Initiation Of First-line Therapy Research Articles

Association of KRAS G12D vs. G12V circulating tumor DNA variant allele fraction and real-world overall survival in metastatic non-small cell lung and colorectal cancers.

3041 Background: We previously reported KRAS G12D but not G12V variant allele fraction (VAF), as measured in circulating tumor DNA (ctDNA), was associated with overall survival (OS) in metastatic treatment-naïve pancreatic cancer (mPDAC). However, this has not been examined in other RAS-driven cancers. Here we assessed association of real-world OS (rwOS) with KRAS G12D and G12V VAF in metastatic colorectal cancer (mCRC) and non-small cell lung cancer (mNSCLC). Methods: We queriedGuardantINFORM, a real-world evidence database of aggregated commercial payer health claims and de-identified results from Guardant360 (G360) ctDNA testing from 2014 to 2023, to identify mNSCLC/mCRC patients who were treatment-naive and had KRAS G12D or G12V mutations identified < 30 days prior to first-line therapy initiation. Those with co-occurring KRAS alterations, KRAS amplifications, and/or MSI-H were excluded. Outcomes were assessed as above vs. below median VAF and stratified by treatment type. The Cox regression model was run for continuous VAF, adjusting for age, gender, summary comorbidity score [Elixhauser Comorbidity Index (ECI)], and year of G360. Results: For mCRC, KRAS VAF above median was significantly associated with shorter rwOS for both G12D and G12V (Table 1); subgroup analysis of the predominant standard-of-care chemotherapy, FOLFOX, showed similar findings. For mNSCLC, KRAS VAF above median was associated with shorter rwOS for G12V, but not G12D (Table). Subgroup analysis by first-line treatment type revealed this association to be similar for chemotherapy-containing regimens but not immunotherapy (IO) alone. Conclusions: While a variant-specific association of KRAS VAF with rwOS was observed in mNSCLC overall (G12V associated, G12D not), above vs below median VAF was not associated with rwOS for the subset of patients receiving IO only. In contrast, for mCRC both G12D and G12V VAF were associated with rwOS, including for the subset of patients who received chemotherapy. These data suggest a complex interplay between KRAS variant, ctDNA shedding, first-line treatment, and OS that will be important in the interpretation of the prognostic implications of ctDNA-identified KRAS alterations. [Table: see text]

Abstract PS17-04: Clinical and Genomic Features of ER-Positive/HER2-negative Metastatic Breast Cancer in AURORA Molecular Screening Initiative (BIG 14-01): Mechanisms of Endocrine Therapy Resistance and Implications for Adjuvant Approaches

Abstract Background: Up to 30% of patients (pts) with ER-positive early breast cancers develop metastatic relapse. The molecular differences between endocrine therapy (ET)-sensitive and ET-resistant relapses, as well as the impact of specific adjuvant ET-based therapies, remain unclear. Methods: The AURORA program (NCT02102165) analyzed multi-omics data of paired primary (prim) and metastatic (meta) tumor tissue, along with plasma samples, from 1,156 patients with metastatic breast cancer (MBC). Targeted genome sequencing (TGS), RNA sequencing, and circulating tumor DNA analysis were performed. ET-resistance at MBC diagnosis was defined following the 5th ESO-ESMO ABC Guidelines. Results: We studied 628 pts with metastatic ER+/HER2- disease. Patient´s median age was 56 years, 133 (21%) were premenopausal, 314 (50%) had ET-resistance at recurrence (9% primary, 41% secondary), 132 (21%) had ET-sensitive recurrence, and the rest were ET-naive recurrences or de novo MBC. Adjuvant treatment was aromatase inhibitor (AI) +/- ovarian function suppression (OFS) in 288 (46%) pts, while 159 (25%) had tamoxifen only (+/- OFS). Gene expression correlation significantly differed (p < 0.005) based on ET-resistance in 92 paired samples. ET-sensitive (n=11) and de-novo tumors (n=41) showed higher correlation than primary (n=7) and secondary ET-resistance (n=32), regardless of adjuvant ET type. Prim and meta showed concordance in 91% of IHC subtypes and 62% of intrinsic subtypes. Intrinsic subtype showed 9% of prim luminal tumors switching to meta non-luminal, with 66% of Luminal A switching to Luminal B. Neither IHC nor intrinsic subtype switching was associated with the type of adjuvant ET or ET resistance. Pts with meta non-luminal intrinsic subtype (18%) had worse PFS on CDK4/6i (HR 4.0, 95% CI 1.9-8.7) and OS (HR 3.6, 95% CI 2.0-5.7) than luminal subtypes. TGS was performed in 534 meta (365 before 1L, 305 pairs). In meta before 1L, the dN/dS algorithm revealed selection in 17 genes, including TP53, PIK3CA, and ESR1. Mutations (mut) in ESR1, ERBB2, ERBB3, and RB1 among others, were specifically identified in meta. The incidence of ESR1mut was 3% in prim, 12.6% before 1L, 23.4% after 1L, and 4.7% in meta from ET-naive tumors (Table). Before 1L, ESR1mut was higher after adjuvant AI vs tamoxifen (21% vs. 4%, p< 0.001). ESR1mut incidence varied with ET-resistance (16% primary, 19% secondary, 9% sensitive, 4% ET-naïve/de novo, p< 0.01). Paired samples showed that ESR1mut were mainly acquired events and associated with higher ER mRNA signaling (hallmark estrogen response) compared to ESR1wt (p < 0.05). The agreement between ESR1mut detected in ctDNA and tissue was high before 1L (90%), and slightly lower after 1L (84%). In a multivariate model with relevant clinical factors, ESR1mut were associated with worse OS (HR 1.76, 95% CI 1.2-2.5, p=0.003), independently of TP53 and PIK3CA mutational status. Conclusion: AURORA study sheds light on metastatic tumor alterations acquired under anti-cancer therapy, in ER+/HER2- MBC. We observed a high prevalence of acquired ESR1mut prior to the initiation of first-line therapy, particularly in tumors exposed to adjuvant AI or with primary or secondary ET_resistance. The association of ESR1muts with poorer OS underscores the importance of implementing effective adjuvant ET strategies to prevent the emergence of these mutations. Frequency of driver gene mutations in primary and metastastic tumors before 1st-line treatment according to adjuvant ET and type of ET resistance Table. Citation Format: Angel Guerrero-Zotano, Matteo Benelli, Alexandre Irrthum, David Cameron, Lorenzo Ferrando, Dario Romagnoli, Marta Paoli, Arnau Llinas, Maya Dadiani, Danai Fimereli, Mafalda Oliveira, Carmela Caballero, Thayane Crestani, Elisa Agostinetto, Diogo Martins-Branco, Florentine Hilbers, Einav Gal-Yam, Marija Balic, Fatima Cardoso, Jorge Reis-Filho, Christos Sotiriou, Giuseppe Curigliano, Barbro Linderholm, Evandro de Azambuja, Susan Knox, Cristina Rotaru, Eva Ciruelos, Nancy E Davidson, Giuseppe Viale, Donatienne Taylor, Jean-Luc Canon, Lourdes Calvo, Joan Albanell, Marco Colleoni, Caroline Duhem, Nadia Harbeck, Catherine Herremans, Sibylle Loibl, Sandrine Marreaud, Elsemieke Scheepers, Alice Raimbault, Theodora Goulioti, Andrea Vingiani, Chiara Biagioni, Sebastian Vosberg, Gabriele Zoppoli, Jose Seoane, David Venet, Philippe Aftimos, Martine Piccart. Clinical and Genomic Features of ER-Positive/HER2-negative Metastatic Breast Cancer in AURORA Molecular Screening Initiative (BIG 14-01): Mechanisms of Endocrine Therapy Resistance and Implications for Adjuvant Approaches [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS17-04.

