Abstract 4293: Final result of lenvatinib and capecitabine in combination with external beam radiation in treatment of locally advanced rectal cancer: Phase I clinical trial

3606 Background: Chemoradiotherapy (CRT) with surgery (S) is standard for patients (pts) with locally-advanced rectal cancer (LARC), and nivolumab (nivo) is active in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivo and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: Phase I included testing of a recommended phase II dosing schedule (RP2S). Efficacy and safety were studied in phase II pts and those given RP2S in phase I. In Cohort A-1, for microsatellite stable (MSS) LARC pts, the primary endpoint was centrally confirmed pathologic complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. Cohort A-2 was exploratory and included a maximum of 5 MSI-H pts. Results: Nivo 240 mg q2 weeks x 5 cycles, following CRT but pre-S, was the RP2S. From 1/17 to 6/18, 37 pts were enrolled in Cohort A-1. Eleven pts (30%; 90% CI 18-44%) showed pCR (AJCC grade (gr) 0). Including the 3 pts (8%) graded AJCC 1, 14 (38%) had major pathologic responses. In addition, clinical CR was observed in 1 pt (3%) refusing S after nivo. Both MSI-H LARC Cohort A-2 pts showed pCRs. Immune-related severe adverse events were observed in 2 pts (gr 3 myasthenia and gr 2 interstitial nephritis); both fully recovered and had S. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (p = 0.038, Fisher exact test) were seen in pts with tumor cells with PD-L1 ≥1% and < 1% IHC staining, respectively, performed on biopsy samples taken pre-CRT. Rates of 62% (8/13) and 10% (1/10) (p = 0.029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8+ lymphocyte /regulatory T cell (CD8/Treg) ratios ≥2 and < 2, respectively. Conclusions: A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical S. PD-L1 expression and elevated CD8/Treg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort. Clinical trial information: NCT02948348.

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Phase I study of preoperative capecitabine and lenvatinib with external radiation therapy in locally advanced rectal adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.694 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 694-694

Author(s):

Jessica Frakes ◽

Rutika Mehta ◽

Sarah E. Hoffe ◽

Iman Imanirad ◽

Maria E Martinez Jimenez ◽

...

Keyword(s):

Clinical Trial ◽

Rectal Cancer ◽

Radiation Therapy ◽

Phase I ◽

Phase I Study ◽

Locally Advanced ◽

Vascular Endothelial Cell ◽

Rectal Adenocarcinoma ◽

External Beam Radiation ◽

Beam Radiation

694 Background: Despite routine use of neoadjuvant chemoradiation, patients with advanced rectal tumors experience significant rates of treatment failure and recurrence. Radiation resistance is a particular problem. Dual targeting of PDGF and VEGFR (Vascular endothelial cell growth factor receptor) in combination with radiation can enhance tumor response. Lenvatinib inhibits the kinase activities of VEGFR1-3, FGFR1-4, PDGFRα, KIT, and RET and in vivo results show that it effectively delays the growth of human colorectal xenografts. Methods: This is a phase I clinical trial of lenvatinib in combination with capecitabine administered with radiation. Patients with stage II or III rectal cancer confirmed by endoscopic ultrasound or MRI were eligible for the study. In this 3+3 phase I study with 3 cohorts, patients were treated with escalating doses of lenvatinib administered in combination with standard doses of capecitabine (850 mg/m2 PO BID D1-5 weekly for 5 ½ to 6 weeks) and external beam radiation therapy (180 cGY on D1-5 weekly for 5 ½ to 6 weeks). Patients underwent surgery 6-10 weeks after neoadjuvant therapy. Results: Nine patients have been enrolled in the 3 cohorts with the median age of 51 years. Lenvatinib dosing started at 14 mg PO daily (cohort 1) and was safely escalated to 20 mg PO daily (cohort 2) followed by 24 mg PO daily (cohort 3). There were no DLTs at the maximum tested dose of lenvantinib (24 mg). 5 patients have undergone low anterior resection and 4 have had abdominoperineal resection. The pathological complete response (pCR) rate was 33.33%, and downstaging was observed in 100% of patients. Median neoadjuvant rectal cancer score (NAR) was 8.7. Three pts had grade 3 events (2 hypertension (HTN), 1 lymphopenia) without any grade 4 events. Most common AEs were HTN and fatigue. No perioperative complications were observed. Tissues for all pts have been collected for planned correlative studies. Conclusions: This study shows that the combination of lenvatinib with capecitabine, and EBRT is well tolerated. NAR score and downstaging rates are encouraging. Currently we are enrolling 10 additional pts at the maximum tested dose of lenvatinib to further evaluate efficacy and safety. Clinical trial information: NCT02935309.

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A phase I/II study of bevacizumab (beva), erlotinib (erl), and 5-fluorouracil (5-FU) with concurrent external beam radiation therapy (RT) in locally advanced rectal cancer (LARC)

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4106 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4106-4106

Author(s):

L. S. Blaszkowsky ◽

T. S. Hong ◽

A. X. Zhu ◽

E. L. Kwak ◽

H. J. Mamon ◽

...

Keyword(s):

Rectal Cancer ◽

Growth Factor ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Cardiac Ischemia ◽

External Beam Radiation ◽

Beam Radiation ◽

Study Therapy

4106 Background: The German Rectal Cancer Study Group established neoadjuvant therapy as a standard of care in patients with T3/T4 rectal cancer. Beva, a vascular endothelial growth factor (VEGF) inhibitor with demonstrated activity in colorectal cancer, and erl, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor may both serve as radiation sensitizers. Methods: Twenty one pts with LARC, defined as T3 or T4 disease by MRI or endorectal ultrasound, were enrolled from May 2006-December 2008. Pts had adequate hepatic, renal and hematopoietic function, and an ECOG performance status of ≤2. Treatment consisted of 5-FU 225 mg/M2/day by continuous infusion for the duration of radiation (50.4 Gy). Beva 5 mg/kg was administered on days 1, 15 and 29. The first cohort received erl 50 mg, the second cohort 100 mg, and third cohort 150 mg daily until completion of radiation. Pts underwent surgery 6–9 weeks following the radiation. The primary endpoints were determination of the maximally tolerated dose (MTD) and pathologic complete response (pCR). Secondary endpoints included toxicity (TOX), local control (LC), progression free survival and median survival. A total of 25 pts will be treated at the MTD. Results: Twenty-one pts began study therapy: 2 withdrew consent prior to completing study therapy, and 2 pts were removed prior to completion for clostridium difficile colitis and cardiac ischemia. No dose limiting toxicities were achieved. Erl 100 mg was chosen as the MTD. Two pts have not yet completed study treatment. Fifteen pts have completed study therapy and have undergone surgery, of whom 7 (47%) have demonstrated a pCR. At a median follow-up of 7 months, there have been no local recurrences in patients who completed study therapy. Grade 3–4 treatment related TOX included: lymphopenia 6 (59%), diarrhea 4 (24%), rash 2(12%), cardiac ischemia 1(6%), transaminitis 1(6%), mucositis 1(6%). One pt developed an anastomotic leak. Conclusions: Beva and erl in combination with infusional 5-FU and RT appears to be a highly active preoperative regimen for locally advanced rectal cancer. [Table: see text]

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