. In ECHELON-1 (NCT01712490), 5-year follow-up analyses supported a long-term progression-free survival (PFS) benefit with 1L brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients with stage Ill/IV cHL. A+AVD had a manageable long-term safety profile, with fewer second malignancies and more pregnancies reported vs ABVD (Connors et al, NEJM 2018; Straus et al, Lancet Haematol 2021). We report a prespecified OS analysis after approximately 6 years' follow-up. Patients were randomized 1:1 to receive up to 6 cycles of A+AVD (n=664) or ABVD (n=670) on day 1 and 15, every 28 days. OS was the key prespecified secondary endpoint. At a median follow-up of 73 months, 39 and 64 deaths occurred in A+AVD and ABVD arms, respectively; OS significantly favored A+AVD (hazard ratio [HR] 0.590; 95% confidence interval [Cl] 0.396-0.879; p = 0.009). Estimated 6-year OS rates (95% Cl) were 93.9% (91.6-95.5) vs 89.4% (86.6-91.7) with A+AVD vs ABVD, respectively, with a consistently higher OS across prespecified subgroups. The 6-year PFS estimate was 82.3% (79.1-85.0) vs 74.5% (70.8-77.7) with A+AVD vs ABVD, respectively (HR 0.678 [95% Cl 0.532-0.863]). Overall, A+AVD and ABVD had comparable long-term safety profiles. By the last follow-up, 86% (379/443) of treatment-related peripheral neuropathy cases in the A+AVD arm and 87% (249/286) in the ABVD arm either completely resolved (72% vs 79%, respectively) or were improving (14% vs 8%, respectively). Fewer second malignancies (23 vs 32) and more pregnancies (49 vs 28) were reported in the A+AVD vs ABVD arm, respectively. No new safety signals were identified. In this updated analysis, A+AVD treatment resulted in a 41% reduction in risk of death vs ABVD, with a manageable safety profile. These outcomes are important in advancing treatment of patients with previously untreated stage Ill/IV cHL.

STEM CELL TRANSPLANTATION IN BRAIN TUMORS

Central nervous system (CNS) tumors are the second most common pediatric malignancies after acute leukemias and are the most common pediatric solid tumors. Although cure rates have improved with numerous technical advances in multimodal therapy, the prognosis remains poor for some high-risk histological type and for patients with residual, recurrent or disseminated disease. Radiotherapy (RT) remains an integral part of treatment for childhood brain tumors; however, the profound and irreversible sequelae of brain irradiation in the younger children are now well documented. In an effort to decrease irradiation toxicity while improving survival and quality of life in these patients, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HD-CT&autoHSCT) has been incorporated in both up-front as well as recurrent therapies. In up-front treatment, it is used in patients under the age of 3 years to delay RT or not to use RT at all. It can be used tandem non-myeloablatively in patients older than 3 years of age, after dose-intensive chemotherapy, both to shorten the neutropenic period and to give more intense chemotherapy in a shorter time when compared to conventional chemotherapy treatment approaches. AutoHSCT may also be considered after a myeloablative conditioning regimen for relapsed embryonal brain tumors, as either once or tandem, in cases with good response to salvage therapy as consolidation. In this talk, the role of autoHSCT in childhood brain tumors will be discussed by giving the results from international studies.

MM-171 Upfront Treatment Practice Patterns in Multiple Myeloma

Multiple myeloma (MM) is a hematologic malignancy characterized by neoplastic plasma cells in the bone marrow and monoclonal paraprotein in the serum and urine. Treatment goals for MM address management of acute issues and prompt treatment to avoid further end-organ damage. The recent GRIFFIN trial (ASH 2020) demonstrated the efficacy (improved sCR and MRD) of daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVD) vs RVD without daratumumab in transplant eligible patients. Given the GRIFFIN trial's findings, this study was conducted to assess practice patterns and determine the most common upfront treatment physicians prescribe in their newly diagnosed, untreated MM patients. We conducted a survey of hematologist-oncologists actively treating MM in our region defined as Hudson Valley, upstate New York, and Southern Connecticut. Providers were informed of the region under study as well as the intended use for research for their voluntary participation. If no response was recorded, up to two follow-up requests were sent. 85 physicians were included in the study, and responses were recorded by email from 12/26/2021 to 02/13/2022. This study aims to measure the percentage of providers that have adopted the D-RVD protocol compared to other popular drug combinations indicated for MM one year after publication of the GRIFFIN trial results at ASH in December, 2020. Responses were recorded for 30 physicians and thus 35% of the population sample. There was a mean average of 1.4 requests to elicit provider response. Only 20% (6/30) of providers responded with D-RVD as their preferred front-line for standard-risk patients. The remaining 80% (24/30) preferred RVD without daratumumab as their standard upfront treatment. In the region under study, MM treating physicians have a disproportionately higher preference for the traditional RVD protocol compared to the more effective, although more recent, D-RVD protocol. This may reflect the need for a higher degree of research-informed practice among MM treating physicians within the region. Alternatively, given the fairly recent publication of the GRIFFIN trial, this finding may reflect the normal gap between published results and provider implementation of change in standard practice. Follow-up in late 2022 may demonstrate further permeation of this data as demonstrated in practice patterns.

