A phase II study of bevacizumab in combination with irinotecan plus S-1 as first-line treatment in patients with KRAS mutant-type metastatic colorectal cancer.

676 Background: FOLFIRI+bevacizumab (BV) is considered as a first-line treatment in patients (pts) with metastatic colorectal cancer (mCRC). The FIRIS study showed the non-inferiority of irinotecan plus S-1 (IRIS) to FOLFIRI. Therefore, we conducted a phase II study to evaluate the efficacy and safety of BV in combination with IRIS as first-line chemotherapy for KRAS mutant-type (mt) mCRC (clinical trial information: UMIN000004630). Methods: Eligibility criteria included histologically confirmed mCRC, KRAS mt, no previous chemotherapy, ECOG performance status (PS) of 0/1, and adequate organ function. S-1 was administered at 80 mg/m2 on days 1–14 and irinotecan at 100 mg/m2 on days 1 and 15 every 28 days. BV was administered at 5 mg/kg on days 1 and 15 every 28 days. The primary endpoint was response rate (RR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. The sample size was calculated to reject a RR of 25% in favor of a target RR of 50% with a significance level of 0.05 and a statistical power of 80%. Results: Of 26 patients enrolled for the study between December 2010 and September 2015, 23 met the inclusion criteria. The patient characteristics were as follows: median age, 66 (range, 46–77) years; male/female, 15/8; PS 0/1, 9/14; number of metastatic tumors 1/ ≥ 2, 8/15; colon/rectum as the primary tumor site, 13/10; primary tumor +/−, 15/8; and unresectable/recurrent, 15/8. The RR was 60.9% (95% confidence interval (CI): 40.8%–77.8%) with complete response, 0; partial response, 14; stable disease, 8; progressive disease, 0; and not evaluable, 1. With a median follow-up period of 58.1 months, the median PFS and OS were 10.7 (95% CI: 4.7–16.8) and 28.5 (95% CI: 17.6–39.3) months, respectively. The most common grade 3 or 4 adverse events were neutropenia (35%), diarrhea (22%), leukopenia (17%), febrile neutropenia (13%), anemia (13%), and hypoalbuminemia (13%). Conclusions: BV in combination with IRIS as first-line chemotherapy showed promising anti-tumor effects and manageable toxicities for KRAS mt mCRC. Clinical trial information: UMIN000004630.

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

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3501 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3501-3501

Author(s):

Akihito Tsuji ◽

Hisatsugu Ohori ◽

Tatsuro Yamaguchi ◽

Masato Matsuura ◽

Atsujiro Nishioka ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Trial ◽

Primary Endpoint ◽

Line Treatment ◽

Wild Type ◽

First Line ◽

Randomized Phase Ii ◽

Secondary Endpoints ◽

Clinical Trial Information ◽

First Line Treatment

3501 Background: Triplet regimens, FOLFOXIRI, combined with bevacizumab (bev) or panitumumab have been shown to be superior in terms of early tumor shrinkage (ETS) and depth of response (DpR) compared to doublet combinations in patients with RAS wild-type metastatic colorectal cancer (mCRC), in the TRIBE trial ( N Engl J Med 2014) or the VOLFI trial ( J Clin Oncol 2019), respectively. There have been few studies which directly compared cetuximab (cet) with bev when combined with triplet regimen. Therefore, we investigated the efficacy and safety of bev vs. cet in combination with FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. Methods: This 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 first-line treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the 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. Secondary endpoints included ETS rate at week 8, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), secondary resection rate, and toxicity. Results: A total of 359 patients were enrolled between July 2015 and June 2019. For the full analysis set (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 83%/17%), 173 and 175 patients were randomly assigned to the cet and bev arms, respectively. On the cutoff date of September 2020, the median number of cycles administered was 10 (range, 1-51) for the cet arm and 12 (range, 1-51) for the bev arm. Safety data was already reported at the ASCO GI symposium 2021 (J Clin Oncol 39, 2021 suppl 3; abstr 86). The primary endpoint was met (p =.001); 57.4%（-15.0̃100）for the cet arm versus 46.0% （-0.6̃100）for the bev arm. As for primary tumor sidedness, median DpR were 60.3% versus 46.1% (p =.0007) in the left-side and 50.0% versus 41.2% (p =.46) in the right-side. The ETS rate and ORR as the secondary endpoints were 77.8% and 69.1% in the cet arm versus 74.6% and 71.7% in the bev arm, respectively, with no statistical significance. Although the survival data were immature, PFS and OS of both arms were 12.7 months (95%CI 11.5-14.0) and 37.6 months (95%CI 30.8 to 43.0), respectively. Conclusion: The mFOLFOXIRI plus cet has been shown to be significantly superior to the mFOLFOXIRI plus bev in terms of DpR as the primary endpoint in first-line treatment for RAS wild-type mCRC. Clinical trial information: NCT02515734. Clinical trial information: UMIN000018217.

