bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repeat sequential oxaliplatin-based chemotherapy (FLOX) and nivolumab versus FLOX alone as first-line treatment of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): Initial results from the randomized METIMMOX study.
Authors: Ree Anne Hansen , Hamre Hanne , Kersten Christian , Hofsli Eva , Guren Marianne Grønlie , Sorbye Halfdan , Johansen Christin , Negård Anne , Flatmark Kjersti , Meltzer Sebastian 
Published: June 2021

3556 Background: Immune checkpoint blockade (ICB) has revolutionized patient outcome for the small mCRC subgroup with highly immunogenic disease. The majority of mCRC cases, however, are MSS without innate ICB susceptibility. In our ongoing METIMMOX study, we hypothesize that MSS mCRC can be transformed into an immunogenic condition by short-course oxaliplatin-based therapy (FLOX), enabling patients with unresectable, previously untreated metastases to obtain durable disease control when adding ICB therapy. Here we present the protocol-planned interim analysis. Methods: Eligibility criteria include infradiaphragmatic metastasis and C-reactive protein < 60 mg/L. At analysis 15 January 2021, 54 patients stratified according to primary tumor sidedness and mutational status and evaluable for the primary end point (progression-free survival; PFS) had been randomly assigned to a standard-of-care schedule of 8 FLOX cycles Q2W (control arm) or repeat sequential 2 FLOX cycles and 2 nivolumab cycles (240 mg Q2W) to a total of 8 cycles (experimental arm), for both arms before treatment break until disease progression and reintroduction of a new treatment sequence. Radiologic response assessment is every 8 weeks. Safety, tolerability, objective response rate, and duration of response are among secondary end points. Results: At median follow-up of 6.4 (range, 0.5-20) months, patients were well balanced between the treatment arms with regard to the predefined strata and single-organ or multiple-organ metastases. Median PFS for the entire groups of control and experimental arm patients was 5.6 (range, 0.5-15; n = 26) and 6.6 (range, 0.5-20; n = 28) months, respectively. The number of FLOX-related CTCAE grade 3 or higher adverse events, including 2 deaths after initial FLOX administration, was comparable in the two arms. Twelve immune-related grade 3-4 adverse events (no new safety signals) were recorded. In the experimental arm, 4 (16%) patients, all RAS/BRAF-mutant cases, had experienced complete response and 9 (32%) patients had ongoing objective response at 8 months. The control arm cases had 0 with complete response and 6 (23%) with ongoing objective response at 8 months, 1 of whom had proceeded to curative-intent liver surgery. Conclusions: MSS mCRC patients may hold the opportunity of ICB responsiveness evoked by short-course oxaliplatin-based chemotherapy. The search for predictive biomarkers of ICB responsiveness is ongoing in the specifically designed METIMMOX correlative study program. Clinical trial information: NCT03388190.
Differential impact of different TP53 gain-of-function mutations on overall survival of patients with metastatic colorectal cancer: Results from a large integrated healthcare system.
Authors: Pan Minggui , Jiang Chen , Tse Pamela , Chung Elaine , Solorzano Aleyda , Hu Wenwei , Truong Thach-Giao , Arora Amit , Sundaresan Tilak Kumar , Suga Jennifer Marie Marie , Habel Laurel A. , Thomas Sachdev P. 
