The liver cancer test was full of joy and sorrow, and the biliary tract tumor made a milestone breakthrough

"NEJM Medical Frontiers" every Tuesday [Tumor Deep Observation] column on clinical oncology hot issues, combing through the recent papers of top journals such as the New England Journal of Medicine, reviewing the cutting-edge progress, and insight into the future direction

In June this year, NEJM Medical Frontiers reviewed the progress made in the systemic treatment of advanced hepatocellular carcinoma (HCC) in the past two years and the current challenges (click for details).

Cabozantinib + atilizumab for HCC

Recently, Lancet Oncol reported the results

The benefit of PFS in the combination therapy group was mainly due to the Asian subgroup of patients, the subgroup of hepatitis B virus (HBV)-induced hepatocellular carcinoma, and patients with extrahepatic metastases or macrovascular invasion, while there was no difference

The ORIENT-32 and RESCUE studies included only East Asian patients, whose main cause of HCC was HBV

Retrospective studies and some clinical trial subgroup analyses suggest that OS improvement in patients with HBV or HCV-associated HCC is associated

Based on the above analysis, the benefit of cabozantinib + atilizumab in HCC therapy appears to be seen primarily in patients with viral HCC, and antiviral therapy may have an adjunctive therapeutic effect

tremelimumab + dulvalizumab for HCC

In August 2022, NEJM Evidence reported the results of

In this clinical trial, patients with unresectable HCC were randomly assigned to receive tremelimumab single dose + intermittent administration of dulvalizumab, dulvalizumab monotherapy or sorafenib, the primary endpoint being tremelimumab + dulvalizumab and sorafenib group overall survival (OS); Duvalizumab is not inferior to sorafenib is a secondary endpoint

In this randomized trial, a total of 1171 patients included median OS of 16.
4 months in the tremelimumab + dulvaliumab group and 13.
8 months in the sorafenib group, and the risk of death in the tremelimumab + dulvarizumab group was reduced by 22%.


The efficacy of duvalizumab is not inferior to that of sorafenib, HR is 0.
86, the median OS is 16.
6 months, and the results are even higher than those in the tremelimumab + dulvalizumab group
.

However, the statistical efficacy of this study was insufficient to compare
the efficacy of tremelimumab + dulvalizumab with dulvalizumab.

The incidence of grade 3/4 treatment-related adverse events was 25.
8% in the combination group, 12.
9% in the duvalizumab group, and 36.
9%
in the sorafenib group.

Based on the findings, first-line treatment for patients with advanced HCC may have added two treatment options, and this study may represent a new milestone
in the treatment of patients with HCC.

When the HIMALAYA trial began, sorafenib was the only drug approved for first-line treatment of HCC
.

Thereafter, the IMbrave150 trial published in NEJM in 2020 established attilizumab + bevacizumab as the first-line therapy
for advanced HCC.

Currently, the best choice of HCC immunotherapy regimen will depend on the toxicity associated with three different regimens
.

Immunotherapy + thymidine kinase inhibitors or immunotherapy + topical therapy are being studied, and it is expected that these treatment strategies will further promote the benefits
of HCC therapy.

Carrelizumab + apatinib for HCC

The results of Phase 3 trial SHR-1210-III.
-310 led by Professor Qin Shukui of Nanjing Jinling Hospital were reported
in ESMO 2022 in the form of Late Breaking Abstract (LBA).

This is a randomized, open-label Phase 3 trial completed
at 95 research centers in 13 countries.

Enrolled patients with locally advanced or metastatic HCC were randomized 1:1 and treated with carrelizumab plus apatinib or sorafenib
, respectively.

The primary endpoints were overall survival and progression-free survival
.

A total of 543 patients (ITT population), 272 in the carrelizumab plus apatinib group and 271 in the sorafenib group were
enrolled in the study.

After median follow-up of 7.
8 months, the carrelizumab combined with apatinib group had a significant improvement in the median PFS compared with the sorafenib group (5.
6 months vs.
3.
7 months; HR, 0.
52; 95% CI, 0.
41 to 0.
65; 1-sided P<0.
0001).


After a median follow-up of 14.
5 months, the median OS of carrelizumab combined with apatinib was significantly prolonged (22.
1 months vs.
15.
2 months; HR, 0.
62; 95% CI, 0.
49 to 0.
80; 1-sided P<0.
0001).


