Selection of Second-line Anti-angiogenic Agents After Failure of Bevacizumab-containing First-line Chemotherapy in Metastatic Colorectal Cancer

Accepted Manuscript Selection of second-line anti-angiogenic agents after failure of bevacizumabcontaining first-line chemotherapy in metastatic colorectal cancer Narikazu Boku, MD, PhD, Shun Yamamoto, MD PII:

S1533-0028(18)30370-0

DOI:

10.1016/j.clcc.2018.07.012

Reference:

CLCC 492

To appear in:

Clinical Colorectal Cancer

Please cite this article as: Boku N, Yamamoto S, Selection of second-line anti-angiogenic agents after failure of bevacizumab-containing first-line chemotherapy in metastatic colorectal cancer, Clinical Colorectal Cancer (2018), doi: 10.1016/j.clcc.2018.07.012. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Clinical Commentary

Title:

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Selection of second-line anti-angiogenic agents after failure of bevacizumab-containing first-line chemotherapy in metastatic colorectal cancer.

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Narikazu Boku, MD, PhD, Shun Yamamoto, MD

Department of Gastrointestinal Medical Oncology, National Cancer Center 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

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TEL: +81-3-3542-2511 FAX: +81-3-3547-6611 E-mail: [email protected]

Key words:

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Second-line therapy, anti-angiogenic agent, bevacizumab, ramucirumab, aflibercept, beyond progression, metastatic colorectal cancer

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Word counts: 1984 in the text and 2454 including references.

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Introduction Continuation of anti-angiogenic agents in the second-line therapy is recognized as a standard care for metastatic colorectal cancer (mCRC) patients who showed disease progression during bevacizumab-containing first-line therapy, and there are three available options: bevacizumab

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(1), ramucirumab (2) and aflibercept (3). However, selection of these three agents depends on the physician’s preference because there are no established biomarkers for selecting the optimal agent. Moreover, the overall results of the three randomized phase III trials, ML18147 (1), RAISE (2) and VELOUR (3), showed nearly identical hazard ratios, ranging 0.81-0.84, compared with the control arm, which di not include an anti-angiogenic agent (Table 1).

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However, there are differences in the study population among these three studies with respect to their different eligibility criteria. In the ML18147 trial (1), patients were excluded if they had a diagnosis of progressive disease for more than 3 months after the last bevacizumab

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administration, if first-line progression-free survival (PFS) was less than 3 months, and if bevacizumab was given for less than 3 months (consecutive) in the first-line therapy. In contrast, the RAISE trial did not exclude patients based on these criteria (2). In the VELOUR trial (3), patients were to have documented progression during or after completion of a single prior oxaliplatin-containing regimen with or without bevacizumab (not selected for the timing of their progression), and patients who experienced relapse within 6 months after completion of

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oxaliplatin-based adjuvant therapy were eligible. Moreover, the chemotherapy backbone combined with anti-angiogenic agents in the second-line therapy was 5-fluorouracil/leucovorin and irinotecan (FOLFIRI) in the RAISE and VELOUR trials, while it was not unified in the ML18147 trial. Therefore, the fact that there were similar hazard ratios in these three trials of second-line therapy with different anti-angiogenic agents does not mean that these three drugs

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have similar clinical activity.

The specific targets and mode of action of bevacizumab, ramucirumab, and aflibercept

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are different. Bevacizumab is a humanized monoclonal IgG1 antibody that binds specifically to vascular endothelial growth factor (VEGF)-A, and inhibits its binding to vascular endothelial growth factor receptor (VEGFR)-1 and -2 (4,5). Ramucirumab is a human IgG1 monoclonal antibody that specifically binds to the extracellular domain of VEGFR-2, preventing binding of the ligands VEGF-A, VEGF-C, and VEGF-D (6). Aflibercept is a recombinant fusion made up of portions of the extracellular domains of human VEGFR-1 and VEGFR-2 fused to the Fc portion of the human IgG1 molecule. It function as a soluble receptor that binds VEGF-A, VEGF-B, and placental growth factor (PlGF) and prevents their binding to their endogenous VEGF receptors by acting as a high-affinity ligand trap (7). Of note, aflibercept binds with much higher affinity to VEGF-A than bevacizumab. Although the precise mechanisms of resistance to bevacizumab have not been well-identified as of yet, studies have shown that 2

