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.

Background

First-line therapies based on programmed death ligand 1 (PD-L1) inhibitors are standard of care (SOC) in uHCC and demonstrate improved outcomes over SOR; however, prognosis remains poor and there is an unmet need for alternative therapies with long-term benefits. Second-line NIVO + IPI demonstrated clinically meaningful efficacy and manageable safety in SOR-treated patients (pts) with HCC in CheckMate 040, leading to its accelerated approval in the United States.

Aim

This study report first results from the preplanned interim analysis of the phase 3, open-label, randomized CheckMate 9DW trial evaluating the efficacy and safety of NIVO + IPI vs LEN or SOR as first-line therapy for pts with uHCC.

Methods

Adult pts with previously untreated HCC not eligible for curative surgical or locoregional therapies, Child-Pugh score 5–6, and ECOG performance status 0–1 were included.

Pts were randomly assigned 1:1 to receive NIVO 1 mg/kg + IPI 3 mg/kg Q3W (up to 4 cycles) followed by NIVO 480 mg Q4W or investigator’s choice of LEN 8 mg or 12 mg QD or SOR 400 mg BID until disease progression or unacceptable toxicity.

NIVO was given for a maximum of 2 years. The primary endpoint was overall survival (OS).

Secondary endpoints included objective response rate (ORR) and duration of response (DOR) per blinded independent central review (BICR) using RECIST v1.1.

Results

• In total, 668 pts were randomized to NIVO + IPI (n = 335) or LEN/SOR (n = 333); among 325 pts treated in the LEN/SOR arm, 275 (85%) received LEN.
• After a median (range) follow-up of 35.2 (26.8–48.9) months (mo), median OS was 23.7 mo with NIVO + IPI vs 20.6 mo with LEN/SOR (HR, 0.79; 95% CI, 0.65–0.96; P = 0.0180) (Table), with respective 24-mo OS rates (95% CI) of 49% (44–55) vs 39% (34–45).
• ORR was higher with NIVO + IPI (36%) vs LEN/SOR (13%; P< 0.0001); complete response was observed in 7% of pts with NIVO + IPI vs 2% with LEN/SOR.
• Median DOR was 30.4 mo with NIVO + IPI vs 12.9 mo with LEN/SOR (Table). A summary of treatment-related adverse events (TRAEs) is shown in the Table.

Conclusion

NIVO + IPI demonstrated statistically significant OS benefit vs LEN/SOR in pts with previously untreated uHCC, as well as higher ORR and durable responses with a manageable safety profile. These results support this combination as a potential new first-line SOC for uHCC.

Efficacy	NIVO + IPI (n = 335)	LEN/SOR (n = 333)
Median OS (95% CI), mo	23.7 (18.8–29.4)	20.6 (17.5–22.5)
HR (95% CI);Pvaluea	0.79 (0.65–0.96); 0.0180
ORR,bn (%); 95% CI	121 (36); 31–42	44 (13); 10–17
Pvaluea	< 0.0001
Median DORb(95% CI), mo	30.4 (21.2–NE)	12.9 (10.2–31.2)
Safety, n (%)	(n = 332)	(n = 325)
Any-grade/grade 3–4 TRAEs	278 (84)/137 (41)	297 (91)/138 (42)
Any-grade/grade 3–4 TRAEs leading to discontinuation	59 (18)/44 (13)	34 (10)/21 (6)

Reference

Peter Robert Galle 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.JCO 42, LBA4008-LBA4008(2024).

ctDNA Analysis of Patients (Pts) with Unresectable Hepatocellular Carcinoma (uHCC) Treated with Lenvatinib (LEN) or Sorafenib (SOR) as 1L Therapy.

Background

In REFLECT, LEN had superior ORR and PFS versus SOR in pts with uHCC (P<0.0001); OS was noninferior.

Aim

This post-hoc analysis, determined baseline mutation (MUT) status by plasma ctDNA and analyzed its association with clinical outcomes.

Methods

In REFLECT, pts with untreated uHCC received either LEN 8 or 12 mg daily or SOR 400 mg twice daily. Tumor responses were measured per mRECIST by independent review.

Baseline MUT status in ctDNA was measured by a PGDx elio Plasma Complete panel. We explored associations between ctDNA MUT status and ORR via Fisher's exact test or PFS/OS via Cox regression/log rank test.