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Phase II study of irinotecan and bevacizumab plus alternate day S-1 as second-line treatment in patients with metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.749 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 749-749

Author(s):

Chihiro Tanaka ◽

Chu Matsuda ◽

Ken Kondo ◽

Yukihiko Tokunaga ◽

Takao Takahashi ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Phase Ii Study ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Grade 3 ◽

Clinical Trial Information ◽

First Line Treatment

749 Background: The recommended dose of combination chemotherapy of irinotecan, bevacizumab and oral S-1 is 100mg/m2, 5mg/kg and 80-120mg/body respectively. To evaluate whether the dose of irinotecan could be raised to 150mg/m2 with modified administration of S-1, we have conducted a phase II study of irinotecan and bevacizumab plus alternate day S-1 in patients with metastatic colorectal cancer (UMIN000008947). Methods: Patients with metastatic colorectal cancer after failure with first-line treatment of oxaliplatine and fluoropyrimidine were enrolled. Irinotecan (150 mg/m2) and bevacizumab (5mg/kg) were given intravenously on day 1. Oral S-1was administered on alternate days at a dose of 40-60mg twice a day. Cycles were repeated every two weeks. Results: A total of 51 patients were evaluated in the first fouur cycles. Grade 3 and 4 neutropenia were 10% (10/51) and 13.7%(7/10), grade 3 and 4 thrombocytopenia were 0%(0/51) and 2.0% (1/51). Grade 2 and 3 mucositis were 13.7% (7/51) and 3.9% (2/51). Grade 2 and 3 nausea were 11.8% (6/51) and 2.0% (1/51). Grade 2 and 3 diarrhea were 17.6% (9/51) and 15.7% (8/51). The relative dose intensities were 84.8% for irinotecan, 87.5% for bevacizumab, and 84.8% for S-1 respectively in the first four cycles. Conclusions: Our data suggest that irinotecan (150 mg/m2) and bevacizumab was administered safely with alternate day S-1 as second-line tratment in patients with metastatic colorectal cancer. Clinical trial information: 000008947.

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PARADIGM study: A multicenter, randomized, phase III study of mFOLFOX6 plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.85 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 85-85

Author(s):

Takayuki Yoshino ◽

Hiroyuki Uetake ◽

Katsuya Tsuchihara ◽

Kohei Shitara ◽

Kentaro Yamazaki ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Trial ◽

Primary Tumor ◽

Phase Iii ◽

Line Treatment ◽

Wild Type ◽

First Line ◽

Primary Analysis ◽

Phase Iii Study ◽

First Line Treatment

85 Background: The optimal choice of monoclonal antibodies (mAbs) for first-line treatment in patients (pts) with RAS ( KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC) remains controversial. The meta-analyses of subgroup analyses in phase III studies of pts with KRAS exon 2 wild-type mCRC suggested a longer overall survival (OS) with an anti-EGFR mAb over bevacizumab in pts with RAS wild-type mCRC or with left-sided primary tumors. However, there has been no prospective study comparing the two mAbs in these pt populations. This randomized phase III study was originally designed to demonstrate the superiority of panitumumab versus bevacizumab, both in combination with mFOLFOX6, for RAS wild-type mCRC, but we have revised the protocol to analyze efficacy in pts with a left-sided primary tumor as the primary (final) analysis. Methods: Eligible pts are aged 20-79 years with histologically/cytologically confirmed RAS wild-type chemotherapy-naive mCRC, and ECOG performance status 0-1. Between May 29, 2015 and Jun 8, 2017, 823 pts were randomized 1:1 to panitumumab plus mFOLFOX6 or bevacizumab plus mFOLFOX6 by the minimization method and the randomisation was stratified by institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). The primary analysis was revised to adopt a hierarchical testing procedure; we first compare OS between the two arms in left-sided primary tumor population, and only if there is statistically significant difference, then ITT population analysis will be performed. In this revised plan, the expected number of deaths is 420 in the left-sided population to provide 80% power to detect an OS hazard ratio of 0.74 at a one-sided significance level of 0.02101 determined on the alpha spending function approach after one interim analysis. A large-scale exploratory biomarker substudy to identify potential biomarker candidates using tumor tissue and circulating tumor DNA is also underway (Clinical trial no.: NCT02394834). The data cut off for the primary analysis is expected to be during 1Q 2021. Results: Results are expected in 2021. Conclusions: Results are expected in 2021. Clinical trial information: NCT0239475.

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