Colorectal cancer

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01)

Author(s)：: Hisato Kawakami¹, Takayuki Yoshino², Maria Di Bartolomeo³, Kanwal Raghav⁴, Toshiki Masuishi⁵,
Kensei Yamaguchi⁶, Tomohiro Nishina⁷, Kapil Saxena⁸, Kojiro Kobayashi⁸, Emarjola Bako⁸, Yasuyuki Okuda⁹, Gerold Meinhardt⁸,
Axel Grothey¹⁰, Salvatore Siena^11,12
Affiliation(s)：: ¹Faculty of Medicine Hospital, Kindai University, ²National Cancer Center Hospital East,³Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy,⁴The University of Texas MD Anderson Cancer Center, Houston, TX, USA,⁵Aichi Cancer Center,⁶The Cancer Institute Hospital,⁷National Hospital Organization Shikoku Cancer Center,⁸Daiichi Sankyo Inc., Basking Ridge, NJ, USA,⁹Daiichi Sankyo, Co., Ltd., Tokyo, Japan,¹⁰West Cancer Center, Germantown, TN, USA,¹¹Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy,¹²Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy

Background: T-DXd is an antibody-drug conjugate of a humanized anti-HER2 antibody bound to a topoisomerase I inhibitor by a cleavable linker. The primary analysis of DESTINY-CRC01 (NCT03384940), a phase 2, open-label, multicenter study of T-DXd in pts with HER2+ mCRC showed promising antitumor activity and a manageable safety profile. We present updated longer-term efficacy and safety data.
Methods: Pts had centrally confirmed HER2-expressing, RAS wild-type mCRC that progressed after ≧2 prior regimens. 6.4 mg/kg of T-DXd was administered every 3 weeks (Q3W) in 3 cohorts (A: HER2 IHC3+ or IHC2+/ISH+; B: IHC2+/ISH-; C: IHC1+). The primary end point was confirmed ORR by independent central review in cohort A. Secondary end points were DCR, DOR, PFS, and OS.
Results: At data cutoff (Dec 28, 2020), 86 pts (A, 53; B, 15; C, 18) received T-DXd. Median prior regimens for metastatic disease was 4. All pts had prior irinotecan; 30.2% in cohort A had prior anti-HER2 therapy. Median treatment duration (all pts) was 3.0 mo (cohort A, 5.1 mo).
In cohort A (N=53, mFU, 62.4 weeks), confirmed ORR was 45.3%, DCR was 83.0%, mDOR was 7.0 mo, mPFS was 6.9 mo with 37 (69.8%) PFS events, and mOS was 15.5 mo with 36 (67.9%) OS events. These results are consistent with the primary analysis. Confirmed ORR was 43.8% in pts with prior anti-HER2 therapy, 57.5% in pts with IHC3+ status, and 7.7% in pts with IHC2+/ISH+ status. In cohorts B and C, mPFS was 2.1 mo and 1.4 mo; mOS was 7.3 mo and 7.7 mo, respectively. TEAEs of grade (G) ≧3 occurred in 56 pts (65.1%). TEAEs leading to drug discontinuation occurred in 13 pts (15.1%). Eight pts (9.3%) had ILD adjudicated by an independent committee as related to T-DXd (4 G2; 1 G3; 3 G5).
Conclusions: T-DXd showed promising activity and durability with longer-term FU. The safety profile was consistent with prior results; ILD continues to be recognized as an important identified risk that requires careful monitoring and intervention as needed.

Safety of laparoscopic surgery for elderly rectal cancer patients in Japan

Author(s)：: Ryo Seishima¹, Hirotoshi Hasegawa², Koji Okabayashi¹, Kohei Shigeta¹, Shimpei Matsui¹, Hiroaki Miyata³,
Yuichi Yamashita⁴, Masafumi Inomata⁵, Go Wakabayashi⁶, Yoshihiro Kakeji⁷, Masahiko Watanabe⁸, Yuko Kitagawa¹
Affiliation(s)：: ¹Department of Surgery, School of Medicine, Keio University, ²Department of Surgery, Ichikawa General Hospital, Tokyo Dental College,³Department of Health Policy and Management, School of Medicine, Keio University,⁴4Department of Gastroenterological Surgery, Faculty of Medicine, Fukuoka University,⁵5Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine, Oita University,⁶Department of Surgery,, Ageo Central General Hospital,⁷Division of Gastrointestinal Surgery, Graduate School of Medicine, Kobe University,⁸Department of Surgery, Hospital, Kitasato Insutitute