Abstract 3821: Real world outcomes among patients with newly diagnosed acute myeloid leukemia

Abstract Introduction: Treatment options for patients with acute myeloid leukemia (AML) have expanded in recent years. Although new treatments have demonstrated efficacy in clinical trials, less is known about their effect on outcomes in routine clinical practice. We examined outcomes for patients with newly-diagnosed AML (ND-AML) using real world data (RWD). Methods: This retrospective observational study was conducted using the COTA real-world (rw) database, a de-identified source of longitudinal electronic health record data pertaining to the diagnosis, management, and outcomes of patients with cancer. Adult patients with ND-AML, diagnosed January 1, 2013 to March 20, 2023 were included. First-line treatment regimens were grouped into therapeutic categories and outcomes were summarized. The index date was defined as date of initiation of first-line therapy. Results: Among 2516 patients with ND-AML included (Table), the most common regimens used were intensive chemotherapy with cytarabine (IC w/ara-C), hypomethylating agents with venetoclax (HMA+ven), and HMA alone. Complete response rate was highest in patients treated with IC w/ara-C or investigational regimen(s). Median overall survival (OS) was 16 mo overall, with highest median OS seen in patients treated with IC w/ara-C and investigational regimen(s). Median OS for patients treated with HMA+ven was 13.5 mo. Thirty-day mortality was lowest in patients treated with IC w/ara-C, CPX-351 (liposomal daunorubicin + cytarabine), and HMA+ven. Conclusions: Results suggest that IC w/ara-C remains the standard of care for most patients with ND-AML and this regimen has a higher CR rate and median OS. Variation of patient demographics and clinical characteristics across treatment groups did not permit cross-treatment comparisons, though future analyses evaluating these subgroups may provide further insight into effectiveness and safety of AML regimens in routine care for populations underrepresented in clinical trials. rwCR rate Median rwOS 30-day mortality N % (95% CI) Months (95% CI) % (95% CI) Overall 2516 45.3 (43.2, 47.3) 16.0 (14.9, 17.3) 5.9 (5.0, 6.8) IC w/ara-C 1171 60.6 (57.8, 63.4) 36.4 (31.0, 46.0) 1.6 (0.9, 2.3) HMA+ ven 300 33.7 (28.3, 39.3) 13.5 (11.4, 15.5) 3 (1.1, 4.9) Decitabine 242 12.8 (8.9, 17.7) 8.4 (6.7, 9.9) 10.4 (6.5, 14.2) Azacitidine 206 7.8 (4.5, 12.3) 7.2 (5.3, 9.6) 10.7 (6.4, 14.8) Investigational 206 61.6 (54.6, 68.3) 21.3 (15.2, 27.8) 3.4 (0.9, 5.9) Lower dose cytarabine 62 12.9 (5.7, 23.9) 8.7 (5.4, 16.1) 14.9 (5.4, 23.4) CPX-351 based 61 55.7 (42.4, 68.5) 9.3 (7.3, 15.1) 0.0 No treatment 188 NA 1.9 (1.5, 2.8) 30 (22.7, 36.6) Citation Format: Elizabeth D. Pulte, Laura L. Fernandes, Joseph Wynne, Eric Hansen, Andrew J. Belli, Anna Barcellos, Christina M. Zettler, Rebecca Bystrom, Jonathon Vallejo, Wenjuan Gu, Catherine Lerro, Kelly Norsworthy, Angelo DeClaro, Marc R. Theoret, Donna Rivera, Ching-Kun Wang. Real world outcomes among patients with newly diagnosed acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3821.

Trends over time in the proportion of sequential treatment and overall survival in patients with metastatic urothelial carcinoma in real-world practice.

