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An article summarizing anti-HER2 therapy for gastroesophageal adenocarcinoma

 Last Update: 2023-02-03
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In 2020, there were 1.
1 million new cases of gastric cancer worldwide, ranking fifth in the number of new cancer cases in the world.
There were 600,000 new cases of esophageal cancer, the eighth highest number of new cancer cases in the world¹
.
The prognosis for gastroesophageal adenocarcinoma (GEA) is poor, with a 5-year survival rate of 20%~30% for gastric cancer and 15%~25%²
for esophageal cancer in high-income countries.

Targeted therapy is a major therapy in GEA in recent years, among which HER2 target is the most prominent therapeutic target in targeted therapy
.
More than 20% of GEAs exhibit HER2 amplification, which lays the foundation
for HER2-targeted therapies such as trastuzumab.
With the further development of molecular technology, antibody drug conjugates (ADCs) have ushered in a vigorous development
in this field.
This article will briefly introduce the pathological molecular typing of GEA and summarize the anti-HER2 therapeutic strategies in GEA³
.

Pathological and molecular typing of GEA

Regarding the pathological classification of GEA, the most common clinical classification is Lauren classification, according to which gastric cancer can be divided into four types⁴: intestinal, diffuse, mixed and unclassified.

Intestinal gastric cancer is based on intestinal metaplasia and has obvious glandular structure; Diffuse gastric cancer usually does not form a glandular structure and has a worse
prognosis than the intestinal type.
The proportion of HER2 amplification in intestinal gastric cancer is high, about 28% of enteric gastric cancers are HER2 amplified, compared with 10%
of diffuse gastric cancer.
In addition, some untyped gastric cancers also have HER2 amplification, so for newly diagnosed GEA patients in the clinic, regardless of pathological classification, doctors should recommend HER2 testing to provide a more accurate and effective treatment plan
.

In terms of molecular typing, according to the Cancer Genome Atlas (TCGA) study, GEA is divided into four categories: Epstein–Barr virus (EBV) positive (accounting for about 9%), microsatellite unstable (MSI) (accounting for about 22%), genomically stable (GS) type (accounting for about 20%) and chromosomal unstable (CIN) type (accounting for about 50%), and the HER2 amplification rates of the four are 11.
5%, 0%, 3.
5% and 22.
4%, respectively
。 The Asian Organization for Cancer Research (ACGR) also classifies GEA into four molecular types, namely epithelial-mesenchymal transition (accounting for about 15.
3%), MSI type (accounting for about 22.
7%), microsatellite stable (MSS)/TP53+ type (accounting for about 26.
3%), and MSS/TP53- group (accounting for about 35.
7%)
.
The HER2 amplification rates of the four were 0%, 0%, 3% and 17.
4%, respectively.

In addition, other studies on tumor heterogeneity have shown that tumors with higher tumor mutational burden (TMB) are more likely to have HER2 amplification⁷.

Trastuzumab

Trastuzumab is a humanized monoclonal antibody targeting the HER2 extracellular domain that kills tumor cells
primarily through antibody-dependent cell-mediated cytotoxicity (ADCC).
。 A number of studies have evaluated the use of trastuzumab in GEA, such as the ToGA trial, which evaluated the efficacy of trastuzumab in combination with chemotherapy in first-line treatment in patients with advanced or metastatic GEA, and showed a significant improvement in overall survival (OS) compared with chemotherapy alone (median OS: 13.
8 months vs.
11.
1 months, P=0.
0046) and better progression-free survival (PFS) (median PFS: 6.
7 versus 5.
5 months).
, P=0.
0002), this advantage is more prominent in tumor patients with high HER2 expression⁸.

In addition to advanced patients, trastuzumab has also been evaluated in patients with locally advanced GEA
.
The RTOG 1010 trial, which explored the efficacy of trastuzumab in combination with chemoradiotherapy in neoadjuvant therapy, showed that the combination of trastuzumab did not improve disease-free survival (DFS), OS, and pathologic complete response (pCR) rates⁹.

Therefore, the use of trastuzumab in the perioperative treatment of patients with locally advanced stage compared with the success in advanced systemic therapy needs to be further evaluated
.

Trastuzumab combination therapy

Based on the mechanism of action of trastuzumab, some studies have attempted to enhance the antitumor effect of trastuzumab by enhancing the ADCC effect
.
One such strategy is to enrich effector immune cells, for example, a phase Ib study evaluating the efficacy of NK cells in combination with trastuzumab and bevacizumab in patients with HER2-positive solid tumors found that 1 in 9 patients achieved a partial response (PR) and 6 had stable disease (PD) for more than 6 months¹⁰
.