Results

• 167 Pts enrolled to LEN and 86 pts enrolled to SOR had evaluable baseline ctDNA. The ctDNA population had a lower % of Asian pts (27% vs 67%) and pts with HBV etiology (27% vs 53%), and a higher % of Western pts (73% vs 33%) and pts with alcohol etiology (14% vs 6%) than the intention to treat (ITT) population.
• In the ctDNA population, a lower % of pts treated with LEN versus SOR had an AFP of <200 ng/mL (57% vs 70%) and HCV etiology (27% vs 44%); a higher % with LEN versus SOR had HBV etiology (32% vs 17%).
• In SOR-treated pts, slight differences in the median (m) PFS/mOS were observed between the ITT and ctDNA populations (Table).
• Among the ctDNA population (n=253), the most frequent MUT genes were TERT(48%), TP53(38%), and CTNNB1(27%). TERT/CTNNB1MUT rates were higher in SOR-treated pts (56%/40%) than in LEN-treated pts (44%/20%).
• Gene MUT status was generally not associated with ORR in either arm. Similarly, MUT status was not associated with PFS with LEN; with SOR, pts with TP53 and TERT MUT showed shorter trends in PFS.
• OS with LEN was shorter in pts with TP53 MUT than WT; OS with SOR was shorter in pts with TERT, TP53,and CTNNB1 MUT. Results of LEN versus SOR by MUT subgroups will be presented.

Conclusion

TERT, TP53, and CTNNB1 MUT had little effect on tumor response in either treatment arm; TP53 MUT appeared to be a factor for poor OS prognosis in both arms. Further analysis is needed due to the differences in baseline characteristics between ctDNA and ITT pts, and the difference in sample size between arms.

	LEN								SOR
	ITT (n=478)	ctDNA (n=167)	TERT		TP53		CTNNB1		ITT (n=476)	ctDNA (n=86)	TERT		TP53		CTNNB1
			WT (n=94)	MUT (n=73)	WT (n=105)	MUT (n=62)	WT (n=133)	MUT (n=34)			WT (n=38)	MUT (n=48)	WT (n=51)	MUT (n=35)	WT (n=52)	MUT (n=34)
ORR, n (%)	194 (41)	60 (36)	30 (32)	30 (41)	37 (35)	23 (37)	46 (35)	14 (41)	59 (12)	9 (10)	5 (13)	4 (8)	6 (12)	3 (9)	4 (8)	5 (15)
OR (95% CI)			1.5 (0.8–2.8)		1.1 (0.6–2.1)		1.3 (0.6–2.9)				0.6 (0.1–2.4)		0.7 (0.2–3.0)		2.1 (0.5–8.3)
mPFS, mos	7.3	7.4	7.4	7.4	7.8	7.4	7.4	7.5	3.6	4.2	5.6	3.6	5.5	3.7	4.6	4.2
HR (95% CI)			0.9 (0.6–1.3)		1.2 (0.8–1.7)		1.0 (0.6–1.5)				1.6 (0.9–2.9)		1.8 (1.0–3.1)		1.1 (0.6–2.0)
mOS, mos	13.6	13.4	14.3	11.9	15.3	8.5	13.8	13.0	12.3	11.7	16.8	10.6	15.8	8.8	18.5	8.7
HR (95% CI)			1.3 (0.9–1.9)		1.8* (1.3–2.6)		1.2 (0.8–1.9)				1.8* (1.0–3.0)		1.7* (1.0–2.8)		2.2* (1.3–3.7)

* P <0.05.

Reference

T.R. Jeffry Evans et al., ctDNA analysis of patients (pts) with unresectable hepatocellular carcinoma (uHCC) treated with lenvatinib (LEN) or sorafenib (SOR) as 1L therapy. JCO 42, 4094-4094(2024).

Perioperative Pembrolizumab and Lenvatinib for Resectable Hepatocellular Carcinoma: A Single-Arm, Multi-Center, Phase II Trial (NeoLEAP-HCC).

Background

The high recurrence rate after resection hinders the survival of patients with resectable hepatocellular carcinoma (HCC). Perioperative treatment has the potential to reduce the burden of micrometastasis and improve outcomes in many types of cancers.

Aim

This study aims to evaluate the efficacy and safety of pembrolizumab plus lenvatinib as perioperative treatment in patients with resectable HCC

Method

This was a single-arm, multi-center, phase II study (NCT05389527). Resectable HCC patients with a high risk of recurrence and naïve to systemic therapy received pembrolizumab 200 mg Q3W and lenvatinib 12 or 8 mg QD for 3 cycles followed by resection.