606 Background: New approaches involving immune checkpoint inhibitors (ICIs) and antibody-drug conjugates prolong overall survival (OS) in patients with metastatic urothelial carcinoma (mUC). However, the access to such systemic therapy in clinical practice is suboptimal, and whether these agents improve OS in patients with mUC over time remains unclear. In the present study, we investigated the OS trend from the initiation of first-line therapy with these agents to identify changes due to the medication and time of treatment initiation. Methods: We retrospectively evaluated 195 patients who received platinum-based chemotherapy as a first line treatment. The patients were treated with chemotherapy, pembrolizumab, avelumab, or enfortumab vedotin (EV) sequentially and were divided into the following three groups: chemotherapy period (April 2009–June 2017; P1), pembrolizumab period (July 2017–December 2020; P2), and avelumab and EV period (January 2021–August 2022; P3) based on the regulatory approval. Data cutoff was set at July 31, 2023. Results: OS was prolonged over time by the new therapeutic agents, and median OS was 11, 25, not reached, and 35.5 months for patients who were treated with chemotherapy, pembrolizumab, avelumab, or EV, respectively. However, median OS was 14, 18 months, and not reached in P1, P2 and P3, respectively. Analysis by periods showed that OS was significantly longer in P2 than in P1 (HR = 0.62, 95% CI: 0.43–0.89, P = 0.009) and in P3 than in P1 (HR = 0.47, 95% CI: 0.28–0.78, P = 0.015). No difference was observed in OS between P2 and P3 (HR = 0.66, 95% CI: 0.36–1.20, P = 0.21). Overall, the proportion of patients who received ICIs increased over time, as indicated by the fact that 77 and 95 patients received ICIs (pembrolizumab or avelumab) in P2 and P3, respectively. However, the prevalence of the treatment with EV was only 24%, and 43% of patients who received pembrolizumab received best supportive care. Conclusions: This study showed an improvement in OS over time in patients with mUC in real-world practice and may indicate the importance of not missing the appropriate opportunity to receive sequential treatments.

Real-world economic burden of metastatic castration-resistant prostate cancer before and after first-line therapy initiation

Aims To describe healthcare costs of patients with metastatic castration-resistant prostate cancer (mCRPC) initiating first-line (1 L) therapies from a US payer perspective. Methods Patients initiating a Flatiron oncologist-defined 1 L mCRPC therapy (index date) on or after mCRPC diagnosis were identified from linked electronic medical records/claims data from the Flatiron Metastatic Prostate Cancer (PC) Core Registry and Komodo’s Healthcare Map. Patients were excluded if they initiated a clinical trial drug in 1 L, had <12 months of insurance eligibility prior to index, or no claims in Komodo’s Healthcare Map for the Flatiron oncologist-defined index therapy. All-cause and PC-related total costs per-patient-per-month (PPPM), including costs for services and procedures from medical claims (i.e. medical costs) and costs from pharmacy claims (i.e. pharmacy costs), were described in the 12-month baseline period before 1 L therapy initiation (including the baseline pre- and post- mCRPC progression periods) and during 1 L therapy (follow-up). Results Among 459 patients with mCRPC (mean age 70 years, 57% White, 16% Black, 45% commercially-insured, 43% Medicare Advantage-insured, and 12% Medicaid-insured), average baseline all-cause total costs (PPPM) were $4,576 ($4,166 pre-mCRPC progression, $8,278 post-mCRPC progression). Average baseline PC-related total costs were $2,935 ($2,537 pre-mCRPC progression, $6,661 post-mCRPC progression). During an average 1 L duration of 8.5 months, mean total costs were $13,746 (all-cause) and $12,061 (PC-related) PPPM. The cost increase following 1 L therapy initiation was driven by higher PC-related outpatient and pharmacy costs. PC-related medical costs PPPM increased from $1,504 during baseline to $5,585 following 1 L mCRPC therapy initiation. Limitations All analyses were descriptive; statistical testing was not performed. Conclusion Incremental costs of progression to mCRPC are significant, with the majority of costs driven by higher PC-related costs. Using contemporary data, this study highlights the importance of utilizing effective therapies that slow progression and reduce healthcare resource demands despite the initial investment in treatment costs.

Evaluation of Clinical Risk Factors and Thrombosis-Related Biomarkers in Newly Diagnosed Patients with Multiple Myeloma at Risk for Cancer-Associated Thrombosis. the Observational Roadmat-CAT-MM Study

