tbuckley/cabot-search huggingface dataset:
A phase II trial of abemaciclib in patients with p16ink4a negative, relapsed mesothelioma.
Authors: Dean Anthony Fennell, Amy King, Seid Mohammed, Amy Branson, Alastair Greystoke, Sam Moody, Margaret Hutka, Alan G. Dawson, Liz Darlison, Molly Scotland, Vina Bhundia, Amrita Bajaj, Bruno Morgan, Adrian Nicholson, Cassandra Brookes, Aarti Gaba, Peter Wells-Jordan, Catherine Jane Richards, Anne Thomas
Journal: Journal of Clinical Oncology (2021)

8558 Background: Genetically stratified therapy for malignant mesothelioma (MM) is lacking. MMs frequently harbour loss of chromosome 9p21.3 locus (CDKN2A) associated with shorter survival. CDKN2A encodes the tumour suppressor p16ink4a, an endogenous suppressor of CDK4 and CDK6. Genetic reconstitution of p16ink4a into CDKN2A suppresses MM in preclinical models, underpinning the rationale for targeting of CDK4/6 in p16ink4a negative MM. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis as arm 2 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST2). Methods: Patients with histologically confirmed MM (pleural or peritoneal) were molecularly screened by immunohistochemistry for p16ink4a, BAP1, BRCA1, and PDL1 (Dako 22C3). Patients with p16ink4a negative MM were eligible. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1 st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Abemaciclib (Ab) 200mg bd po daily in q21 day cycles. Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Results: Between November 2019 and March 2020, 26 patients with p16ink4a negative MM received at least one dose of Ab. The median age of pts was 67 (range, 64-74) years, 89% were male, 80.8% epithelioid, 84.6% ECOG PS1, &gt; 1 prior systemic therapy 62%. All patients received at least one cycle with 27% completing 6 cycles. No dose reductions occurred in 53.9% of pts. DCR12w: 54% (95% confidence limit (CI), 36% – 71%), DCR24w: 23% (95%CI, 9% – 44%). Best responses (within 24w): partial - 15% (95%CI, 4- 35%), one occurring after 18 weeks; stable disease - 53.8% (33.4 – 73.4%); progression - 7.7% (0.9 – 25.1%). Adverse events (any cause): ≥ grade 3 toxicities affected 5.7% of pts. Conclusions: MiST2 met its primary endpoint, warranting further clinical evaluation of Ab. Whole exome sequencing of the cohort is ongoing to explore genomic correlates of de novo and acquired resistance. Clinical trial information: NCT03654833.
Efficacy and safety of pan-ErbB inhibitor pyrotinib combined with antiangiogenic agent apatinib for HER2-mutant or amplified metastatic NSCLC: A phase II clinical study.
Authors: Guangjian Yang, Haiyan Xu, Lu Yang, Shuyang Zhang, Fei Xu, Hongshuai Li, Yaning Yang, Xin Ai, Yan Wang
Journal: Journal of Clinical Oncology (2021)

9035 Background: Tumor angiogenesis could be induced by activation of HER2 receptor, and currently, there is lack of clinical evidence of anti-HER2 tyrosine kinase inhibitors (TKIs) combined with antiangiogenic therapy for HER2-mutant or amplified non-small cell lung cancer (NSCLC). We conducted a study to explore the efficacy and safety of a pan-ErbB inhibitor pyrotinib combined with apatinib for metastatic NSCLC patients harboring HER2 amplification or activating mutations. Methods: This was a single-center, single-arm phase II study with Simon’s optimal two-stage design. Metastatic NSCLC patients with ECOG scores of 0-1 and harboring primary HER2 amplification, exon 20 insertion or activating missense mutations who had failed to prior chemotherapies or anti-HER2 TKIs were eligible to be enrolled. All patients received oral pyrotinib (400mg once daily) combined with apatinib (250mg once daily) therapy. The primary endpoint was objective response rate (ORR), and second endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR), overall survival (OS) and safety. Results: Between March 5, 2019, and December 1, 2020, 33 metastatic NSCLC patients with HER2 alterations were enrolled, including exon 20 insertions (A775_G776insYVMA, 20/33; P780_Y781insGSP, 6/33; other variants, 2/33), missense mutations (3/33), and primary HER2 amplification (2/33). Seventeen patients (51.5%) were pretreated with first-line platinum-based chemotherapies or anti-HER2 TKIs, and the remaining had received at least 2 lines of prior therapies (range, 2-6). At the last follow-up time January 23, 2021, the