Background: This study aimed to analyse the perioperative results from a national dataset of rectal cancer resections in elderly patients.Methods: The clinical records of patients undergoing rectal cancer surgery between 2012 and 2014 were retrieved from the Japanese National Clinical Database and analysed retrospectively. Patients were categorized according to age and those 80 years or older were defined as elderly. Subgroups were also defined according to the surgical approach (laparoscopy versus open surgery). The short-term outcomes, including mortality, anastomotic leak, surgical site infections and medical complications were compared between subgroups.Results: Of 56 175 patients undergoing rectal cancer surgery, some 6717 patients were elderly and laparoscopy was performed in 46.8% of the sample. When comparing laparoscopy and open surgery in elderly patients, the operative mortality rate (1.5 versus 2.8%; P<0.001), the incidence of anastomotic leakage (5.2 versus 6.5%; P=0.026), surgical site infections (6.0 versus 8.0%; P=0.001), pneumonia (1.4 versus 2.5%; P=0.001), renal failure (0.7 versus 1.3%; P=0.016) and cardiac events(0.3 versus 0.8%; P=0.008) were lower for laparoscopy than for open surgery. The overall complication rate in elderly patients (19.5%) was comparable to that in the younger group (P=0.07). However, incidence of systemic complications was significantly higher in elderly than in younger patients (all P<0.001).
Conclusion: Laparoscopy was safe and feasible in elderly patients compared with open surgery. However, the rates of systemic complications were significantly higher than in younger patients.

Monitoring molecular residual disease by circulating tumor DNA in resectable colorectal cancer: Initial report of a prospective observational study GALAXY in CIRCULATE-Japan

Author(s)：: Hiromichi Shirasu¹, Hiroya Taniguchi², Jun Watanabe³, Masahito Kotaka⁴, Kentaro Yamazaki¹, Alexey Aleshin⁵, Daisuke Kotani⁶, Saori Mishima⁶, Hiroki Yukami⁶, Eiji Oki⁷, Ichiro Takemasa⁸, Takeshi Kato⁹, Yoshiaki Nakamura⁶, Masaki Mori¹⁰,
Takayuki Yoshino¹⁰
Affiliation(s)：: ¹Division of Gastrointestinal Oncology, Shizuoka Cancer Center, ²Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi Cancer Center,³Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center,⁴Gastrointestinal Cancer Center, Sano Hospital,⁵Natera, Inc.,⁶Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East,⁷Department of Surgery and Science, Graduate School of Medical Sciences, Graduate School, Kyushu University,⁸Department of Surgery, Surgical Oncology and Science, Sapporo Medical University,⁹Department of Colorectal Surgery, National Hospital Organization Osaka National Hospital,¹⁰Faculty of Medicine, Tokai University

Background
Circulating tumor DNA (ctDNA) can be used to predict the risk of recurrence by detecting molecular residual disease in patients with colorectal cancer (CRC). GALAXY study is designed to monitor ctDNA status for patients with clinical stages II to IV CRC who can undergo complete surgical resection.
Methods
The ctDNA status is being investigated using Signatera^TM, a personalized, tumor-informed ctDNA assay. The association of ctDNA status with tumor biomarkers status, and disease recurrence are also being investigated.
Results
This study enrolled 884 patients between 5 June 2020 and 29 December 2020. In this analysis, 809 patients with pathological, and tumor biomarker status were evaluated. RAS, BRAF V600E mutations, and MSI-high were identified in 348 (43%), 55 (7%), and 71 (9%) patients, respectively. Pre-operative ctDNA was detected in 92% (735/800) of the patients with 0% (0/1), 77% (50/65), 95% (267/280), and 96% (288/301) in pathological stage (pStage) 0, I, II, and III, respectively. Multivariate analysis showed pre-operative ctDNA status was independently associated with advanced pT (p<0.001), but not associated with RAS/BRAF and MMR status. Moreover, post-operative (4weeks) ctDNA positive status was detected in 18% (140/798) of the patients with 0% (0/1), 5% (3/66), 5% (15/278), and 25% (74/301) in pStage 0, I, II, and III, respectively. Multivariate analysis showed post-operative (4w) ctDNA status was independently associated with advanced pN (p < 0.001), but not associated with RAS/BRAF and MMR status. Patients with positive post-operative (4w) ctDNA status were 20 times more likely to experience disease recurrence than those with negative ctDNA status (hazard ratio, 19.5; 95% CI, 7.9-47.8; p<0.001).
Conclusions
Preoperative and post-operative (4w) ctDNA status were independently associated with pT, and pN, but not associated with RAS/BRAF and MMR statuses. Moreover, post-operative (4w) ctDNA status has potential to detect early recurrence.

