tbuckley/cabot-search huggingface dataset:
Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer.
Authors: Andrea Cercek, Jenna Cohen Sinopoli, Jinru Shia, Jill A. Weiss, Lindsay Temple, Jesse Joshua Smith, Leonard B. Saltz, Maria Widmar, Gerard Fumo, Santiago Aparo, Paul Bernard Romesser, Henry S. Walch, Mitesh Patel, Vetri Sudar Jayaprakasam, Tae-Hyung Kim, Philip Paty, Mithat Gonen, Julio Garcia-Aguilar, Martin R. Weiser, Luis A Diaz
Journal: Journal of Clinical Oncology (2024)

LBA3512 Background: Early results have demonstrated that locally advanced mismatch repair deficient rectal cancers can become undetectable with PD-1 blockade alone and do not require chemotherapy, radiation, or surgery. Yet, the durability of this approach is unknown. Methods: We enrolled 47 mismatch repair deficient rectal cancers to a phase II study of 6-months of dostarlimab, a PD-1blocking monoclonal antibody. Co-primary endpoints were response rate that was previously met and the sustained clinical complete response rate, which has not yet been reported. A sustained clinical complete response was defined as complete pathologic response at surgery or no evidence of tumor by MRI, endoscopy, and digital rectal exam for at least 12 months following completion of therapy. If 13 or more patients achieved a sustained clinical complete response out of the first 30 patients, the study would be deemed successful. Results: All of the 41 patients who completed treatment achieved a clinical complete response. No patients required any additional therapy, and no patients experienced local or distant disease recurrence. Twenty patients achieved a sustained clinical complete response with a median follow-up of 28.9 months (95% CI 22.9 -37.1) from first treatment, which satisfied the second co-primary endpoint. No serious adverse events greater than grade 2 were observed. Ultrasensitive tumor-informed circulating tumor DNA levels and tumor bed biopsies normalized earlier than endoscopy, MRI or PET/CT. Conclusions: PD-1 blockade for 6-months alone yields durable recurrence-free responses in locally advanced mismatch repair deficient rectal cancer without the need for chemotherapy, radiation, or surgery. Clinical trial information: NCT04165772 .
Effect of chemotherapy/targeted therapy alone vs. chemotherapy/targeted therapy followed by radical surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction: The IKF-575/RENAISSANCE phase III trial.
Authors: Salah-Eddin Al-Batran, Sylvie Lorenzen, Jorge Riera, Karel Caca, Christian Mueller, Daniel E Stange, Thomas Zander, Claus Bolling, Nils Homann, Jochen Gaedcke, Peter C. Thuss-Patience, Patrick Michl, Wolfgang Blau, Kai Wille, Christine Koch, Claudia Pauligk, Daniel Wilhelm Mueller, Ulli Simone Bankstahl, Stefan Paul Mönig, Thorsten Goetze
Journal: Journal of Clinical Oncology (2024)

LBA4001 Background: The IKF-575 trial investigates the long-standing question about the role of surgical intervention in limited-metastatic gastric / esophagogastric junction cancer after systemic induction therapy. Methods: Previously untreated patients (pts) with limited metastatic disease (retroperitoneal lymph node (RPLN) metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) received 4 cycles of FLOT, + trastuzumab if Her2+ or + nivolumab if PD-L1 positive. Pts without progression after 4 cycles were randomized to receive additional FLOT (Arm B) or radical complete surgical resection of primary and metastases followed by the same treatment (Arm A). It was planned to randomize 176 pts for which 271 pts had to enrolled. The primary endpoint was overall survival in the ITT population using Kaplan-Meier estimates. Recruitment was stopped after enrollment of 183 patients (141 patients randomized) with minimal impact on statistical power, due to a slow enrollment rate. Results: The ITT comprised 139 pts (A, 67; B, 72): 20% had RPLN metastases only, 58% organ metastases only, and 22% had both. Surgery in Arm A (ITT) was performed in 91% of pts and R0-resection rate (primary) was 82%. 30-d and 90-d mortalities in the surgery population were 3% and 8%. At least 4 additional cycles of post-op or post-randomization chemotherapy were achieved in 42% of pts in Arm A vs. 71% of pts in Arm B. The primary endpoint ovrall survival was not met due to increased early mortality in the surgery Arm leading to crossing survival curves with OS 25%- and 75%-Quantiles being 10 vs. 14 months and 65 vs. 41 months for Arms A vs. B, respectively. Pts with RPLN metastases only seemed to benefit most from the surgical approach (mOS, 30 vs. 17 months; 5y OS 38% vs. 19%; still having increased early mortality), while pts showing no response to chemo (mOS, 13 vs. 22 months) or pts with peritoneal disease (mOS, 12 vs. 19 months) derived a detrimental effect. Conclusions: The IKF-575/RENAISSANCE trial is negative but informs future research. Future protocols should focus on pts with RPLN only disease and exclude non-responding pts or those with peritoneal disease. There is a need for strategies against the early mortality caused by chemotherapy interruption. Clinical trial information: NCT02578368 .
