Cyramza ® (ramucirumab)

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Cyramza® (Ramucirumab): Biomarkörer

En prediktiv biomarkör för aktivitet har ännu inte identifierats för behandling med ramucirumab.

Biomarker Analyses in Gastric Cancer

REGARD Study

Study Design

The REGARD trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients with metastatic or locally advanced gastric or GEJ adenocarcinoma treated previously with fluoropyrimidine- or platinum-based combination therapy with an ECOG PS of 0 or 1. Patients were randomly assigned in a 2:1 ratio (stratified by weight loss, region, and location of the primary tumor) to receive ramucirumab (8 mg/kg every 2 weeks) plus best supportive care (n=238) or placebo (every 2 weeks) plus best supportive care (n=117) until disease progression, unacceptable toxicity, withdrawal, or death.1

Biomarker Analysis

Based on the positive efficacy outcomes of single-agent therapy, the REGARD study provided a suitable clinical database to explore potential candidate

  • tumor

    • HER2 and

    • VEGFR2, and

  • serum

    • VEGF-C

    • VEGF-D

    • sVEGFR1, and

    • sVEGFR3

biomarkers for correlation with OS and PFS.2

Exploratory candidate biomarker analysis of tumor biopsies and serum did not identify a significant predictive marker for ramucirumab efficacy.2

RAINBOW Study

Study Design

The RAINBOW trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial in patients with metastatic or locally advanced nonresectable gastric or GEJ adenocarcinoma following disease progression during or within 4 months after last dose of first-line platinum plus fluoropyrimidine combination chemotherapy with or without an anthracycline and an ECOG PS of 0 or 1. Patients were randomly assigned in a 1:1 ratio (stratified by region, measurable vs non-measurable disease, and time to progression on first–line therapy) to receive ramucirumab (8 mg/kg days 1 and 15) plus paclitaxel (80 mg/m2 days 1, 8, and 15) (n=330) or placebo (days 1 and 15) plus paclitaxel (80 mg/m2 days 1, 8, and 15) (n=335) of a 28-day cycle until disease progression, unacceptable toxicity, withdrawal, or death.3

Biomarker Analysis

In order to assess the relationship between biomarkers and efficacy of ramucirumab, plasma samples were collected from patients at

  • baseline

  • prior to the 4th infusion

  • prior to the 7th infusion, and

  • at the 30-day follow-up visit.4

The following biomarkers were evaluated:

  • VEGF-C

  • VEGF-D

  • sVEGFR1

  • sVEGFR2

  • sVEGFR3, and

  • placental growth factor.4

For each biomarker evaluated, patients were divided into low- or high-marker subgroups. None of the biomarkers evaluated demonstrated a predictive relationship with ramucirumab efficacy.4

Biomarker Analysis in Colorectal Cancer

RAISE Study

Study Design

The RAISE trial was a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that evaluated FOLFIRI and ramucirumab vs FOLFIRI and placebo in the second-line treatment of patients with mCRC who had progressed on first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Patients were randomly assigned in a 1:1 ratio (stratified by region, KRAS mutation status, and time to progressive disease after beginning first-line treatment) to receive IV infusions of either FOLFIRI plus ramucirumab 8 mg/kg (n=536) or FOLFIRI plus placebo (n=536) once every 2 weeks.5

Biomarker Analysis

For this analysis, patients were randomly and prospectively divided into 2 groups in a 1:2 ratio: ME and MC. 

A dual-monoclonal sandwich assay was used to evaluate plasma that was collected from whole blood prior to cycle 1 to assess marker

  • VEGF-C

  • VEGF-D

  • sVEGFR-1

  • sVEGFR-2, and

  • sVEGFR-3.5,6

Archived tumor samples were utilized to assess VEGFR-2 by immunohistochemistry.5,6

Evaluation of the combined populations (ME + MC) found that the median OS in the FOLFIRI plus ramucirumab arm compared with FOLFIRI plus placebo arm showed an improvement of 2.4 months in the high VEGF-D subgroup (13.9 months vs 11.5 months, respectively; p=.0022), and a decrease of 0.5 month in the low VEGF-D subgroup (12.6 months vs 13.1 months, respectively; p=.0344). Worse outcomes were observed among patients within the FOLFIRI plus placebo group with high VEGF-D (median OS 11.5 months) compared with patients with low VEGF-D (median OS 13.1 months) with a prognostic HR=1.42 (95% CI 1.1 - 1.8; p=.0025).6 Efficacy outcomes according to VEGF-D levels for both the ME and MC populations are summarized in Table 1. Efficacy Outcomes According to VEGF-D Levels.

