tbuckley/cabot-search huggingface dataset:
A phase 1b study of sotorasib combined with panitumumab as second-line treatment of <i>KRAS</i> G12C<i>-</i>mutated colorectal cancer.
Authors: Rona Yaeger, Corey J. Langer, Jose Carlos Ruffinelli, Marwan Fakih, Muhammad Furqan, Jean-Pascal H. Machiels, Yaneth Saportas, Jane Nolte-Hippenmeyer, Emily Chan, Caihong Xia, Toshiki Masuishi
Journal: Journal of Clinical Oncology (2024)

128 Background: In the CodeBreaK 101 phase 1b study, sotorasib, a KRAS G12C inhibitor, plus panitumumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, showed acceptable safety and promising efficacy for patients with chemorefractory KRAS G12C–mutated metastatic colorectal cancer: an objective response rate (ORR) of 30% and median progression-free survival (PFS) of 5.7 months were observed. Here, we evaluated sotorasib plus panitumumab in the second-line (2L) setting. Methods: CodeBreaK 101 (NCT04185883) subprotocol H includes dose exploration and expansion in multiple cohorts. Patients eligible for the 2L sotorasib plus panitumumab dose-expansion cohort were KRAS G12C inhibitor–naïve and had received no more than one prior regimen for metastatic disease. Patients received oral sotorasib at 960 mg daily and IV panitumumab 6 mg/kg every 2 weeks. The primary endpoint was safety. Secondary endpoints included efficacy endpoints. Results: As of May 23, 2023, this cohort was fully enrolled; all 20 patients (50% female, median age 60.0 years) were included in this analysis. All patients received fluoropyrimidine-based treatment and 17 (85%) patients received oxaliplatin-based treatment as first-line therapy. Any-grade treatment-related adverse events (TRAEs) occurred in 19 (95%) patients. The most common any-grade TRAEs were dermatitis acneiform (60%), dry skin (55%), pruritus (45%), and hypomagnesemia (30%). Grade ≥3 TRAEs occurred in 4 (20%) patients and included fatigue, hypomagnesemia, decreased appetite, and rash (5% each). No TRAEs were grade ≥4 or resulted in treatment discontinuation or deaths. Confirmed ORR was 30% (95% CI: 11.9, 54.3). The disease control rate was 90% (95% CI: 68.3, 98.8). At a median follow-up of 11.3 months (95% CI: 5.6, not estimable), median PFS was 8.3 months (95% CI: 4.3, 14.1). Conclusions: This is the first report of safety and efficacy from a 2L cohort evaluating a KRAS G12C inhibitor plus an anti-EGFR antibody in KRAS G12C-mutated metastatic colorectal cancer. The toxicities of sotorasib plus panitumumab were consistent with the expected safety profile of the individual agents and with that reported previously for this combination; the ORR was similar to that previously observed for this combination in a more chemorefractory population. The ORR and PFS of sotorasib plus panitumumab compare favorably to current standard approaches in the 2L treatment of metastatic colorectal cancer. Clinical trial information: NCT04185883 .
First safety and efficacy data from phase Ib/IIa study of fostroxacitabine bralpamide (fostrox, MIV-818) in combination with lenvatinib in patients with hepatocellular carcinoma (HCC).