TRUSTY: A randomized phase 2/3 study of trifluridine/tipiracil + bevacizumab versus fluoropyrimidine + irinotecan + bevacizumab as second-line treatment in patients with metastatic colorectal cancer

Author(s)：: Tetsuji Terazawa¹, Yasutoshi Kuboki^2,14, Toshiki Masuishi³, Masato Nakamura⁴, Jun Watanabe⁵, Hitoshi Ojima⁶,
Yudai Shinohara⁷, Eiji Oki⁸, Yu Sunakawa⁹, Soichiro Ishihara¹⁰, Hiroya Taniguchi³, Takako Nakajima¹¹, Satoshi Morita¹²,
Kuniaki Shirao¹³, Takayuki Yoshino¹⁴
Affiliation(s)：: ¹Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University, ²Department of Experimental Therapeutics, National Cancer Center Hospital East,³Department of Clinical Oncology, Aichi Cancer Center,⁴Aizawa Comprehensive Cancer Center, Aizawa Hospital,⁵Department of Surgery, Gastroenterological Center, Medical center, Yokohama City University,⁶Gastrointestinal Surgery, Gunma Prefectural Cancer Center,⁷Department of Hematology/Oncology, Japan Community Health care Organization Kyushu Hospital,⁸Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University,⁹Department of Clinical Oncology, St.Marianna University,¹⁰Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo,¹¹Kyoto Innovation Center for Next Generation Clinical Trials and iPS Cell Therapy, Hospital, Kyoto University,¹²Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University,¹³Oita University,¹⁴Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East

Background: The efficacy of trifluridine/tipiracil (FTD/TPI) + bevacizumab (BEV) as a later-line treatment for metastatic colorectal cancer (mCRC) has been demonstrated in clinical trials. Therefore, we conducted a randomized phase 2/3 study to determine whether FTD/TPI + BEV is non-inferior to either FOLFIRI or S-1 and irinotecan + BEV in terms of overall survival (OS) as second-line treatment in patients with mCRC.
Methods: Patients with histologically confirmed mCRC who failed first-line chemotherapy including fluoropyrimidine + oxaliplatin with either BEV or an anti-EGFR antibody were eligible. Patients were randomized to receive either FTD/TPI + BEV (BEV 5 mg/kg on days 1 and 15, FTD/TPI 35 mg/m² twice daily on days 1-5 and 8-12 of each 28-day cycle) or either FOLFIRI or S-1 and irinotecan + BEV (control group). The primary endpoint was OS. The non-inferiority margin of a hazard ratio (HR) was set at 1.33.
Results: As a result of the interim analysis for futility, the study was terminated in July 2020, and 397 patients were finally enrolled at 65 institutions from October 2017. The baseline characteristics were similar between the groups. The Median OS were 14.8 mo in the FTD/TPI + BEV group and 18.1 mo in the control group [HR: 1.38; 95% CI: 0.99-1.93; p=0.5920 for non-inferiority]; non-inferiority of FTD/TPI + BEV was not demonstrated. The median PFS were 4.5 mo in the FTD/TPI plus BEV group and 6.0 mo in the control group (HR: 1.45; 95% CI: 1.14-1.84). The RR and DCR were 3.8% and 61.2% in the FTD/TPI plus BEV group, and 7.1% and 71.7% in the control group, respectively. The main grade 3 or 4 adverse events in the FTD/TPI + BEV and control groups were neutropenia (65.8% and 41.6%), diarrhea (1.5% and 7.1%).
Conclusion: FTD/TPI + BEV did not show non-inferiority to FOLFIRI or S-1 and irinotecan + BEV as second-line treatment in patients with mCRC. Post hoc subgroup analyses are ongoing to investigate patients who likely benefit from FTD/TPI plus BEV.