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expression of various angiogenic factors other than VEGF-A such as VEGF-D and PlGF, which are targets of ramucirumab and aflibercept, are increased during the first-line chemotherapy containing bevacizumab (8). These different modes of action may play some role to overcome the resistance to bevacizumab in the second-line therapy after disease progression during

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bevacizumab-containing first-line chemotherapy.

Discussion

In a collaborative study of the RAISE trial, which investigated the efficacy of ramucirumab

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combined with FOLFIRI as second-line therapy for patients with mCRC that progressed during or after the first-line therapy with bevacizumab, plus oxaliplatin, and a fluoropyrmidine (FOLFOX), it was reported that VEGF-D may be a predictive marker for remucirumab efficacy

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(9). The ramucirumab plus FOLFIRI arm showed improved clinical efficacy compared with placebo plus FOLFIRI in the high VEGF-D subgroup (median survival time [MST]: 13.9 months versus 11.5 months, Hazard Ratio [HR]: 0.73 95% Confidence Interval [CI]: 0.60-0.89, p=0.0022), while it showed worse outcomes in the low VEGF-D subgroup (MST: 12.6 months versus 13.1 months, HR 1.32 95% CI 1.02-1.70, p=0.034). A similar type of biomarker analysis was performed in the CALGB/SWOG Trial 80405, which compared between the doublet

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chemotherapy with bevacizumab and that with cetuximab in the first-line therapy, and it supports the benefit of bevacizumab in patients with low VEGF-D (10). Moreover, low expression of VEGF-D assessed by immunohistochemistry was reported to be related with favorable efficacy of bevacizumab containing first-line therapy in the AGITG MAX trial (11). Although these results were based on different patients and methods, it is expected that the

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VEGF-D may serve as a predictive marker for selecting an optimal anti-angiogenic agent not only in the second-line but also in the first-line therapy of mCRC. However, the median levels

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of VEGF-D reported in the RAISE trial (9) and in the CALGB/SWOG Trial 80405 (10) were numerically different (median: 0.135 ng/mL in the RAISE trial and 1.1 ng/mL in the CALGB trial). Thus, establishment of the standard method for assessing VEGF-D and its validation are eagerly awaited to select the patients to be treated with ramucirumab. However, until establishment of this and/or other biomarkers, the decision for selecting an anti-angiogenic agent should be made clinically. In the ML18147 trial (1) investigating the clinical significance of continuing bevacizumab administration after progression on bevacizumab-containing first-line therapy, the HRs for overall survival of the subgroups divided by progression-free survival (PFS) in the first-line therapy < and > 9 months were 0.89 (95% CI 0.73–1.09) and 0.73 (95% CI 0.58–0.92), respectively (Table 1). It has been suggested that short PFS in the first-line therapy may be 3

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related to a reduced benefit of bevacizumab in the second-line therapy. Actually, in 12 patients treated at our institution here in Japan, who did not meet the eligibility criteria of the ML18147 trial but received bevacizumab containing second-line therapy continuously beyond the first-line therapy, median PFS was 3.8 months, shorter than that in the ML18147 trial. In particular, in six

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patients with PFS in the first-line therapy <3 months, the median PFS in the second-line chemotherapy was as short as 2.3 months while the PFS was 5.8 months in a separate cohort of 12 patients who were ineligible for the ML18147 trial and received second-line therapy without bevacizumab (not reported). Thus, it can be guessed that the hazard ratio of the subset with first-line PFS < 9 months would be larger than 0.89 if patients with first-line PFS < 3 months

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had been included in the ML18147 trial. In the post hoc analysis of VELOUR trial (12) after excluding the adjuvant rapid-relapser during or within 6 months, aflibercept showed very similar hazard ratios (unadjusted) to those of ML18147 trial in both subgroups divided by time

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to progression (TTP) < and > 9 months during the first-line therapy with bevacizumab (Table 1). Both bevacizumab and aflibercept bind to VEGF ligands in the blood and tissues. It is speculated that short PFS/TTP in the first-line therapy with bevacizumab may have some adverse impacts on the efficacy of anti-angiogenic therapy targeting VEGF ligands in the second-line therapy.