Authors: Maria Reig, T.R. Jeffry Evans, Hong Jae Chon, Ho Yeong Lim, Min-Hee Ryu, Do Young Kim, Teresa Macarulla, Carlos Gomez-Martin, Victor Moreno, Beate Haugk, Thomas Ness, Pia Baumann, Sujata Bhoi, Malene Jensen, Karin Tunblad, Hans Wallberg, Fredrik Oberg, Jeong Heo
Journal: Journal of Clinical Oncology (2024)

476 Background: Fostrox is an orally administered troxacitabine-based nucleotide prodrug in clinical development in combination with lenvatinib (NCT03781934). Fostrox is rapidly metabolized by human hepatocytes, directing high levels of the active metabolite to the liver. Phase I fostrox monotherapy demonstrated selective intra-tumoral activity in on-treatment liver biopsies. The anti-angiogenic activity of lenvatinib has the potential to synergize with fostrox by hypoxia-induced increase in the enzymatic generation of the active metabolite of fostrox in the tumor. Methods: In a phase Ib/IIa study with an inter-patient dose escalation 3+3 cohort design followed by a dose expansion phase, fostrox was administered orally QD for 5 days in 21-day cycles in combination with lenvatinib according to local prescription information. Patients (pts) with &lt;2 prior lines systemic treatment for advanced, unresectable HCC were recruited at 10 sites in Spain, South Korea and UK. Pts with histologically, radiologically, or cytologically confirmed HCC, Child-Pugh A, ≥18 years, ECOG PS ≤ 1 and adequate organ function were eligible. The primary objective was to assess safety and tolerability. Key secondary endpoints were ORR based on RECIST 1.1 and mRECIST. Exploratory endpoints included pharmacokinetics (PK) and pharmacodynamic effects of fostrox in combination with lenvatinib. Results: At interim data cut-off 18 pts (6 pts in Ib and 12 pts in IIa) were enrolled at fostrox QD doses of 20mg (3 pts) and 30mg (15 pts) in combination with lenvatinib. Median age was 63 years (range: 42-82). No DLTs and only 1 discontinuation of fostrox due to AEs with a median FU of 3.8 months, were observed. Most common grade 3/4 AEs were transient neutrophil count decrease, platelet count decrease and hypertension. No febrile neutropenia, bleeding events or proteinuria were reported. The safety profile was consistent with each individual agent. In phase Ib, central independent review based on RECIST 1.1 showed SD in 5/6 pts, while mRECIST showed CR in 1 pt, PR in 2 pts and SD in 2 pts. Updated phase Ib data and efficacy data from phase IIa by central independent review, together with PK for fostrox and lenvatinib, and liver biopsy biomarker data, will be presented. Conclusions: Fostrox in combination with lenvatinib, in pts with HCC who progressed on previous systemic treatment, had an acceptable safety and tolerability profile with promising interim efficacy results from the completely enrolled phase Ib/IIa study. Clinical trial information: NCT03781934 .
Camrelizumab plus apatinib after progression on immune checkpoint inhibitors in patients with advanced esophageal squamous cell carcinoma (CAP 02 Re-challenge): A single-arm multicenter, phase II trial.
Authors: Xiangrui Meng, Junsheng Wang, Jin Xia, Tao Wu, Zhiquan Luo, Yong-Gui Hong, Ping Lu, Yanzhen Guo, Yinghua Ji, Min Zhang, Liuzhong Yang, Peng Cheng, Wenchang Liang, Zhengzheng Shan, Qingxia Fan, Feng Wang
Journal: Journal of Clinical Oncology (2024)

364 Background: The optimal therapies for patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed after immune checkpoint inhibitors (ICIs) are unclear. This phase II single-arm study aimed to assess the efficacy and safety of re-challenge with camrelizumab plus apatinib in this population. Methods: This study enrolled patients with unresectable locally advanced, locally recurrent, or metastatic ESCC who had experienced prior progression on ICI treatment. Enrolled patients received camrelizumab 200 mg intravenously every two weeks along with daily oral apatinib 250 mg. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal of consent. The primary endpoint was the confirmed objective response rate (ORR). Secondary endpoints included disease control rate (DCR), duration of response (DOR), time to response (TOR), progression-free survival (PFS), overall survival (OS), 3- and 6-month PFS rates, 6-, 9- and 12-month OS rates, and safety. Results: From September 1, 2021, to March 29, 2023, 49 eligible patients were enrolled and given treatment. Among 38 treated patients who had at least one post-baseline efficacy measurement, the ORR and confirmed ORR were 36.8% (95% CI 21.8–54.0) and 13.2% (95% CI 4.4–28.1); the DCR was 89.5% (95% CI 75.2–97.1); the median DOR was 3.0 months; and the median TOR was 2.2 months. Among the 49 treated patients, the median PFS was 4.6 months (95% CI 3.8–6.5) and OS was 7.5 months (95% CI 5.5–13.6). Patients who were both PD-L1 positive and had responded to previous ICI therapy had the longest median PFS (5.7 months, 95% CI 3.9–not reached) and OS (9.6 months, 95% CI 7.5–not reached). Grade ≥ 3 treatment-related adverse events occurred in 34.7% of patients (17/49). Conclusions: This study showed promising efficacy and an acceptable safety profile of camrelizumab plus apatinib for patients with advanced ESCC who had progressed after ICI therapy. The subset of patients who were both PD-L1 positive and had a prior ICI response seemed to benefit most. Clinical trial information: NCT03736863 .
