The 2022 ESMO Roundtable sent Professor Lu Shun to lead a team of experts to talk about immunity

The European Society for Medical Oncology (ESMO) Congress is a prestigious and influential oncology conference in Europe, and the ESMO Congress 2022 has successively announced many innovative therapies
in the field of lung cancer.
Among them, Professor Lu Shun's team from the Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine was awarded the ESMO oral report and issued a strong voice
in China.

On this occasion, Yimaitong specially invited Professor Lu Shun as the chair of the roundtable party, and joined hands with Professor Wang Ziping of Peking University Cancer Hospital, Professor Wu Lin of Hunan Cancer Hospital and Professor Zhou Chengzhi of the First Affiliated Hospital of Guangzhou Medical University to form an expert group to discuss the highlights of this year's ESMO Conference, share their insights on the diagnosis and treatment of lung cancer, and talk freely about the enlightenment and thinking
brought by the progress of research.

Pinnacle discussion, exploring the unsolved mysteries of immunotherapy

The emergence of immune checkpoint inhibitors (ICIs) has reshaped the treatment landscape of non-small cell lung cancer (NSCLC), and the long-lasting nature of response has brought significant efficacy advantages to patients
.
However, apart from disease progression, intolerability, or death, there is no uniform standard for the upper limit of ICI use, and the optimal treatment time for ICI remains an open question
.

Topic: The long-lasting nature of immunotherapy response brings significant efficacy advantages to patients, but there is currently no uniform standard
for the duration of immunotherapy.
This conference gradually disclosed the long-term follow-up data of the Poseidon study and Keynote189/407 study, please talk about your views on the optimal treatment duration of immunotherapy, and what treatment indicators do you use to judge the treatment duration at the clinical meeting?

Prof.
Wu Lin: The 4-year follow-up results of Poseidon's study demonstrate the long-term survival advantages
of immunotherapy.
Duvalumab (D) + tremelimumab (T) + chemotherapy confers OS benefit (HR 0.
75) compared with chemotherapy (CT), with an estimated 3-year overall survival (OS) rate of 25.
0% compared with 13.
6%
in the CT group.
In particular, the OS benefit of D+T+CT regimens is more pronounced in patients with refractory lung cancer with STK11 mutations, KEAP1 mutations, or KRAS mutations1.

The Keynote189 study showed impressive 5-year OS rates of 19.
4% and 11.
3% in the pembrolizumab and placebo groups, respectively, and 71.
9% in patients who completed 35 cycles of pembrolizumab treatment, demonstrating a significant demonstration of long-term benefits of immunotherapy2
.
The Keynote407 study showed durable remission in patients who completed 35 cycles of pembrolizumab with a 3-year (approximately 5 years of randomization) OS rate of 69.
5%3
.

There is no clinical consensus
on the optimal duration of immunotherapy.
Based on the current clinical study design, the duration of 35 cycles or 2 years of first-line immunotherapy is a "threshold"
.
In real-world studies, even if immunotherapy is resistant, prolonging the duration of immunotherapy can still confer OS benefit
to patients.
For late-line immunotherapy, we suggest continuing the drug until the patient progresses
.
In the future, more prospective studies are expected to be carried out to explore potential biomarkers such as circulating tumor DNA (ctDNA), and to guide clinical practice
by detecting minimal residual lesions (MRD) through ctDNA.

Figure 1 Poseidon study 4-year follow-up results

Figure 2 Results of 5-year follow-up of Keynote189 study

Figure 3 Results of 5-year follow-up of Keynote407 study

Professor Lu Shun: The clarion call for immunotherapy has been sounded, but there are still some unsolved mysteries and developments worth looking forward to in immunotherapy for lung cancer
.
At present, the data show that some patients have no tumor progression within 5 years after 2 years of immunotherapy, and whether metastatic lung cancer patients can achieve radical cure through immunotherapy needs to be studied and analyzed
.
In addition, the exploration of immunotherapy-related biomarkers to guide clinical practice still needs to be explored
clinically.