Therapy for Recurrent High-Grade Epithelial Ovarian Cancer—The Current Status and Future Trends

AbstractOvarian malignancy is the seventh most frequently diagnosed cancer among women. The most common type is epithelial ovarian cancer. Several subtypes with distinct biological and molecular properties exist, and there is inconsistency in availability of and access to different modalities of treatment. The standard first-line management is combining surgery and platinum-based chemotherapy. Most of them are diagnosed at an advanced stage due to which they have poor outcomes. The existing screening tests have a low predictive value. Even with the best available upfront treatment, high rates of recurrences are observed. As a result, there have been major advances in the treatment of recurrences with the development of anti-angiogenic agents and PARP inhibitors. It has led to the improvement in survival and quality of life among the relapsed epithelial ovarian cancers. This review is focused on the management of recurrent epithelial ovarian cancers and future directions based on current evidence. The application of a personalized and structured approach will meaningfully bring changes in the paradigm of care in these groups of patients.

Mutational Landscape and Expression of PD-L1 in Patients with Non-Small Cell Lung Cancer Harboring Genomic Alterations of the MET gene.

Mesenchymal-to-epithelial transition (MET) exon 14 skipping mutations and MET gene amplification occur in 3-5% of non-small cell lung cancer (NSCLC) patients. Tyrosine kinase inhibitors (TKIs) targeting MET alterations have shown promising results in these patients. The aim of this study was to describe the genomic profile, PD-L1 expression and clinicopathological features of MET dysregulated NSCLC. We identified 188 patients with advanced-stage NSCLC with data on MET expression by immunohistochemistry (IHC). IHC for PD-L1 expression was performed in 131 patient samples, and next-generation sequencing (NGS) analysis was performed in 109 patient samples. MET exon 14 skipping alterations were identified in 16 (14.7%) samples, MET amplifications with cut-off ≥4 copy number variations were identified in 11 (10.1%) samples, and an oncogenic MET mutation (MET p.D1228N) was identified in 1 (0.9%) sample. 12/15 tumors (80.0%) harboring MET exon 14 alterations and 7/11 (63.6%) MET-amplified tumors expressed PD-L1 in ≥1% of tumor cells. Tumors harboring MET exon 14 skipping alterations expressed PD-L1 more frequently than MET wild-type IHC-positive tumors (p=0.045). Twenty-five percent of MET exon 14-altered cases and 33% of MET-amplified cases harbored potentially targetable oncogenic co-mutations in KRAS, BRAF, and EGFR. The most frequent co-occurring mutations in all MET-altered tumors were TP53, KRAS, BRAF, and CDK4. We demonstrated that MET exon 14 skipping alterations and MET amplification are not mutually exclusive to other oncogenic co-mutations, and report the association of genomic MET alterations with PD-L1 expression. Since genomic MET alterations are emerging targets requiring upfront treatment, optimal understanding of the co-mutational landscape for this patient population is needed.

P198 Persistent Fungemia with Candida auris in a patient with enterocutaneous fistula

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PM Objective Candida auris (C. auris) is a major emerging threat to the healthcare sector in view of the difficulty in early identification by standard methods, multidrug resistance, and ease of spread in healthcare settings. Here, we report a case of persistent C. auris fungemia (>2 months) in a patient with enterocutaneous fistula.MethodsA 57-year-old man without any comorbidities underwent surgery for diverticular perforation which was complicated by intra-abdominal abscesses, anastomotic leak, and multidrug-resistant bacteremia requiring higher antibiotics, total parenteral nutrition, and prolonged ICU stay. Patient was admitted to our center with sepsis and blood culture grew C. auris. Patient was managed with injection of caspofungin (in the absence of sensitivity breakpoints). Patient continued to grow C. auris in the blood so flucytosine was added as a part of combination antifungal therapy. On dual antifungal therapy for 28 days there was a transient clearance of fungemia. Work up for endocarditis, intrabdominal collection, and endophthalmitis were negative. But Patient was continued on total parenteral nutrition via central line in view of enterocutaneous fistula. Patient developed a recurrence of fungemia after 4 days of stopping antifungal treatment. Patient was started on injection of mycafugin and voriconazole (in view of on treatment resistance to flucytosine), on which cultures turned sterile and patient improved. Plan was made to give total 6 weeks of parenteral combination antifungal therapy.Results C. auris management complexities stem from multiple factors. The above case emphasizes the urgent need for C. auris specific minimum inhibitory concentration breakpoints and standard guidelines for treatment. Currently, treatment is based on the Center for Disease Control's proposed breakpoints (extrapolated from other Candida spp.). Upfront combination antifungal treatment might be the answer till further studies.ConclusionManagement of invasive C. auris infection presents a major therapeutic challenge to clinicians and a major threat to healthcare sector even after timely identification.

