Perseverance ｜ Advanced history of immunotherapy for gastroesophageal cancer

Foreword 2021 is a year of change for esophageal cancer (EC) and gastric cancer (GC) treatment, based on four clinical studies of CheckMate - 577, CheckMate - 649, KEYNOTE - 590 and KEYNOTE - 811, U.
S.
Food and Drug Administration (FDA) Approved immunotherapy for gastroesophageal cancer could change the treatment landscape for both early and advanced disease
.

Although there is room for further improvement in the current status of gastroesophageal cancer treatment, traditional surgery, radiotherapy and chemotherapy cannot greatly improve the efficacy of cancer patients, so new treatment methods need to be explored
.

In recent years, more attention has been paid to tumor immunotherapy
.

The success of immunotherapy has revolutionized the effect of cancer treatment, illuminating the path of survival for patients in areas such as lung cancer and melanoma
.

Immunotherapy ranks alongside traditional surgery, radiotherapy and chemotherapy as the four pillars of cancer treatment
.

While "immunotherapy" is a broad term, it currently refers primarily to immune checkpoint inhibitors (ICIs)
.

Progress has been made in incorporating ICIs into the treatment of EC and GC, rewriting the treatment paradigm for EC and GC
.

Immunogenic The immune system plays an important role in controlling tumor growth and progression
.

The Cancer Genome Atlas (TCGA) project performed a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas and 164 ECs
.

In GC, the TCGA panel identified genomic and molecular types, with two main GCs—EpsteinBarr virus (EBV)-infected tumors and microsatellite unstable tumors (MSI)—that upregulate immune-related genetic pathways
.

EBV-infected GC subtypes exhibit higher frequencies of PIK3CA mutations, hypermethylation of DNA, JAK2, programmed death-ligand 1 (PD-L1), and PD-L2 amplification
.

In addition, tumor-infiltrating lymphocytes (TILs) can also be found in resected tumors, which are closely related to prognosis
.

Meanwhile, among EC patients receiving neoadjuvant chemotherapy, TIL density was higher in responders than in non-responders, so CD3+ cell density was found to be an independent prognostic factor
.

The immune response demonstrated by the presence of TILs in the tumor is not sufficient to completely eliminate the tumor, and immune escape has occurred
.

PD-L1, the most compelling immune escape biomarker, has been shown to play a key role in the progression of esophageal squamous cell carcinoma (ESCC)
.

As a predictive biomarker, PD-L1 has therapeutic relevance in addition to reflecting immunogenicity
.

The PD-L1 Combined Positive Score (CPS), which is the ratio of all PD-L1-expressing cells (tumor cells, lymphocytes, macrophages) to the number of all tumor cells, compared to the originally used Tumor Proportion Score (TPS) was shown to is a better predictive biomarker
.

Post-line immunotherapy ICI for gastroesophageal cancer was first clinically tested in chemotherapy-refractory EC and GC
.

Early evaluation results of pembrolizumab in advanced EC and GC showed encouraging antitumor activity, with objective response rates (ORR) of 33% and 30%, respectively
.

Based on this result, the researchers further conducted the Phase II KEYNOTE-059 study
.

The study included patients with metastatic GC who had received second-line or more prior therapy to evaluate the efficacy of pembrolizumab
.

The results showed an ORR of 16.
4%, an ORR of 22.
7% in PD-L1-positive patients, and an ORR of 8.
6% in PD-L1-negative patients
.

The ATTRACTION-2 study enrolled patients with advanced gastric/esophagogastric junction cancer (GC/GEJC) who had failed two prior systemic therapies and were treated with nivolumab or placebo
.

The 2-year follow-up results showed that nivolumab significantly reduced the risk of death by 38%, and the median overall survival (OS) of the two groups was 5.
26 vs 4.
14 months (HR 0.
62, P < 0.
0001)
.

The 1-year survival rate was 27.
3% in the nivolumab group (11.
6% in the chemotherapy group), and the 2-year survival rate was 10.
6% in the chemotherapy group (3.
2% in the chemotherapy group)
.

Combination therapy with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death 1 (PD-1) immunotherapy has shown significant benefit in preclinical studies
.

CheckMate-032 is an open-label, phase I/II, multi-cohort trial evaluating nivolumab monotherapy or the nivolumab/ipilimumab combination in patients with progressive disease or resistance to at least one chemotherapy Safety and efficacy in patients with adversely affected advanced gastroesophageal cancer
.