Lorlatinib vs crizotinib in treatment-naïve patients with advanced <i>ALK</i>+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study.
Authors: Benjamin J. Solomon, Geoffrey Liu, Enriqueta Felip, Tony S. K. Mok, Ross Andrew Soo, Julien Mazieres, Alice Tsang Shaw, Filippo de Marinis, Yasushi Goto, Yi-Long Wu, Dong-Wan Kim, Jean-Francois Martini, Rossella Messina, Jolanda Paolini, Anna Polli, Despina Thomaidou, Francesca Toffalorio, Todd Michael Bauer
Journal: Journal of Clinical Oncology (2024)

LBA8503 Background: Lorlatinib, a brain-penetrant, 3rd-generation ALK tyrosine kinase inhibitor, demonstrated improved progression-free survival (PFS) and intracranial (IC) activity vs crizotinib in the phase 3 CROWN study in treatment-naïve patients (pts) with advanced ALK+ non-small cell lung cancer (NSCLC). We report long-term efficacy and safety outcomes from the CROWN study after 5 years of follow-up. Methods: 296 treatment-naïve pts with advanced ALK+ NSCLC were randomized 1:1 to receive lorlatinib 100 mg once daily (n = 149) or crizotinib 250 mg twice daily (n = 147). In this post hoc analysis, we present investigator-assessed efficacy outcomes, safety, and biomarker analyses. Formal statistical testing was not performed. Results: As of October 31, 2023, 74 of 149 pts (50%) vs 7 of 142 pts (5%) were still receiving lorlatinib vs crizotinib. With a median duration of follow-up for PFS (95% CI) of 60.2 months (57.4-61.6) in the lorlatinib and 55.1 months (36.8-62.5) in the crizotinib arm, median PFS (95% CI) was not reached (NR; 64.3-NR) with lorlatinib and 9.1 months (7.4-10.9) with crizotinib (HR, 0.19; 95% CI, 0.13-0.27). 5-year PFS (95% CI) was 60% (51-68) with lorlatinib and 8% (3-14) with crizotinib. Median time to IC progression (95% CI) was NR (NR-NR) with lorlatinib and 16.4 months (12.7-21.9) with crizotinib (HR, 0.06; 95% CI, 0.03-0.12). In pts without baseline brain metastases in the lorlatinib arm, only 4 of 114 developed brain progression, occurring within the first 16 months of treatment. Efficacy outcomes by baseline brain metastases are shown in the Table. Grade 3/4 adverse events (AEs) occurred in 77% of pts with lorlatinib and in 57% of pts with crizotinib. Treatment-related AEs led to treatment discontinuation in 5% and 6% of pts in the lorlatinib and crizotinib arms, respectively. Safety profile was consistent with that observed in prior analyses. Emerging new ALK mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment (n = 31). Conclusions: After 5 years of follow up, the median PFS in the lorlatinib arm has yet to be reached, corresponding to the longest PFS ever reported in advanced NSCLC. Coupled with prolonged IC efficacy and absence of new safety signals, these results indicate an unprecedented improvement in outcomes for pts with advanced ALK+ NSCLC. Clinical trial information: NCT03052608 . [Table: see text]
Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM).