Randomized Phase II trial comparing UFT/LV to UFT/LV + PSK in high risk Stage II and Stage III colorectal cancer.

Author(s)：: Hiroomi Ogawa¹, Ken Shirabe¹, Hiroshi Saeki¹
Affiliation(s)：: ¹Department of General Surgical Science, Graduate School of Medicine, Gunma University

Purpose: Uracil and tegafur plus leucovorin (UFT/LV), an oral adjuvant therapy for stage II/III colorectal cancer, is non-inferior to standard weekly fluorouracil and folinate. In addition, although protein-bound polysaccharide K (PSK) has been evaluated as a postoperative adjuvant drug for colorectal cancer, it is still not fully understood. This randomized phase II trial compared UFT/LV plus PSK to UFT/LV as adjuvant chemotherapy for patients with high-risk stage II/III colorectal cancer.
Patients and Methods: From April 2011 to Aug 2016, 186 patients who underwent radical resection were randomly assigned to receive 6 months of UFT/LV (Group A; 300 mg/m2/day UFT and 75 mg/day LV on days 1-28, every 35 days for five cycles) or 6 months UFT/LV+PSK (Group B; standard UFT/LV regimen and administration of every day 3g/body PSK) or 12 months UFT/LV+PSK (Group C). The primary endpoint was the 3-year disease-free survival.
Results: 37, 73, and 71 patients were assigned to groups A, B, and C, and the treatment was completed by 33 (89.2%), 62 (84.9%), and 50 (70.4%) patients in groups A, B, and C, respectively, with significant differences (P=0.035). The incidence of adverse events of all grades was 54.1%, 52.1%, and 62.0% in groups A, B, and C, and Grade ≧3 adverse events were observed in 10.8%, 8.2%, and 17.0% of patients in group A, B, and C, respectively. The 3-year disease-free survival rate was 75.3%, 84.5%, and 77.3% in Groups A, B, and C, respectively with no significant difference. Patients with a preoperative lymphocyte ratio >35% had significantly higher 3-year DFS in group B (100% vs 72.0%, p=0.034).
Conclusions: UFT/LV+PSK is an additional adjuvant chemotherapy option for high-risk stage II/III colorectal cancer, especially patients with a high preoperative lymphocyte ratio may significantly benefit.

Exploratory randomized phase II trial for optimizing treatment dosage and duration of adjuvant S-1 plus oxaliplatin in patients with stage III colon cancer; SOAP trial

Author(s)：: Yusuke Suwa^1,2, Jun Watanabe¹, Kazuya Nakagawa², Hirokazu Suwa³, Mayumi Ozawa², Masashi Momiyama⁴, Atsushi Ishibe¹, Nobuhiro Sugano¹, Kotaro Nagamine⁵, Shigeru Yamagishi⁶, Mitsuyoshi Ota⁷, Tadao Fukushima⁸, Hitoshi Sekido⁹,
Yusuke Saegusa¹⁰, Itaru Endo²
Affiliation(s)：: ¹Gastroenterological Center, Medical center, Yokohama City University, ²Department of Gastroenterological Surgery,, Graduate School of Medicine, Yokohama City University,³Department of Surgery, Yokosuka Kyosai Hospital,⁴Department of Surgery, NTT Medical Center Tokyo,⁵Department of Surgery, Yokosuka City Hospital,⁶Department of Surgery, Fujisawa City Hospital,⁷Department of Surgery, Yokohama City Minato Red Cross Hospital,⁸Department of Surgery, Saiseikai Yokohamasi Nanbu Hospital,⁹Department of Surgery, National Hospital Organization Yokohama Medical Center,¹⁰Department of Biostatistics, Yokohama City University

