Cyramza ® (ramucirumab)

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Cyramza® (ramucirumab): AFP Analys i REACH-2

Kvalificerade deltagare för REACH-2 var tvungna att ha en basnivå av AFP ≥400 ng/ml, bekräftat med lokala laboratorietester.

Study Design

A global, randomized, double-blind, placebo-controlled study compared ramucirumab plus BSC and placebo plus BSC in patients with advanced HCC and elevated baseline AFP following first-line sorafenib.1

Patients were stratified by

  • geographic region (Americas, Europe, Israel, and Australia vs Asia [except Japan] vs Japan)

  • baseline ECOG PS (0 vs 1), and

  • macrovascular invasion (yes vs no).1

Patients were randomly assigned (2:1) to receive ramucirumab 8 mg/kg plus BSC (n=197) or placebo plus BSC (n=95) every 14 days until disease progression or unacceptable toxicity, or until discontinuation criteria were met.1 

The primary endpoint was OS.1

Alpha-Fetoprotein and the REACH-2 Study

Protocol Requirements

Eligible participants were required to have a baseline AFP ≥400 ng/mL, as determined by local laboratory testing. The baseline serum AFP testing was determined by the local laboratory using a legally marketed AFP assay for the region in which the site was located.2

Serum AFP was assessed through a blood sample

  • at baseline (within 14 days prior to randomization)

  • every third cycle (every 6 weeks), and

  • within 7 days of study discontinuation.2

Selection of 400 ng/mL as Threshold

An AFP concentration above the threshold of 400 ng/mL has consistently defined a poorer prognostic group in several treatment settings and is an established parameter in prognostic scoring systems.3-6 The REACH trial results showed that ramucirumab was well tolerated in patients with HCC, with a potential OS benefit in a prespecified subpopulation of patients with baseline AFP ≥400 ng/mL, and no OS benefit in the subpopulation of patients with an AFP <400 ng/mL.2,7 Among the subgroup of patients with AFP ≥400 ng/mL in the REACH trial, patients who received ramucirumab had a median OS of 7.8 vs 4.2 months for the patients in the placebo group (HR=0.67; 95% CI: 0.51-0.90; p=.006).7 The results of the REACH trial provided justification for the continued exploration of ramucirumab in the population of patients with HCC and AFP ≥400 ng/mL after prior sorafenib (discontinued due to progression or intolerance). REACH-2 was designed to confirm the efficacy and safety of ramucirumab as a single agent for the treatment of patients with HCC who have an AFP ≥400 ng/mL after prior sorafenib therapy.2

Baseline Imbalance in AFP Between Treatment Arms

There was an imbalance in baseline AFP levels, with a 43% higher median AFP level in the ramucirumab arm (AFP=3920 ng/ml in ramucirumab arm vs AFP=2741 ng/ml in the placebo arm).2

The imbalance in baseline AFP was corrected by creating a pooled analysis of the prespecified subgroup of patients with AFP ≥400 ng/mL in REACH with patients in REACH-2. Among patients included in this pooled analysis, the baseline AFP was

  • 4101.6 in patients who received ramucirumab plus BSC (n=316), and

  • 4047.5 in patients who received placebo plus BSC (n=226).8

By pooling both sources it allows for a larger sample size, yielding a more precise estimate of treatment effects for the overall population and subgroups.8

Response According to AFP

Additional analyses of response and efficacy according to AFP are currently being conducted. At this time, no additional information on response or efficacy for other AFP levels is available. 

References

1. Zhu AX, Kang YK, Yen CJ, et al. REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib. Presented as an oral presentation at: 54th Annual Meeting of the American Society of Clinical Oncology (ASCO); June 1-5, 2018; Chicago, IL. Abstract #4003. https://meetinglibrary.asco.org/record/159169/abstract

2. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3. [CLIP Investigators] The Cancer of the Liver Italian Program investigators. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology. 1998;28(3):751-755. http://dx.doi.org/10.1002/hep.510280322

4. Tangkijvanich P, Anukulkarnkusol N, Suwangool P, et al. Clinical characteristics and prognosis of hepatocellular carcinoma: analysis based on serum alpha-fetoprotein levels. J Clin Gastroenterol. 2000;31(4):302-308. https://insights.ovid.com/pubmed?pmid=11129271

5. Zhang XF, Meng B, Qi X, et al. Prognostic factors after liver resection for hepatocellular carcinoma with hepatitis B virus-related cirrhosis: surgeon's role in survival. Eur J Surg Oncol. 2009;35(6):622-628. http://dx.doi.org/10.1016/j.ejso.2008.08.003

6. Mailey B, Artinyan A, Khalili J, et al. Evaluation of absolute serum α-fetoprotein levels in liver transplant for hepatocellular cancer. Arch Surg. 2011;146(1):26-33. http://dx.doi.org/10.1001/archsurg.2010.295.

7. Zhu AX, Park JO, Ryoo B-Y et al. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol. 2015;16(7):859-870. http://dx.doi.org/10.1016/S1470-2045(15)00050-9

8. Zhu AX, Finn RS, Galle PR, et al. Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha-fetoprotein (AFP) following first-line sorafenib: Pooled efficacy and safety across two global randomized phase 3 studies (REACH-2 and REACH). Presented as an oral presentation at: 20th Annual Meeting of the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer; June 20-23, 2018; Barcelona, Spain. Abstract #LBA-001. https://www.postersessiononline.eu/pr/aula_poster.asp?congreso=519481837&direccion_posters=Seleccion&pagina_posters=1&ordenacion=n_poster&cod_congreso_integracion=&pst_clave=&buscar=&swAcceso=&swAccesoAdmin=&cod_congreso_aula_rel=&busqueda_rapida=&tipo=autor&texto=&texto2=&grupo2_aula=&grupo=&texto_ident=

Glossary

AFP = alpha-fetoprotein

BSC = best supportive care

ECOG = Eastern Cooperative Oncology Group

HCC = hepatocellular carcinoma

HR = hazard ratio

OS = overall survival

PS = performance status

Datum fӧr senaste ӧversyn 2018 M11 30

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