On the cloud, famous experts said, nivolumab helps the upper gastrointestinal tumor immunotherapy fire "full"

The column "Cloud Discussion - Upper Gastrointestinal Cloud Dialogue Series" is a platform for in-depth communication among oncologists, which focuses on the latest research progress of upper gastrointestinal tumor immunotherapy, focuses on clinical hot topics and practices, and is committed to creating a standardized diagnosis and treatment position
for tumors.
Professor He Yifu of the Department of Oncology, The First Affiliated Hospital of University of Science and Technology of China was invited as the host, Professor Wu Hao of the Department of Oncology of Jiangsu Provincial People's Hospital and Professor Luo Tianhang of the Department of Gastrointestinal Surgery of the First Affiliated Hospital of the Navy Military Medical University were invited as guests, and the experts took a detailed inventory of the progress of immunotherapy for upper gastrointestinal tumors in recent years and shared their insights in clinical treatment
.

In the era of "three perfections", immunotherapy for upper gastrointestinal tumors is colorful

With the success of CheckMate-649, CheckMate-577 and CheckMate-648, nivolumab has added indications for advanced first-line gastric cancer, adjuvant therapy for esophageal cancer and advanced first-line treatment, leading China's upper gastrointestinal tumor immunotherapy to officially enter the "three complete" era
of all locations, all types and all disease course.

1

The latest research progress and breakthrough in upper gastrointestinal tumor immunotherapy

Professor Wu Hao: In the first-line treatment of advanced gastric cancer, ESMO GI 2022 announced the latest results
of the 2-year follow-up of the Chinese subgroup 。 In terms of efficacy, the median overall survival (OS) of nivolumab combined with chemotherapy in PD-L1 CPS≥5 population was extended by six months (15.
5 months vs 9.
6 months), the two-year survival rate reached 39%, the objective response rate (ORR) was nearly 70%, the median progression-free survival (PFS) was nearly doubled (8.
5 months vs 4.
3 months), and the duration of remission (DOR) was nearly doubled (12.
5 versus 6.
9 months).

。 Nivolumab plus chemotherapy also had significant benefits compared with chemotherapy in all randomized (ITT) populations, and no new safety events were identified in the nivolumab ^group1
.
It can be seen that nivolumab has brought comprehensive five-star benefits
to first-line patients with advanced gastric cancer.

Fig.
1 OS, PFS, ORR and DOR in PD-L1 CPS≥5 and ITT populations in nivolumab combined chemotherapy group and chemotherapy group

In the field of esophageal cancer, immunotherapy is also gradually getting better
.
The CheckMate-648 study observed OS prolongation
in both PD-L1≥1% and ITT populations.
In ITT, the OS benefit of nivolumab plus chemotherapy was statistically significant (13.
2 versus 10.
7 months, P=0.
002), indicating that the benefit of nivolumab plus chemotherapy was not limited
by PD-L1 expression.
In PD-L1≥1% of patients, the benefit of OS was more significant in the nivolumab plus chemotherapy group (15.
4 months vs 9.
1 months, HR=0.
54), with an absolute increase of 6.
3 ^months2
.

Fig.
2 OS of nivolumab combined with chemotherapy and chemotherapy in PD-L1≥1% population and total population

Perioperative immunotherapy for upper gastrointestinal tumors started late, and during the postoperative adjuvant therapy phase for esophageal cancer, the CheckMate-577 study confirmed for the first time that nivolumab can double the disease-free survival (DFS) benefit for esophageal cancer and gastroesophageal junction cancer that still have pathological residual (non-pCR) after neoadjuvant chemoradiotherapy and complete surgical resection.
In the general population, the DFS of nivolumab versus placebo was 22.
4 and 11.
0 months, respectively (HR = 0.
69); In adenocarcinoma, DFS was 19.
4 months and 11.
1 months, respectively (HR=0.
75); In squamous cell carcinoma, DFS was 29.
7 months and 11.
0 months (HR = 0.
61), respectively, with better ^benefit3
.
In addition, in the perioperative treatment of gastric cancer, research on various modes such as immunity + chemotherapy and immunization + targeting is also being carried out
.

Figure 3 DFS in the general population in nivolumab and placebo

Fig.
4 DFS in esophageal adenocarcinoma and esophageal squamous cell carcinoma in nivolumab and placebo

Professor Luo Tianhang: Perioperative treatment is a part of special concern for surgeons, at present, chemotherapy has limited improvement in perioperative gastric cancer patients and some patients are intolerant
to chemotherapy.
Therefore, it is expected that nivolumab combined with chemotherapy can achieve the application effect
of 1+1>2 in the perioperative period of gastric cancer in the future.