Pre-specified subgroup analyses showed that in most subgroups, carrelizumab combined with apatinib PFS and OS had a significantly better HR than sorafenib
.

This is the world's first and so far only successful clinical trial
of PD-1 monoclonal antibody combined with oral antivascular targeted small molecule tyrosine kinase inhibitor for first-line treatment of patients with advanced hepatocellular carcinoma.

Although it is difficult to directly compare the results of different trials, the median OS of carrelizumab plus apatinib in the SHR-1210-III.
-310 trial reached 22.
1 months, the longest median OS of
any trial so far.

These findings support carrelizumab + apatinib as a first-line treatment option for unresectable HCC
.

Lönvatinib + pabolizumab for HCC

At ESMO 2022, the results of the LEAP-002 trial of lenvatinib + pabolizumab and lenvatinib monotherapy for advanced HCC were also reported
in the form of LBA.

Enrolling HCC patients were randomly assigned to the lenvatinib + pabolizumab group (n=395) or the lenvatinib group + placebo group (n=399)
1:1.

The combination of primary endpoint OS and PFS was evaluated
using a hierarchical logarithmic test.

The key secondary endpoint is ORR
.

The study protocol provides for 2 mid-term analyses and 1 final analysis
of the OS.

The predetermined efficacy boundaries are: the difference in PFS significance in the first phase analysis (pre-defined final PFS analysis) was unilateral P=0.
002, and the OS significance difference in the final analysis was P=0.
0185
.

After a median follow-up of 32.
1 months, a total of 534 OS events
occurred.

36 patients (9.
1%) of lenvatinib + pabolizumab and 24 patients (6.
1%) of the lenvatinib group were still receiving the
trial regimen.

The HR of PFS in the first midterm analysis was 0.
867 (95% CI, 0.
734 to 1.
024; P=0.
0466).


The median OS of lenvatinib + pabolizumab was 21.
2 months, compared with 19.
0 months in the lenvatinib group (HR, 0.
840; 95% CI, 0.
708 to 0.
997; P=0.
0227).


At the time of final analysis, the ORR of lenvatinib + pabolizumab was 26.
1% and that of the lenvatinib group was 17.
5%.

Grade 3 to 5 treatment-related adverse events were 62.
5% vs.
57.
5% (grade 5 adverse events, 1.
0% vs.
0.
8%)
, respectively.

By the end of the study, 44.
1 percent and 52.
1 percent of patients in both groups had received systemic anti-cancer treatment
.

Neither the primary endpoints OS (final analysis) nor PFS (first midterm analysis) of LEAP-002 achieved pre-specified statistical significance
.

Although lenvatinib + pabolizumab achieved the second-longest median OS (21.
2 months, second only to carrelizumab plus apatinib) in a Phase 3 trial of first-line treatment of HCC, its primary endpoint
was not reached.

Tirelizumab for HCC

ESMO 2022 also reported the results of the RATIONALE-301 trial in LBA, confirming that OS with tirelizumab monotherapy that cannot remove HCC is not inferior to sorafenib
.

RATIONALE-301 is an international, open-label, randomised phase 3 trial of patients with unresectable HCC who
had not previously been treated.

The 674 enrolled participants were randomly treated with tirelizumab (n=342) or sorafenib (n=332) in a 1:1 ratio
.

The primary endpoint is OS, and the secondary endpoint includes ORR, PFS, etc
.

In the final analysis, RATIONALE-301 reached the primary endpoint of OS non-inferiority (15.
9 months vs.
14.
1 months; Stratified HR, 0.
85; 95.
003% CI, 0.
712 to 1.
019]).


The ORR in the tirelizumab group was higher than in the sorafenib group (14.
3% vs.
5.
4%), and the duration of remission was also longer (36.
1 months vs.
11.
0 months).

The safety of both treatments is consistent
with previous reports.

Compared with sorafenib, the incidence of grade 3≥ adverse events (48.
2% vs.
65.
4%) and adverse events leading to discontinuation (10.
9% vs.
18.
5%) was lower
in the tirelizumab group.

Patients with unresectable HCC who are treated with tirelizumab monotherapy alone show clinically significant OS benefits that are not inferior to sorafenib and have good safety
.

Molecular markers of immunotherapy in combination therapy

The IMbrave150 trial demonstrated that the combination of anti-alizumab + bevacizumab significantly prolongs OS in advanced HCC, and this regimen has been approved in more than 70 countries for first-line treatment
of unresectable HCC.

