FDA Accepts sBLA for First-Line Nivolumab Plus Ipilimumab in Unresectable HCC

FDA

The FDA has accepted a supplemental biologics license application (sBLA) seeking the approval of the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the first-line treatment of adult patients with unresectable hepatocellular carcinoma (HCC).¹

The sBLA is supported by data from the phase 3 CheckMate 9DW trial (NCT04039607), which showed that treatment with the doublet led to a statistically significant and clinically meaningful improvement in overall survival (OS) compared with investigator’s choice of sorafenib (Nexavar) or lenvatinib (Lenvima) monotherapy (HR, 0.79; 95% CI, 0.65-0.96; P = .018).² Findings presented at the 2024 ASCO Annual Meeting showed that at a median follow-up of 35.2 months (range, 26.8-48.9), patients treated with the combination (n = 335) experienced a median OS of 23.7 months (95% CI, 18.8-29.4) compared with 20.6 months (95% CI, 17.5-22.5) for those who received sorafenib or lenvatinib (n = 333). The 24- and 36-month OS rates in the experimental arm were 49% and 38%, respectively; in the control arm, those respective rates were 39% and 24%.

“HCC is the most common form of liver cancer and is often diagnosed when surgery is no longer an option. With the number of individuals diagnosed with HCC in the United States increasing over the last decade, new treatment options are urgently needed,” Dana Walker, MD, MSCE, vice president and global program lead of Gastrointestinal and Genitourinary Cancers at Bristol Myers Squibb, stated in a news release.1 “[Nivolumab] plus [ipilimumab] showed superior survival benefit compared [with] other available treatment options, and we look forward to working with the FDA to advance our application to potentially bring a new first-line treatment option to patients.”

In March 2020, the FDA granted accelerated approval to nivolumab plus ipilimumab for the treatment of patients with HCC who received prior treatment with sorafenib, based on data from the phase 1/2 CheckMate 040 trial (NCT01658878).³

CheckMate 9DW was a global, randomized, open-label study that enrolled patients with unresectable HCC who were naive to systemic therapy.2 Patients were required to have at least 1 measurable lesion per RECIST 1.1 criteria, a Child-Pugh score of 5 or 6, an ECOG performance status of 0 or 1, and no main portal vein invasion.

Investigators randomly assigned patients 1:1 to receive 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab once every 3 weeks for up to 4 cycles, followed by 480 mg of nivolumab once every 4 weeks; or investigator’s choice of 8 mg or 12 mg of lenvatinib once per day depending on body weight or 400 mg of sorafenib twice per day. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. In the experimental arm, the maximum treatment duration was 2 years.

Patients were stratified by etiology (hepatitis B vs hepatitis C vs uninfected), macroscopic vascular invasion/extrahepatic spread (yes vs no), and alpha-fetoprotein level (<400 ng/mL vs ≥400 ng/mL).

OS served as the trial’s primary end point. Key secondary end points included blinded independent central review (BICR)–assessed overall response rate (ORR) and duration of response (DOR) per RECIST 1.1 criteria; and time to symptom deterioration. BICR-assessed progression-free survival (PFS) per RECIST 1.1 criteria and safety were key exploratory end points.

Additional data showed that patients treated with nivolumab plus ipilimumab achieved an ORR of 36% (95% CI, 31%-42%) compared with 13% (95% CI, 10%-17%) for those given sorafenib or lenvatinib (P < .0001). In the experimental arm, the complete response, partial response, stable disease, and progressive disease rates were 7%, 29%, 32%, and 20%, respectively. These respective rates were 2%, 11%, 62%, and 14% in the control arm. Twelve percent and 11% of patients, respectively, were not evaluable for response.

The median time to response was 2.2 months (range, 1.1-11.6) in the nivolumab plus ipilimumab arm compared with 3.7 months (range, 0.6-11.2) in the sorafenib or lenvatinib arm. The median DOR was 30.4 months (95% CI, 21.2-not evaluable) for nivolumab plus ipilimumab vs 12.9 months (95% CI, 10.2-31.2) for sorafenib or lenvatinib.