Background: Hypercoagulability is a common blood alteration in newly diagnosed chemotherapy naïve patients with multiple myeloma. Multiple myeloma (MM) figures among malignancies that significantly increase the risk of venous thromboembolism (VTE). The rate of VTE is higher at the time of diagnosis and during the first months following initiation of first line therapy; approximately 10% of newly diagnosed MM (NDMM) will develop a VTE. Despite adequate thromboprophylaxis as per guidelines, the risk of residual VTE is not eliminated and remains as high as 12%. The optimization of VTE prevention in patients with MM is an unmet need. The exact mechanism of the increased risk of VTE is not yet fully understood. The identification of the procoagulant potential of cancer cells, which is related principally to tissue factor (TF) expression, attracts particular interest. Aim: We conducted a longitudinal prospective observational study, to explore the relationship of MM with cellular and plasma hypercoagulability as well as tissue factor positive microparticles, aiming to identify the most relevant biomarkers, which could be used in a Risk Assessment Model (RAM) for VTE in combination with clinical risk factors. Methods: Newly diagnosed patients (182) with multiple myeloma (NDMM) were prospectively enrolled. Patients were followed up for 12 months and the primary end-point was symptomatic objectively confirmed VTE. Patients were risk stratified and received thromboprophylaxis (none, aspirin on low molecular weight heparin (LMWH) based on previously published recommendations by the IMWG and EMN. Prior to treatment initiation and thromboprophylaxis initiation baseline biomarkers were obtained: Thrombin generation (TGT) in citrated PPP was assessed with the Thrombogram-Thrombinoscope® assay using PPP-reagent® 5 pm TF by Diagnostica Stago. The levels of P-Selectin and heparanase in plasma were measured with ELISA Kit (Cusabio Biotech and R&amp;D Systems respectively). The procoagulant phospholipids clotting time was measured with STA-Procoag-PPL®, Levels of Factor VIIa were measured by Staclot VIIa-rTF®, D-Dimers (DDi) by Liatest D-Di (Diagnostica Stago, France), and Tissue Factor activity (TFa) by specific clotting based home test. TF expression MPC-derived microparticles (MPC-dMPs) were detected using a Zymuphen MP-TF activity kit (Hyphen BioMed, Neuville sur Oise, France). These were compared against values in a population of healthy individuals (n=30). Results: The distribution of patients enrolled in the study is as follows: Median age was 67 years (36-86) and 52% of the population was male. Median time to follow up was 7 months (1-12 months). The control group (30 healthy individuals). The overall rate of symptomatic VTE during follow-up was 11.5% (n = 21 patients). Eleven out of 21 events (52%) occurred within 3 months from treatment initiation. Six of these patients did not receive any thromboprophylaxis; six patients were on aspirin at the time of the event and three were on LMWH.At inclusion, patients showed significantly increased levels of TFa, FVIIa, D-Dimers and FM, and significantly shorter Procoag-PPL® as compared to the group of healthy individuals. Levels of P-selectin and TM were significantly lower in patients as compared to healthy individuals. The levels of heparanase were not significantly different in the group of patients as compared to the healthy individuals. Overall thrombin generation was attenuated in patients compared to healthy individuals. Lag-time and ttPeak were significantly increased and Peak, MRI, and ETP were significantly lower as compared to the control group, MP-TF activity measured in NDMM significantly increased 1.46± 0.38 pg/mL compared to control subjects 0.19 ± 0.05 pg/mL (Table 1). Multivariate logistic regression analysis demonstrated that ETP, Procoag-PPL® and MP-TF were independently associated with VTE occurrence. (Table 2) Conclusion: The prospective ROADMAP-CAT-MM study demonstrates the presence of pronounced cellular hypercoagulability in newly diagnosed chemotherapy naïve patients with MM characterized by decreased Procoag-PPL® clotting time, enhanced endothelial cell activation, and exhausted thrombin generation. The Procoag-PPL clotting time and the ETP and MP-TF were found to be independently associated with the risk of VTE and can be prospectively incorporated into a RAM for VTE in MM.

Trend in overall survival from the start of first-line chemotherapy in patients with metastatic urothelial carcinoma.

New approaches involving immune checkpoint inhibitors and antibody-drug conjugates prolong overall survival in patients with metastatic urothelial carcinoma. However, the access to such systemic therapy in clinical practice is suboptimal, and whether these agents improve overall survival in patients with metastatic urothelial carcinoma over time remains unclear. Hence, we investigated the overall survival trend from the initiation of first-line therapy with these agents to identify changes due to the medication and time of treatment initiation. We retrospectively evaluated 195 patients from a single center. They were treated with chemotherapy, pembrolizumab, or avelumab or enfortumab vedotin. The treatment was categorized into chemotherapy, pembrolizumab or avelumab/enfortumab vedotin period. The new agents prolonged overall survival from the start of first-line therapy. Furthermore, sequential treatment with these agents in real-world clinical practice has been reported to prolong overall survival. These study results will have major implications when a new first-line therapy is approved in the future.

Biomarker Testing, Treatment, and Outcomes in Patients With Advanced/Metastatic Non-Small Cell Lung Cancer Using a Real-World Database.

Little is known about the impact of up-front biomarker testing on long-term outcomes in patients with advanced or metastatic non-small cell lung cancer (a/mNSCLC). This study compared overall survival (OS) by biomarker testing status and by receipt of guideline-concordant therapy in a large real-world cohort of patients with a/mNSCLC in the United States. This retrospective study used an a/mNSCLC database derived from real-world electronic healthcare records. Patients diagnosed with nonsquamous a/mNSCLC who initiated first-line therapy on or after January 1, 2015, were included. We describe the testing of patients for actionable biomarkers and whether they subsequently received guideline-recommended first-line treatment. OS was defined as the number of months from the initiation of first-line therapy to the date of death or end of follow-up, and was described using Kaplan-Meier analysis. Multivariable Cox proportional hazard modeling was conducted to compare OS between groups adjusting for baseline covariates; adjusted hazard ratios (HRs) were reported. A total of 21,572 patients with a median age of 69 years (IQR, 61-76 years) and follow-up of 9.5 months (IQR, 3.5-21.5 months) were included. Among patients in the database, 88% had a record of receiving testing for at least 1 biomarker at any time, and 69% of these patients received testing before or at the start of first-line treatment. The adjusted hazard of death was 30% higher in patients who never (vs ever) received biomarker testing in the database (HR, 1.30; 95% CI, 1.24-1.37), and 12% higher in patients who did not receive (vs did receive) biomarker testing before or at the start of first-line treatment (HR, 1.12; 95% CI, 1.08-1.16). The adjusted hazard of death was 25% higher in patients who did not receive guideline-concordant first-line treatment (vs those who did) after having a biomarker-positive disease (HR, 1.25; 95% CI, 1.13-1.40). Findings suggest that receipt of first-line treatment that is concordant with biomarker testing results and treatment guidelines is associated with improved survival outcomes in patients with a/mNSCLC in the United States.

Systemic treatment of patients with locally advanced or metastatic cholangiocarcinoma - an Austrian expert consensus statement.

Locally advanced or metastatic cholangiocarcinoma is an aggressive carcinoma with a dismal prognosis. For the first-line treatment of locally advanced or metastatic cholangiocarcinoma, cisplatin/gemcitabine has been the standard of care for more than 10 years. Its combination with the immune checkpoint inhibitor durvalumab resulted in an efficiency improvement in the phase III setting. Regarding the use of chemotherapy in the second line, positive phase III data could only be generated for FOLFOX. The evidence base for nanoliposomal irinotecan (Nal-IRI) plus 5-fluorouracil (5-FU) and leucovorin (LV) is contradictory. After the failure of first-line treatment, targeted therapies can be offered if the molecular targets microsatellite instability-high (MSI-H), IDH1, FGFR2, BRAF V600E, and NTRK are detected. These targeted agents are generally preferable to second-line chemotherapy. Broad molecular testing should be performed, preferably from tumor tissue, at the initiation of first-line therapy to timely identify potential molecular targets.