Pembrolizumab and lenvatinib were given for up to 12 months after resection. The primary endpoint was major pathological reactions (MPR), defined as viable tumor cells in ≤ 50% of tumor bed.

Secondary endpoints were complete pathological reactions (pCR), objective response rate (ORR, by RECIST v1.1 and mRECIST), disease-free survival (DFS), overall survival (OS), and safety.

Results

• Between Sep 30, 2022, and Aug 15, 2023, 43 patients were enrolled, and the enrollment has been completed. At the data cutoff (Dec 15, 2023), 42 patients have received at least one post-treatment radiological evaluation, ORR before surgery based on RECIST v1.1 and mRECIST were 11.9% and 47.6%, respectively.

• Forty (93.0%) patients completed neoadjuvant therapy and underwent R0 resection, of which 37 patients were pathologically confirmed HCC, 2 patients were combined HCC and intrahepatic cholangiocarcinoma (ICC), and 1 patient was ICC.
• Three patients did not proceed with planned surgery (1 patient with disease progression,1 with tumor rupture, and 1 refused surgery). Of the 37 patients with resected HCC, 14 (37.8%) patients achieved MPR, of which 3 (8.1%) patients achieved pCR. Eleven (29.7%) patients had significant tumor necrosis (necrosis tumor cells≥50% of tumor bed).
• The pathological response of all resected HCC lesions was evaluated in 39 patients. MPR was achieved in 15 (38.5%) patients, of which 3 (7.7%) patients achieved pCR.
• Twelve (30.8%) patients had significant tumor necrosis. Treatment-related adverse events (TRAE) of any grade during the neoadjuvant period occurred in 32 (74.4%) patients and grade 3 TRAEs occurred in 6 (14.0%) patients.
• No grade 4-5 TRAEs occurred. One patient delayed the surgery due to grade 3 immune-related hyperglycemia with ketoacidosis.
• The most common TRAEs of any grade during the neoadjuvant period were hypertension (10, 23.3%), stomatitis (5, 11.6%), and rash (4, 9.3%). The data of DFS and OS was immature, and follow-up is continuing.

Conclusion

Pembrolizumab plus lenvatinib demonstrated promising anti-tumor efficacy with manageable toxicity in the neoadjuvant setting for resectable HCC.

Reference

Hui-Chuan Sun et al., Perioperative pembrolizumab and lenvatinib for resectable hepatocellular carcinoma: A single-arm, multi-center, phase II trial (NeoLEAP-HCC). JCO 42, 4120-4120(2024).

Transarterial Chemoembolization Combined with Donafenib or Lenvatinib as First-line Treatment for Unresectable Hepatocellular Carcinoma: A Single-Center Real-World Retrospective Study.

Background

Combined Transarterial chemoembolization (TACE) with tyrosine kinase inhibitor (TKI) treatment has been proven to be beneficial.

Aim

This study aimed to retrospectively compare the efficacy and safety of Donafenib (DON)-TACE versus Lenvatinib (LEN)-TACE as first-line treatment for unresectable hepatocellular carcinoma (uHCC).

Method

From May 2020 to May 2023, a retrospective analysis was conducted on the clinical data of 93 patients with previously untreated uHCC who underwent treatment at the department of Interventional Radiology of the Third Affiliated Hospital of Sun Yat-sen University.

Among them, 49 were in the DON-TACE group and 44 in the LEN-TACE group.

The primary endpoint was progression-free survival (PFS) according to mRECIST, and the secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety outcome.

Results

• As of the data cut-off date Aug 26, 2023, the median PFS was 221 days (95% CI 141–366) in the DON-TACE group and 173 days (95% CI 108–215) in the LEN-TACE group (HR = 0.783, 95% CI 0.462–1.325, P = 0.362).
• ORR and DCR of the DON-TACE group were 55.1% (95% CI 40.23–69.33) and 75.51% (95% CI 61.13–86.66), respectively, while those of the LEN-TACE group were 61.36% (95% CI 45.49–75.64) and 81.82% (95% CI 67.29–91.81).
• No significant difference was observed either in ORR(P = 0.689) or DCR(P = 0.627) between the two groups. The incidence rates of total adverse events for any grade (85.71% vs 100.00%, P = 0.027) and ≥Grade 3 (22.496% vs 45.45%, P = 0.019) were significantly lower in the DON-TACE group.
• In addition, the incidence rates of AST increased (27.27% vs 56.82%, P = 0.005), diarrhea (6.12% vs 25.00%, P = 0.011), vomiting (0% vs 40.91%, P < 0.001), proteinuria (0% vs 18.18%, P = 0.011), gastrointestinal hemorrhage (0% vs 13.64%, P = 0.048) and hypertension (2.04% vs 36.36%, P < 0.001) for any grade were also significantly lower in the DON-TACE group.