Another strategy is to combine trastuzumab with immune checkpoint inhibitors in a target-free combination
.
Although the mechanism of action is unclear, previous studies have found that PD-1 expression is upregulated in breast cancer patients after trastuzumab treatment, suggesting that patients may benefit from anti-PD-1 therapy¹¹.

Based on this, several studies have evaluated
this strategy.
Among them, the single-arm study PANTHERA trial has achieved exciting results, which explored the efficacy of pembrolizumab + trastuzumab + chemotherapy in patients with HER2-positive advanced GEA, and showed that 6 of the 43 patients had no disease progression after 2 years of treatment, with an objective response rate (ORR) of 76.
7% and a median OS of 19.
3 months¹²
.

This result was confirmed in a subsequent phase III randomized trial KEYNOTE-811, which included 264 GEA patients who were randomized to pembrolizumab + trastuzumab + chemotherapy (pembrolizumab) or placebo + trastuzumab + chemotherapy (placebo).

The results of the interim analysis showed ORRs of 74% and 52% in the pembrolizumab and placebo groups, respectively, with complete response (CR) rates of 11% and 3.
1%, respectively¹³
.
Based on this result, the U.
S
.
Food and Drug Administration (FDA) approved GEA first-line indications for this combination strategy.

Other anti-HER2 therapies

In addition to trastuzumab, pertuzumab and lapatinib are also drugs
that target HER2 to exert anticancer effects.
The same HER2 monoclonal antibody, pertuzumab and trastuzumab have different binding sites, so the efficacy is also different
.
The JACOB trial suggested that pertuzumab plus trastuzumab + chemotherapy improved PFS in patients with HER2-positive GEA as first-line therapy (median PFS: 8.
5 versus 7.
0 months, P=0.
0001), but failed to improve OS¹⁴
compared with placebo plus trastuzumab + chemotherapy.

Lapatinib is a small molecule drug that regulates the PI3K signaling pathway
by blocking the activation of the intracellular domain of HER2.
Lapatinib has shown clinical benefit in breast cancer, and in GEA, the TyTan study, which evaluated the efficacy of lapatinib plus paclitaxel for second-line therapy, showed that lapatinib plus paclitaxel failed to improve OS and PFS
in patients compared with paclitaxel alone.
However, in patients with HER2 IHC 3+, PFS (P=0.
0176) and OS (P=0.
0101) were significantly improved in the combination therapy group¹⁵, which may provide ideas
for the design of related trials in the future.

In addition to the above two classes of drugs, antibody drug conjugates (ADCs) are also expected in GEA's anti-HER2 therapy field, including a variety of mature drugs
such as T-DM1, T-DXd and vedicitumab.
The phase II/III GATSBY trial, which evaluated the efficacy of T-DM1 versus taxanes in second-line therapy in HER2-positive GEA patients, was shown that the clinical benefit of T-DM1 was not superior to taxane¹⁶
.
However, in the trial design of this study, patients did not reassess HER2 expression after first-line progression in trastuzumab therapy, so possible tumor heterogeneity may have interfered
with the trial results.

Another ADC drug, T-DXd, has gained traction in recent years and has shown clinical benefit
in GEA patients in multiple studies.
The DESTINY-Gastric01 trial suggests that T-DXd as third-line therapy for HER2-positive gastric cancer patients significantly improves ORR (51% vs.
14%, P<0.
001) and OS (median OS: 12.
5 versus 8.
4 months, P=0.
01)¹⁷
compared with physician-selected chemotherapy 。 The results of the single-arm study DESTINY-Gastric02 trial published in ESMO this year showed that for HER2-positive GEA patients, the ORR of T-DXd for second-line therapy could reach 41.
8%, of which the CR rate was 5.
1%.

The median OS was 12.
1 months and the median PFS was 5.
6 months (click here for more information on the study).

Based on these results, NCCN guidelines have adopted T-DXd as the standard of care
for patients with HER2-positive GEA in the second and later lines.
At present, the DESTINY-Gastric03 study evaluating the use of T-DXd for first-line treatment, the DESTINY-Gastric04 study evaluating the efficacy of T-DXd second-line treatment head-to-head and the DESTINY-Gastric06 study with Chinese patients as a sample are ongoing, and we look forward to the announcement
of relevant results.

Vedicitumab is an ADC drug independently developed in China, and the phase II study C008 trial suggests that vedicitumab can achieve ORR of 24.
4% and median OS of 7.
6 months for HER2-positive GEA patients who have previously received ≥ 2nd line therapy.