overall ORR and DCR were 45.5% (15/33) and 93.9% (31/33), respectively. The median PFS was 6.8 (95%CI: 5.4-8.2) months. The median DoR and OS were 5.3 (95%CI: 0-11.8) and 12.9 (95%CI: 8.6-17.2) months, respectively. The mPFS was significantly longer in patients who received second-line pyrotinib combined with apatinib therapy than those in third- or above-line settings (9.8 vs. 5.3 months, P = 0.018, HR = 0.281 [95%CI: 0.098-0.807]). Although pyrotinib combined with apatinib therapy showed similar ORRs in patients with presence (46.2%, 6/13) or absence (45.0%, 9/20) of brain metastases, and those in second-line (47.1%, 8/17) or above-line settings (43.8%, 7/16). Common treatment-related adverse events (AEs) were grade 1-2, mainly including diarrhea (90.9%), hypertension (72.7%), asthenia (63.6%), anorexia (54.5%) and nausea (51.5%). Grade 3 AEs were diarrhea (3.0%) and hypertension (9.1%). No grade 4 or 5 AE or treatment-related deaths were reported. Conclusions: Pyrotinib combined with apatinib showed potent anti-tumor activity and acceptable safety profile in metastatic NSCLC with HER2 amplification or activating mutations. Clinical trial information: ChiCTR1900021684.
Thrombotic events in patients treated with immune checkpoint inhibitors for non-small cell lung cancer: A retrospective multicentric cohort study.
Authors: Xavier Deschenes-Simard, Loik Galland, Florence Blais, Antoine Desilets, Julie Malo, Lena Cvetkovic, Wiam Belkaid, Arielle Elkrief, Andréanne Gagné, Marc-Andre Hamel, Michèle Orain, Philippe Joubert, François Ghiringhelli, Bertrand Routy, Normand Blais
Journal: Journal of Clinical Oncology (2021)

e21198 Background: Venous thromboembolism is a frequent complication of non-small cell lung cancer (NSCLC) and is associated with a worse prognosis, a reduced quality of life, and increased healthcare costs. Immune checkpoint inhibitors (ICI) are revolutionizing the management of NSCLC, but little is known about their impact on thrombosis. This study aims to define the incidence and clinical relevance of thrombosis in NSCLC patients receiving these treatments. Methods: A retrospective multicentric cohort study including 593 patients from three centers in Canada and France was performed. The cumulative incidence of venous thrombotic events after ICIs was calculated, and the impact of these events on survival and response to treatment was determined. Finally, univariate log-rank tests were performed to identify thrombosis risk factors. Results: The incidence of venous thrombosis in the cohort was 9.9% for an incidence rate of 76.5 thrombosis per 1000 person-years, with most thromboses occurring rapidly after treatment initiation. Thrombosis was not correlated with overall survival, progression-free survival, or objective response to ICIs (summarized in the table below). Age ˂ 65 years old (HR = 1.66; 95 % CI = 1.00 – 2.82) and a delay of less than 12 months from diagnosis to the first ICI treatment (HR = 1.74; 95 % CI = 1.03 – 2.87) were associated with an increased risk of thrombosis. Tumors with PD-L1 &gt; 1% were associated with more thrombosis in the first year since the beginning of therapy (HR = 3.06; 95 % CI = 1.19 – 4.76, p=0.015). Conclusions: This study suggests that the time distribution and incidence of thrombotic events in NSCLC patients treated with ICI are comparable to what is reported in other cohorts of patients treated with chemotherapy. In our cohort, thrombosis was not a prognostic factor for survival or response to therapy. Patient age &lt; 65 and tumors with PD-L1 &gt; 1% were associated to a higher risk of thrombotic events.[Table: see text]
A unified framework identifies new links between plasma lipids and diseases from electronic medical records across large-scale cohorts
Authors: Yogasudha Veturi, Anastasia Lucas, Yuki Bradford, Daniel Hui, Scott Dudek, Elizabeth Theusch, Anurag Verma, Jason E. Miller, Iftikhar Kullo, Hakon Hakonarson, Patrick Sleiman, Daniel Schaid, Charles M. Stein, Digna R. Velez Edwards, QiPing Feng, Wei-Qi Wei, Marisa W. Medina, Ronald M. Krauss, Thomas J. Hoffmann, Neil Risch, Benjamin F. Voight, Daniel J. Rader, Marylyn D. Ritchie
Journal: Nature Genetics (2021)
Impact of <i>STK11</i> mutation on first-line immune checkpoint inhibitor (ICI) outcomes in a real-world KRAS G12C mutant lung adenocarcinoma cohort.