Conclusion

DON-TACE and LEN-TACE showed comparable efficacy as first-line therapies for uHCC patients. DON-TACE demonstrated a lower incidence of severe adverse events.

Reference

Huan Liu et al., Transarterial chemoembolization combined with donafenib or lenvatinib as first-line treatment for unresectable hepatocellular carcinoma: A single-center real-world retrospective study.JCO 42, e16137-e16137(2024).

Lenvatinib (Lenv) plus Tislelizumab (Tis) Combined with or without Transarterial Chemoembolization (Tace) In First-Line Treatment of Unresectable Hepatocellular Carcinoma (uHCC): A Prospective, Non-Randomized, Open-Label, Phase II Cohort Study.

Background

The synergistic potential of programmed death protein-1 inhibitors and tyrosine kinase inhibitors in treating uHCC has been established. TACE, a cornerstone in uHCC therapy, primes the tumor microenvironment for immunotherapy by releasing neoantigens and inducing ischemia.

Aim

This study explores the efficacy and safety of Lenv plus Tis, combined with or without TACE, in a first-line setting.

Method

This phase II study enrolled patients (pts) with pathologically and/or radiologically diagnosed uHCC eligible for embolization, with at least one measurable lesion, Child-Pugh class A/B, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Pts received Tis (200mg every 3 weeks) and Lenv (oral dose adjusted by weight: 8mg for <60kg and 12mg for ≥60kg) with or without conventional TACE, as determined by the treating physician.

The primary endpoint was the objective response rate (ORR), with secondary endpoints including overall survival (OS), progression-free survival (PFS), and disease control rate (DCR).

Results

• By the data cutoff on January 27, 2024, 37 pts were enrolled: 12 received Lenv+Tis (cohort 1), and 25 received Lenv+Tis+TACE (cohort 2). Median follow-up time was 10.66 months.
• The ORR was 33.3% in cohort 1 and 68.0% in cohort 2, with DCRs of 100% and 96%, respectively (mRECIST). Median OS was 10.85 months (95% CI, 4.76-16.95) for cohort 1 and 13.61 months (95%CI, NE-NE) for cohort 2.
• Median PFS was 10.85 months (95% CI, NE-NE) for cohort 1, and 11.86 months (95% CI, 6.49-16.73) for cohort 2. Grade 3-4 treatment-emergent adverse events (teAE) occurred in 50% of cohort 1 and 68% of cohort 2.
• No fatal adverse event was reported. The most common grade 3-4 teAE (incidence >10%) were anaemia (17%) in cohort 1, and decreased platelet count (16%), hypertension (16%), rash (16%), fatigue (12%), elevated ALT (12%) in cohort 2.

Conclusion

Both Lenv+Tis and Lenv+Tis+TACE showed promising efficacy and manageable safety in the first-line treatment of uHCC. More pts were recruited to further prove these results.

	Len+Tis (N=12)	Len+Tis+TACE (N=25)
Median age (range)	57.5 (46-77)	57 (42-79)
Sex, No. (%), Male/Female	10 (83.3)/ 2 (16.7)	19 (76.0)/ 6 (24.0)
BCLC stage, No. (%), B/C	1 (8.3)/ 11 (91.7)	10 (40.0)/ 15 (60.0)
ECOG PS, No. (%), 0/1	10 (83.3)/ 2 (16.7)	22 (88.0)/ 3 (12.0)
Child-pugh, No. (%), A/B	10 (83.3)/ 2 (16.7)	25 (100.0)/ 0
PVTT, No. (%)
Vp2	4 (33.3)	2 (8.0)
Vp3	0	0
Vp4	3 (25.0)	0

Reference

Nan Zhang et al., Lenvatinib (Lenv) plus tislelizumab (Tis) combined with or without transarterial chemoembolization (TACE) in first-line treatment of unresectable hepatocellular carcinoma (uHCC): A prospective, non-randomized, open-label, phase II cohort study.JCO 42, e16169-e16169(2024).