Outcomes of patients with brain metastases from renal cell carcinoma treated with first-line therapies: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

600 Background: The outcomes of patients with brain metastases from renal cell carcinoma (RCC) are not well characterized due to exclusion of these patients from clinical trials. Methods: Using the IMDC, patients with brain metastases from RCC at the initiation of first-line therapy were analyzed. Baseline patient characteristics, brain-directed local therapies, clinician assessment of best overall response as per RECIST 1.1, and overall survival (OS) were compared across first-line therapies, namely immuno-oncology (IO)-based combination therapy (IO/IO or IO/vascular endothelial growth factor (VEGF)) and anti-VEGF monotherapy (sunitinib or pazopanib). Results: The overall cohort of patients with brain metastases included 775 patients, consisting of 78/1298 (6.0%) and 697/8633 (8.1%) in the IO-based and anti-VEGF cohorts, respectively (p = 0.009). Among the baseline patient characteristics, only the proportion of patients receiving whole-brain radiotherapy differed significantly across the IO-based and anti-VEGF cohorts with proportions of 25.0% and 55.7%, respectively (p &lt; 0.001). Best overall response in all disease sites was 3.4% complete response (CR), 25.9% partial response (PR), 39.7% stable disease (SD), and 31% progressive disease (PD) in the IO-based cohort, whereas it was 0.7% CR, 29.6% PR, 36.7% SD, and 33.0% PD in the anti-VEGF cohort (p = 0.223). The following factors were significantly associated with longer OS on multivariable analysis: IMDC favourable-/intermediate-risk (HR 0.49, 95% CI 0.37–0.65; p &lt; 0.001), IO-based combination therapy (HR 0.51, 95% CI 0.29–0.92; p = 0.026), neurosurgery (HR 0.62, 95% CI 0.47–0.83; p = 0.001), and stereotactic radiosurgery (HR 0.64, 95% CI 0.49–0.84; p = 0.001). Conclusions: Patients with brain metastases receiving IO-based combination therapy may have longer OS than those receiving anti-VEGF monotherapy. Brain-directed local therapies including neurosurgery and stereotactic radiosurgery were associated with longer OS. [Table: see text]

Identifying Primary Refractory Disease and Early Relapses in Peripheral T-Cell Lymphoma Using Baseline Characteristics, Minimal Residual Disease, and Mutational Profiling

INTRODUCTION: Despite approvals in the relapsed/refractory setting for T-cell lymphomas, upfront advances have been more difficult to realize. A critical component in improving treatment paradigms is a greater ability to identify patients at diagnosis with high-risk for chemorefractory disease who may benefit from alternative induction programs and distinguish them from patients who fare well with standard approaches. In order to characterize such cases, we analyzed patients treated at Memorial Sloan Kettering (MSK) with curative intent to identify features associated with primary refractoriness or early relapse (<1 year). METHODS: We identified patients ≥ 18 years of age with PTCL-NOS, AITL, or ALCL who either were consecutively treated at our center at the time of diagnosis or were seen during initial therapy from 1/1/2001-10/1/2021. All patients had histologically-confirmed disease and were treated with curative intent. Patients were grouped into two sub-cohorts: (1) primary refractory disease/early relapse (< 1 year), or (2) relapse-free at 1 year from initiation of first-line therapy. Patients without relapse but < 1 year of followup were excluded. A univariate logistic regression was performed to compare baseline features between the sub-cohorts using the Wilcoxon rank sum test and Pearson's Chi-squared test. A multivariate model was then constructed using histology and baseline IPI apriori and any factor significant in univariate analyses to produce odds ratios (OR) for primary refractory disease/early relapse. In a separate analysis of patients who underwent autologous transplant (autoHCT) in 1st remission, the impact of bone marrow (BM) minimal residual disease (MRD) on PFS was evaluated. Finally, in a subset of patients who underwent targeted mutational profiling at diagnosis (Ptashkin et al., Cancer Res 2019), genomic results were analyzed. Genes were characterized into oncogenic pathways (Sanchez-Vega et al., Cell 2018) and included in analyses if mutations were present in ≥ 5% of patients. A Cox regression model was performed for altered genes/pathways to obtain hazard ratios (HR) for progression/death, with significance testing using the false discovery rate correction for multiple testing (q-value). RESULTS: A total of 349 patients were identified (Table 1). With a median followup time of 60 months (m) among survivors (IQR: 23-95), median PFS and OS of the entire cohort was 19 (95% CI 13-28) and 73 m (60-128), respectively. By histology, 2-year PFS for PTCL-NOS, AITL, ALK- ALCL, and ALK+ ALCL was 33%, 43%, 66%, and 79%, respectively (p<0.001); 5-year OS was 41%, 54%, 75%, and 92%, respectively (p<0.001, Figure 1). In comparing those with primary refractory disease/early relapse versus those relapse-free at 1-year, patients with PTCL-NOS, stage III/IV disease, >1 extranodal site, BM involvement, and cutaneous involvement were significantly more likely to have primary refractory disease/early relapse. On multivariable analysis, a diagnosis of PTCL-NOS (OR for AITL: 0.42, 95% CI 0.22-0.81), advanced IPI (OR for IPI 4-5: 4.88, 95% CI 1.56-16.8), BM involvement (OR: 2.28, 95% CI 1.14-4.68), and cutaneous involvement (OR: 2.47, 95% CI 1.04-6.21) all conferred increased risk of primary refractory disease/early relapse. In the subgroup analysis of BM MRD status in patients who underwent autoHCT, the presence of MRD did not significantly impact PFS (5-year PFS 45% MRD+ vs. 45% MRD, p=0.55). Finally, in evaluation of mutational profiles (n=86), mutations in TET2 (59%), RHOA (30%) and DNMT3A (23%) were the most commonly altered genes. Although rare (n=6), alterations in DNA damage response pathways significantly increased risk of progression (HR 5.08, 95% CI 2.05-12.6, q-value=0.007) and death (HR 9.9, 95% CI 3.22-30.8, q-value=0.001). CONCLUSIONS: This is one of the largest cohorts of nodal PTCL in the 21st century. Despite prolonged survival in some patients, primary refractory disease/early relapses remain common. On multivariate analyses, a histological diagnosis of PTCL-NOS, advanced IPI, BM involvement, and cutaneous involvement predicted primary refractoriness/early relapse. Efforts to improve frontline strategies in PTCL should focus on identifying and exploiting biological vulnerabilities in such patients, and trials of intensified regimens/alternative platforms should prioritize evaluation of these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Transcriptional Biomarkers of Differentially Detectable Mycobacterium tuberculosis in Patient Sputum.