The median PFS was 9.1 months (95% CI, 6.6-10.5) for nivolumab plus ipilimumab compared with 9.2 months (95% CI, 7.9-11.1) for sorafenib or lenvatinib (HR, 0.87; 95% CI, 0.72-1.06). The respective 18- and 24-month PFS rates in the experimental arm were 34% and 28%. In the control arm, these rates were 18% and 12%, respectively.

Regarding safety, the median treatment duration was 4.7 months (range, <1 to 24.4) for nivolumab plus ipilimumab (n = 332) vs 6.9 months (range, <1 to 45.8) for sorafenib or lenvatinib (n = 325). Any-grade treatment-related adverse effects (TRAEs) occurred in 84% of patients in the experimental arm vs 91% of those in the control arm; rates of grade 3/4 TRAEs were 41% and 42%, respectively. Serious any-grade TRAEs were reported in 28% of patients in the nivolumab plus ipilimumab arm, including 25% who had serious grade 3/4 TRAEs. Fourteen percent of patients treated with sorafenib or lenvatinib experienced serious any-grade TRAEs, including 13% who had serious grade 3/4 TRAEs.

Any-grade TRAEs led to treatment discontinuation in 18% of patients in the nivolumab plus ipilimumab group vs 10% of those in the sorafenib or lenvatinib group. The rates of grade 3/4 TRAEs that led to treatment discontinuation were 13% and 6%, respectively.

The most common any-grade TRAEs reported in at least 10% of patients included hypertension (nivolumab plus ipilimumab, 2%; sorafenib or lenvatinib, 41%), diarrhea (14%; 35%), Palmar-plantar erythrodysesthesia syndrome (2%; 30%), pruritus (28%, 3%), hypothyroidism (12%; 24%), decreased appetite (7%; 22%), increased aspartate aminotransferase (20%; 8%), proteinuria (0%; 20%), increased alanine aminotransferase (19%; 6%), rash (19%; 9%), asthenia (10%; 16%), fatigue (8%; 15%), dysphonia (<1%; 15%), increased lipase (11%; 6%), decreased weight (2%; 11%), hyperthyroidism (10%; 2%), and nausea (6%; 10%).

In the nivolumab plus ipilimumab arm, the rates of any-grade and grade 3/4 immune-mediated AEs were 58% and 28%, respectively. Twenty-nine percent of patients received high-dose steroids due to immune-mediated AEs, and these toxicities led to treatment discontinuation in 13% of patients.

The most common immune-mediated AEs reported in the experimental arm included hepatitis (any grade, 19%; grade 3/4, 15%), hypothyroidism/thyroiditis (19%; <1%), rash (15%; 4%), hyperthyroidism (11%; <1%), diarrhea/colitis (8%; 5%), adrenal insufficiency (5%; 2%), hypophysitis (3%; 1%), pneumonitis (2%; <1%), nephritis and renal dysfunction (2%; <1%), hypersensitivity (1%; 0%), and diabetes mellitus (<1%; <1%).

References

1. Bristol Myers Squibb receives US Food and Drug Administration sBLA acceptance for first-line treatment of unresectable hepatocellular carcinoma. News release. Bristol Myers Squibb. August 21, 2024. Accessed August 21, 2024. https://news.bms.com/news/details/2024/Bristol-Myers-Squibb-Receives-U.S.-Food-and-Drug-Administration-sBLA-Acceptance-for-First-Line-Treatment-of-Unresectable-Hepatocellular-Carcinoma/default.aspx
2. Galle PR, Decaens T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): first results from CheckMate 9DW. J Clin Oncol. 2024;42(suppl 17):LBA4008. doi:10.1200/JCO.2024.42.17_suppl.LBA4008
3. FDA grants accelerated approval to nivolumab and ipilimumab combination for hepatocellular carcinoma. FDA. March 10, 2020. Accessed August 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-nivolumab-and-ipilimumab-combination-hepatocellular-ca