Published: June 2021

3585 Background: TP53 mutation is present in approximately 50% of metastatic colorectal cancer (CRC). The spectrum of the TP53 mutations is extremely broad including approximately 80% missense mutations. Several missense mutations have been found to possess gain-of-function (GOF) properties in cell line and animal studies, however, confirmation of the concept of GOF in human malignancies is still lacking. Methods: We investigated the impact of TP53 GOF mutations in patients with metastatic CRC using the NGS data within Kaiser Permanente Northern California (KPNC), a large integrated healthcare system. Results: From November 2017 to January 2021, genomic profiling by StrataNGS was performed on 8658 patients, with 1056 patients being metastatic CRC, among whom 740 patients harbored a TP53 mutation (TP53mut) and 316 patients had wild-type TP53 (TP53wt). Ras (KRAS and NRAS) and BRAF mutation appropriately discriminated the overall survival (OS) of patient populations with either TP53wt or TP53mut, confirming the validity of our dataset. We identified seven GOF TP53 mutations (R175H, R248W, R248Q, R249S, R273H, R273L, R282W) in these CRC patients. We show that different GOF mutation differentially impacts the OS. Patients whose CRC harbored TP53mut R248W, R249S, and R282W (poor prognostic TP53mut, N = 47) had significantly worse OS versus patients whose CRC harbored TP53mut R248Q, R175H, R273H and R273L (N = 160, median OS 29.4 vs 44.2 months, HR 0.47, p = 0.007). The OS of the poor prognostic TP53mut patients was also significantly inferior compared to patients whose CRC harbored all other TP53 mutations (N = 1099, median OS 50.1 months, HR 0.55, p = 0.01) or TP53wt (N = 316, median OS 47,5 months, HR 0.54, p = 0.01). The demographics and the percent of Ras, BRAF, and PI3KCA mutations were similar except that the patients with the poor prognostic TP53mut had significantly higher percent of Ras mutation compared to the rest of the GOF TP53mut patients (p = 0.035). When compared to R248Q alone, R248W confers worse OS (median OS 36.3 vs 63.2 months, p = 0.05). Conclusions: Our data suggest that different TP53 GOF mutations are associated with very different clinical outcomes. Additional studies identifying specific TP53 GOF mutations that impact outcomes may provide further insight for drug development and clinical trial design.
Real-world survival outcomes associated with completion of adjuvant chemotherapy for stage III colon cancer.
Authors: Boyle Jemma Megan , Kuryba Angela , Cowling Thomas E , van der Meulen Jan , Fearnhead Nicola S , Walker Kate , Braun Michael , Aggarwal Ajay 
Published: June 2021

3596 Background: The optimal duration of adjuvant combination chemotherapy administered to patients with stage III colon cancer is debated. Our study assessed the effect of completed chemotherapy cycles on 3-year colon cancer-specific mortality, as well as the effect of dose reduction and early discontinuation of oxaliplatin in patients with 100% completion, within a real-world population. Methods: 4,147 patients undergoing major resection between 01 June 2014 and 30 April 2017 with pathological stage III colon cancer in the English National Health Service were identified. Chemotherapy data were obtained from linked administrative hospital records and a national chemotherapy dataset. Patients were stratified according to completion of < 50% ( < 6 FOLFOX cycles or < 4 CAPOX cycles), 50-92% (6-11 FOLFOX cycles or 4-7 CAPOX cycles) or 100% of cycles (12 FOLFOX cycles or 8 CAPOX cycles). Competing-risk regression analysis for 3-year colon cancer-specific death was performed with adjustment for patient, tumour and hospital-level characteristics to estimate subdistribution hazard ratios (sHR) as a measure of relative risk. Results: Patients included within our study were less fit and had increased rates of high-risk disease (T4 and/or N2 pathological staging) compared to the IDEA study. For FOLFOX, the 3-year cumulative incidence of colon cancer-specific death in patients completing 100% of cycles was 15.1% (95% CI, 12.8% to 17.6%), 18.2% (95% CI, 15.3% to 21.3%) for 50-92% of cycles and 26.4% (95% CI, 20.6% to 32.5%) for < 50% of cycles. For CAPOX, this was 12.0% (95% CI, 10.2% to 14.0%) for 100% completion of cycles, 18.2% (95% CI, 15.6% to 21.0%) for 50-92% of cycles, and 19.8% (95% CI, 15.8% to 24.1%) for < 50% cycles. Compared to 100% completion of FOLFOX cycles, colon cancer-specific death was higher in patients recorded as completing < 50% (sHR 2.17; 95% CI, 1.56 to 3.03; P = < 0.001) and 50-92% of FOLFOX cycles (sHR 1.40; 95% CI, 1.09 to 1.78; P = 0.007). Compared to 100% completion of CAPOX cycles, colon cancer-specific death was higher in patients recorded as completing < 50% (sHR 2.02; 95% CI 1.53 to 2.67; P< 0.001) and 50-92% of CAPOX cycles (sHR 1.63; 95% CI 1.27 to 2.10; P< 0.001). Dose reduction and early discontinuation of oxaliplatin did not have a statistically significant effect on mortality. Conclusions: Patients within the real world setting were more likely to have poor prognostic factors. Those who completed adjuvant chemotherapy for stage III colon cancer had improved survival rates regardless of dose reduction or early discontinuation of oxaliplatin.