Precise management, find the optimal solution of treatment sequence

First-line treatment of EGFR-TKI provides effective disease control for EGFR mutation-positive patients, but most patients are resistant to drugs
.
The emergence of new treatment modes such as precise targeted therapy and immunotherapy for different drug resistance mechanisms has brought vitality to NSCLC patients with EGFR mutation resistance, and the arrangement of treatment plans has become the focus
of clinical attention.

Topic: For patients with EGFR mutation-resistant non-small cell lung cancer, how should clinical treatment be arranged to optimize treatment?

Professor Zhou Chengzhi: For the drug resistance of EGFR independent pathway, it can be clinically treated
by combining drugs with different targets such as MET, HER2, and HER3.
The fourth-generation EGFR-TKI developed so far can effectively overcome the C797S mutation in the EGFR-dependent drug resistance pathway, and based on the good application prospects of the fourth-generation EGFR-TKI, the use of first-line clinical therapy may achieve better benefits
.
In fact, the drug resistance mechanism of EGFR-TKI is very complex, and there are still some patients in the clinic that have not yet elucidated
.

In recent years, with the application of immunotherapy, some studies have explored the immune microenvironment of EGFR-mutant NSCLC, in order to find opportunities for such patients to receive immunotherapy after targeted therapy resistance
.
Both the ORIENT-31 study and the IMpower150 study showed significant benefits
of immunotherapy combined with antiangiogenic drug therapy and chemotherapy compared to chemotherapy alone.
In addition, the maturity of antibody drug conjugate (ADC) research and development also provides new hope for EGFR-TKI resistant patients, and combination ADC drugs may become a feasible strategy
to overcome drug resistance.
In the future, combination immunotherapy and ADC combination therapy are worthy of clinical analysis
.

Professor Lu Shun: The treatment regimen of immune combined with anti-angiogenic drugs and chemotherapy has important clinical value in patients with EGFR-TKI-resistant NSCLC, but the tolerance of patients and the management of drug toxicity are important issues in clinical practice
.

Born from scratch, the ORIENT-31 was carefully designed

Immunotherapy has developed rapidly in patients with driver-negative NSCLC, but there have been few breakthroughs
in patients with driver-positive NSCLC.
Based on this, the strategy of immune combination therapy after targeted therapy resistance has become a hot research direction, and many clinical innovative studies have been born
.

Topic: The selection of treatment regimen after EGFR targeted therapy after drug resistance is a difficult point that needs to be solved urgently in clinical practice
.
The ORIENT-31 study, published at ESMO this year, is the first prospective study
to show benefit from the combination of chemotherapy + VEGF inhibitor + sindilimab in patients who progress after EGFR-TKI treatment.
ORIENT-31 is groundbreaking research, can you please tell us about the highlights of ORIENT-31's research design?

Prof.
Wu Lin: The ORIENT-31 study is the world's first prospective, randomized, double-blind, phase III.
clinical study to demonstrate the benefits of PD-1 immunosuppressants combined with antiangiogenic drugs and chemotherapy compared with current standard treatments4
.
The main highlights of the study design are as follows:1.
Fit the clinical reality
.
Different from the carboplatin + paclitaxel + bevacizumab regimen selected in the IMpower150 study design, the ORIENT-31 study chose pemetrexed + cisplatin, which is commonly used in Chinese patients in clinical practice, as the control regimen
in the study.
2.
The ORIENT-31 study is a prospective study analysis very different from the retrospective analysis of EGFR and ALK subgroups in the IMpower150 study
.
3.
The statistical design is clever, and the ORIENT-31 study carried out two centralized analyses, while allowing the control group patients to conditionally cross-receive immunotherapy after the disease progression on imaging, which better ensured the benefit
of the control group patients.
4.
The randomized, double-blind design ensured the rigor of the study, and the ORIENT-31 study submitted a satisfactory answer to patients with EGFR-TKI-resistant NSCLC with its advanced design
.

From the perspective of research design, there are still some innovative designs in the future, such as "deplatinization" research, ADC combined with antiangiogenic therapy or immunotherapy, and Biomarker selection of different treatment modalities that deserve further exploration
.

