CSCO's first live broadcast room | upper gastrointestinal system tumors ushered in an immunotherapy feast

On the occasion of the 25th National Clinical Oncology Conference and the 2022 CSCO Academic Annual Conference, the Chinese Society of Clinical Oncology and Yimaitong jointly launched the "CSCO First Live Room - Food Power in Wo, Protect the Stomach" interview column
。 Professor Yuan Xianglin of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology was invited as the interview moderator, and Professor Liu Ming of West China Hospital of Sichuan University, Professor Li Yuanfang of Sun Yat-sen University Cancer Prevention and Treatment Center, Professor Peng Jianjun of the First Affiliated Hospital of Sun Yat-sen University and Professor Peng Zhi of Peking University Cancer Hospital were invited to discuss the latest research progress of digestive system tumors and hot topics
in clinical practice.

Upper digestive system tumors have opened the era of "three complete" immunotherapy with all positions, all types, and all disease courses

As the first approved PD-1 immunotherapy drug in China, nivolumab continues to explore and improve in the field of upper digestive system tumors, and CheckMate-649, CheckMate-577, CheckMate-648 research has successively obtained positive results, leading China's upper digestive system tumor immunotherapy into all positions, all types and all disease course The era
of "three perfections".

1.
Please talk about the latest research progress and breakthrough in immunotherapy for tumors in the upper digestive system?

Professor Li Yuanfang: Immunotherapy has made many explorations in the field of gastric cancer, and new breakthroughs
have been made from third-line to first-line, and from advanced to perioperative treatment.
Based on the CheckMate-649 study, which marked the successful conquest of immunotherapy in the first-line treatment of advanced gastric cancer, nivolumab became the first PD-1 inhibitor
approved for the first-line population-wide indication of gastric cancer in China.
Encouragingly, the 2022 ESMO GI released additional two-year follow-up data for the China subgroup of CheckMate-649¹, continuing the five-star
benefit advantage of nivolumab plus chemotherapy in the PD-L1 CPS≥5 population and all randomized populations.

Figure 1: OS, PFS, ORR, and duration of response (DOR) in PD-L1 CPS≥5 and all randomized populations in nivolumab plus chemotherapy versus chemotherapy

Immunotherapy is also gaining momentum in the field of esophageal cancer, and a number of advanced first-line phase III clinical studies have been published, consolidating the position
of immunotherapy combined with chemotherapy in the first-line treatment of esophageal cancer.
The CheckMate-648 study²² continued the excellent performance in CheckMate-649, with nivolumab plus chemotherapy observed to be superior to chemotherapy
in both PD-L1≥1% and the general population.
In the general population, median overall survival (OS) was 13.
2 months versus 10.
7 months, respectively, and the risk of disease progression or death was reduced by 26%; Median progression-free survival (PFS) was 5.
8 versus 5.
6 months, with a 19%
lower risk of disease progression or death.
It has been shown that the benefit of nivolumab in combination with chemotherapy is not limited
by PD-L1 expression.

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

As a surgeon, we are also very concerned about whether immunotherapy that benefits advanced patients can bring survival benefits
to perioperative patients.
CheckMate-577³ is another study
that has changed clinical practice in the field of esophageal cancer.
The results demonstrated for the first time that the benefit of nivolumab monotherapy (DFS) benefit was doubled by adjuvant nivolumab monotherapy in patients with oesophageal and gastroesophageal junction carcinoma who did not achieve complete pathologic remission by neoadjuvant chemoradiotherapy and surgical resection (total population: 22.
4 versus 10.
4 months; HR=0.
69）³
。

Professor Yuan Xianglin: After the advent of immune drugs, breakthrough effects
have been continuously achieved in advanced digestive system tumors.
At the same time, immunotherapy has gradually achieved good results in the perioperative period, so that there are more treatment options
in the clinic.
Immunotherapy represented by nivolumab has pushed upper digestive system tumors to the era
of "three perfections" of all locations, all types and all disease courses.

Walking by light, the field of locally advanced esophageal cancer treatment needs to be broken

At present, surgery is still the main treatment for early and locally advanced esophageal cancer, and neoadjuvant concurrent chemoradiotherapy (nCRT) + surgery can significantly improve the efficacy
compared with surgery alone.
For patients with locally advanced oesophageal cancer, this model has been listed as a first-level recommendation
for class IA evidence in the CSCO guidelines for the diagnosis and treatment of esophageal cancer.
However, this pattern is still inevitable after surgery, and esophageal cancer, especially esophageal squamous cell carcinoma, has lacked effective treatment drugs
to delay postoperative recurrence.