Phase I study of transarterial chemoembolization of lung metastases.
Authors: Boas Franz Edward , Kemeny Nancy E. , Sofocleous Constantinos T. , Yeh Randy , Thompson Vanessa R , Hsu Meier , Moskowitz Chaya S. , Ziv Etay , Yarmohammadi Hooman , Bendet Achiude , Solomon Stephen Barnett 
Published: June 2021

3602 Background: Lung chemoembolization (via the bronchial or pulmonary artery) is a new treatment option for unresectable and unablatable lung metastases. Methods: 10 patients with unresectable and unablatable lung, endobronchial, or mediastinal metastases, who failed systemic chemotherapy, were enrolled in this single center, single arm, phase I trial. Pulmonary and bronchial angiography was performed in all patients, to determine the blood supply to the lung metastases. Based on the angiographic findings, bronchial or pulmonary artery chemoembolization was performed, using a lipiodol / mitomycin emulsion, followed by spherical particles. Technical success, safety, efficacy, and pharmacokinetics were evaluated. Wilcoxon signed-rank test was used to compare change in size of treated versus untreated tumors. Results: On angiography, all patients had lung metastases that were hypervascular compared to normal lung. 90% of patients had lung metastases supplied by the bronchial artery, and 10% were supplied by the pulmonary artery. Technical success rate of intra-tumoral drug delivery was 100% (95% CI: 76-100%). There were no severe adverse events, and all patients met criteria for discharge 4 hours post procedure. Response rate of treated lesions was 10% by RECIST and 40% by PERCIST. Treated tumors were mostly stable to decreased in size after chemoembolization (median change in size: 0%; IQR: -11% to 2%; mean: -4%), and untreated tumors were mostly increased in size (median change in size: 10%; IQR: 0% to 17%; mean 9%; p= 0.02). Intra-tumoral lipiodol retention at 4-6 weeks was correlated with decreased tumor size and metabolic activity. Pharmacokinetics showed that 45% of the mitomycin dose underwent burst release in 2 minutes, and 55% of the dose was retained intratumorally with a half-life > 5 hours. Initial tumor-to-plasma ratio of mitomycin concentration was 380. Half-life of intratumoral lipiodol retention was 16 days. In vitro experiments showed 50% emulsion separation in 6.2 days, and 50% drug release in 7.1 hours. Conclusions: Lung chemoembolization can safely treat lung, mediastinal, and endobronchial metastases, with minimal systemic toxicity. High intratumoral drug concentrations after chemoembolization can overcome chemoresistance. Clinical trial information: NCT04200417.
Plasma exosome microRNA-155 expression in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors: A potential biomarker of response to systemic therapy.