Certain populations of Mycobacterium tuberculosis go undetected by standard diagnostics but can be enumerated using limiting dilution assays. These differentially detectable M. tuberculosis (DD M. tuberculosis) populations may have relevance for persistence due to their drug tolerance. It is unclear how well DD M. tuberculosis from patients is modeled by a recently developed in vitro model in which M. tuberculosis starved in phosphate-buffered saline is incubated with rifampin to produce DD M. tuberculosis (the PBS-RIF model). This study attempted to answer this question. We selected 14 genes that displayed differential expression in the PBS-RIF model and evaluated their expression in patient sputa containing various proportions of DD M. tuberculosis. The expression of 12/14 genes correlated with the relative abundance of DD M. tuberculosis in patient sputa. Culture filtrate (CF), which promotes recovery of DD M. tuberculosis from certain patient sputa, improved these correlations in most cases. The gene whose reduced expression relative to M. tuberculosis 16S rRNA showed the greatest association with the presence and relative abundance of DD M. tuberculosis in patient sputa, icl1, was recently shown to play a functional role in restraining DD M. tuberculosis formation in the PBS-RIF model. Expression of icl1, combined with two additional DD M. tuberculosis-related genes, showed strong performance for predicting the presence or absence of DD M. tuberculosis in patient sputa (receiver operating characteristic [ROC] area under the curve [AUC] = 0.88). Thus, the in vitro DD M. tuberculosis model developed by Saito et al. (K. Saito, T. Warrier, S. Somersan-Karakaya, L. Kaminski, et al., Proc Natl Acad Sci U S A 114:E4832-E4840, 2017, https://doi.org/10.1073/pnas.1705385114) bears a resemblance to DD M. tuberculosis found in tuberculosis (TB) patients, and DD M. tuberculosis transcriptional profiles may be useful for monitoring DD M. tuberculosis populations in patient sputum. IMPORTANCE Differentially detectable M. tuberculosis (DD M. tuberculosis), which is detectable by limiting dilution assays but not by CFU, is present and enriched for in TB patient sputum after initiation of first-line therapy. These cryptic cells may play a role in disease persistence due to their phenotypic tolerance to anti-TB drugs. A recently developed in vitro model of DD M. tuberculosis (the PBS-RIF model) has expanded our understanding of these cells, though how well it translates to DD M. tuberculosis in patients is currently unknown. To answer this question, we selected 14 genes that displayed differential expression in the PBS-RIF model and evaluated their expression in TB patient sputa. We found that 12/14 of these genes showed a similar expression profile in patient sputa that correlated with the relative abundance of DD M. tuberculosis. Further, the expression of three of these genes showed strong performance for predicting the presence or absence of DD M. tuberculosis in patient sputa. The use of DD M. tuberculosis transcriptional profiles may allow for easier monitoring of DD M. tuberculosis populations in patient sputum in comparison to limiting dilution assays.

Pembrolizumab-combination therapy for previously untreated metastatic nonsquamous NSCLC: Real-world outcomes at US oncology practices.

The availability of immunotherapies has expanded the options for treating metastatic NSCLC, but information is needed regarding outcomes of immunotherapy for patients treated outside of clinical trials. The aim of this retrospective study was to evaluate the outcomes of therapy with first-line pembrolizumab plus pemetrexed and carboplatin (pembrolizumab-combination) for patients with metastatic nonsquamous NSCLC in the real-world setting of oncology clinics in the United States (US). Using deidentified, longitudinal patient records from a nationwide, electronic health record-derived US database, we identified patients with metastatic nonsquamous NSCLC, without EGFR/ALK/ROS1 genomic alterations, who had received no previous systemic anticancer therapy. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and initiated first-line pembrolizumab-combination therapy from 11-May-2017 to 31-January-2019; data cutoff was 31-August-2020. Patients treated in a clinical trial were excluded. Manual chart review supplemented technology-enabled abstraction to identify disease progression and tumor response. Time-to-event endpoints from initiation of pembrolizumab-combination therapy were determined using Kaplan-Meier. Of 377 patients with metastatic nonsquamous NSCLC, 105 (28%), 104 (28%), and 103 (27%) had programmed death-ligand 1 (PD-L1) expression ≥50%, 1-49%, and <1%, respectively; PD-L1 expression was not documented for 65 patients (17%). Median age was 66 years, and 227 patients (60%) were men. Median follow-up time from first-line therapy initiation to data cutoff was 31.2 months (range, 19.0-39.6 months). Median pembrolizumab real-world time on treatment (rwToT) was 5.8 months (95% CI, 5.0-6.7); 12- and 24-month on-treatment rates for pembrolizumab were 28.0% and 14.9%, respectively. Median overall survival (OS) was 17.2 months (95% CI, 13.6-19.9). For patients in PD-L1 expression ≥50%, 1-49%, <1%, and unknown cohorts, the 12-month survival rates were 66.0%, 58.5%, 54.5%, and 58.3%, respectively, and 24-month survival rates were 43.1%, 37.2%, 35.6%, and 42.0%, respectively. Median real-world progression-free survival was 6.2 months (95% CI, 5.5-7.1); and the real-world response rate was 39.3%, with median duration of response of 13.1 months (95% CI, 10.5-16.8). These findings demonstrate the benefits of first-line pembrolizumab-combination therapy for patients with EGFR/ALK-wild-type, metastatic nonsquamous NSCLC and good performance status who are treated at US community oncology clinics.