In the RAISE trial (2) investigating ramucirumab, which prevents binding of the

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agonist ligands, VEGF-A, VEGF-C, and VEGF-D, to the target VEGFR-2 receptor, consistent hazard ratios were originally reported in the subgroup analysis divided by time to disease progression (TTP) < and > 6 months during the first-line therapy containing bevacizumab: 0.855 (95% CI 0.644–1.134) for TTP < 6 months and 0.855 (95% CI 0.726–1.007) for TTP > 6 months (Table 1). For this commentary, Eli Lilly and Company kindly provided the data (Eli

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Lilly and Company, data on file) on the subgroups divided by TTP < and > 9 months, which showed that the HR was 0.84 (95% CI 0.69-1.02) in patients with TTP < 9 months (246 and 261

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patients in the ramucirumab and placebo arms) while it was 0.80 (95% CI 0.72-1.09) in those with TTP > 9 months (283 and 271 patients in the ramucirumab and placebo arms) (Table 1). Because patients with first-line PFS < 3 months were excluded in the ML18147 trial (1) and patients who had recurrence during or within 6 months of completing adjuvant oxaliplatin-based therapy were excluded from the post hoc analysis of the VELOUR trial (12), there must be some differences in patient background causing some selection bias. Actually, in the post-hoc analysis of the VELOUR trial, the HRs are substantially different after adjusting for baseline values of Eastern Cooperative Oncology Group performance status, prior bevacizumab, age, prior hypertension, and number of organs with metastases (HR=0.82 [0.58-1.18] for patients with PFS < 9 months, and HR=0.75 [0.52-1.08 for PFS > 9 months]). This type of inter-trial subset comparison should be carefully interpreted. Looking at the unadjusted hazard ratios in all 4

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these three trials, however, the hazard ratio of ramucirumab in the subset with first-line TTP < 9 months looks slightly lower than those of bevacizumab and aflibercept, while the hazard ratio of ramucirumab seems higher than those of bevacizumab and aflibercept in the subset with first-line PFS/TTP > 9 months (Table 1). Taken together, it seems reasonable to consider that

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short PFS/TTP in the first-line therapy with bevacizumab may be caused by initially or rapidly induced high VEGF-D expression which can be more effectively blocked by ramucirumab in the second-line therapy, while the potential impact of PlGF and aflibercept have not been well-characterized.

Hypertension, proteinuria, arterial thromboembolic events, hemorrhagic complications,

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and gastrointestinal perforation are well-established toxicities associated with anti-angiogenic agents. There are small differences in safety. In the ML18147 trial, the incidence of grade 3-5 were reported: 2% for hypertension, not reported for proteinuria, 7% for embolism (pulmonary

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embolism 2%, venous thromboembolic events 5%), 2% for bleeding or hemorrhage, and 2% for gastrointestinal perforation. These same toxicities were observed in 11%, 3%, 5% (venous 4%, arterial 2%), 4% (bleeding/hemorrhage 2%, gastrointestinal hemorrhage 2%), and 2%, respectively, in the RAISE trial, and 16%, 9%, 9% (venous 7%, arterial 2%), 4%, 0% in the subset with prior bevacizumab in the VELOUR trial, respectively. Although the incidence of grade 3-5 toxicities specific for anti-angiogenic agents seemed lower in the ML18147 trial than

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those reported for the other agents, the ML18147 trial excluded patients if bevacizumab was given less than 3 months (consecutive) of first-line bevacizumab, leading to selection bias for safety.