Authors: Soleimani Maryam , Thi Marisa , Saxena Neetu , Eigl Bernhard J. , Khalaf Daniel Joseph , Chi Kim N. , Kollmannsberger Christian K. , Nappi Lucia 
Published: June 2021

4570 Background: The search for a reliable predictive biomarker of response to immune checkpoint-based therapy (ICBT) remains a critically unmet need in the management of metastatic renal cell carcinoma (mRCC). We sought to evaluate the biomarker potential of plasma exosome microRNAs (miRNAs) implicated in RCC and in augmentation of the tumour microenvironment (TME) for such a role. Methods: Eleven miRNAs that are over-expressed in RCC and/or immune-associated were evaluated in 40 patients with mRCC (prior to initiating ICBT) and in 30 healthy volunteers. Exosomes were extracted from 500 uL of plasma and were used for miRNAs extraction. MiRNAs expression was evaluated by RT-PCR. Cycle threshold values were normalized to miR-30-3b, and the relative quantity of the expression (RQ) was compared to those of healthy volunteers and calculated using the 2ΔΔCt method. Mann-Whitney U test was used to evaluate the expression of miRNAs between mRCC pts and healthy volunteers according to best response to first line ICBT between responders (n = 27) v non-responders (n = 13). The cut-off value of significant expression was established by Youden’s index. Responders were defined as those patients experiencing complete response, partial response or stable disease and non-responders were those who experienced progressive disease. Results: The most common first line ICBT was nivolumab + ipilimumab (n = 32), followed by pembrolizumab + axitinib (n = 5), and avelumab + axitinib (n = 3). A significantly higher expression of miRNA-1233 (median 1.85 v 0.81 p = 0.008) and miRNA-155 [miR-155] (3.69 v 0.21 p = 0.006) were found in patients compared to healthy volunteers. Higher miR-155 expression was associated with higher Fuhrman grade (p = 0.002). There was no association with other clinical prognostic factors. MiR-155 was expressed at a significantly lower level in responders than in non-responders (median 0.61 v 35.29, p = 0.042). Response rate amongst patients with low and high expression of miR-155 (RQ ≤ 2.5) was statistically different (p = 0.042) and 84.2% of the pts with low miR-155 expression responded to the treatment. Conclusions: Lower expression of miR-155 was associated with response to ICBT in patients with mRCC. Functionally, miR-155 is involved in regulation and modulation of the TME. These results underscore the need for further work in this area to elucidate the role of this and other miRNAs as biomarkers of response in mRCC.
SWOG S1216: A phase III randomized trial comparing androgen deprivation therapy (ADT) plus TAK-700 with ADT plus bicalutamide in patients (pts) with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) (NCT01809691).
Authors: Agarwal Neeraj , Tangen Catherine , Hussain Maha H. A. , Gupta Shilpa , Plets Melissa , Lara Primo "Lucky" N. , Harzstark Andrea , Twardowski Przemyslaw , Paller Channing Judith , Zylla Dylan M. , Zibelman Matthew R. , Levine Ellis Glenn , Roth Bruce J. , Goldkorn Amir , Vaena Daniel A. , Kohli Manish , Crispino Tony , Vogelzang Nicholas J. , Thompson Ian Murchie , Quinn David I. 
