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Professor Zhou Caicun: 2022 important clinical research in the field of lung cancer

 Last Update: 2023-02-02
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NEJM Medical Frontiers invited Professor Zhou Caicun from the Department of Oncology, Shanghai Pulmonary Hospital affiliated to Tongji University, to review important advances in the field of lung cancer in 2022, including perioperative treatment of NSCLC, and targeted therapy and immunotherapy progress
of advanced NSCLC.

NEJM Medical Frontiers is a collaboration between Jiahui Medical Research and Education Group (J-Med) and the New England Journal of Medicine (NEJM
).
For the fifth consecutive year, we have launched a clinical research inventory of all important disease areas, so stay tuned
.

SU Chunxia,ZHOU Caicun*

Department of Oncology, Shanghai Pulmonary Hospital, Tongji University

*Corresponding author

In recent years, new treatment methods for lung cancer have developed rapidly, new drugs represented by immunotherapy drugs and targeted drugs have continued to emerge, and clinical lung cancer treatment concepts and treatment plans have been continuously innovated
.
The author takes stock of the important research progress in the field of lung cancer in 2022 as follows
.

Advances in perioperative NSCLC therapyPerioperative

immunotherapy1.
Impower010 study of adjuvant immunotherapy [1] It is the first phase 3 trial
to demonstrate that adjuvant immunotherapy after platinum-containing chemotherapy significantly improves disease-free survival (DFS) after surgery for early-stage non-small cell lung cancer (NSCLC).
At the 2022 World Congress on Lung Cancer (WCLC), the IMpower010 study updated overall survival (OS) data
.
The results showed that at a median follow-up of 45.
3 months, atezolizumab≥ adjuvant immunotherapy significantly prolonged the OS of PD-L1 tumor cells (TCs), compared with the best supportive therapy≥ 1% of patients with stage II.
~III.
A NSCLC (risk ratio [HR], 0.
71; 95% CI, 0.
49~1.
03), and the improvement of OS was more prominent in PD-L1 TC50% (HR, 0.
42; 95% CI, 0.
23~0.
78).

。 After an additional 13 months of survival follow-up, atezolizumab was generally well tolerated as adjuvant therapy with NSCLC, with no emerging safety signals
.
Atezolizumab has been the standard regimen for postoperative adjuvant immunotherapy with stage II.
~III.
A NSCLC with a ≥1% of PD-L1 TC
.

The PEARLS/KEYNOTE-091 study [2,3] is a global multicenter, randomized, triple-blind phase 3 clinical trial in the population with completely resected phase I.
B~IIIA NSCLC to evaluate the efficacy
of adjuvant therapy with pembrolizumab in patients with early-stage lung cancer 。 Interim results presented at the 2022 European Society for Medical Oncology (ESMO) [4] Annual Meeting showed that adjuvant pembrolizumab significantly extended DFS to 53.
6 months in the general population, compared with 42.
0 months in the placebo group (HR, 0.
76; P = 0.
0014).

In advanced NSCLC, PD-L1 expression was positively correlated
with the benefit of pembrolizumab monotherapy.
However, unexpectedly, pembrolizumab did not confer a significant DFS benefit for 50% of the PD-L1 tumor ratio score (TPS) ≥ in the early NSCLC population in this study (HR, 0.
82; P = 0.
14).

This may be due to the better-than-expected efficacy in the placebo group and the relatively small sample size ≥ 50% of the population with PD-L1 TPS, resulting in no statistically significant difference
between the two groups.
For this population, follow-up longer follow-up and efficacy analyses are needed to determine whether there is a difference
in DFS.

2.
The NADIM II study of neoadjuvant immunotherapy [5] is a multicenter, randomized controlled phase 2 clinical trial in patients with phase III.
NSCLC to evaluate the efficacy of nivolumab + chemotherapy versus chemotherapy for neoadjuvant therapy with resectable NSCLC, Patients received 3 cycles of neoadjuvant carboplatin and paclitaxel combined with nivolumab, followed by adjuvant therapy for half a year
.
The 2022 WCLC reported 24-month progression-free survival (PFS) and OS data
.
The results showed that the 24-month PFS rates in the nivolumab combined chemotherapy group and chemotherapy group were 67.
3% (95% CI, 55.
5~81.
6) and 52.
6% (95% CI, 36.
8~75.
2), respectively (HR, 0.
56; 95% CI, 0.
28~1.
15).

The 24-month OS rates were 85.
3% (95% CI, 75.
7~96.
1) and 64.
8% (95% CI, 47.
4~86.
4) (HR, 0.
37; 95% CI, 0.
14-0.
93).