160 patients were randomly assigned to receive nivolumab 3 mg/kg (NIVO3) every 2 weeks, nivolumab 1 mg/kg + ipilimumab 3 mg/kg (NIVO1 + IPI3) every 3 weeks, for a total of 4 cycles, or nivolumab 3 mg/kg + ipilimumab 1 mg/kg (NIVO3 + IPI1) every 3 weeks for a total of 4 cycles
.

All regimens were followed by NIVO3 every 2 weeks until disease progression or unacceptable toxicity
.

The study found that the highest ORR of 24% was observed in NIVO1 + IPI3-treated patients
.

The ORR was 12% and 8% in the NIVO3 and NIVO3 + IPI1 treatment groups, respectively
.

The 12-month OS rates in the NIVO3, NIVO1 + IPI3, and NIVO3 + IPI1 groups were 39%, 35%, and 24%, respectively
.

The NIVO1 + IPI3 arm had the highest rate of grade ≥3 adverse events (47%), with 20% of patients discontinuing treatment due to treatment-related adverse events
.

The KEYNOTE-181 study is a global, multicenter, randomized, controlled, open-label Phase III clinical study to evaluate the efficacy and safety of pembrolizumab versus second-line single-agent chemotherapy in the treatment of advanced or metastatic EC or GEJC
.

Global cohort data showed that among patients with PD-L1 CPS ≥ 10, median OS was 9.
3 months in the pembrolizumab group compared with only 6.
7 months in the single-agent chemotherapy group, meeting the primary study one of the end points
.

In ESCC, there was also a clinically meaningful improvement in OS in the pembrolizumab group, reaching 8.
2 months versus 7.
1 months in the chemotherapy group (HR 0.
78; 95% CI 0.
63-0.
96; P=0.
0095)
.

KEYNOTE-590, a first-line immunotherapy for gastroesophageal cancer, is a randomized, double-blind, phase III clinical trial designed to evaluate pembrolizumab plus chemotherapy versus placebo plus chemotherapy for the first-line treatment of locally advanced or metastatic esophageal cancer ( Efficacy and safety of ESCC, adenocarcinoma and Siewert type I GEJC)
.

The primary endpoints of the study were OS and progression-free survival (PFS)
.

Secondary endpoints included ORR, duration of response (DoR) and safety
.

Overall, the study met the primary endpoints of OS and PFS, compared with the current standard first-line chemotherapy regimen, the pembrolizumab combination regimen showed in the overall study population, as well as the treatment of each study subgroup.
Statistically and clinically meaningful improvements in OS and PFS were observed
.

Among them, the Asian population had more significant benefits in terms of OS (HR=0.
64, 95%CI 0.
51-0.
81) and PFS (HR=0.
59, 95%CI 0.
47-0.
73)
.

The CheckMate-649 and ATTRACTION-4 studies evaluated the efficacy of nivolumab in combination with chemotherapy in first-line treatment of patients with advanced gastroesophageal cancer
.

The CheckMate-649 study is a randomized phase III clinical trial evaluating oxaliplatin-based first-line chemotherapy (FOLFOX or CAPOX) in previously untreated patients with locally advanced or metastatic GC/GEJC (HER2 negative or unknown), Efficacy and safety of chemotherapy plus nivolumab or ipilimumab/nivolumab
.

Patients were stratified according to PD-L1 expression (≥1% or <1%), ECOG performance status, geographic region, and chemotherapy regimen
.

The primary endpoint of the study was OS and PFS based on blinded independent central review committee (BICR) assessments in patients with PD-L1 CPS ≥ 5 with nivolumab in combination with chemotherapy compared with chemotherapy alone
.

Key secondary endpoints included OS in patients with CPS ≥ 1 and in all randomized patients who received nivolumab plus chemotherapy, and OS and time to symptomatic deterioration in patients who received nivolumab plus ipilimumab versus chemotherapy alone (TTSD)
.

The final results showed that for patients with CPS ≥5, the median OS of nivolumab plus chemotherapy was 14.
4 months, compared with chemotherapy alone (11.
1 months), and the risk of death was reduced by 29%; The median PFS of the monoclonal antibody combined with chemotherapy group was 7.
7 months, and compared with the chemotherapy group alone (6 months), the risk of cancer progression or death was reduced by 32%; both the primary endpoints passed the hypothesis test with a P<0.
0001 result
.

ATTRACTION-4 was similar to the CheckMate-649 study, except that it was conducted only in Asian patients, which did not find a similar improvement in OS as CheckMate-649, but demonstrated a significant improvement in PFS
.

Although the CheckMate-649 and ATTRACTION-4 studies both suggest that first-line PD-1 inhibitors combined with chemotherapy can be beneficial, the Chinese population is limited in these studies, and the guiding significance for the Chinese population is still open to question
.