Based on this, the 2022 CSCO gastric cancer guidelines have listed vedicitumab as a level II recommended regimen
for the third-line and above treatment of HER2-positive gastric cancer patients.

brief summary

HER2 is an important target in GEA therapy, and HER2-targeted therapy is also developing
rapidly.
The use of trastuzumab has significantly improved the survival prognosis of patients with advanced gastric cancer, but the ensuing drug resistance problems have hindered the further application
of HER2-targeted therapy.
In recent years, ADC drugs are booming, which may provide more and better treatment options for gastric cancer patients, meet more patient needs, and further improve patient survival
.

References (swipe up to view):

1.
https://gco.
iarc.
fr/

2.
https://gco.
iarc.
fr/survival/survmark

3.
Augustin JE, Soussan P, Bass AJ.
Targeting the complexity of ERBB2 biology in gastroesophageal carcinoma.
Ann Oncol.
2022; 33(11):1134-1148.

4.
P.
Lauren The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma.
An attempt at a histo-clinical classification.
Acta Pathol Microbiol Scand, 64 (1965), pp.
31-49

5.
Cancer Genome Atlas Research Network Comprehensive molecular characterization of gastric adenocarcinoma.
Nature, 513 (7517) (2014), pp.
202-209

6.
R.
Cristescu, J.
Lee, M.
Nebozhyn, et al.
Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.
Nat Med, 21 (5) (2015), pp.
449-456

7.
S.
Jammula, A.
C.
Katz-Summercorn, X.
Li, et al.
Identification of subtypes of Barrett’s esophagus and esophageal adenocarcinoma based on DNA methylation profiles and integration of transcriptome and genome data.
Gastroenterology, 158 (6) (2020), pp.
1682-1697.
e1

8.
Y.
J.
Bang, E.
Van Cutsem, A.
Feyereislova, et al.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial.
Lancet, 376 (9742) (2010), pp.
687-697

9.
H.
P.
Safran, K.
Winter, D.
H.
Ilson, et al.
Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): a multicentre, randomised, phase 3 trial.
Lancet Oncol, 23 (2) (2022), pp.
259-269

10.
T.
H.
Kang, S.
T.
Jung Boosting therapeutic potency of antibodies by taming Fc domain functions.
Exp Mol Med, 51 (11) (2019), pp.
1-9

11.
V.
Varadan, H.
Gilmore, K.
L.
S.
Miskimen, et al.
Immune signatures following single dose trastuzumab predict pathologic response to preoperative trastuzumab and chemotherapy in HER2-positive early breast cancer.
Clin Cancer Res, 22 (13) (2016), pp.
3249-3259

12.
S.
Y.
Rha, kun Lee C, H.
S.
Kim, et al.
A multi-institutional phase Ib/II trial of first-line triplet regimen (Pembrolizumab, Trastuzumab, Chemotherapy) for HER2-positive advanced gastric and gastroesophageal junction cancer (PANTHERA Trial): molecular profiling and clinical update.
J Clin Oncol, 39 (suppl 3) (2021), p.
218

13.
Y.
Y.
Janjigian, A.
Kawazoe, P.
Yañez, et al.
The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer.
Nature, 600 (7890) (2021), pp.
727-730

14.
J.
Tabernero, P.
M.
Hoff, L.
Shen, et al.
Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study.
Lancet Oncol, 19 (10) (2018), pp.
1372-1384

15.
T.
Satoh, R.
H.
Xu, H.
C.
Chung, et al.
Lapatinib plus paclitaxel versus paclitaxel alone in the second-line treatment of HER2-amplified advanced gastric cancer in Asian populations: TyTAN--a randomized, phase III study.
J Clin Oncol, 32 (19) (2014), pp.
2039-2049

16.
P.
C.
Thuss-Patience, M.
A.
Shah, A.
Ohtsu, et al.
Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international randomised, open-label, adaptive, phase 2/3 study.
Lancet Oncol, 18 (5) (2017), pp.
640-653

17.
T.
Doi, K.
Shitara, Y.
Naito, et al.
Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody–drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.
Lancet Oncol, 18 (11) (2017), pp.
1512-1522

18.
Z.
Peng, T.
Liu, J.
Wei, et al.
A phase II study of efficacy and safety of RC48-ADC in patients with locally advanced or metastatic HER2-overexpressing gastric or gastroesophageal junction cancers.
J Clin Oncol, 38 (suppl 15) (2020), p.
4560

Editor: Babel

Reviewed: Faline

Typesetting: Babel

Execution: Babel

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