2.
What are the design highlights and data advantages of the CheckMate-577 study?

Professor Peng Jianjun: The CheckMate-577 study³ first clarified the value of immunotherapy in postoperative adjuvant therapy for esophageal cancer, and the adjuvant treatment of nivolumab showed good efficacy, compared with placebo, patients with DFS doubled the benefit (22.
4 months vs 10.
4 months), among which the benefit of esophageal squamous cell carcinoma patients was more obvious (29.
7 months vs 11.
0 months).

Another exploratory endpoint, distant metastasis survival (DMFS), was also impressive (29.
4 versus 16.
6 months).

This endpoint design provides data support
for immunotherapy to reduce the risk of distant recurrence and metastasis.
In addition, compared with chemoradiotherapy, patients receiving adjuvant immunotherapy were more tolerable, no new adverse events were identified, the overall safety was controllable, and the quality of life remained unchanged
from baseline.
Therefore, CheckMate-577 is a study
that guides clinical practice and changes the pattern of postoperative adjuvant therapy for locally advanced esophageal cancer.

Figure 3 Nivolumab vs.
placebo DFS in all populations

Fig.
4 DFS with nivolumab versus placebo in esophageal squamous cell carcinoma

Figure 5 Nivolumab versus placebo for DMFS

Professor Yuan Xianglin: Immunotherapy has been advancing all the way, from single drug to combination, from late stage to early stage, covering more and more threads, and the success of CheckMate-577 has enhanced the confidence
of immunotherapy in the perioperative period.

Cracking the mechanism of drug resistance and the comeback of immunotherapy is unknown

The number of immunotherapy application lines is getting earlier and earlier, and for patients with initial immunotherapy progression, subsequent regimen selection may face the problem
of immune cross-line application.
The research experience on targeted and chemotherapy cross-line is relatively mature, and whether immunotherapy with completely different mechanisms of action is suitable for cross-line use is still being
explored.

3.
What is the application prospect of immune cross-line therapy in advanced gastric cancer?

Professor Peng Zhi: There are no data to support immune cross-line therapy for advanced gastric cancer, but PD-1/PD-L1 has the initial efficacy
in the cross-line use of multitumors.
After tumor progression in the OPLAR⁴ phase II study, patients continued to receive atezolizumab for mOS for 12.
6 months compared to 9.
7 months
in the control group.
In a placebo-controlled, double-blind, randomized phase II study, continued pembrolizumab plus chemotherapy showed no survival benefit
in patients with NSCLC progression following prior treatment with second- or third-line PD-1/PD-L1 inhibitors.
However, there was a trend of benefit in cross-line treatment of PD-1 monoclonal antibody in subgroup patients with high PD-L1 expression and 6 months of prior PD-1/PD-L1 inhibitor therapy achieving partial remission or disease stabilization≥⁵.

More and more basic and clinical studies at home and abroad are elucidating the mechanism of immune resistance, and the cross-line application of advanced gastric cancer immunity needs to design corresponding joint strategies
through different immune resistance mechanisms according to the results of basic research or translational research.
For example, in patients with MSI-H, this combination may make sense
if the CTLA-4 pathway is altered.
In addition, there are now other combination strategies, such as anti-angiogenic combination immunotherapy
.
This has a lot of room for the future, and some patients will also benefit
from immune cross-line therapy.

Professor Yuan Xianglin: The evidence on whether immunotherapy can cross the line is not sufficient, the immune resistance mechanism is complex, and guiding further treatment strategies based on the drug resistance mechanism is the direction of immune cross-line therapy in the future, and more basic and clinical studies are expected to solve this problem
.

Recognising immune-related adverse reactions

With the widespread application of immunotherapy in clinical practice, doctors have accumulated some experience in the management of adverse reactions of immune monotherapy, but because immunotherapy is becoming more and more front-line drugs, combination models are becoming more and more diverse
.
Whether there is a difference
in type and severity of toxicity in immune-related adverse effects versus monotherapy.
Under the combination of immune strategies, immune-related adverse reactions
need to be re-recognized.