Figure 4 ORIENT-31 study design

Professor Lu Shun: Looking back at the IMpower150 study subgroup data, it only shows that the immunotherapy + antiangiogenic therapy + chemotherapy regimen is superior to the immunotherapy + chemotherapy or antiangiogenic therapy + chemotherapy regimen, and does not answer how immunotherapy and antiangiogenic therapy have made their respective contributions
.
The three sets of design of the ORIENT-31 study meet the requirements of the State Food and Drug Administration for factorial analysis, which is also the current mainstream research design
in the world.

Breaking drug resistance, immune blessing to shape a new pattern of drug resistance treatment

The effective treatment of EGFR-TKI resistance is a common problem around the world, and many explorations are currently in
full swing.
The ORIENT-31 study was the first to come to the forefront with high-level positive results in an era of increasingly heated immune competition, reviving patients with NSCLC who are resistant to EGFR-TKI
.

Topic: What core findings were presented orally by ORIENT-31 at the ESMO meeting? What do you think the findings have for the clinical treatment of targeted resistant lung cancer patients?

Prof.
Wang Ziping: Patients in the ORIENT-31 study were randomly assigned to trial group A (sindilimab + IBI305 + chemotherapy), experimental group B (sindilimab + chemotherapy) and control group C (chemotherapy alone).

The analysis of the interim results released by the ESMO conference showed that the mPFS (95% CI) of experimental group A, experimental group B and control group C were 7.
2 months (6.
6, 9.
3), 5.
5 months (4.
5, 6.
1) and 4.
3 months (4.
1, 5.
3),
respectively.
The PFS benefit of experimental group A versus control group C was consistent
with the first interim analysis.
Compared with control group C, the experimental group B obtained a significant mPFS extension, and the HR was 0.
72 (95% CI: 0.
552, 0.
948, P=0.
0181)4, which reached the preset validity criteria
.

Based on the fact that the proportion of EGFR mutations in the East Asian lung cancer population is much higher than that in the Western population, the clinical needs of EGFR-TKI resistant patients in China are more urgent
.
The ORIENT-31 study confirmed for the first time that PD-1 immunosuppressant combined with antiangiogenic drug therapy and chemotherapy can significantly prolong the PFS of EGFR-TKI-resistant NSCLC patients compared with standard treatment, change the treatment mode of these patients, and provide an important decision-making basis
for clinical practice.

Figure 5 Interim results of the ORIENT-31 study

Prof.
Lu Shun: The ORIENT-31 study demonstrated that the four-drug regimen of sindilimab combined with IBI305 and platinum-containing double-agent chemotherapy has considerable PFS benefit in EGFR-TKI mutant-resistant NSCLC, and is well tolerated in clinical practice, which can better balance the efficacy benefit and toxicity risk
of the drug.

Detection assistance to seize the treatment opportunity of lung cancer patients

With the clinical application of many treatment options for lung cancer, whether the disease progression can be monitored earlier and the plan can be adjusted in time has become the focus
of clinical attention.
At present, the efficacy evaluation of advanced NSCLC often adopts the imaging-based efficacy evaluation criteria for solid tumors (RECIST criteria), and the development of innovative technologies in laboratory medicine also provides new opportunities
for early monitoring of tumor burden.

This year's ESMO Conference has released many outstanding treatment options and data for lung cancer treatment, can you share 1-2 studies that have impressed you? In your opinion, what will be the clinical significance of this research?

Prof.
Wang Ziping: The study that impressed me at this year's ESMO Conference was a phase II study to evaluate the feasibility of monitoring plasma EGFR T790M in patients with treatment-naïve NSCLC and the best strategy for switching from gefitinib to osimertinib – the APPLE study
。 The study was divided into group A (osimertinib, group B (gefitinib treatment until EGFR T790M mutation detected in ct-DNA and/or disease progression assessed according to RECIST 1.
1 criteria and subsequent conversion to osimertinib treatment) and group C (gefitinib treatment to switch to osimertinib treatment after disease progression assessed according to RECIST 1.
1 criteria), and the results showed that the 18-month PFS rate in groups B and C was 67.
2% (84% CI).
56.
4-75.
9%) and 53.
5% (84% CI 42.
3-63.
5%), median PFS were 22.
0 months (95% CI 18.
6-NR) and 20.
2 months (95% CI 14.
6-35.
0), respectively, and 18-month OS rates were 87% and 77%, respectively5
.
APPLE studies have shown that monitoring T790M by ctDNA can identify patients with molecular progression before disease progression, guiding earlier osimertinib switching therapy
.