ORIENT-16 is the first randomized double-blind phase III study in China to demonstrate the significant benefit of immunotherapy combined with chemotherapy in the first-line treatment of advanced GC in the whole population
.

The results showed that sintilimab combined with chemotherapy showed significant OS benefit and significantly prolonged PFS in the whole population
.

All subgroups, including populations with different CPS expression, benefited from OS
.

HER-2 positive GC is a special type of GC, accounting for about 15% of all GC
.

KEYNOTE-811 is a randomized phase III clinical study of pembrolizumab combined with chemotherapy and targeted therapy in HER2-positive metastatic GC/GEJC
.

The results of the study showed that the ORR of pembrolizumab combined with trastuzumab and chemotherapy reached 74.
4%, which was 22.
7% higher than the placebo + trastuzumab + chemotherapy group
.

Based on the results of this study, in May 2021, the U.
S.
FDA granted accelerated approval to pembrolizumab in combination with trastuzumab and chemotherapy for the first-line treatment of HER-2-positive advanced GC
.

First-line immunotherapy for esophageal squamous cell carcinoma As mentioned above, immunotherapy has been shown to be effective in ESCC
.

Recently, there have been many studies looking at the use of anti-PD-1 therapy in the first-line treatment of this EC subset
.

The randomized, double-blind, placebo-controlled, phase III ESCORT-1st study was designed to evaluate the efficacy and safety of camrelizumab plus paclitaxel and cisplatin versus placebo plus paclitaxel and cisplatin as first-line therapy
.

The results of the study showed that compared with chemotherapy alone, camrelizumab combined with chemotherapy significantly prolonged the median OS of patients (15.
3 months vs 12.
0 months), reduced the risk of death by 30%, and also significantly prolonged the median OS of patients.
PFS (6.
9 months vs 5.
6 months), reduced risk of disease progression by 44%
.

Patients in the camrelizumab-chemotherapy group had higher ORR (72.
1% vs 62.
1%) and longer duration of remission (DoR, 7.
0 vs 4.
6 months)
.

In addition, the JUPITER-06 study included 514 newly treated patients with advanced or metastatic ESCC, who were randomly assigned 1:1 to toripalimab combined with paclitaxel + cisplatin chemotherapy (TP regimen) or placebo + TP regimen
.

OS was significantly improved with toripalimab compared with placebo, with median OS of 17.
0 vs.
11.
0 months, and 1-year OS rates of 66.
0% vs.
43.
7%, respectively
.

Toripalimab also showed a significant improvement in PFS compared to placebo
.

Immunotherapy CheckMate-577 for locally advanced esophageal cancer is a phase III trial evaluating nivolumab as adjuvant therapy for neoadjuvant concurrent chemoradiotherapy (CRT) followed by surgery in patients who did not achieve pCR after surgery Efficacy and safety in patients with locally advanced EC/GEJC
.

A total of 794 patients were enrolled and randomly assigned 2:1 to receive nivolumab or placebo for a total treatment duration of 1 year
.

PD-L1 positivity (TPS ≥ 1%) was detected in 89 (17%) patients receiving nivolumab and 40 (15%) patients receiving placebo
.

The analysis showed that 57% of patients in the nivolumab group and 54% of patients in the placebo group had a baseline PD-L1 CPS ≥5
.

The first analysis found that adjuvant nivolumab doubled the median disease-free survival (DFS) of patients to 22.
4 months and reduced the risk of disease recurrence or death by 31% with a minimum follow-up of 6.
2 months (control group).
11.
0 months, HR=0.
69, P=0.
0003)
.

The HR for disease recurrence or death was more favorable in EC patients compared with GEJC, although nivolumab was superior to the original HR (0.
87) with longer follow-up
.

Based on the results of this study, nivolumab was approved in the United States in May 2021, becoming the world's first adjuvant immunotherapy for EC
.

Trials such as EORTC VESTIGE and KEYNOTE-585 are ongoing to evaluate the role of checkpoint inhibitors in locally advanced gastroesophageal cancer, and the results of these trials are awaited
.

SUMMARY In recent years, immunotherapy, especially ICI combination therapy, has changed the treatment paradigm for many cancers
.

In EC and GC we also see the impact of ICI, which has become the standard of care to a certain extent
.

In immunotherapy, identifying biomarkers that predict response is an important challenge, and the selection of immunotherapy regimens and the screening of patients most likely to benefit will be future research directions
.

References: 1.
Weadick CS, Duffy AG, Kelly R J.
Recent advances in immune-based approaches for the treatment of esophagogastric cancer[J].
Expert opinion on emerging drugs, 2021