Table 1. Efficacy Outcomes According to VEGF-D Levelsa6

Efficacy Outcome

FOLFIRI + Ramucirumab
(n=270)

FOLFIRI + Placebo
(n=266)

FOLFIRI + Ramucirumab
(n=176)

FOLFIRI + Placebo
(n=172)

High VEGF-D (≥115 pg/mL)

Low VEGF-D (<115 pg/mL)

Median OS, months (95% CI)

13.9 (12.5-15.6)

11.5 (10.1-12.4)

12.6 (10.7-14.0)

13.1 (11.8-17.0)

HR (95% CI); p value

0.73 (0.60-0.89); .0022

1.32 (1.02-1.70); .0344

Median PFS, months (95% CI)

6.0 (5.6-7.0)

4.2 (4.1-4.5)

5.4 (4.2-5.8)

5.6 (5.3-6.9)

HR (95% CI); p value

0.62 (0.52-0.74); <.0001

1.16 (0.93-1.45); NS

Abbreviations: FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; HR = hazard ratio; NS = not significant; OS = overall survival; PFS = progression-free survival; VEGF-D = vascular endothelial growth factor-D.

a Includes data from both the marker exploratory and marker confirmatory population.

The most common grade ≥3 TEAEs in both treatment arms were diarrhea, neutropenia, fatigue, and hypertension.6

Additional Biomarker Analyses In Clinical Trials

Two additional trials have collected tissue and blood to help understand potential biomarkers:

  • phase 3 trial in second-line treatment of NSCLC7 and

  • phase 2 randomized trial in the first-line treatment of gastric cancer.8

Results are not yet available.

References

1. Fuchs CS, Tomasek J, Yong CJ, et al. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383(9911):31-39. http://dx.doi.org/10.1016/S0140-6736(13)61719-5.

2. Fuchs CS, Tabernero J, Tomášek J, et al. Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab. Br J Cancer. 2016;115(8):974-982. https://doi.org/10.1038/bjc.2016.293.

3. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014a;15(11):1224-1235. http://dx.doi.org/10.1016/S1470-2045(14)70420-6

4. Van Cutsem E, Muro K, Cunningham D, et al. Biomarker analysis of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study [abstract]. Ann Oncol. 2016;27(suppl 2):ii120. https://doi.org/10.1093/annonc/mdw198.07.

5. Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499-508. http://dx.doi.org/10.1016/S1470-2045(15)70127-0

6. Tabernero J, Hozak RR, Yoshino T, et al. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study [published online December 7, 2017]. Ann Oncol. 2017[E-pub ahead of print]:mdx767-mdx767. http://dx.doi.org/10.1093/annonc/mdx767.

7. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. http://dx.doi.org/10.1016/S0140-6736(14)60845-X

8. Yoon HH, Bendell JC, Braiteh FS, et al. Ramucirumab combined with FOLFOX as frontline therapy for advanced adenocarcinoma of esophagus, gastroesophageal junction, or stomach: randomized, double-blind, multicenter phase 2 trial [abstract]. J Clin Oncol. 2014;32(supp 15):4004. https://meetinglibrary.asco.org/record/94629/abstract.

Glossary

ECOG = Eastern Cooperative Oncology Group

FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil

GEJ = gastroesophageal junction

HER2 = human epidermal growth factor receptor 2

HR = hazard ratio

IV = intravenous

MC = marker confirmatory

mCRC = metastatic colorectal cancer

ME = marker exploratory

NSCLC = non-small cell lung cancer

OS = overall survival

PFS = progression-free survival

PS = performance status

sVEGFR-1 = soluble vascular endothelial growth factor receptor 1

sVEGFR-2 = soluble vascular endothelial growth factor receptor 2

sVEGFR-3 = soluble vascular endothelial growth factor receptor 3

TEAE = treatment-emergent adverse event

VEGF-C = vascular endothelial growth factor-C

VEGF-D = vascular endothelial growth factor-D

VEGFR-2 = vascular endothelial growth factor receptor 2

Datum fӧr senaste ӧversyn 2018 M03 01

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