FIGURE 6 APPLE RESEARCH REPORT

Professor Lu Shun: With the advancement of medicine and the iterative innovation of technology, the diagnosis and treatment of lung cancer has undergone earth-shaking changes
.
Detecting MRD through ctDNA to find drug resistance and adjust the protocol in time is the key to clinical decision-making, and APPLE research has the courage to challenge the RECIST standard, which provides new ideas
for the whole treatment strategy of patients with EGFR mutations.

Combination of dual immunity therapy is in the ascendant

From PD-1 inhibitors to CTLA-4 inhibitors, from "veterans" who have made "great achievements" to fledgling "recruits", in the field of rapid development of lung cancer, various immune checkpoint inhibitors are using data to confirm one point - the program of dual immune combination therapy is becoming the only way for the development of
immunotherapy.

This year's ESMO Conference has released many outstanding treatment options and data for lung cancer treatment, can you share 1-2 studies that have impressed you? In your opinion, what will be the clinical significance of this research?

Prof.
Chengzhi Zhou: The Poseidon study is a study
that I would like to share with you.
Subgroup analysis of the Poseidon study showed that the first-line treatment of NSCLC patients with the D+T+CT regimen was superior to the CT
regimen alone in patients with STK11/KEAP1/KRAS mutant and wild type 。 Among them, the 3-year OS rates of patients with STK11 mutation using D+T+CT protocol and CT regimen were 25.
8% and 4.
5%, respectively.
In the population with KEAP1 mutation, a significant OS benefit was observed between T+D+CT and CT, with an HR of 0.
43 (small sample), and the 3-year OS rate of D+T+CT and CT regimen was 40.
0% and 15.
8%, respectively1
.
This study demonstrates the trend of immunotherapy regimens benefiting OS in patients with poor prognosis and poor response to treatment, especially for patients with refractory lung cancer with STK11, KEAP1 and KRAS mutations, and immunocombination therapy
should be started clinically as early as possible.

Figure 7 Results of Poseidon subgroup analysis

Prof.
Lu Shun: The subgroup analysis of Poseidon study shows that for patients with STK11/KEAP1/KRAS mutation NSCLC with poor prognosis at the molecular level, D+T+CT regimen can bring OS benefits, PD-L1 inhibitors play an important role in D+T+CT treatment regimens, and prospective studies are needed to prove the therapeutic status
of CTLA-4 inhibitors in NSCLC patients in the future.

epilogue

The diagnosis and treatment of lung cancer has entered the era of precision diagnosis and treatment based on molecular typing, and the iterative innovation of targeted drugs and the continuous exploration of immunotherapy have significantly improved the survival benefits and quality of
life of lung cancer patients.
In this roundtable party, four experts took the latest cutting-edge progress of ESMO conference as the core, expressed their views on the hot issues of lung cancer immunotherapy, and talked freely about the current situation and development direction
of lung cancer diagnosis and treatment.
It is expected that more new drugs and clinical evidence will emerge in the future to maximize
the survival benefits of lung cancer patients.

References: 1.
M.
Johnson, et al.
2022 ESMO ABSTRACT LBA59.
2.
M.
C.
Garassino, et al.
2022 ESMO ABSTRACT 973MO.
3.
S.
Novello, et al.
2022 ESMO ABSTRACT 974MO.
4.
S.
Lu, et al.
2022 ESMO ABSTRACT LBA58.
5.
J.
Remon Masip, et al.
2022 ESMO ABSTRACT LBA51.