Published: June 2021

5001 Background: Tak is an oral selective nonsteroidal 17, 20-lyase inhibitor that blocks the synthesis of gonadal and adrenal androgens. We evaluated the clinical benefit of Tak with ADT in pts with newly diagnosed mHSPC. Methods: Pts with mHSPC with a Zubrod performance status (PS) of 0-2 and a PSA of ≥ 2 ng/ml were randomized 1:1 to ADT+Tak (300 mg twice daily) or ADT+Bic (50 mg daily). Stratification factors included PS (0-1 vs ≥2), extent of disease (minimal vs extensive), and receipt of ADT prior to registration (yes vs no). The primary endpoint was overall survival (OS). Secondary endpoints were progression free survival (PFS; based on PSA, imaging or clinical progression), PSA at 7 months (≤0.2 vs 0.2 < PSA; ≤-4 vs. > 4 ng/ml) and adverse event (AE) profile. With 2.75 yrs to accrue 1,186 eligible pts and 3 additional yrs of follow-up, we would have 90% power to determine a 33% improvement in OS from 54 to 72 mos (1-sided α = 0.025). A final analysis was pre-specified after 523 deaths using a 1-sided α = 0.022 to account for interim analyses. Results: Between 3/2013 and 7/2017, 1,313 pts were randomized and 1,279 were included in the intention-to-treat (ITT) analysis (32 pts were ineligible and 2 pts withdrew consent). Median age was 68 yrs and 10% of subjects were Black. Median PSA was 30 ng/mL (range 2-6710) and 49% of pts had extensive disease. After a median follow-up of 4.9 yrs, PFS and PSA response were significantly improved with Tak over Bic but no significant improvement in OS was observed (Table). More grade 3/4 AEs occurred in Tak vs. Bic arms (43% vs. 14%), and included hypertension (20% vs. 5%) and fatigue (5% vs. 2%). Five pts in Tak and 1 pt in the Bic arm had grade 5 AE. Conclusions: Despite clinically meaningful improvement in various outcome measures with Tak+ADT over Bic+ADT in this representative population of mHSPC, the improvement in OS did not meet the pre-specified criteria for statistical significance. The median OS of 70 mos in the control arm (standard ADT) was higher than that reported in contemporary phase 3 trials in this setting, and 16 mos higher than originally estimated. This trial sets a new landmark for survival estimates when pts with mHSPC have access to multiple approved subsequent life-prolonging therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820; U10CA180821; and in part by Millennium Pharmaceuticals, Inc. (Takeda Pharmaceutical Company LTD) Clinical trial information: NCT01809691. [Table: see text]
Complementary detection of genomic alterations in metastatic castration-resistant prostate cancer (mCRPC) from CheckMate 9KD through analyses of tumor tissue and plasma DNA.
Authors: Sausen Mark , Baden Jonathan F. , Kalinava Natallia , Wang Xuya , Li Jun , Anguiano Esperanza , Unsal-Kacmaz Keziban , Wind-Rotolo Megan , Quinn Katie , Green George 
Published: June 2021

5038 Background: Accurate analysis of the genomic alteration landscape within tissue- and plasma-derived tumor DNA using next-generation sequencing (NGS) may provide insights into specific patient populations that benefit from different therapies. The interchangeable use of tissue- and plasma-based assessments may benefit patients when tissue availability is limited, a common occurrence in individuals with mCRPC. To understand the potential sources of technical and biological variability in this setting, we performed comprehensive comparative analyses across 3 NGS platforms, using samples from patients enrolled in CheckMate 9KD, a phase 2 study of nivolumab combined with docetaxel, rucaparib, or enzalutamide for patients with confirmed mCRPC (NCT03338790). Methods: We performed retrospective integrated analyses of sequence and structural alterations identified through comprehensive genomic profiling (CGP) of DNA obtained from formalin-fixed, paraffin-embedded tissue specimens and cell-free DNA obtained from plasma. Tissue-based analysis was performed using the FoundationOne assay (F1, 395 genes), while the FoundationACT (FACT, 70 genes) and GuardantOMNI (OMNI, 500 genes) assays were used for plasma-based analysis. Analysis was performed on samples from 103 patients for which datasets from all 3 assays were available. Inter-platform analysis considered variants with ≥ 0.50% variant allele fraction and common to the shared pairwise targeted regions, while excluding synonymous variants. Results: Through broad profiling of DNA obtained from tissue and plasma, we uncovered previously identified recurrent alteration of AR, TP53, PTEN, and TMPRSS2 fusion with ETS genes. Additionally, we found that 42% (F1), 45% (FACT), and 34% (OMNI) of patients harbored a combination of germline and somatic mutations in homologous recombination repair pathway genes. Across all samples, median tumor mutational burden was 3.5 mutations per megabase (mut/Mb) by F1 and 8.6 mut/Mb by OMNI. Inter-platform variant analyses demonstrated concordance of 52% for F1 vs FACT, 40% for F1 vs OMNI, and 75% for FACT vs OMNI. Conclusions: Overall, these data demonstrate the value of integrated tissue and liquid biopsy profiling in mCRPC. Both technical and biological sources of variation, including panel size, mutation detection algorithms, variant annotation and reporting, analytical performance, circulating tumor DNA levels, and tumor heterogeneity, may be captured differently by tissue- and plasma-based techniques, accounting for the discordance in reported results. Clinical trial information: NCT03338790.