Assessment of hematological toxicity in patients with advanced neuroendocrine tumors and extensive/innumerable bone metastases undergoing lutetium-177 DOTATATE treatment.
Authors: Osama M Mosalem, Tucker Coston, Tanmayi Pai, Bassam Bassam Sonbol, Ephraim E. Parent, Jason R. Young, Geoffrey Johnson, Ayse T. Kendi, Thorvardur Ragnar Halfdanarson, Jason S. Starr
Journal: Journal of Clinical Oncology (2024)

592 Background: The introduction of peptide receptor radionuclide therapy (PRRT) using Lutetium-177 ( 177 Lu) DOTATATE has led to a paradigm shift in the treatment of neuroendocrine tumors (NETs). Hematological toxicity is a well-recognized adverse effect (AE) of 177 Lu DOTATATE. Most cytopenias are transient, with an estimated incidence of 10-25%, typically mild to moderate in severity (grade G1-2). The most dreaded AE of PRRT is therapy-related myeloid neoplasm (t-MN), with an estimated 2-8% incidence and a higher incidence reported in patients who also received prior chemotherapy. We sought to evaluate the hematological safety of 177 Lu PRRT in the setting of NETs with extensive (i.e., innumerable) bone metastases. Methods: We retrospectively reviewed the medical records of all Mayo Clinic patients (pts) with extensive/innumerable osseous metastases, defined as &gt;50% skeletal involvement by positron emission tomography (PET) DOTATATE, who were treated with 177 Lu DOTATATE. Pts characteristics and laboratory results were collected before, during, and after 177 Lu DOTATATE treatment. Hematotoxicity was graded according to the NCI-CTCAE v5. Results: Out of 27 pts, 13(48%) developed cytopenia(s) of any grade after treatment with one or more cycles of 177 Lu DOTATATE. In total, there were 13(48%) pts with anemia, 13(48%) with thrombocytopenia, and 6(22%) with neutropenia. Six (22%) pts had severe hematological toxicity (G3-4). Twelve months post-PRRT, 7(26%) pts continued to experience cytopenia(s) of any grade, of whom 4(15%) had G3-4 hematotoxicity. One pt developed t-MN, and two pts had myelophthisis on bone marrow biopsy from infiltrating NET. 16(59%) pts received cytotoxic chemotherapy before PRRT, and 7(25.9%) developed subsequent cytopenia(s). Overall, 15(55%) pts completed four cycles, while 3 pts didn’t complete four cycles of 177 Lu DOTATATE due to hematotoxicity. Conclusions: Pts with advanced NETs and extensive/innumerable bone metastases treated with PRRT could be at higher risk for myelosuppression than historical controls. Our study highlights the importance of carefully monitoring and assessing hematological parameters in pts being considered for 1 77 Lu DOTATATE with extensive/innumerable bone metastasis. [Table: see text]
Anlotinib plus chemotherapy as first-line therapy for patients with gastrointestinal tumor with unresectable liver metastasis: Updated results from multi-cohort, multi-center phase II trial ALTER-G-001-cohort A.