Background: The recent combined analysis by the IDEA Collaboration for stageIII colon cancer suggested that shortening the oxaliplatin (L-OHP) based adjuvant (Adj) chemotherapy may be possible. And S-1 and L-OHP treatment (SOX)+Bevacizumab (Bev) was shown to be non-inferior to FOLFOX+Bev as 1st-line chemotherapy to metastatic colorectal cancer patients. The aim of this study was to optimize treatment dosage and duration of adj SOX in patients with stageIII colon cancer.
Methods: This trial was as open-label multi-center randomized phase II study (UMIN000013825). Patients who had undergone curative resection for stage III colon cancer were randomly assigned to 3-month or 6-month of adj SOX delivered every 3 weeks in different doses. Treatment in SOX included intravenous infusion of 130mg/m²(3-month) or 100mg/m²(6-month) of L-OHP on day1 and S-1 80mg/m²twice a day from day1 to 15. The primary endpoint was 3-year disease-free survival (DFS). The null hypothesis for the primary endpoint was that threshold 3-year DFS was 72% in each arm with a one-sided α of 10%.
Results: From May, 2014, to November, 2017, 163 eligible patients were enrolled. 8 cases were excluded. Of the 155 patients, 76 were assigned to the 6-month and 79 to the 3-month arm. The median follow-up for all patients was 52.1 months. The 3-year DFS was 75.0% (80%CI 67.95-80.72%, p=0.282) in the 6-month and 76.9% (80%CI 70.1-82.38%, p=0.171) in the 3-month arm and 3-year OS was 97.3% and 97.4%. Treatment completion rate was 73.7% and 86.1% (p=0.070), and the mean RDI of L-OHP and S-1 were 77.4% and 76.9%, and 85.0% and 82.6, relatively (p=0.002, p=0.030). The rate of gradeIII and more AE was 42.1% and 34.2% (p=0.326).
Conclusions: The 3-year DFS was not significantly superior to 72% in 3-month and 6-month arms. RDI was significantly greater in 3-month and the grade≧3 AE was similar. SOX adj chemotherapy for 3-month with 130mg/m²of L-OHP was feasible and safe compare to for 6-month with 100mg/m²dose.

Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer

Author(s)：: Akira Inoue^1,2, Frederick Robinson², Rosalba Minelli², Hideo Tomihara², Takahiro Kodama³, Angela Harris², Ningping Feng², Angela Deem², Timothy Heffernan², Andrea Viale², Christopher Bristow², Scott Kopetz², Giulio Draetta², Giannicola Genovese², Alessandro Carugo²
Affiliation(s)：: ¹Department of Gastroenterological Surgery, Osaka General Medical Center, ²The University of Texas MD Anderson Cancer Center,³Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University

＜Background and Aims＞
Understanding the mechanisms by which tumors adapt to therapy is critical for developing effective combination therapeutic approaches to improve clinical outcomes for patients with cancer.
＜Methods＞
To identify promising and clinically actionable targets for managing colorectal cancer (CRC), we conducted a patient-centered functional genomics platform that includes approximately 200 genes and paired this with a high-throughput drug screen that includes 262 compounds in four patient-derived xenografts (PDXs) from patients with CRC.
＜Results＞
Both screening methods identified exportin 1 (XPO1) inhibitors as drivers of DNA damage-induced lethality in CRC. Molecular characterization of the cellular response to XPO1 inhibition uncovered an adaptive mechanism that limited the duration of response in TP53-mutated, but not in TP53-wild-type CRC models. Comprehensive proteomic and transcriptomic characterization revealed that the ATM/ATR-CHK1/2 axes were selectively engaged in TP53-mutant CRC cells upon XPO1 inhibitor treatment and that this response was required for adapting to therapy and escaping cell death. Administration of KPT-8602, an XPO1 inhibitor, followed by AZD-6738, an ATR inhibitor, resulted in dramatic antitumor effects and prolonged survival in TP53-mutant models of CRC.
＜Conclusions＞
Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.

Prediction of lymph node metastasis in colorectal submucosal(SM) invasive cancer using endoscopic imaging with Artificial Intelligence

Author(s)：: Masatoshi Kitakaze¹, Norikatsu Miyoshi¹, Shiki Fujino¹, Chu Matsuda², Masayoshi Ysui², Masayuki Ooue², Yuki Sekido¹, Tsuyoshi Hata¹, Takayuki Ogino¹, Hidekazu Takahashi¹, Mamoru Uemura¹, Tsunekazu Mizushima¹, Yuichiro Doki¹, Hidetoshi Eguchi¹
Affiliation(s)：: ¹Gastroenterological Surgery, Graduate School of Medicine, Osaka University, ²Osaka International Cancer Institute