Authors: Suzanne Trudel, Meral Beksac, Luděk Pour, Sosana Delimpasi, Hang Quach, Vladimir I. Vorobyev, Michele Cavo, Kazuhito Suzuki, Pawel Robak, Kristin Morris, Amy Phillips-Jones, Xiaoou Linnette Zhou, Giulia Fulci, Neal Sule, Brandon Kremer, Joanna Opalinska, Maria-Victoria Mateos, Meletios Athanasios Dimopoulos
Journal: Journal of Clinical Oncology (2024)

LBA105 Background: Use of triplet/quadruplet therapies for 1L MM raises the need for novel combinations at first relapse, which belantamab mafodotin (belamaf) combos may address. In DREAMM-7, BVd led to a significant improvement in progression-free survival (PFS) and a strong trend in improved overall survival (OS) vs daratumumab-Vd in patients (pts) with ≥1 prior therapy. We report results from DREAMM-8 (NCT04484623), which tested a different belamaf combo (BPd) and met its primary endpoint of independent review committee–assessed PFS at a prespecified interim analysis. Methods: DREAMM-8 is a phase 3, open-label, randomized, multicenter trial evaluating the efficacy and safety of BPd vs PVd in RRMM pts who received ≥1 prior line of therapy (LoT), including lenalidomide. Pts were randomly assigned 1:1 to BPd (28-d cycles): belamaf 2.5 mg/kg IV (D1, C1), 1.9 mg/kg (D1, C2+) + pom 4 mg (D1-21, all C) + dex 40 mg (D1, QW, all C), or PVd (21-d cycles): pom 4 mg (D1-14, all C) + bortezomib 1.3 mg/m 2 SC (D1, 4, 8, 11 [C1-8]; and D1, 8 [C9+]) + dex 20 mg (day of and 1 day after bortezomib dose). Results: 155 pts were randomly assigned to BPd and 147 to PVd. With a median (range) follow-up of 21.78 mo (0.03-39.23), median PFS (95% CI) was not reached (NR; 20.6-NR) with BPd vs 12.7 mo (9.1-18.5) with PVd (HR, 0.52; 95% CI, 0.37-0.73; P&lt;0.001). 12-month PFS rate (95% CI) was 71% (63-78%) with BPd vs 51% (42-60%) with PVd. ORR (95% CI) was 77% (70.0-83.7%) with BPd vs 72% (64.1-79.2%) with PVd; rate of complete response or better (95% CI) was 40% (32.2-48.2%) with BPd vs 16% (10.7-23.3%) with PVd. Median duration of response (95% CI) was NR (24.9-NR) with BPd vs 17.5 mo (12.1-26.4) with PVd. A positive trend favoring BPd was seen for OS (HR, 0.77; 95% CI, 0.53-1.14); follow up for OS is ongoing. Adverse events (AEs) were reported in &gt;99% and 96% of pts in the BPd and PVd arms, respectively. Of pts treated with BPd, 89% had ocular AEs (CTCAE grade 3/4, 43%) vs 30% (grade 3/4, 2%) in the PVd arm. AEs were generally manageable, and broadly consistent with known safety profile of individual agents. Conclusions: The DREAMM-8 study demonstrated a statistically significant and clinically meaningful PFS benefit with BPd vs PVd in RRMM with &gt;1 prior LoT. BPd also led to deeper and more durable responses, showed a favorable OS trend, and had a manageable safety profile. Clinical trial information: NCT04484623 . [Table: see text]
A randomized, double-blind, placebo-controlled trial of metformin in reducing progression among men on expectant management for low-risk prostate cancer: The MAST (Metformin Active Surveillance Trial) study.