Authors: Junwei Wu, Lingjun Zhu, Chenfei Zhou, Min Shi, Jun Chen, Liqin Zhao, Zhengxiang Han, Chunbing Wang, Jinling Jiang, Jun Yan, Chun Wang, Xiaowei Wei, Yong Mao, Donghai Cui, Xiuli Yang, Zhiquan Qin, Xinyu Tang, Jun Zhang
Journal: Journal of Clinical Oncology (2024)

112 Background: Advanced gastrointestinal (GI) tumors, such as colorectal, gastric and pancreatic cancers (CRC, GC, and PC), and esophageal squamous cell carcinoma (ESCC), 20%-50% with liver metastases (LMs). The prognosis of CRC with unresectable LMs is poor, with a 5-year survival rate of less than 5%. Previous trials showed that anlotinib plus chemotherapy has promising clinical activity and a tolerable safety profile for advanced CRC and ESCC, especially with LMs. In this phase II trial, we assessed the efficacy and safety of anlotinib plus chemotherapy as first-line treatment for LMs GI tumors. Methods: Patients with unresectable LMs GI tumors and without previous systemic treatment would be divided into cohort A (CRC), cohort B (ESCC), and cohort C (other GI tumors, such as PC, GC, etc.). In cohort A, CRC patients received induction therapy (6 cycles, q3w): anlotinib (12 mg, PO, QD, days 1-14), oxaliplatin (130 mg/m 2 , IV, day 1), capecitabine (850 mg/m 2 , PO, BID, days 1-14). Patients without PD and radical resection received anlotinib and metronomic capecitabine (500 mg, PO, BID, days 1-21, q3w) maintenance until PD or unacceptable toxicity. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints were DoR, PFS, OS, DCR, radical resection rate for LMs, and safety. Results: As of September 14, 2023, 45 patients were enrolled in cohort A, the median age was 67 years (35-75), 66.7% male, 91.1% ECOG-PS 1 and 60% had LMs only. After induction therapy, 8 patients received surgical resection. Currently, 13 patients are receiving induction therapy and 10 are undergoing maintenance therapy, with a maximum duration of treatment (DOT) of 13.7 months. Of 39 evaluable patients in cohort A, ORR and DCR were 48.7% and 97.4% (PR, n=19; SD, n=19, 16 SD had reduced tumor size). The median PFS was not reached. 36 patients had TEAEs and ≥ grade 3 TEAEs (33.3%) mainly included neutropenia (11.1%), hypertension (6.7%), and white blood cell decreased (6.7%). Conclusions: Anlotinib plus chemotherapy as first-line treatment has shown promising efficacy and acceptable safety and maybe a favorable option for advanced LMs CRC tumors. Clinical trial information: NCT05262335 .
Lenvatinib in recurrent hepatocellular carcinoma after liver transplantation.
Authors: Mehmet Akce, Olumide B. Gbolahan, Jeffrey M. Switchenko, Mohamad B. Sonbol, Giorgio Roccaro, Robert M Cannon, Saulat S Sheikh, Olatunji B. Alese, Tanios S. Bekaii-Saab, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2024)

TPS578 Background: Liver transplantation is a curative treatment option in hepatocellular carcinoma (HCC) however; up to 20% of patients develop recurrent disease. HCC recurrence post-transplant is usually extrahepatic (up to 67%) hence requires effective systemic therapy options. Available data are limited and restricted to small non-randomized studies and case series. Lack of prospective clinical trial data and limited data indicates an area of unmet need in treatment of recurrent HCC after liver transplantation. This phase II study aims evaluate the safety and efficacy of lenvatinib in patients with recurrent HCC after liver transplantation. Methods: This is a multi-institutional phase II trial with lenvatinib in patients with recurrent HCC after transplantation. Lenvatinib is administered 12 mg daily orally in patients ≥60 kg, and 8 mg daily orally in patients &lt;60 kg. Each cycle is 28 days. Restaging scans will be performed every 8 weeks. Eligible patients must have histologically proven HCC that has recurred after liver transplantation and not amenable for surgical resection, age ≥18 years, ECOG PS 0-1, Child Pugh Class A, measurable disease per RECIST version 1.1, adequate organ function, no prior systemic therapy with lenvatinib or another systemic therapy in the post-transplant setting. Prior liver directed therapy is allowed, should be at least &gt;28 days prior to the study enrollment, and should have at least one measurable untreated lesion by RECIST 1.1 Primary endpoint is overall response rate (ORR). Secondary endpoints are safety/tolerability, progression free survival, and overall survival. Pre-treatment and on-treatment peripheral blood samples will be collected for correlative research. A Simon`s two stage Minimax design is employed (H 0 : ORR = 5%; H 1 : ORR = 24%; Type I error = 0.05; power = 80%). In the first stage, 11 patients will be accrued, and if there is no objective response among them, the study will be stopped for futility. Otherwise, additional 6 patients will be accrued for a total of 17 patients. This study is currently enrolling patients. Clinical trial information: NCT05103904 .