Furthermore, the financial costs of these three agents should be considered for selection in the second-line therapy. For Japanese patients (body weight 60 kg, 1 dollar = 110

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Japanese yen), the monthly costs of bevacizumab, ramucirumab, and aflibercept are $2,168, $6,204, and $3,348, respectively. However, because all three drugs are reimbursed by the

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government and there is High-Cost Medical Expense Benefit (Ceiling Amount) system in Japan, the actual costs to the patient are not a significant issue in Japan. In sharp contrast, however, in the U.S. (body weight 82 kg) the costs of these three agents are $6,081, $15,338 and $5,792, respectively (13), and there are also significant differences in costs in the various E.U. countries. These pharmaco-economic factors are also important and should be incorporated in the decision-making process.

Conclusion Based on the observation that VEGF-D may be a key angiogenic factor that is expressed in early disease progression during the first-line chemotherapy with bevacizumab for mCRC 5

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patients, it appears that switching to ramucirumab in the second-line chemotherapy may be preferable for patients with short PFS/TTP, e.g. < 9 months, in the first-line therapy than bevacizumab or aflibercept. In contrast, bevacizumab or aflibercept appear to be appropriate anti-angiogenic agents to consider rather than ramucirumab for those patients with long

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PFS/TTP.

Take-Home Message

In clinical practice at the Division of Gastrointestinal Medical Oncology in National Cancer

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Center Hospital in Japan, our selection of an anti-angiogenic agent in the second-line chemotherapy is based on the PFS in the first-line chemotherapy plus bevacizumab. In patients who achieve a PFS < 9 months in the first-line setting, we typically use ramucirumab as our In all other settings where the PFS

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anti-angiogenic agent of choice in the second-line setting.

> 9 months, our choice is bevacizumab, as it seems to have a potential for better outcome with similar cost to the patients in Japan.

Fund: Eli Lilly and Company performed additional analysis and provided the data on the

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author’s request, and there was no fund for this letter.

Disclosure: N.B. has received honoraria for lectures from Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Merck

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Serono Co., Ltd. and Ono Pharmaceutical Co., Ltd. S.Y. has no COI to disclose.

References

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leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol. 2012; 1; 30(28): 3499-506 4. Kim KJ, Li B, Houck K, et al. The vascular endothelial growth factor proteins:

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6. Spratlin JL, Cohen RB, Eadens M et al. Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. J Clin Oncol 2010; 28: 780–787.

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Randomized, Double-Blind, Phase III Ann Oncol 2018; 29(3): 602-609 10. Nixon A, Sibley A, Hatch AJ et al. Blood-based biomarkers in patients (pts) with metastatic colorectal cancer (mCRC) treated with FOLFOX or FOLFIRI plus bevacizumab (Bev), cetuximab (Cetux), or bev plus Cetux: Results from CALGB 80405 (Alliance). J Clin Oncol 2016; 34 (Suppl): abstract 3597

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Table 1. Hazard ratios (HR) in the subgroups divided by progression survival or time to progression in the first-line chemotherapy with bevacizumab.

ML18147 VELOUR

Overall

0M

3M

6M

HR=0.81

HR=0.89

(0.69–0.94)

(0.73–1.09)

HR=0.817

HR=0.91**

(0.713–0.937) *

(0.64-1.29) HR=0.84

HR=0.84 (0.73–0.98)

(0.69-1.02) HR=0.855

(0.644–1.134)

HR=0.73

(0.58–0.92)

HR=0.73** (0.51-1.04)

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RAISE

9M

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Trial

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PFS or TTP in first-line chemotherapy with bevacizumab

HR=0.80

(0.72-1.09)

HR=0.855

(0.726–1.007)

PFS: progression survival, TTP: time to progression, HR: hazard ratio (

): 95% confidential interval *: 95.34% confidential interval

**: subsets of prior bevacizumab (+), excluding adjuvant rapid-relapser during or within 6

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months

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