Can machine learning predict pharmacotherapy outcomes? An application study in osteoporosis

Background and objectiveThe specific aim of this study is to develop machine learning models as a clinical approach for personalized treatment of osteoporosis. The model performance on outcome prediction was compared between four machine learning algorithms. MethodsRetrospective, electronic clinical data for patients with suspected or confirmed osteoporosis treated at Wan Fang Hospital between 2011 to 2018 were used as inputs for building the following predictive machine learning models,i.e., artificial neural network (ANN), random forest (RF), support vector machine (SVM) and logistic regression (LR) models. The predicted outcome was defined as an increase/decrease in T-score after treatment. A genetic algorithm was employed to select relevant variables as input features for each model; the leave-one-out method was applied for model building and internal validation. The model with best performance was selected by a separate set of testing. Area under the receiver operating characteristic curve, accuracy, precision, sensitivity and F1 score were calculated to evaluate model performance. Main analysis for all the patients with subclinical or confirmed osteoporosis and subgroup analysis for the patients with confirmed osteoporosis (T score < -2.5) were carried out in this study. ResultsA genetic algorithm was employed to select 12 to 18 features from all 33 variables for the four models. No difference was found in accuracy (ANN, 71.7%; LR, 70.0%; RF, 75.0%; SVM, 66.7%), precision (ANN, 80.0%; LR, 59.3%; RF, 70.0%; SVM, 63.6%), and AUC (ANN, 0.709; LR, 0.731; RF, 0.719; SVM, 0.702) among the ANN, LR, RF and SVM models. Main analysis in performance revealed significant recall in the LR model, as compared to ANN and SVM model; while subgroup revealed significant recall in ANN model, compared to LR and SVM model. ConclusionsMachine learning-based models hold potential in forecasting the outcomes of treatment for osteoporosis via early initiation of first-line therapy for patients with subclinical disease; or a switch to second-line treatment for patients with a high risk of impending treatment failure. This convenient approach can assist clinicians in adjusting treatment tailored to individual patient for prevention of disease progression or ineffective therapy.

RWD99 Initial Treatment Patterns for Newly Diagnosed, Commercially Insured Patients with Psoriasis

Psoriasis is a common chronic inflammatory immune-mediated skin disease which affects 3% of the US population and remains undertreated. This study examined utilization rates and time-to-treatment initiation of first-line therapy among newly diagnosed, commercially insured patients.

The utility of liquid biopsies for management of stage IV non-small cell lung cancer (NSCLC) in an academic community medical center.

e20577 Background: The management of stage 4 non-squamous non-small cell lung cancer (NSCLC) relies heavily on the use of tumor genotyping that allows for the preferential use of targeted therapies as first-line treatment to eligible patients. Recently, the “liquid biopsy”, a non-invasive genomic analysis of circulating tumor DNA, has been deemed a suitable complementary method to identify actionable mutations and guide therapy in NSCLC patients. At our community-based academic medical system in suburban Philadelphia, liquid biopsies began to be used more regularly for these patients in 2018. All patients in the study received tissue biopsies with molecular testing. Our study compared patients who also underwent liquid biopsy with patients who did not, in order to determine whether performance of this biopsy affected their treatment. Methods: This retrospective cohort study used a bank of Main Line Health patients diagnosed with Stage 4 non-squamous NSCLC from 2014-2020. Chart review was used to extract variables from these patients regarding dates of tissue biopsies and treatments, information on liquid biopsies, and demographic information. The primary objective was to compare the rate of detection of actionable mutations in the liquid biopsy vs. non-liquid biopsy cohorts. A secondary objective was to assess the time interval between the identification of a potential lung cancer by imaging and the initiation of first line therapy. Results: 152 patients met inclusion criteria and of these 68 patients underwent liquid biopsy testing and 84 patients did not. Of the 68 patients who underwent liquid biopsy testing, 34 patients (50% patients) did not have sufficient tissue on their tissue biopsy for a molecular diagnosis. Of these 34 patients, 15 patients (44%) had an actionable mutation detected with liquid biopsy. Thus, 28 patients (41%) of the liquid biopsy group had actionable mutations detected. In comparison, only 18 patients (21%) in the cohort without liquid biopsy testing had actionable mutations detected. The initiation of first line treatment occurred sooner for the group undergoing liquid biopsies, an average of 48.3 days (median 40.5 days, range 13-317) compared to 72.7 days (median 50.5 days, range 14-534), p = 0.012 by two-tailed T-test. Conclusions: In our community academic medical center, patients with stage IV non-squamous, NSCLC who underwent a liquid biopsy as part of their initial diagnostic workup had a higher rate of detection of actionable mutations and initiated first line therapy sooner than patients who received only tissue-based molecular diagnostic testing.

Treatment heterogeneity and overall survival in patients with advanced/metastatic gastric or gastroesophageal junction adenocarcinoma in the United States.