Authors: Rebecca Suk Heist, Junhua Yu, Elifnur Yay Donderici, Nicole Zhang, Carin R. Espenschied, Kathryn Lang, Beata Korytowsky, Andrew S. Chi, James G Christensen
Journal: Journal of Clinical Oncology (2021)

9106 Background: The introduction of KRAS G12C inhibitors into clinical trials has demonstrated promise and may provide a new therapeutic option for patients (pts) harboring KRAS G12C mutations. Recent data has also indicated that immune checkpoint inhibitors (ICI) have shown benefit in KRAS G12C mutant lung adenocarcinoma (LUAD); however, data on the impact of co-occurring STK11 mutations on outcomes are conflicting. We utilized the Guardant INFORM real-world clinical-genomic database to assess the impact of co-occurring STK11 mutations on outcomes in pts with KRAS G12C mutant LUAD treated with a first-line ICI containing regimen. Methods: This retrospective matched cohort observational study was conducted in a nationally representative clinical-genomic database covering over 137,000 pts with comprehensive ctDNA results and associated clinical information. Adult pts with metastatic LUAD who received ≥ 1 dose of first-line anti-PD1/PD-L1 ± chemotherapy and had at least 90 days follow-up after first KRAS G12C detection were included. A cohort of pts without KRAS G12C, including KRAS wildtype pts and pts with other KRAS mutations, were matched 3:1 for age, gender, year of index and baseline comorbidity. Time to next treatment (TTNT), time to discontinuation (TTD), real-world overall survival (rwOS) were compared with vs. without STK11 mutations for both cohorts using cox proportional-hazards model. Results: Among 330 pts in the KRAS G12C cohort, 21% (n = 70) had an STK11 mutation. Among the matched cohort (n = 938), 754 pts were KRAS wildtype, of whom 6% (n = 49) had STK11 mutations. Within the KRAS G12C cohort, pts with STK11 mutations had statistically significant shorter TTNT (hazard ratio [HR] 2.7, 95% confidence internal [CI] 1.8-4.0, p &lt; 0.0001), TTD (HR 1.4, 95% CI 1.0-2.0, p &lt; 0.04) and rwOS (HR 3.2, 95% CI 2.0-5.1, p &lt; 0.0001) than pts without STK11 mutations. Within the matched KRAS wildtype cohort, the differences in TTD (HR 1.4, 95% CI = 1.0-2.0, p = 0.08) and rwOS (HR 1.4, 95% CI = 0.8-2.4, p = 0.3) in patients with vs. without STK11 mutation did not reach statistical significance (Table). Conclusions: This study provides real-world evidence that STK11 co-mutations are associated with worse outcomes among pts with KRAS G12C mutant LUAD treated with first-line ICI. These inferior outcomes indicate a high unmet medical need among LUAD pts harboring co-occurring KRAS G12C and STK11 mutations and demonstrate the need for effective targeted and/or combination therapies in this patient population.[Table: see text]
Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.