However, the potential predictive biomarkers and mechanisms of resistance in this combination therapy are not well studied
.

A study led by Dr.
Andrew X.
Zhu, honorary director of Shanghai Jiahui International Cancer Center and former professor at Harvard Medical School, analyzed tumor tissue specimens of HCC patients enrolled in the GO30140 Phase 1b and IMbrave150 Phase 3 trials to clearly predict anti-PD-L1+ anti-VEGF treatment response and potential biomarkers of drug resistance, while hoping to understand how anti-VEGF enhances anti-tumor immunity and enhances the mechanism of anti-PD-L1 immunotherapy
。
The findings were published in Nature Medicine, published last month
.

By integrating transcriptome, gene, in situ multiple immunohistochemistry and digital pathology data of 358 HCC patients, the researchers found molecular factors
related to the clinical response and drug resistance of anti-PD-L1 and anti-VEGF combination therapy.

The authors found that the immunity already present in baseline tumor tissues (manifested by high expression of CD274, effector T cell characteristics, and intratumor CD8+ T cell density) is the main driver of the clinical activity of altelizumab + bevacizumab in advanced HCC
.

In patients with unresectable HCC, the correlation between high expression of PD-L1 protein and improvement in clinical outcomes of atyrizumab + bevacizumab was relatively weak, which may be due to
the heterogeneity of PD-L1 expression detection methods.

In addition, the researchers also found that high expression of PD-L1 mRNA and Teff gene features, enrichment of inflammatory response pathways, and high density of CD8+ T cells in the tumor microenvironment were all associated
with the clinical benefit of combination therapy.

By further developing and optimizing PD-L1 and CD8 immunohistochemical assays, or diagnostic or enrichment strategies based on Teff gene expression characteristics, it will be possible
to predict the clinical response of atilizumab + bevacizumab in unresectable HCC.

The exploratory analysis also revealed that potentially relevant molecules with reduced benefits of attilizumab + bevacizumab included a high Treg/Teff ratio and high expression
of AFP/GPC.

The Treg/Tesf ratio has been identified as a major factor
in disease progression and immunosuppression in many types of cancer.

HCC takes advantage of the liver's anti-inflammatory immune environment to evade immune surveillance
.

Macrophages and Kupffer cells in the liver, as well as hepatic sinus endothelial cells and hepatic stellate cells, may coordinate to promote Treg cell activation, migration, and accumulation
.

In other tumors, tumor mutation load (TMB) is associated with the clinical efficacy of immune checkpoint inhibitors, but no relationship between
TMB and PD-1 monotherapy has been found in HCC.

On the other hand, the researchers found that patients with TERT promoter mutations had better clinical outcomes with atyrizumab + bevacizumab, while patients with CTNNB1 mutations had less
clinical benefit from using combination therapy.

The study also further understood the mechanisms
by which anti-VEGF enhances anti-tumor immunity and strengthens anti-PD-L1 immunotherapy.

Anti-VEGF can exert synergistic effects with anti-PD-L1 to promote an increase in the number of regular dendritic cells and CD8+ T cells, which may reduce the number of blood vessels in tumors and peritumor-surrounding regions through anti-VEGF, reduce the number of monocyte-derived macrophages, and alleviate the inhibitory effect
of proliferating Tregs.

Most of the malignancies of the biliary system are diagnosed in the advanced stage, and it is difficult to undergo radical surgery, and the prognosis is very poor
.

Clinical trials of various targeted drugs, including cedenib, erlotinib, cetuximab, panimumab, remolucumab and mesatinib, have been carried out, but the results have been poor
.

For nearly a decade, the first-line treatment standard for advanced disease has remained gemcitabine + cisplatin chemotherapy, with a median overall survival of 11.
7 months, with an estimated 24-month survival rate of about 15%.

In October 2021, we reported the results of a randomized, double-blind, placebo-controlled Phase 3 trial (ClarIDHy)
led by Dr.
Andrew X.
Zhu.

Studies have shown that in patients with unresectable or metastatic IDH1 mutation cholangiocarcinoma, the median OS of oral and small molecule inhibitors in the ivosidenib group and placebo group with IDH1 mutation targeting was 10.
3 months and 7.
5 months, respectively (HR, 0.
79; 95% CI, 0.
56 to 1.
12; unilateral P=0.
09).