Atezolizumab plus Bevacizumab (A+B) as First-Line Systemic Therapy for Advanced Hepatocellular Carcinoma (Hcc): A Multi-Institution Analysis of Patient Outcomes Based on Child Pugh (CP) and ALBI Liver Function.

Background

A+B is standard of care for advanced HCC in the first line setting, although was only evaluated in patients with CP class A liver function in IMbrave150.

Aim

To determine outcomes of patients in the real-world setting.

Methods

• A multi-institution retrospective analysis of patients with HCC who received A+B as first-line systemic therapy between March 2018 and November 2023, at Mayo Clinic and University Hospitals Seidman Cancer Center.
• Treatment response was evaluated, and progression free survival (PFS) and overall survival (OS) were determined using the Kaplan Meier method.
• Multivariate analyses were performed using Cox proportional hazard regression method.

Results

• Among patients with HCC (n=322)-
  • CP-A = 226
  • CP-B = 86
  • CP-C = 10
    • Albumin-Bilirubin (ALBI) grade 1 = 120
    • ALBI grade 2 = 177
    • ALBI grade 3 = 25
• Liver disease causes – Hepatitis B (5.3%) and C (34.8%), ethanol use (26.1%), and non-alcoholic steatohepatitis (15.5%)
• Macrovascular invasion - 42.9%, Extrahepatic metastatic disease - 30.4%
• mOS by CP Score:
  • CP-A5/6 = 21.6 months (Among patients with CP-A, those with ALBI grade 1 had mOS of 34.9 mo vs 14.2 mo for those with grade 2)
  • CP-B7 = 9.1 months
  • CP-B8-C12 = 4.7 mo (p<0.0001).
• mOS by ALBI grade :
  • ALBI grade 1 = 34.9 months
  • ALBI grade 2 = 11.7 months
  • ALBI grade 3 =4.7 months
• mPFS by CP score:
  • CP-A5/6 = 8.9 mo
  • CP-B7 = 6.4 mo
  • CP-B8-C12 = 2.7 mo (p<0.0001)
• mPFS by ALBI grade:
  • ALBI grade 1 = 11.0
  • ALBI grade 2 = 6.4
  • ALBI grade 3 = 3.7 mo, p=0.0001.
• Partial response was seen in 29.2%, 19.8% and 10.0% of patients with CP-A, -B, and -C, while 32.7%, 33.7%, and 40.0% had stable disease.
• There was significant interaction between CP and ALBI grade.

	OS
	Comparison	HR (95% CI)	p-value	p-value
ALBI	Grade 2 vs 1 in CP-A5/6	1.97 (1.31, 2.97)	0.0138*	0.0012
	Grade 2 vs 1 in CP-B7	0.18 (0.04, 0.8)		0.0247
Hepatitis B	Yes vs No	2.83 (1.52, 5.26)		0.0010
ECOG PS	1 vs 0	1.59 (1.13, 2.24)	0.0066**	0.0085
	2 vs 0	2.16 (1.22, 3.80)		0.0080
	2 vs 1	1.36 (0.79, 2.32)		0.2657
Macrovascular Invasion	Yes vs No	1.52 (1.11, 2.09)		0.0100

Conclusion

A+B remains a viable option in patients with CP-B7 liver function, although benefit is significantly less than those with CP-A. ALBI score has predictive value and can identify two prognostic groups among those with CP-A liver function.

Reference

Michael H. Storandt et al., Atezolizumab plus bevacizumab (A+B) as first-line systemic therapy for advanced hepatocellular carcinoma (HCC): A multi-institution analysis of patient outcomes based on Child Pugh (CP) and ALBI liver function. JCO 42, 4099-4099(2024).

Atezolizumab + Bevacizumab Versus Lenvatinib as First-Line Systemic Therapy for Treatment of Hepatocellular Carcinoma in A Real-World Population: Outcomes from the HCC CHORD Database.

Background

• Lenvatinib (LEN) and the combination of atezolizumab with bevacizumab (AB) are widely considered first-line systemic therapies for the treatment of advanced hepatocellular carcinoma (HCC), but have never been compared directly in a randomized clinical trial.
• Cross-trial comparisons between IMbrave150 and LEAP-002 appear to show similar survival outcomes for AB compared to LEN, respectively, while survival with LEN was shorter in the REFLECT trial.