Background: In colorectal cancer with submucosal invasion (sm cancer), the possibility of lymph node(LN) metastasis is approximately 10%, and surgical resection is generally recommended. However, endoscopic resection is used for early-stage colorectal cancer with a low risk of LN metastasis and curative potential. In contrast, advances in Deep Learning have led to the development of neural network algorithms which good performance in vision tasks and have successfully been applied to medical imaging analysis. However, LN metastasis has not been directly predicted based on endoscopic images findings.
Purpose: To examine the feasibility of deep learning approach to predict LN metastasis in patients with sm cancer from endoscopic images of colon cancer.
Materials and Methods: The convolutional neural network (CNN) were trained on preoperative endoscopic images of colorectal cancer patients who resected with LN dissection at our hospital from 2014 to 2017 with MATLAB software (Mathworks, R2021a). The CNN tested on the independent set that is endoscopic images in SM CRC patients from 2014 to 2017 at Osaka International Cancer Institute. Statistical tests were performed using the X² test.
Results: A learning data set of 1723 endoscopic images in 181 cases and an independent validation set of 1071 endoscopic images in 154 cases were collected. This CNN achieved 32.3% sensitivity and 81.3% specificity. The CNN model was significantly associated with LN metastasis(OR=1.74(95%CI; 1.15-2.64), P=0.009). At the cut-off value obtained from the ROC curve, the CNN achieved 72.7% sensitivity and 45.5% specificity. The CNN model was significantly associated with LN metastasis(OR=2.22(95%CI; 1.47-3.35), P<0.001).
Conclusion: We demonstrated that a deep learning algorithm can predict LN metastasis from endoscopic images of sm cancer. We will improve CNN-based model with further validation in a larger population and model calibration.

Trastuzumab deruxtecan in patients with HER2-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC): A randomized, multicenter, phase 2 study (DESTINY-CRC02)

Author(s)：: Takayuki Yoshino¹, Kanwal Raghav², Rosine Guimbaud³, Ian Chau⁴, Marc Van Den Eynde⁵, Joan Maurel⁶, Jeanne Tie⁷,
Tae Won Kim⁸, Kun-Huei Yeh⁹, Daniel Barrios¹⁰, Kojiro Kobayashi¹⁰, Emarjola Bako¹⁰, Mehreteab Aregay¹⁰,
Gerold Meinhardt¹⁰, Salvatore Siena^11,12
Affiliation(s)：: ¹National Cancer Center Hospital East, ²The University of Texas MD Anderson Cancer Center, Houston, TX, USA,³CHU Toulouse, Toulouse, France,⁴The Royal Marsden Hospital, Sutton, United Kingdom,⁵Cliniques Universitaires St-Luc, UCLouvain, Brussels, Belgium,⁶Hospital Clínic Barcelona, Barcelona, Spain,⁷Peter MacCallum Cancer Centre, Melbourne, VIC, Australia,⁸Asan Medical Center, Seoul, South Korea,⁹National Taiwan University Hospital, Taipei City, Taiwan,¹⁰Daiichi Sankyo Inc., Basking Ridge, NJ, USA,¹¹Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy,¹²Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy

Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate consisting of an anti-HER2 antibody linked to a potent topoisomerase I inhibitor. T-DXd has been approved to treat HER2+ mBC (US, Japan, EU, UK) and advanced GC (US, Japan). The Ph2 DESTINY-CRC01 study (NCT03384940) included patients (pts) with RAS wild-type mCRC, with median 4 prior lines of therapy. Preliminary results in pts with HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) mCRC showed that T-DXd treatment (6.4 mg/kg intravenously every 3 wks) resulted in a confirmed ORR of 45.3% and a median PFS of 6.9 mo. Although 5.4 mg/kg and 6.4 mg/kg doses of T-DXd have shown clinical efficacy in multiple cancer indications, the lower dose has not yet been tested in pts with HER2-overexpressing mCRC. Preliminary data also suggest T-DXd may be active in RAS mutant mCRC, unlike other anti-HER2 therapies. The DESTINY-CRC02 study aims to determine efficacy and safety of T-DXd 5.4 and 6.4 mg/kg doses in pts with HER2-overexpressing, RAS wild-type or mutant mCRC.
Methods: DESTINY-CRC02 (NCT04744831) is a multicenter, 2-arm, parallel Ph2 study. Eligible pts will have HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) locally advanced, unresectable or mCRC and have previously received chemotherapy, anti-EGFR therapy, anti-VEGF treatment, and/or anti-PD-1/PD-L1 therapy, as clinically indicated. Prior anti-HER2 therapy will be allowed. In stage 1, pts will be randomly assigned 1:1 to receive T-DXd 5.4 mg/kg (n = 40; arm 1) or 6.4 mg/kg (n = 40; arm 2). Randomization will be stratified by ECOG PS, HER2 status, and RAS status. After stage 1, eligible pts in stage 2 (n = 40) will receive T-DXd 5.4 mg/kg until disease progression or other treatment discontinuation criteria are met. The primary objective is to assess efficacy of T-DXd at two doses, with a primary end point of confirmed ORR by blinded independent central review. Secondary end points include investigator-assessed ORR, PFS, DOR, DCR, CBR, OS, PKs, and safety.