The median OS in the placebo group after cross-treatment correction was 5.
1 months (HR, 0.
49; P<0.
001).


The U.
S.
Food and Drug Administration (FDA) has approved ivosidenib for the treatment of treated locally advanced or metastatic IDH1 mutant cholangiocarcinoma (see details
).

There is immune checkpoint molecule expression in the tumor microenvironment of biliary system malignancies, and early studies have demonstrated that immune checkpoint inhibitors have clinical activity
in biliary system malignancies.

In addition, studies have demonstrated that chemotherapy has an immunomodulatory effect in many types of cancer, and immunotherapy + chemotherapy is better than chemotherapy
alone.

Based on this, a Phase 2 trial of dulvalizumab combined with gemcitabine and cisplatins in the treatment of biliary system malignancies showed an objective response rate of 72%, a median overall survival of 20.
2 months, and no dose-limiting toxicity
.

NEJM Evidence, published last month, reported the results
of a randomized, double-blind, global multicenter Phase 3 trial TOPAZ-1.

The objective of this trial was to assess the efficacy and safety of dulvalizumab + gemcitabine and cisplatin first-line treatment of biliary system malignancies
.

TOPAZ-1 included patients with histically proven non-resectable, locally advanced, or metastatic adenocarcinoma of the biliary system, including intrahepatic or extrahepatic cholangiocarcinoma and gallbladder cancer, and were randomly assigned to receive
duvalliumab + gemcitabine and cisplatin, or placebo + gemcitabine and cisplatin.

The results showed that the median overall survival (OS) of dulvalizumab group was 12.
8 months (95% CI, 11.
1-14.
0), which was better than that of 11.
5% CI, 10.
1-12.
5) in the placebo group (HR, 0.
80; 95% CI, 0.
66-0.
97; P=0.
021).


The 24-month survival rate was 24.
9% in the duvalizumab group compared with 10.
4%
in the control group.

Subgroup analyses showed that Asian patients appeared to benefit more easily from the treatment of dulvalizumab than non-Asian patients
.

In patients with a PD-L1 tumor region positive (TAP) score ≥ 1%, the OS-risk ratio of dullizumab compared with placebo was 0.
79 (95% CI, 0.
61 to 1.
00).


The OS-risk ratio was 0.
86 (95% CI, 0.
60 to 1.
23) in patients with a TAP score of <1%, suggesting that PD-L1 status is of limited value in predicting the clinical benefit of<b12> using dulliumab + chemotherapy in this patient population.

It is worth noting that the patients in the trial group received maintenance therapy with dullizumab after 8 cycles of chemotherapy, which raised the question of whether dullizumab had a maintenance effect
.

This important study, which applies immunotherapy in combination with chemotherapy to the first-line treatment of advanced biliary malignancies, is a landmark breakthrough, but whether OS extension of 1.
3 months is important for patients remains to be explored
.

References

1.
Kelley RK, Rimassa L, Cheng AL, et al.
Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): a multicentre, open-label, randomised, phase 3 trial.
Lancet Oncol 2022; 23:995-1008.

2.
Abou-Alfa G, Lau G, Kudo M, et al.
Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.
NEJM Evid 2022; 1(8).
DOI: 10.
1056/EVIDoa2100070.

3.
Qin SK, Chan LS, Gu S, et al.
Camrelizumab (C) plus rivoceranib (R) vs.
sorafenib (S) as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A randomized, phase III trial.
An Oncol 2022; 33 (suppl_7): S808-S869.

4.
Finn RS, Kudo M, Merle P, et al.
Primary results from the phase III LEAP-002 study: Lenvatinib plus pembrolizumab versus lenvatinib as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC).
An Oncol 2022; 33 (suppl_7): S808-S869.

5.
Qin S, Kudo M, Meyer T, et al.
Final analysis of RATIONALE-301: Randomized, phase III study of tislelizumab versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma.
An Oncol 2022; 33 (suppl_7): S808-S869.

6.
Zhu AX, Abbas AR, de Galarreta MR, et al.
Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma.
Nat Med 2022; 28:1599-11.

7.
Oh DY, Ruth He A, Quin S, et al.
Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer.
NEJM Evid 2022; 1(8).
DOI: 10.
1056/EVIDoa2200015.

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