Overall, the NADIM II study was the first clinical study to demonstrate the OS benefit of neoadjuvant immunotherapy combined with chemotherapy in patients with resectable stage IIIA NSCLC, confirming that nivolumab combined with platinum-based chemotherapy improved the 24-month PFS rate and OS rate in patients, and the side effects were tolerated without affecting the feasibility of
surgery.
This strategy still needs to be better validated
in large phase 3 trials.

Perioperative targeted therapy 1.
Adjuvant targeted therapy ADAURA is a randomized, double-blind Phase 3 clinical trial designed to evaluate I.
B~ Efficacy and safety
of osimertinib adjuvant therapy after complete surgical resection ± adjuvant osimertinib in patients with stage III.
A with EGFR-sensitive mutation NSCLC.
In the first analysis, osimertinib significantly reduced the risk of disease recurrence or death in these patients (DFS HR, 0.
20; P< 0.
001) [6].

At the 2022 ESMO Annual Meeting, the ADAURA study published data on the efficacy and safety of osimertinib adjuvant therapy at longer follow-up and after medication: osimertinib adjuvant targeted therapy showed sustained DFS improvement
compared to data published in the American Society of Clinical Oncology (ASCO) in 2020 。 In the overall population (stage I.
B~III.
A), the median DFS was 65.
8 months in the osimertinib group and 28.
1 months in the placebo group, reducing the risk of disease recurrence or death by 73% (HR, 0.
27), and the DFS benefit
of osimertinib relative to placebo was observed in all preset subgroups.

The EVAN study [7] was a randomized, open-label Phase 2 clinical trial to evaluate the efficacy and safety
of erlotinib versus vinorelbine/cisplatin for adjuvant therapy in patients with R0 resection of EGFR mutation stage III.
A NSCLC 。 The OS results updated in 2022 showed that the 5-year DFS rates in the erlotinib group were 48.
2% and 46.
2%, respectively, in the intention-to-treat (ITT) and protocol-compliant populations (5-year DFS rates were not assessable in the chemotherapy group due to disease progression or censoring).

DFS was significantly improved
in both the ITT population (HR, 0.
38) and the PP population (HR, 0.
46) compared with the chemotherapy group.
The median OS of erlotinib and chemotherapy was 84.
2 and 61.
1 months (HR, 0.
318), respectively, and the 5-year OS rates were 84.
8% and 51.
1%, respectively.
OS was significantly prolonged
in both ITT populations (HR, 0.
373) and PP populations (HR, 0.
375).
This study is the first clinical study to report the benefits of OS from EGFR tyrosine kinase inhibitor (EGFR-TKI) adjuvant therapy, and its results are subject to validation in a Phase 3 trial
.

2.
The phase 2 clinical trial of EMERGING-CTONG1103 published in 2019 [8] found that compared with gemcitabine + cisplatin chemotherapy, erlotinib neoadjuvant therapy significantly prolonged PFS, but did not significantly improve OS and objective response rate (ORR).

The NEOS study [9] is a phase 2 single-arm trial designed to evaluate the efficacy and safety
of osimertinib as a neoadjuvant therapy in patients with stage II~III.
B NSCLC with EGFR mutations.
Participants received osimertinib neoadjuvant therapy
for 6 weeks before surgery.
Data updated at the 2022 European Lung Cancer Congress showed that among the 38 patients who completed 6 weeks of neoadjuvant therapy, the ORR was 71.
1% and the disease control rate (DCR) was 100%.

32 patients underwent surgery, and 30 patients achieved R0 resection; The pathologically significant response rate of 28 pathologically evaluable patients was 11%, of which 1 patient (4%) achieved pathologic complete remission and 13 (46%) had a pathologically significant response ≥50
%.
Neoadjuvant therapy with osimertinib was well tolerated, with the most common adverse events consistent with previous reports, including rash (50%), diarrhoea (30%), and mouth ulcers (30%)
.
There were no unexpected adverse events during treatment, which ensured that the patient could undergo surgery in a timely manner
.

These findings suggest that stage III NSCLC may benefit
from neoadjuvant targeted therapy.
At present, a number of neoadjuvant targeting studies are underway, among themThe NeoADAURA study [10] (NCT04351555) is a global multicenter Phase 3 trial designed to evaluate the efficacy and safety
of osimertinib alone or in combination with chemotherapy or chemotherapy alone as neoadjuvant therapy in patients with resectable stage II~III.
B NSCLC with EGFR mutations.
We still need to further explore the best regimen
of neoadjuvant targeted therapy, including duration.