Authors: Carlo Gambacorti-Passerini, Tim H. Brümmendorf, Dong-Wook Kim, Yeow Tee Goh, Irina S Dyagil, Katia Pagnano, Arpad Batai, Anna G. Turkina, Eric Leip, Simon Purcell, Jocelyn M Leone, Andrea Viqueira, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2021)

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR 4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR 4 &gt; 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]
Use of strain rate imaging for early detection of epirubicin-induced cardiotoxicity in patients with breast cancer.
Authors: Vasiliki Michalaki, George Koutroulis, Ioannis Kontis, Nikolaos Dafnios, Dina Tiniakos, Christos Papadimitriou
Journal: Journal of Clinical Oncology (2021)

e12531 Background: Although epirubicin has improved outcome in breast cancer (BC) patients, its application is limited by its cardiotoxicity . Assessment of left ventricular (LV) ejection fraction (EF) is performed to demonstrate cardiac dysfunction. Changes in cardiac function induced by this therapy, however, are difficult to quantitate by conventional echocacardiography. Tissue Doppler myocardial imaging (TDI) derived wall motion velocity, and strain rate (SR) have been shown to sensitively quantify abnormalities in cardiac function. The aim of this study was to determine if sensitive indices of LV dysfunction, would be useful for addressing the early detection of cardiotoxic side effects of epirubicin. Methods: BC patients (N = 45 median age 60.2years) without cardiovascular risk factors were prospectively included. All patients received epirubicin. Twenty patients received further trastuzumab. Conventional and TDI echocardiography were obtained at baseline , every 2cycles of treatment and 3 months after chemotherapy. Segmental peak systolic longitudinal and radial velocity, SR and strain, were measured. Results: at baseline, median LV-EF was &gt; 55 %. There was no overall change in LV dimensions, EF and peak systolic velocity. In contrast, a significant reduction in longitudinal and radial SR and strain was found after 3 cycles (longitudinal strain -10.2% +/- 1.3 % vs baseline 22 +/- 4.1 %, P = .001; radial strain 26.1% +/-4,2% vs baseline 47.3% +/- 9.2 %, P &lt; .001). Changes in radial strain appeared earlier and were more pronounced than longitudinal strain. Conclusions: In this study we confirm the clinical use of TDI parameters for early detection of epirubicin mediated cardiac dysfunction. TDI detected subtle changes of LV function after 3 cycles of therapy. Use of Strain Rate Imaging detects subclinical LV dysfunction and can predict further changes in EF ,therefore can be used to monitor epirubicin-induced cardiotoxicity.
Efficacy and safety of systemic treatments for patients with recurrent/metastatic head and neck squamous cell carcinoma: A systematic review and network meta-analysis.