Authors: Neil E. Fleshner, Rui Miguel Bernardino, Katherine Lajkosz, Fred Saad, Jonathan Izawa, Darrel Drachenberg, Jeff W. Saranchuk, Simon Tanguay, Ricardo A. Rendon, Michael Leveridge, Bobby Shayegan, Adrian Fairey, Jessica Grace Cockburn, Doron Berlin, Robert James Hamilton, Tiiu Sildva, Rodney H. Breau, Patrick O. Richard, Laurence Klotz, Anthony M. Joshua
Journal: Journal of Clinical Oncology (2024)

LBA5002 Background: Active Surveillance (AS) involves vigilant monitoring of selected prostate cancer (PCa) patients, with radical treatment initiation upon significant disease progression. AS eligibility varies, generally including low-risk PCa men. Metformin, a widely-used oral hypoglycemic agent, is known for its excellent tolerability and efficacy in diabetes management. Extensive preclinical data suggested that metformin may slow PCa progression. The purpose of this study is to examine the effect of metformin on the rates of progression among men with low-risk localized PCa on AS. Methods: A randomized double blind placebo controlled trial was carried out in 14 centres across Canada.Eligible patients had biopsy-proven, low-risk, localized PCa diagnosed within the past 6 months, with a Gleason score of &lt;6 observed in ≤1/3 of the total cores, less than 50% positivity in any one core, a PSA level of ≤10 ng/ml, and a clinical stage between T1c-T2a. Additionally, they chose active surveillance as their primary treatment. Subjects that met eligibility criteria were randomly assigned (1:1) to receive metformin 850 mg BID or placebo for 3 years. All patients underwent repeat prostate biopsy at 18 and 36 months. The primary endpoint indicated was time to progression, defined as the earliest occurrence of primary PCa therapy (e.g., prostatectomy, radiation, hormonal therapy) or pathological progression (&gt;1/3 of total cores involved, at least 50% of any one core involved, or Gleason pattern 4 or higher). Results: In our cohort of 407 patients, 204 were administered metformin, and 203 received a placebo. The median age of the overall cohort was 63 years. Out of the total 407 patients, 141 experienced disease progression. There was no statistically significant difference in progression-free survival (PFS) observed between patients treated with metformin and those receiving placebo (p=0.63). Conclusions: Despite tantalizing preclinical and epidemiological data, metformin consumption does not alter rates of progression among men with low risk PCa on AS. Clinical trial information: NCT01864096 .
Longitudinal circulating tumor DNA monitoring in predicting response to short-course neoadjuvant radiotherapy in locally advanced rectal cancer: Data from a phase III clinical trial (UNION).
Authors: Zhenyu Lin, Menglan Zhai, Linghua Yan, Tao Zhang
Journal: Journal of Clinical Oncology (2024)

LBA3606 Background: The data presented here is from a multicenter, randomized, open-label, controlled Phase III clinical study evaluating the feasibility of short-course radiotherapy (shortRT) sequentially combined with camrelizumab and chemotherapy as neoadjuvant therapy (NAT) for locally advanced rectal cancer (LARC)(UNION). Our aim is to explore the value of circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) in assessing the comparative efficacy of short-course and long-course chemoradiotherapy (CRT). Methods: A total of 244 plasma samples from 79 LARC patients, who underwent NAT prior to curative surgery, were collected at baseline (C1), on-NAT (C2), post-NAT (C3), and post-surgery (C4). Deep targeted panel sequencing of 556 cancer-related genes was performed. The changes in genomic features and ctDNA-MRD status during treatment were monitored, and the relationship between these changes and treatment response were explored. Results: During NAT, the ctDNA-MRD positivity rate showed significant declining trends. Patients with high baseline TMB tend to show a significant inclination towards major pathological response and tumor regression grade 0/1 after NAT, while there is no significant correlation observed between baseline ctDNA-MRD status and treatment response. Interestingly, compared to long-course radiotherapy, microsatellite instability is more pronounced after shortRT ( P=0.042), and ctDNA negativity is significantly associated with pathological complete response (pCR) ( P=0.022). Furthermore, both ctDNA clearance ( P=0.049) and MRD clearance ( P=0.015) after shortRT are significantly correlated with pCR. A risk scoring predictive model based on ctDNA-MRD was established, with achieving the highest C-index at the C2 time point. This model, combining MRD clearance and CEA, outperforms models using only MRD clearance (AUC=0.917, 95% CI=0.753 to 1.000) or only CEA (AUC=0.733, 95% CI=0.449 to 1.000), demonstrating superior performance in predicting pCR/non-pCR (AUC=0.983, 95% CI=0.937 to 1.000). Conclusions: These findings offers valuable insights into the dynamic landscape of NAT for LARC management and emphasize the potential of ctDNA-based MRD assessment as a valuable tool for tailoring treatment strategies. The differences observed between shortCRT and longCRT regimens underscore the need for personalized treatment approaches. Overall, our study contributes valuable insights into optimizing treatment decision-making and predicting treatment response in LARC patients, ultimately advancing the field of rectal cancer management.
