Innovent Biologics, Inc...is pleased to see that the National Medical Products Administration (NMPA) of China has approved the supplemental New Drug Application (sNDA) for CYRAMZA® (ramucirumab) in patients with hepatocellular carcinoma (HCC, also known as liver cancer), who have an alpha fetoprotein of ≥400 ng/mL and have been treated with sorafenib.

Cyramza monotherapy is indicated for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma who have a serum alpha fetoprotein (AFP) of ≥ 400 ng/ml and who have been previously treated with sorafenib.

CYRAMZA, as a single agent, is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have an alpha fetoprotein (AFP) of ≥400 ng/mL and have been treated with sorafenib.

Recommendations...First-Line Therapy...Where there are contraindications to atezolizumab and/or bevacizumab, tyrosine kinase inhibitors (TKIs) sorafenib or lenvatinib may be offered as first-line treatment of patients with advanced HCC…Second-Line Therapy...second-line therapy with a TKI (ie, sorafenib, lenvatinib, cabozantinib, or regorafenib) may be recommended...second-line therapy with another TKI (cabozantinib or regorafenib), ramucirumab (AFP ≥ 400 ng/mL)...

The panel now recommends several subsequent-line therapy options for patients with disease progression following systemic therapy. Category 1 options include regorafenib, cabozantinib, and ramucirumab. Regorafenib and cabozantinib are recommended only for patients with C-P A liver function, while ramucirumab is recommended only for patients with a baseline AFP level of 400 ng/mL or greater.

Management of advanced disease...Ramucirumab can be considered for patients in second-line patients with baseline AFP ≥400 ng/mL, well-preserved liver function and ECOG PS 0–1, pending EMA approval [I, A]

Ramucirumab demonstrated clinically meaningful improvement in OS compared to placebo for Chinese patients with advanced HCC and elevated AFP…

Ramucirumab demonstrated consistent and meaningful clinical activity with no new safety signals following non-sorafenib therapies in patients with advanced HCC and AFP ≥400 ng/mL.

This open-label, single-arm, global OLE study investigates ramucirumab in patients with advanced HCC (BCLC stage C or B disease), Child-Pugh (CP) A, ECOG PS 0/1, and baseline AFP ≥400 ng/mL...With a median follow-up of 6.5 months (range: 1.2–20.7), the median PFS was 5.5 months (18 events; 95% CI 1.3–7.5). The ORR was 16.7% (95% CI: 1.8-31.6).

This open-label, single-arm, global OLE study investigates ramucirumab in patients with advanced HCC (BCLC stage C/B), Child-Pugh (CP) A, ECOG PS 0/1, and baseline AFP ≥400 ng/mL who received 1-2 prior systemic therapy regimens for HCC...With a median follow-up of 6.5 months (range: 1.2-20.7), the median PFS was 5.5 months (18 events; 95% CI 1.3-7.5). The ORR was 16.7% (95% CI: 1.8-31.6).

Eligible pts were ≥18 yrs, had HCC with BCLC stage C or B disease refractory or not amenable to locoregional therapy, baseline AFP ≥400 ng/mL...REACH-2 met its primary endpoint showing a significant survival benefit, with RAM treatment reducing the risk of death (29%) in pts with HCC and AFP ≥ 400 ng/mL who progressed on or were intolerant to sorafenib.

...patients were randomly assigned, 197 to the ramucirumab group and 95 to the placebo group. At a median follow-up of 7·6 months (IQR 4·0-12·5), median overall survival (8·5 months [95% CI 7·0-10·6] vs 7·3 months [5·4-9·1]; hazard ratio [HR] 0·710 [95% CI 0·531-0·949]; p=0·0199) and progression-free survival (2·8 months [2·8-4·1] vs 1·6 months [1·5-2·7]; 0·452 [0·339-0·603]; p<0·0001) were significantly improved in the ramucirumab group compared with the placebo group...REACH-2 met its primary endpoint, showing improved overall survival for ramucirumab compared with placebo in patients with hepatocellular carcinoma and α-fetoprotein concentrations of at least 400 ng/mL who had previously received sorafenib...