4.
What are the common adverse reactions and clinical management of immunotherapy for advanced gastric cancer?

Professor Liu Ming: The emergence of immune checkpoint inhibitors is a lifesaver for many tumor patients, but it is also a double-edged sword, which will produce serious side effects, especially immune hepatitis, pneumonia, myocarditis, etc.
, and can even be life-threatening
in severe cases.
Facing these adverse reactions is by no means prohibitive, as the incidence of serious immune-related adverse reactions (irAEs) is very low
.
With the development of immunotherapy mode to combination mode, we pay more attention to the safety performance
of immune combination therapy.

In the CheckMate-649 study, there was no significant difference in the incidence of any grade of AE compared with chemotherapy with nivolumab, and common immune-related adverse reactions in the combination group mainly included: endocrine adverse reactions, the incidence of any grade was 21%, of which the incidence of grade 3-4 was 0%; Gastrointestinal adverse reactions, the incidence of any grade is 15%, of which the incidence of grade 3-4 is only 1%; Adverse hepatic reactions, the incidence of any grade is 58%, of which the incidence of grade 3-4 is only 4%; Pulmonary adverse reactions, the incidence of any grade is 4%, of which the incidence of grade 3-4 is 0%; Renal adverse reactions, the incidence of any grade is 5%, of which the incidence of grade 3-4 is 0%; Adverse skin reactions, the incidence of any grade is 22%, of which the incidence of grade 3-4 is only 5%.

It is not difficult to find that immunotherapy combined with chemotherapy did not increase the overall incidence of adverse reactions, among which the incidence of gastrointestinal adverse reactions was significantly reduced compared with chemotherapy.
The overall incidence of immune endocrine, liver-related adverse reactions, and skin-related adverse reactions increased slightly compared with chemotherapy, but the incidence of grade 3-4 was lower
.
These adverse effects can often be identified and managed early with standardized follow-up monitoring, and immunologic drugs usually do not require tapering or discontinuation and do not interfere with the patient's overall antitumor treatment plan
.
For some adverse reactions with a risk of death, such as immune pneumonia, myocarditis, hepatitis, etc.
, it is necessary to ensure that high-dose hormone shock therapy
is given at full dose and course of treatment during the optimal window period for adverse reaction treatment.

As a clinician, you should always be aware of adverse drug reactions
.
At present, NCCN guidelines and CSCO guidelines have issued guidelines for the toxicity management of immune checkpoint inhibitors, and once irAEs occur, they can be treated with reference to the guidelines
.
Only by continuously raising awareness, engaging in multidisciplinary discussions, and acquiring skills in diagnosing and managing irAEs can clinical oncologists make immuno-oncology
safer for patients.

Professor Yuan Xianglin: With the expansion of the immunotherapy population, immunotherapy has become a broad-spectrum treatment, and several key points
need to be paid attention to in the management of immune-related adverse reactions.
First of all, pay more attention, strengthen learning, and do a good job in patient education; Secondly, detailed evaluation before treatment, population screening is essential; Finally, standardize monitoring to achieve early detection and early intervention
of adverse reactions.

epilogue

Immunotherapy has brought new opportunities for the treatment of upper gastrointestinal system tumors and changed the treatment pattern
of upper gastrointestinal system tumors.
With the deepening of research, this pattern will be further opened up
in the future.
Although immunotherapy seems to know a lot, in fact, more
is unknown.
For example: Can immunization be applied across lines? How to change the tumor immune microenvironment to maximize the benefit of immunotherapy? How to make immunotherapy more precise and further improve the advantages of immunotherapy need to be explored by basic disciplines and clinical disciplines
.

References:

1.
Lin Shen, Yuxian Bai, Xiaoyan Lin, et al.
First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis 2-year follow-up.
ESMO World Congress on Gastrointestinal Cancer 2022 Abstr P-86.

2.
Doki Yuichiro,Ajani Jaffer A,Kato Ken et al.
Nivolumab Combination Therapy in Advanced Esophageal Squamous-Cell Carcinoma.
[J].
N Engl J Med,2022,386:449-462.

3.
Kelly RJ, Ajani JA, Kuzdzal J, et al.
Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer.
N Engl J Med.
2021; 384(13):1191-1203.

4.
 Fehrenbacher L et al.
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.
Lancet 2016 Mar.

5.
Jung HA, Park S, Choi YL, Lee SH, Ahn JS, Ahn MJ, Sun JM.
Continuation of Pembrolizumab with Additional Chemotherapy after Progression with PD-1/PD-L1 Inhibitor Monotherapy in Patients with Advanced NSCLC: A Randomized, Placebo-Controlled Phase II Study.
Clin Cancer Res.
2022 Jun 1; 28(11):2321-2328.

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