Professor He Yifu: The success of CheckMate-649, CheckMate-577 and CheckMate-648 proves that nivolumab has truly achieved "three-complete" coverage of all positions (gastric cancer, esophageal cancer, gastroesophageal junction cancer), all types (squamous cell carcinoma, adenocarcinoma), and the whole course of the disease (adjuvant therapy, advanced first-line, and advanced posterior line) in upper digestive tumors.
This is rare in upper digestive tumors with high heterogeneity
.

Multi-point force, nivolumab is the first-line preferred choice for advanced gastric cancer

With the approval of more and more immune checkpoint inhibitors, the choice of different PD-1 monoclonal antibodies has become a clinical problem, especially for drugs
with comparable efficacy and safety.
As an oncologist, it is important
to develop an individualized plan for the patient.

2

Considerations for comprehensively evaluating the clinical benefit of PD-1 monoclonal antibody

Professor Luo Tianhang: The comprehensive benefits of different immune drugs can be considered
from the following four points.
CheckMate-649 is the largest and longest follow-up first-line immunotherapy phase III study for advanced gastric cancer, and the research data has also been updated at international conferences for many times, such as ESMO, AACR, ASCO, ESMO GI, ASCO GI, etc
.
This was followed by superior efficacy, with CheckMate-649 having a risk ratio (HR) of 0.
54 for OS in the Chinese subgroup, the lowest of all published studies, i.
e.
, a 46% reduction in the risk of ^death1
.
Then there is the good safety profile, nivolumab has been approved in 12 tumor types and 20 indications worldwide, and the safety has been continuously verified
in multiple solid tumors.
Finally, reliable product quality, nivolumab has a unique fully human monoclonal antibody design, with lower immunogenicity and higher affinity, its R & D and production after a lot of long-term research and strict management, imported quality for Chinese patients escort
.

Professor He Yifu: There are more and more immune drugs that can be selected clinically, but most of the drugs do not have head-to-head controlled studies, and it is necessary to consider from multiple perspectives in the clinic, scientific interpretation of different studies of different drugs, and the baseline characteristics and follow-up treatment of patients enrolled in different studies are different, and the efficacy
of drugs cannot be measured only by comparing absolute data.

Effective adjuvantant, nivolumab inhibits distant metastasis recurrence after esophageal cancer surgery

In recent years, despite advances in multimodal treatment for resectable esophageal cancer, the high rate of tumor recurrence after radical resection remains a serious problem
.
According to the results of CheckMate-577, adjuvant nivolumab treated with neoadjuvant chemoradiotherapy and surgical resection of esophageal cancer and gastroesophageal junction cancer can significantly improve disease-free survival for 1 ^year3

3

Risk factors, recurrence patterns and effective strategies to delay recurrence after esophageal cancer surgery

Professor Wu Hao: In 2012, the CROSS study was first reported in NEJM, which established the standard treatment status of preoperative concurrent chemoradiotherapy in locally advanced resectable esophageal cancer.
4 In 2021, the 10-year follow-up results of the CROSS study were published again in JCO, further confirming the survival advantages of neoadjuvant chemoradiotherapy
。 Compared with the surgery alone, the 10-year survival rate was 13% higher (38% versus 25%) and the risk of death was reduced by 40%
in the preoperative chemoradiotherapy group.
In the recurrence mode analysis, chemoradiotherapy significantly reduced the local recurrence rate (21 versus 40 percent), but the cumulative distant metastasis rate in the chemoradiotherapy group was still as high as 40%, which was only slightly lower than the 50% in the surgery ^alone5.

According to literature reports, risk factors for recurrence after esophageal cancer include tumor cell differentiation, depth of tumor invasion, presence or absence of lymph node metastasis and number of lymph node metastasis6, postoperative adjuvant therapy is an effective strategy to delay recurrence, in addition to traditional chemoradiotherapy, immunotherapy is also a new option
。 The CheckMate-577 study showed that its exploratory endpoint, distant metastasis-free survival (DMFS), was 28.
3 months and 17.
6 months higher in the nivolumab and placebo groups, respectively, an improvement of 10.
7 months, and a controllable safety ^profile3.

It was based on this study that nivolumab received a double recommendation from NCCN and CSCO ^guidelines7
.

Fig.
5 DMFS in nivolumab and placebo

Prof.
He Yifu: Immunotherapy has brought earth-shaking changes to the field of upper gastrointestinal tumors, not only setting a new standard for advanced treatment, but also gradually emerging in the perioperative period
.
Adjuvant therapy after nivolumab further eliminates the remaining tumor cells in the patient's body, reduces the possibility of tumor recurrence and metastasis, and brings longer survival to patients after esophageal cancer surgery
.