Gastric or gastroesophageal junction (GEJ) adenocarcinoma is the most common form of gastric cancer diagnosed in the United States (US) each year. Diagnosis typically is in later stages of disease when it has advanced. Patients have been treated with a variety of regimens. The goal of this retrospective study was to understand if treatment patterns were becoming more homogeneous or remaining heterogeneous using the Herfindahl-Hirschman index (HHI) and if treatments were becoming more concordant to treatment guidelines published by the National Comprehensive Cancer Network (NCCN). HHI scores were calculated for each site by 2-year increments. Trend analyses were conducted for HHI scores over time using a linear regression model. Concordance to Category 1 and any category NCCN guidelines was determined based on the date treatment was initiated with the version of the NCCN guidelines at that time. Time trend analyses were conducted using linear regression models. This study utilized data from the Flatiron Advanced Gastric/Esophageal cohort. This study also examined overall survival (OS) rates estimated by the Kaplan-Meier method by line of therapy. There were no statistically significant differences in HHI scores in the first-line setting over time, suggesting heterogeneity has not improved. Concordance to NCCN treatment guidelines for any category significantly increased over time, however Category 1 regimen concordance remained low in the first-line setting. Concordance over time improved in second-line treatment. Median OS from the start of first-line therapy was 13.57 months. There was no relationship between OS time from initiation of first-line therapy and HHI score, concordance with NCCN guidelines, or concordance with NCCN Category 1 guidelines in the first-line setting. Treatment heterogeneity persists in gastric cancer care, though there is a significant association between heterogeneity and concordance with both Category 1 and any category in the NCCN treatment guidelines, and that concordance has increased over time.

Increased adherence to molecular profiling recommendations in non–small cell lung cancer through use of prior authorization and peer review.

9129 Background: National oncology guidelines advocate for broad molecular profiling to detect potentially actionable driver mutations prior to initiation of first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). Results of genomic tests can confirm the presence of specific cancer tumor mutations that are best treated with more targeted therapies. Recent studies have shown that up to 30% of lung cancer patients may not receive the most effective treatment due to a lack of guideline-concordant genomic testing. We analyzed data from our prior authorization medical oncology program to determine adherence to national guidelines recommendations, and then developed a program to improve adherence to broad molecular profiling utilizing our proprietary prior authorization algorithms and our proactive peer consultation model. Methods: eviCore healthcare uses the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to support its proprietary program for medical oncology drug management, and requires attestation on the results of NCCN recommended genomic/molecular test results in advanced NSCLC during prior authorization of systemic therapy. In November 2019, we implemented a next-generation sequencing (NGS) testing results requirement for metastatic non-squamous NSCLC patients prior to first-line therapy approval. If testing had not been completed, a peer to peer consultation was performed to advocate for testing prior to initiation of chemoimmunotherapy regimens. The rate of appropriate tumor testing is defined by provider attestation of test results prior to initiation of therapy. We define the control period (pre- implementation) as October 2018 through September 2019 ( n = 667). The measurement period (post-implementation) is January 2020 through December 2020 ( n = 390). Results: From pre to post there was a 35% increase in testing adherence (p &lt; 0.001). After the testing requirement was implemented, the appropriate tumor testing rate increased to 99% by the second half of 2020, compared to the control period (62%). Additionally, after the testing requirement began, pembrolizumab utilization for advanced stage NSCLC decreased by a net 4.2% per month. This decrease in pembrolizumab utilization likely reflected patients being matched to more appropriate targeted therapy based on genomic testing results. Conclusions: We demonstrate that by combining medical oncology prior authorization with focused peer consultation, adherence to national society recommendations for broad molecular profiling prior to initiating first line therapy in advanced NSCLC can be significantly improved. By improving testing adherence, the most effective and appropriate therapy can be matched to the patient.

Aflibercept as a treatment for malignant tumors

Targeted therapy for colorectal cancer usually includes anti-vEgf and anti-EgfR antibodies. The initiation of first-line therapy for metastatic colorectal cancer depends on the baseline patient’s characteristics, tumor spread, and its mutational status. Despite the wide range of possible combinations of these factors, an oncologist should choose between standard platinum-based chemotherapy regimens and combination of similar chemotherapeutic agents with bevacizumab or cetuximab. Disease progression after first-line therapy poses a dilemma to an oncologist, since the range of potentially beneficial targeted drugs or immunotherapeutic agents is much wider along with the lack of sufficient evidence. This article focuses on the efficacy of aflibercept as a second-line treatment for colorectal cancer, indications for its use, and outlooks.

A209 EXPERT CONSENSUS CRITERIA AND PRACTICAL RECOMMENDATIONS FOR PBC CARE IN THE COVID-19 ERA AND BEYOND

BackgroundPrimary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease that can progress to liver fibrosis and cirrhosis, and requires timely diagnosis, optimal treatment, and risk stratification. Several guidelines for the management of PBC have been published, including the American Association for the Study of Liver Disease (AASLD) and European Association for the Study of the Liver (EASL) Clinical Practice Guidelines, which include goals for standards of PBC care. However, recent audits have identified deficiencies in real-world PBC care. In addition, the global coronavirus (COVID-19) pandemic has generally reduced access to care, diminished healthcare resources and accelerated the use of remote patient management. There is therefore a need for simple, actionable guidance that physicians can implement in order to maintain standards of care in PBC in the new environment.AimsA working group of ten PBC specialists from Europe and Canada were convened by Intercept Pharmaceuticals in January 2020 with the aim of defining key criteria for the care of patients with PBC.MethodsFollowing the outbreak of the COVID-19 pandemic, based on these criteria, a smaller working group of six PBC specialists developed practical recommendations to assist physicians in maintaining standards of care and to guide remote management of patients.ResultsThe working group defined five key criteria for care in PBC, encompassing PBC diagnosis, initiation of first line therapy with ursodeoxycholic acid (UDCA), risk stratification on UDCA, symptom management, and initiation of 2L therapy. The group developed 21 practical recommendations for the management of patients with PBC in the COVID-19 environment including modality, frequency and timing of investigations and monitoring. (Figure 1).ConclusionsThe delivery of PBC care during the COVID-19 pandemic carries significant challenges. These consensus criteria and practical recommendations provide guidance for the management of PBC during the pandemic era and beyond. Funding AgenciesNoneIntercept Pharmaceutical