Clinical outcomes with perioperative nivolumab (NIVO) by nodal status among patients (pts) with stage III resectable NSCLC: Results from the phase 3 CheckMate 77T study.
Authors: Mariano Provencio, Mark M. Awad, Jonathan Spicer, Annelies Janssens, Fedor Vladimirovich Moiseenko, Yang Gao, Yasutaka Watanabe, Aurelia Alexandru, Florian Guisier, Nikolaj Frost, Fabio A. Franke, T.Jeroen Jeroen Nicolaas Hiltermann, Jie He, Fumihiro Tanaka, Shun Lu, Cinthya Coronado Erdmann, Padma Sathyanarayana, Phuong Tran, Vipul Devas, Tina Cascone
Journal: Journal of Clinical Oncology (2024)

LBA8007 Background: In CheckMate 77T, perioperative NIVO showed statistically significant EFS improvement vs neoadjuvant (neoadj) chemo followed by adjuvant (adj) placebo (PBO) in pts with stage (stg) II or III resectable NSCLC. We report clinical outcomes by baseline (BL) stg III N2 status, a subgroup with poor historical 5 y survival (26%–36%; Goldstraw J Thorac Oncol 2016). Methods: Adults with resectable stg IIA–IIIB (N2; AJCC v8) NSCLC were randomized to neoadj NIVO 360 mg Q3W + chemo (4 cycles [cyc]) followed by adj NIVO 480 mg Q4W (13 cyc) or neoadj PBO Q3W + chemo (4 cyc) followed by adj PBO Q4W (13 cyc). Primary endpoint: EFS per BICR. Exploratory analysis: efficacy and safety in pts with BL clinical stg III N2 or non N2 disease (dz). Results: BL characteristics were generally similar between pts with stg III N2 (NIVO, 91; PBO, 90) and non N2 dz (55; 57), and between treatment (tx) arms, except a higher percent of pts with N2 dz had NSQ histology and ECOG PS 0 (both arms). Pts with N2 dz had improved EFS with NIVO vs PBO (HR 0.46; 1 y EFS 70% vs 45%) and higher pCR (22.0% vs 5.6%; median f/u 25.4 mo; Table). Pts with non N2 also had EFS benefit with NIVO vs PBO (HR 0.60; 1 y EFS 74% vs 62%) and higher pCR (25.5% vs 5.3%; Table). Surgical feasibility was similar between pts with N2 and non N2 dz and numerically higher with NIVO vs PBO. Of pts with N2 dz, 77% (NIVO) vs 73% (PBO) had definitive surgery (pneumonectomy 1% vs 14%; R0 resection 86% vs 86%); of pts with non N2 dz, 82% vs 79% had definitive surgery (pneumonectomy 13% vs 9%; R0 resection 84% vs 87%). Tumor downstaging postsurgery was seen in most pts with stg III dz and was deeper with NIVO vs PBO: 61% vs 50% (N2; 33% vs 14% to ypT0), 87% vs 76% (non N2; 27% vs 11% to ypT0). Of all pts with stg III dz, nodal downstaging postsurgery was 52% (NIVO) vs 45% (PBO); 46% vs 36% to ypN0. Grade 3–4 TRAEs occurred in 34% (NIVO) and 26% (PBO) of pts with N2; 29% and 21% of pts with non N2 dz. Conclusions: In this exploratory analysis, perioperative NIVO showed clinical benefit vs PBO in pts with stg III NSCLC, regardless of N2 status. Over half of pts with stg III dz had nodal downstaging with NIVO; majority downstaged to ypN0. This first comprehensive analysis by nodal status among pts with stg III dz from a global phase 3 study of perioperative immunotherapy further supports perioperative NIVO as a tx option for pts with resectable NSCLC. Clinical trial information: NCT04025879 . [Table: see text]
Long term results of a randomized phase III study of nimotuzumab in combination with concurrent radiotherapy and cisplatin versus radiotherapy and cisplatin alone, in locally advanced squamous cell carcinoma of the head and neck.