A randomized phase II study of FOLFOXIRI plus cetuximab versus bevacizumab as the first-line treatment in metastatic colorectal cancer with RAS wild-type tumors: the DEEPER trial (JACCRO CC-13)

Author(s)：: Hirofumi Ota¹, Akihito Tsuji², Tetsuji Terazawa³, Toru Miyake⁴, Tamotsu Sagawa⁵, Shu Okamura⁶, Mitsugu Kochi⁷,
Masahito Kotaka⁸, Yutaro Kubota⁹, Yu Sunakawa¹⁰, Takashi Sekikawa¹¹, Masato Nakamura¹², Masahiro Takeuchi¹³,
Wataru Ichikawa¹¹, Masashi Fujii¹⁴
Affiliation(s)：: ¹Department of Gastroenterological Surgery, Ikeda Municipal Hospital, ²Department of Clinical Oncology, Faculty of Medicine, Kagawa University,³Cancer Chemotherapy Center, Hospital, Osaka Medical College,⁴Department of Gastroenterological Surgery, Faculty of Medicine, Shiga University of Medical Science,⁵Division of Gastroenterology, National Hospital Organization -Hokkaido Cancer Center-,⁶Department of Surgery, Suita Municipal Hospital,⁷Department of Digestive Surgery, School of Medicine Itabashi Hospital, Nihon University,⁸Gastrointestinal Cancer Center, Sano Hospital,⁹Department of Medical Oncology, Hospital, Showa University,¹⁰Department of Clinical Oncology, St.Marianna University,¹¹Division of Medical Oncology, Fujigaoka Hospital, Showa University,¹²Aizawa Comprehensive Cancer Center, Aizawa Hospital,¹³Department of Clinical Medicine (Biostatistics), School of Pharmacy, Kitasato University,¹⁴Department of Digestive Surgery, school of medicine, Nihon University

Background: Triplet regimen has been shown to be superior to doublet regimens in 1st-line treatment for patients (pts) with metastatic colorectal cancer (mCRC) in previous clinical trials. However, there are no reports which directly compared cetuximab (cet) and bevacizumab (bev) in combination with triplet regimen.
Methods: The DEEPER trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150mg/m², oxaliplatin 85mg/m², 5-FU 2400mg/m²) plus cet vs. bev as 1st-line treatment in terms of depth of response (DpR) during the entire course as the primary endpoint in 360 pts with RAS wild-type mCRC. The aim of this trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05 in the per protocol set (PPS). Secondary endpoints included early tumor shrinkage (ETS), overall response rate (ORR), progression-free survival, overall survival, secondary resection rate, and safety.
Results: In 359 pts enrolled between July 2015 and June 2019, 175 and 173 pts (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 82%/18%) were randomly assigned to the cet and bev arms, respectively, in the full analysis set. On the cutoff date of September 2020, the median number of cycles administered was 10 (range, 1-65) vs. 12 (range, 1-51). The primary endpoint was met; 57.4% (-15.0~100) for the cet arm vs. 46.0% (-0.6~100) for the bev arm (p=.001, t-test by welch) in the per protocol set. The median DpR were 60.3% vs. 46.1% (p=.0007) in the left-side and 50.0% vs. 41.2% (p=.46) in the right-side. There was no statistical significance in the ETS and ORR (cet vs. bev, 78% vs. 75% and 69% vs. 72%). The severe adverse events rate was 25% vs. 26%. No unexpected toxicities were observed in both arms.
Conclusion: This trial demonstrated for the first time that m-FOLFOXIRI plus cet is significantly superior to m-FOLFOXIRI plus bev in terms of DpR in 1st-line treatment for RAS wild-type mCRC.