CheckMate 9KD cohort A1 final analysis: Nivolumab (NIVO) + rucaparib for post-chemotherapy (CT) metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pachynski Russell Kent , Retz Margitta , Goh Jeffrey C. , Burotto Mauricio , Gravis Gwenaelle , Castellano Daniel , Flechon Aude , Zschaebitz Stefanie , Shaffer David R. , Vazquez Limon Juan Carlos , Grimm Marc-Oliver , McCune Steven L. , Amin Neha P. , Li Jia , Wang Xuya , Unsal-Kacmaz Keziban , Saad Fred , Petrylak Daniel P. , Fizazi Karim 
Published: June 2021

5044 Background: CheckMate 9KD is a phase 2 trial of NIVO (anti-PD-1) combined with either rucaparib, docetaxel, or enzalutamide for mCRPC. PARP inhibitors, like rucaparib, increase cellular DNA damage, particularly in tumors with DNA repair defects, leading to genomic instability and cell death. This DNA damage promotes immune priming and adaptive PD-L1 upregulation. Consequently, dual PD-(L)1 and PARP inhibition is a plausible therapeutic strategy for mCRPC. We report final results for cohort A1 (NIVO + rucaparib for post-CT mCRPC) of CheckMate 9KD. Methods: Cohort A1 enrolled patients (pts) with post-CT mCRPC (1–2 prior taxane regimens), ongoing ADT, ≤ 2 prior novel hormonal therapies (abiraterone, enzalutamide, etc) for mCRPC, and no prior PARP inhibitor treatment. Pts received NIVO 480 mg Q4W + rucaparib 600 mg BID until disease progression/unacceptable toxicity (NIVO dosing limited to 2 yrs). Coprimary endpoints: objective response rate (ORR) per PCWG3 criteria and prostate-specific antigen response rate (PSA-RR; ≥ 50% PSA reduction) in all treated pts and pts with homologous recombination deficiency positive (HRD+) tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety. Results: Of 88 treated pts, median age 66 yrs (range, 46–85), 34.1% had visceral metastases and 65.9% had measurable disease. Median follow-up was 11.9 mo. Pts had a median of 4.5 NIVO doses and 3.8 mo of rucaparib. The table summarizes primary and key secondary efficacy results, and shows better outcomes for HRD+ vs HRD–/not evaluable (NE) tumors. In pts with BRCA2 mutations, confirmed ORR was 37.5% (3/8 pts) and confirmed PSA-RR was 45.5% (5/11 pts). Any-grade treatment-related AEs (TRAEs) occurred in 93.2% of pts, most commonly nausea (40.9%) and fatigue (33.0%). Grade ≥ 3 TRAEs occurred in 54.5% of pts, most commonly anemia (20.5%) and neutropenia (10.2%). TRAEs led to discontinuation in 27.3% of pts. One pt had a stroke, considered related to rucaparib by the investigator, after 28 days on rucaparib and 2 NIVO doses and died 2 months later due to post-thrombolysis hematoma. Conclusions: NIVO + rucaparib is active in pts with HRD+ post-CT mCRPC, although the trial design and short follow-up limit assessment of benefits of the combination vs individual components. Pts with HRD– tumors did not appear to benefit from either drug. No new safety signals were observed with NIVO + rucaparib. Additional biomarker analyses are ongoing. Clinical trial information: NCT03338790. [Table: see text]