Median percent AFP increase from baseline was smaller in the ramucirumab than in the placebo arm throughout treatment. Time to AFP progression (HR 0.621; P < 0.0001) and to radiographic progression (HR 0.613; P < 0.0001) favoured ramucirumab. Association between AFP and radiographic progression was shown at 6 (OR 6.44, 95% CI 4.03, 10.29; P < 0.0001) and 12 weeks (OR 2.28, 95% CI 1.47, 3.53; P = 0.0002). AFP response was higher with ramucirumab compared with placebo (P < 0.0001). More patients in the ramucirumab arm experienced tumour shrinkage and AFP response compared with placebo. Survival was longer in patients with AFP response (13.6 months) than in patients without (6.2 months), irrespective of treatment (HR 0.457, P < 0.0001)...

The PFS was significantly longer in the ramucirumab group than in the sorafenib group...Subsequent systemic therapy with ramucirumab showed a better ability to control tumor progression than sorafenib in HCC patients with serum AFP levels ≥400 ng/ml.

Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2)….AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001)....AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit.

The overall response rate (ORR) and disease control rate (DCR) were significantly higher in the ramucirumab arm compared to the placebo arm for Asian patients (ORR: 4.2 vs. 0.8%; DCR: 53.6 vs. 33.3%) and non-Asian patients (ORR: 6.8 vs. 1.0%; DCR: 59.5 vs. 41.7%)....This pooled analysis of the REACH-2/REACH trials demonstrates significant benefits, with a manageable safety profile, of ramucirumab treatment in Asian and non-Asian patients with advanced HCC and baseline AFP ≥400 ng/mL.

In conclusion, this post‐hoc subgroup analysis in patients with HCC and elevated AFP, who had progressed on or were intolerant to sorafenib, showed that ramucirumab had a survival benefit with a trend for a delay in deterioration of PROs, irrespective of age, including patients ≥75 years of age.

The present study evaluated the efficacy and safety of ramucirumab (RAM) in clinical practice as post-treatment, following atezolizumab plus bevacizumab (Atz/Bev) for advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP) levels of ≥400 ng/ml....The objective response rate by Response Evaluation Criteria in Solid Tumours at 6 weeks was 15.4%, and the disease control rate was 69.2%.

Ramucirumab was initiated as second-line treatment in 8 patients and as fourth-line treatment in 2 patients...Concerning antitumor response at 6 weeks according to mRECIST, there were 0 CR, 1 PR, 7 SD and 2 PD designations. The ORR was 10%, and the DCR was 80%. The median TTP of 3.1 months (range=1.4-5.8 months) was the same by both RECIST and mRECIST. As for the AFP changes (Figure 1A), the median AFP ratios at 2, 4, and 6 weeks were 1.01 (range=0.71-3.20); 1.09 (range=0.34-3.38); and 1.23 (range=0.27-3.05), respectively. An AFP ratio of ≤1.0 was seen in 5 patients (50%) at 2 weeks and in 3 patients (30%) at 6 weeks...Case 1 was judged as SD by both RECIST and mRECIST (Figure 2A and B) and had an AFP level change from 1,993 ng/ml at baseline to 1,996 ng/ml at 6 weeks. Case 2 was judged as SD by RECIST and as PR by mRECIST (Figure 2C-F) and had an AFP level change from 82,429 ng/ml at baseline to 22,490 ng/ml at 6 weeks....our results suggested that ramucirumab after lenvatinib failure has potential therapeutic efficacy and safety in patients with advanced HCC and AFP levels of ≥400 ng/ml...

In EA patients with AFP ≥400 ng/mL (n = 139), median OS for the ramucirumab arm (n = 66) was 7.8 months and 4.2 months for the placebo arm (n = 73) (HR, 0.749; 95% CI, 0.519–1.082; p = 0.1213) (Figure 3). In non-EA patients with AFP ≥ 400 ng/mL (n = 111), median OS for ramucirumab-treated patients was 8.2 months (n = 53) and 4.5 months for placebo-treated patients (n = 58) (stratified HR, 0.579; 95% CI, 0.371–0.904; p = 0.0149)...Patients with AFP ≥400 ng/mL appeared to have a more favorable OS benefit in both the EA and non-EA groups, consistent with the findings in the overall intent-to-treat (ITT) population with AFP ≥ 400 ng/mL...