High-resolution transcriptional signature to predict survival benefit in colorectal cancer (CRC) treated with EGFR inhibitors (EGFRi) independent of <i>RAS/BRAF</i> mutation status or tumor sidedness.
Authors: Ramya Thota, Timothy Yeatman, Nishant Gandhi, Mingli Yang, Michael Schell, Lance Pflieger, Andrey Loboda, Michael Nebozhyn, Andrew Elliott, Joanne Xiu, George W. Sledge, Moh'd M. Khushman, Emil Lou, Sanjay Goel, Warren Jack Pledger
Journal: Journal of Clinical Oncology (2024)

203 Background: Cetuximab (CTX) and Panitumumab (PMB) therapies directed at EGFR have been restricted to left-sided CRC harboring wild-type KRAS ( KRAS WT ), limiting their utility. Approximately 50% of mCRC fail to respond to EGFRi, thus identification of predictive biomarkers is an unmet need. Here we evaluate a CTX sensitivity score (CTX-S) that we previously reported (Yang M. et al., 2019), in a large, real-world population of RAS/BRAF mutant vs wild-type and in right- vs left-sided tumors. Methods: CTX/PMB-treated CRC specimens (n=1124) with clinical outcomes, NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). 1097 specimens were MSS as determined by IHC of MMR proteins and/or NGS. Association of CTX-S with RAS/BRAF mutation and tumor sidedness was performed in MSS tumors. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RAS MUT /BRAF MUT , or RAS WT /BRAF WT if no mutation was detected for each gene. Samples were stratified based on CTX-S quintiles. Survival on EGFRi was calculated from the initiation of EGFRi to last contact using Kaplan-Meir method. Results: Higher CTX-S quintiles were significantly associated with longer survival on EGFRi in RAS/BRAF wild-type as well as -mutant subpopulations. Similar results were seen in left- vs. right-sided tumors (Table). Higher CTX-S quintiles were associated with a survival benefit in all CMS classes but CMS2; however, the vast majority of CMS2 tumors (460/467) were among the top 3 CTX-S quintiles. As the median survival among the top 3 quintiles was ~2-fold higher than the bottom 2 quintiles, we used stratification by the 40 th percentile for the genomic analysis. CTX-S &gt;40 th percentile was associated with an increased prevalence in APC (91 vs 47%) and TP53 (93 vs 76%) mutations and decreased prevalence in BRAF (6 vs 32%), SMAD4 (8 vs 19%), RNF43 (1 vs 12%) and ATM (2 vs 5%) mutations (all q&lt;0.05). Conclusions: Our data suggest that CTX-S may predict longer survival on EGFRi, surprisingly independent of RAS/BRAF mutation status as well as tumor sidedness. Patients with high CTX-S had increased prevalence of CMS2 and harbored more APC and TP53 mutations. A strong EGFRi biomarker would likely expand the utility of EGFRi to right-sided tumors and possibly to RAS MUT tumors. Further validation of these biomarkers in a prospective clinical trial is warranted and could change our current standard of care for CRC.[Table: see text]
Subgroup analyses of the effect of ramucirumab in pretreatment with immune checkpoint inhibitor in RINDBeRG: A randomized clinical trial in third- or further-line treatment of gastric cancer.