OS03.7.A Clinical characteristics, treatment and long-term outcome of patients with brain metastases from thyroid cancer - an analysis of the Vienna Brain Metastasis Registry

Abstract Background The incidence of brain metastases (BM) in patients with thyroid cancer (TC) depends on the histological subtype. About 1% of patients with differentiated (DTC), 3% with medullary (MTC) and up to 10% with anaplastic thyroid cancer (ATC) develop BM. The diagnosis of BM drastically worsens the prognosis of TC. Given the rare incidence, little is known about the presentation and outcome of this cohort. Material and Methods Patients with a histologically verified diagnosis of TC and BM were identified from the Vienna Brain Metastasis Registry, a comprehensive database managed by the Division of Oncology, Medical University of Vienna, including patients with cerebral metastasis since 1990. Data were obtained from medical records comprising clinicopathological features, treatment, BM-specific characteristics and outcome. Results 20/6074 patients included in the registry had a diagnosis of TC and radiologically verified BM. 13/20 (65%) were female and the median age at diagnosis of TC and manifestation of BM was 56 years (range 21-75) and 68 years (range 45-75), respectively. In terms of histology, 18/20 (90%) had DTC, one MTC and one ATC. Interestingly, 10/18 DTC presented with follicular histology which underlines the more aggressive course of this rare subtype. 6/20 (30%) had BM at primary diagnosis (DTC n=5, ATC n=1), while the remaining developed BM during follow-up. The median time to diagnosis of BM was 2.6 years for DTC (range 0-42), 22 years in the MTC patient and 2 months for ATC. Regarding BM-specific characteristics, all but one patient had symptoms due to BM (neurological deficits n=11, increased intracranial pressure n=5, seizures n=3). Most patients (13/20) had a singular BM, commonly located in the left hemisphere (8/13), and only one had more than three BMs. Upfront treatment for BM was local therapy (resection n=9, stereotactic radiosurgery n=7, whole brain radiotherapy n=3); one patient received supportive care only. The median overall survival (mOS) from diagnosis of TC was 6 years for DTC (range 2.5 months-42 years), 33 years for the MTC and 9 months for the ATC. The mOS from diagnosis of BM was 14 months for DTC (1.8 months-16 years), 22 years for the MTC and 3 months for the ATC. Conclusion Few patients with TC develop BM, which present commonly as single lesion. While in general BM constitute a poor prognostic factor, individual patients experience long-term survival following local therapy. More information about the optimal management of BM in TC is needed to enable guideline recommendations.

EP08.02-101 Real-world Data from KRAS-mutant Advanced NSCLC: the ATLAS Multicenter Cohort Study

Kirsten rat sarcoma (KRAS) mutations are the most common oncogenic driver in non-squamous Non-Small Cell Lung Cancer (NSCLC), occurring in approximately 25-30% of cases. Despite recent advent of novel selective KRAS inhibitors, the majority of KRAS-mutant patients still receive either immunotherapy alone or in combination with chemotherapy as upfront treatment in the routine practice. This study investigated real-world clinical features and survival outcomes of patients with advanced NSCLC harboring KRAS mutation who received standard first-line therapies in Italy.

EGFR T790M testing through repeated liquid biopsy over time: a real-world multicentric retrospective experience.

BackgroundAbout 15% of non-small cell lung cancers (NSCLCs) harbor epidermal growth factor receptor (EGFR) mutations. Upfront treatment with first and second generation EGFR tyrosine kinase inhibitors (1-2gen TKIs) is superior to chemotherapy. The most frequent resistance mechanism to 1-2gen TKIs is EGFR T790M mutation, which is targeted by osimertinib. T790M mutation can be revealed by liquid biopsy (LB) or by tissue rebiopsy (TB). LB is easily feasible but less sensitive than TB. We focused on repeated LBs and analyzed clinical features associated with EGFR T790M detection.MethodsThis is a retrospective multicenter observational study including EGFR-mutant NSCLC consecutive patients with disease progression (PD) after 1-2gen TKIs and with a first EGFR LB negative for T790M mutation, referred between 2016 and 2019. Aims of the study were to determine the prevalence of T790M mutation using LB in a real-life setting and the prevalence of T790M mutation by repeated LBs. We explored the association of T790M with clinical-pathological features and, through a survey, we evaluated the decision-making process behind LB request. Data on TBs were also collected.ResultsOne hundred and ten patients were included in the study, for a total of 326 LBs. Median number of LB per patient was 3.0. The T790M prevalence through LB was 34.5%. Over time, significantly more LBs were requested “at clinical and radiological PD” and “at radiological PD” compared to “arbitrarily”. The probability of finding the T790M mutation for a patient across each subsequent LB did not significantly change. Liver and lymph node PD were significantly correlated to T790M positivity. Notably, “at PD” compared to “arbitrarily” LB request and liver, bone or lymph node PD were correlated to the detection of any EGFR mutation in cfDNA. TB was performed in 59.7% of patients with a T790M negative LB and 18.8% of them were T790M positive. In most cases, TB was not feasible due to anatomical reasons. In our study population, the overall T790M prevalence—detected with both LB and TB—was 42.7%.ConclusionsRepeated LB testing can be useful in a real-life scenario to detect EGFR T790M mutation.