Authors: Lingbin Meng, Rui Ji, Huanhuan Wang, Xin Jiang
Journal: Journal of Clinical Oncology (2021)

e18001 Background: A variety of systemic chemotherapy regimens have been used for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). However, most guidelines were derived from a single clinical trial, and no studies have comprehensively compared their efficacy and safety. This study is aimed to compare the efficacy and safety of systemic chemotherapies for patients with R/M HNSCC. Methods: We conducted a systematic review of published studies in PubMed, Embase, Web of Science, and Cochrane Library databases up to July 31, 2020. Studies were included if they were randomized controlled clinical trials including treatment regimens recommended by the latest NCCN guidelines. Eligible studies should report at least one of the following outcomes: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and ≥3 adverse events rate (AEs). Literature screening, data extraction and quality assessment were independently conducted by two researchers. Disputes were settled by a panel of other researchers. Network meta-analysis was used to compare the efficacy and safety of various treatment regimens. Heterogeneity and consistency using the Bayesian model were evaluated in the network meta-analysis. Results: Eighteen eligible trials involving 4930 patients and 15 treatment regimens were included. Cetuximab/platinum/5-FU regimen showed higher ORR values than the following agents, including cisplatin/5-FU (odds ratio 2.96, 95% credible interval 1.42 to 6.15), cisplatin (5.43, 1.90-15.54), 5-FU (8.12, 2.22-29.61), methotrexate (8.25, 2.86-23.79), cetuximab (10.16, 1.44-71.48), and afatinib (3.64, 1.00-13.32). Immunotherapy regimens pembrolizumab/platinum/5-FU and pembrolizumab alone also showed significantly higher ORR values than these agents, while nivolumab alone showed higher ORR than the single agents. However, no significant difference was observed between Cetuximab/platinum/5-FU and pembrolizumab/platinum/5-FU. Regarding ≥3 AEs, cisplatin/paclitaxel caused the highest toxicity. No significant difference was observed on OS and PFS among all these treatment regimens. Conclusions: Cetuximab/platinum/5-FU, pembrolizumab/platinum/5-FU or pembrolizumab alone displayed high ORR with low AE rate. Nivolumab also showed better efficacy than other single agents. Although it was reported that pembrolizumab/platinum/5-FU showed better efficacy than cetuximab/platinum/5-FU, we did not find a statistically significant improvement in ORR, OS or PFS when comparing the two regimens. Therefore, further prospective trials comparing these treatment regimens remain warranted.
Effectivness of a shortened cycle of monoimmunotherapy in NSCLC.
Authors: Elizaveta Artemeva, Fedor Vladimirovich Moiseenko, Nuriniso Abduloeva, Nikita Volkov, Vitaly Egorenkov, Albina Zhabina, Semen Artemiev, Vladimir Moiseyenko
Journal: Journal of Clinical Oncology (2021)

e21179 Background: Monoimmunotherapy for NSCLC is performed in all patients with a high level of PD-L1 expression ( &gt; 50%) or patients with severe comorbidity and contraindications to therapy with platinum drugs with intermediate level of PD-L1 expression (1-49%).Therapy is carried out up to 2 years, disease progression or intolerable toxicity. An important issue is determining the optimal duration of treatment in order to find a balance between effectiveness, toxicity, cost and burden on the healthcare system. To date, there are no prospective studies with sufficient power devoted to this issue. Methods: The analysis included patients with histologically verified inoperable NSCLC who received the first line of therapy in 2018-2020. 25/230 patients received monoimmunotherapy in the first line (16 men, 9 women; mean age 65.4 years; PD-L1 level &gt; / = 50% - 18 patients (72%), 1-49% - 3/25 ( 12%), 0% - 1/25 (4%), not assessed - 3/25 (12%), adenocarcinoma - 13 (52%), squamous cell - 12 (48%); All patients received pembrolizumab therapy 200 mg 1 once every 21 days. Results: The mean follow-up time was 5.3 months (95% CI 3.4–7.2). The average number of immunotherapy injections (min-max) is 6.4 (1–28). The objective response rate (ORR) in 1 line was 16/23 (64%) (complete regression - 2 patients (8%), partial regression - 3 (12%), stabilization - 11 (44%), progression - 3 (12 %), not assessed - 6 (24%), 2 (8%) patients died after the 1st injection of immunotherapy. Before the progression of the disease or until the end of the planned duration, 16 (64%) of 25 patients interrupted therapy: (10/16 (62%) due to the tightening of the requirements of the epidemiological situation, 6/16 (38%) refused to visit medical institutions. Average follow-up after the end of treatment 7.0 (1.3 - 12.2) months (min-max). 11/16 (68%) are observed without progression 9.3 months (4.0 - 12.1) (min-max PD in 4/16 (25%) after a mean follow-up time of 4.4 months (2.9 - 7.9) (min-max), 1 (6%) patient was lost to follow-up. Conclusions: The obtained data indirectly indicate the absence of a tendency towards a decrease in mPFS and mOS in the group of NSCLC patients who received MIT in the first line of treatment, for whom treatment was discontinued unscheduled, and not continued until 2 years or until the progression of the tumor process was recorded.