Methods

• N= 453 Patients treated with AB (n = 159) or LEN (n = 294) first-line for HCC from August 2018 to August 2022 in the Canadian provinces of British Columbia, Alberta, Manitoba, Nova Scotia and two centers in Ontario.
• Demographic and clinical outcomes data were gathered.
• Statistical analysis identified the median OS, PFS, and physician-assess response rate (RR) associated with each treatment.

Results

• Male - 85%
• HBV - 14%; HCV - 32%; Cirrhosis - 70%
• BCLC B - 27%; BCLC C - 69%
• Distant metastasis - 37%
• Child-Pugh A - 88%
• ECOG PS 0-1 - 87%
• Previous locoregional treatment - 55%
• The two cohorts were balanced with respect to most demographic factors, but patients in the LEN cohort had-
  • Higher incidence of ECOG Performance Status ≥ 2 (11% vs 5%; p = 0.047)
  • Lower incidence of HBV (12% vs 19%; p=0.047)
  • Higher incidence of HCV (36% vs 25%; p=0.03)
• Median follow-up - 9.9 months (mos) for AB cohort compared to 11.8 mos for LEN.
• mOS - 15.4 mos in the overall population
• mOS - 19.7 mos (95% CI: 14.5-NR) in the AB cohort and 14.4 mos (95% CI: 12.2-17.1) in the LEN cohort (HR 0.72; 95% CI: 0.54-0.95; p=0.021)
• mPFS - 6.9 mos in the overall population, 8.3 mos for AB and 6.3 mos for LEN (HR 0.85; 95% CI: 0.68-1.06; p=0.20)
• RR - 29% overall, 31% for AB and 28% for LEN (p=0.50).
• LEN was the most common second-line treatment after AB (86%), while after LEN 46% of patients received regorafenib and only 21% received second-line AB.

Conclusion

This study provided real-world efficacy outcomes for AB directly compared to LEN in the first-line treatment of HCC in a Western country. AB was correlated with superior OS compared to LEN, but PFS and RR appear to be similar.

Reference

Mark Freeman et al., Atezolizumab + bevacizumab versus lenvatinib as first-line systemic therapy for treatment of hepatocellular carcinoma in a real-world population: Outcomes from the HCC CHORD database.. JCO 42, 4111-4111(2024).

EMERALD-1: A Phase 3, Randomized, Placebo-Controlled Study Of Transarterial Chemoembolization Combined with Durvalumab with or without Bevacizumab in Participants with Unresectable Hepatocellular Carcinoma Eligible for Embolization.

Background

• For >20 years, TACE has been a standard of care for embolization-eligible uHCC; however, most people with uHCC treated with TACE progress within 1 year.
• Embolization creates a proinflammatory tumor microenvironment and increases VEGF signals; clinical studies have established the role of immune checkpoint inhibitors (ICIs; e.g. D) and VEGF inhibitors (e.g. B) in advanced HCC.

Methods

• Double-blind, global, Phase 3 study
• N = 616 Participants (pts) with embolization-eligible uHCC, Child-Pugh A to B7 liver function, Eastern Cooperative Oncology Group performance status 0–1, and no evidence of extrahepatic disease were randomized 1:1:1 to –
  • D+B+TACE (n=204)
  • D+TACE (n=207) or
  • TACE (n=205) arms
• TACE was cTACE or DEB-TACE (investigator choice).
• Pts received D (1500 mg) or placebo for D (Q4W) plus TACE.
• After completion of last TACE, pts received D (1120 mg) or placebo for D plus B (15 mg/kg) or placebo for B (Q3W).
• Primary endpoint - Progression-free survival (PFS) for D+B+TACE vs TACE
• Secondary endpoints included PFS for D+TACE vs TACE, overall survival (OS), objective response rate (ORR), time to progression (TTP), and safety for D+B+TACE or D+TACE vs TACE.
• PFS, ORR, and TTP were assessed by blinded independent central review (RECIST v1.1).