Authors: Ryohei Kawabata, Daisuke Sakai, Shigenori Kadowaki, Takao Tsuduki, Takahisa Suzuki, Toru Masuzawa, Keitaro Shimozaki, Masahiro Tsuda, Takeshi Yamada, Toshifumi Yamaguchi, Shugo Ueda, Yosuke Kito, Toshiharu Hirose, Tomono Kawase, Takashi Nomura, Kazuhiro Nishikawa, Hisato Kawakami, Toshio Shimokawa, Narikazu Boku, Taroh Satoh
Journal: Journal of Clinical Oncology (2024)

339 Background: To confirm synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment, we evaluated the effect of pretreatment with immune checkpoint inhibitors to ramucirumab plus irinotecan versus irinotecan in the third or later line treatment beyond progression after ramucirumab for advanced gastric cancer from the RINDBeRG trial. Methods: Patients received ramucirumab at 8 mg/kg plus irinotecan at 150 mg/m2 or irinotecan alone. End points were compared between treatment arms and pretreatments with nivolumab (NIVO+, n = 226) or without nivolumab (NIVO-, n = 169). Results: The overall survival hazard ratio was 0.84 (95 % confidence interval, 0.64-1.12) in the NIVO+ population and 1.05 (95 % confidence interval, 0.76-1.44) in the NIVO- population. The progression-free survival hazard ratio was 0.67 (95 % confidence interval, 0.51-0.87) in the NIVO+ population and 0.83 (95 % confidence interval,0.61-1.12) in the NIVO- population. The objective response rate was higher for ramucirumab plus irinotecan in both populations (NIVO+ population, 17.5 % vs 28.8 %; NIVO- population, 10.9 % vs 14.5 %). Safety profiles of the ramucirumab plus irinotecan arm were similar between populations. Conclusions: Progression-free survival and objective response rate improvements were observed for ramucirumab plus irinotecan in both populations and these benefits were enhanced with prior nivolumab therapy. Clinical trial information: jRCTs051180187 .
Bulky nodal disease as distinctive prognosticator in anal cancer management.
Authors: Eui Kyu Chie, Seok-Joo Chun, Eunji Kim, Won Il Jang, Mi-Sook Kim, Hyun-Cheol Kang, Byoung Hyuck Kim
Journal: Journal of Clinical Oncology (2024)

1 Background: This study aimed to investigate the prognostic value of bulky nodal involvement in patients with squamous cell carcinoma of anus treated with definitive chemoradiotherapy. Methods: Medical records of patients with anal squamous cell carcinoma receiving definitive chemoradiotherapy at three medical centers from 2004 to 2021 were retrospectively analyzed. Exclusion criteria were (1) distant metastasis including non-regional nodal involvement at diagnosis, (2) 2D radiotherapy, and (3) salvage treatment for local relapse. Bulky nodal disease was defined as node with long-diameter 2cm or greater. Results: A total of 104 patients were accrued, consisting of 51 patients without, 46 patients with non-bulky, and 7 patients with bulky nodal involvement. Median follow-up duration was 54.0 months (range, 6.4-162.2 months). Estimated progression-free survival (PFS), loco-regional recurrence free survival (LRRFS) and overall survival (OS) at 5 years for patients with bulky nodal disease were 42.9%, 42.9%, and 89.4%, respectively. Compared to without or with non-bulky nodal involvement, bulky nodal involvement was significantly related with poor PFS and LR RFS. New staging incorporating bulky nodal disease as N2 stage was devised: T1-2N0-1 as stage I, T3-4N0-1 as stage II, and N2 as stage III. Estimated PFS, LRRFS, and OS at 5 years were as follows: 83.5%, 85.9%, and 91.3%, 60.9%, 67.7% and 93.3%, and 42.9%, 42.9%, and 55.6% for patients with stage I, II, and III disease, respectively (p = 0.0024 for PFS, 0.0015 for LRRFS, and 0.28 for OS, respectively). Conclusions: Patients with bulky nodal disease receiving standard chemoradiotherapy had poor survival outcomes compared to the other patient groups, suggesting the need for further treatment intensification. Moreover, incorporating bulky nodal disease into the staging system improved the prognosis predictability.