Authors: Vijay Maruti Patil, Vanita Noronha, Nandini Sharrel Menon, Minit Jalan Shah, Sarbani Laskar Ghosh, Ashwini Budrukkar, Monali Swain, Arun Balaji, Devendra Chaukar, Prathamesh S Pai, Pankaj Chaturvedi, Kumar Prabhash
Journal: Journal of Clinical Oncology (2024)

LBA6092 Background: The addition of nimotuzumab to weekly cisplatin as a radiosensitizer had improved progression-free survival (PFS) in a phase 3 study in locally advanced head and neck squamous cell carcinoma (LA HNSCC). However, whether it leads to an improvement in long-term OS is unknown. Hence this analysis was performed to evaluate the efficacy (in terms of OS) and late-term adverse events of the addition of nimotuzumab to concurrent chemoradiation in LA HNSCC. Methods: This was an open-label, investigator-initiated, phase 3 randomized trial conducted from 2012 - 2018. 536 adult patients with LA HNSCC, fit for radical chemoradiation were randomly assigned. Primary sites in the nasopharynx, salivary gland, nasal cavity, and paranasal sinus were excluded. Randomized 1:1 to either radical radiotherapy (66-70 Gy) with concurrent weekly cisplatin (30 mg/m2) (CRT) or the same schedule of chemoradiation with weekly nimotuzumab (200 mg) (NCRT). The primary endpoint was a 10-year OS; the key secondary endpoint was late adverse events. Intent to treat analysis was performed. OS was defined as the time from randomization till death. Kaplan Meier method will be used for the estimation of OS. Landmark analysis was performed to compare 10 OS between the 2 arms. COX proportional hazard model will be used for the calculation of hazard ratio (HR). The adverse events between the 2 arms were compared using a Fisher's test. A p-value of 0.05 will be considered as significant. Results: The median follow-up was 8.86 years (95% CI 8.59-9.16). The primary site of the primary was the oropharynx (269,50.2%) and only 24 cases were HPV positive. The 10-year OS was 22.5% (95% CI 16.7-28.8) versus 33.5% (95% CI 27.6-39.4) in the CRT and NCRT arm respectively (Hazard ratio=0.811; 95%CI 0.664-0.995, P=0.044). The median OS was 2.78 years (95% CI 2.31-3.69) versus 3.69 years (95% CI 2.90-4.49) in the CRT and NCRT arm respectively (P value by log-rank test=0.04). The median OS in HPV negative oropharynx was 1.8 years (95% CI 1.51-2.09) versus 2.48 years (95% CI 1.79-3.16) in the CRT and NCRT arm respectively (P value by log-rank test=0.02; HR 0.724 95%CI 0.546-0.959). Long-term adverse events were captured in 380 patients. There was no statistically significant difference in late-term adverse events between the 2 arms and will be presented at the conference. Conclusions: The addition of nimotuzumab to weekly cisplatin leads to improvement in long-term overall survival in locally advanced HNSCC without any additional increase in late-term adverse events. These results are largely applicable in HPV-negative patients. Clinical trial information: CTRI/2014/09/004980 .