Results

• BCLC Stage A - 25.8%, Stage B - 57.3%, Stage C - 16.1%
• Demographic and baseline characteristics were generally balanced across arms.
• mPFS for D+B+TACE vs TACE - 15.0 vs 8.2 mo; HR 0.77; 95% CI 0.61–0.98; p=0.032 [threshold 0.0434]).
• Results were consistent across most prespecified subgroups.
• Secondary endpoint of PFS for D+TACE vs TACE was not statistically significant (mPFS 10.0 vs 8.2 mo; HR, 0.94; 95% CI, 0.75–1.19; p=0.638).
• D+B+TACE vs D+TACE vs TACE
  • ORR - 43.6% vs 41.0% vs 29.6%
  • mTTP - 22.0 vs 11.5 vs 10.0 mo
• No new safety signals were identified
• Maximum Grade 3/4 treatment-related adverse events (TRAEs) - 32.5% vs 15.1% vs 13.5%
• Discontinuation due to TRAEs - 8.4% vs 4.3% vs 3.5%
• Death due to TRAEs - 0% vs 1.3% vs 2.0%
• Pts continue to be followed for OS.

Conclusion

D+B+TACE is the first ICI-based regimen in a global Phase 3 trial to show statistically significant and clinically meaningful improvement in PFS, vs TACE, in pts with embolization-eligible uHCC. Safety was manageable and consistent with the safety profiles of D, B, and TACE in uHCC. D+B+TACE has the potential to set a new standard of care in uHCC.

Reference

Riccardo Lencioni et al., EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization. JCO 42, LBA432-LBA432(2024).

Identification of a Predictive Phosphoproteomic Signature of Response to Atezolizumab and Bevacizumab (AB) in Patients with Advanced Hepatocellular Carcinoma (aHCC).

Background

• The number of systemic therapy options for aHCC has increased in recent years.
• Whilst AB has become the standard of care since its approval in 2020, most patients will have progressed by 12 months and 25% will have no response to AB.
• In addition, there are no predictive biomarkers to guide aHCC therapy selection.
• Phosphoproteomics have been previously used to identify predictive biomarkers from frozen clinical samples in other cancer types.

Aim

To build a preliminary model of response to AB by performing phosphoproteomic analysis on formalin-fixed and paraffin-embedded (FFPE) resected and Tru-Cut liver biopsies from aHCC patients subsequently treated with AB.

Methods

• Proteins were extracted from 10x10µm sections of FFPE biopsies obtained at diagnosis from aHCC patients (n=30, aetiology: viral, n=16; non-viral, n=14).
• Reversal of crosslinks was followed by tryptic digestion and multiple clean-up/enrichment steps. Peptides were quantified by mass spectrometry, and data quality was assessed using multivariate and enrichment analyses.
• Patients were stratified into ‘good responder’ (GRG, n=20, duration of response (DoR)>7.5 months) and ‘poor responder’ (PRG, n=10, DoR<7.5 month) groups.
• Features distinguishing the two groups were used to train a random forest response prediction model, which was assessed via cross-validation.

Results

• To build an AB response prediction model, 40 phosphopeptides were selected based on their ability to distinguish between PRG and GRG patients.
• These included previously described phosphorylation sites, such as pGSTA1-3S202 and pHSPB1S9, as well as several novel ones. In cross-validation, the model correctly predicted the outcomes of all good (20/20) and of 7/10 poor responders, demonstrating 100% sensitivity, 87% precision and 70% specificity.
• Overall, our model stratified patients with log-rank p<0.001 and HR<0.1 (Table), with similar performances in both viral (mean DoR 17.1 vs 0 months) and non-viral aetiology (mean DoR 14.4 vs 3.1 months).
• Kinase substrate enrichment analysis revealed significant (p<0.01) modulation of several kinases, such as MAP kinases and PRKCI, between responder groups.
• Also of note, a subgroup of PRG patients displayed increased activity of the RAF-MEK-ERK pathway, suggesting that these individuals may have shown sensitivity to drugs targeting RAF kinases, such as sorafenib.

Signature	Cases	Events	Mean DoR	SE	Median DoR
GRG	23	19	16.1	1.9	14.7
PRG	7	7	1.8	1.1	0

DoR in months as a function of model phosphosignature.

Conclusion

We have defined a preliminary predictive model of response to AB using phosphoproteomic data from routine FFPE biopsies in aHCC. Following an ongoing validation in independent patient cohorts, this model will address an unmet clinical need for biomarkers of clinical response in aHCC.

Reference

Debashis Sarker et al., Identification of a predictive phosphoproteomic signature of response to atezolizumab and bevacizumab (AB) in patients with advanced hepatocellular carcinoma (aHCC). JCO 42, 2631-2631(2024).