Advances in advanced NSCLC targeted therapy

EGFR1.
The EGFR Point Mutation FURLONG Study is a multicenter, phase 3 randomized controlled trial comparing the efficacy and safety
of vometinib and gefitinib first-line treatment in patients with locally advanced or metastatic NSCLC with EGFR-sensitive mutations 。 The results presented at the 2022 European Congress on Lung Cancer showed that the PFS assessed by the Independent Review Committee (IRC) in the vometinib treatment group was 20.
8 months, a significant improvement compared with 11.
1 months in the gefitinib group (HR, 0.
44; 95% CI, 0.
34~0.
58; P<0.
0001).

。 2022 ASCO published the results of the baseline population with central nervous system (CNS) metastases in the FURLONG study [12], with median PFS in the vometinib and gefitinib groups for 20.
8 and 9.
8 months, respectively (HR, 0.
40; 95% CI, 0.
23~0.
71; P=0.
0011), and vometinib reduced the risk
of CNS disease progression or death by 60%.
The excellent results of the FURLONG study bring a high level of evidence-based medical evidence
for the first-line treatment of EGFR-sensitive mutations Chinese groups of advanced NSCLC with EGFR-sensitive mutations.

In preclinical models, EGFR/HER2 dual blockade has been shown to reverse osimertinib resistance
.
2022 WCLC announces a single-arm, multicenter, open-label Phase 1b/2 trial [13].

This study aims to determine the recommended Phase 2 dose, safety, tolerability, and preliminary efficacy of osimertinib, cestatumab, and trastuzumab combinations in patients with EGFR-mutant metastatic NSCLC who have progressed after treatment with osimertinib.

The results showed that the safety of the combination regimen was controllable, and the proportion of assessable participants with partial disease remission or stabilization was 62.
5% (5/8).

One participant with the EGFR p.
L861Q mutation achieved a partial response (tumor shrinkage 56% for 5.
5 months), and tumor shrinkage was observed in both participants treated at the highest dose level (27% tumor reduction in participants with EGFR 19 exon deletion and 16% in participants with EGFR p.
L858R mutation).

This combination regimen may be effective in
osimertinib-resistant people.

At present, third-generation EGFR-TKI has become the standard first-line treatment for patients with advanced EGFR-mutant NSCLC, and more and more third-generation EGFR-TKI drugs have entered the market, and the post-drug management scheme for patients receiving third-generation EGFR TKI still needs to be further explored
.

2.
EGFR ex20ins traditional chemotherapy, immunotherapy and existing EGFR-TKI have poor efficacy in patients with EGFR exon 20 insertion mutations (EGFR ex20ins), and it is urgent to find new targeted drugs to improve the survival benefit
of patients.

CLN-081 is a TKI class drug with pyrrolopyrimidine structure as the parent ring, and the biggest difference from other EGFR 20ins targeted drugs is that it has a wide adaptability to EGFR mutations and higher mutation selectivity, and has a larger clinical treatment window
。 The 2022 ASCO Annual Meeting presented the latest data from its Phase 1/2a trial [14], and the results suggested that the ORR of CLN-081 treatment was 38.
4%.

Grade ≥ 3 treatment-related adverse events (TRAEs) included anemia (10%), aspartate aminotransferase elevation (4%), diarrhea (3%), etc.
, and the proportion of treatment discontinuation, dose reduction, and treatment discontinuation due to adverse events was 33%, 14%, and 8%,
respectively.

The results of the study suggest that the pharmacokinetic curve is stable, the difference between the peak and trough values of the drug is small (about 2 times), and the half-life in the human body is about 50 hours, which is conducive to the continuous inhibition of the target by suvortinib in vivotinib in vivo, and at the same time reduce the incidence of
adverse events caused by the high peak concentration of the drug.

The 2022 ESMO and 2022 Chinese Society of Clinical Oncology (CSCO) Annual Meeting presented preliminary results of WU-KONG6, the first Chinese registration study of suvortinib [15].

。 In the general population of patients with EGFR ex20ins mutation advanced NSCLC who had previously received platinum-containing chemotherapy, the ORR was 59.
8% in the suvortinib group, 48.
4% in patients with baseline with brain metastases, and 62% and 50%
in patients with proximal ring (corresponding to amino acids 767 to 772) and distal ring (corresponding to amino acids 773 to 775) insertion mutations, respectively.
Overall, suvortinib monotherapy performed well with ORR
.
In terms of safety, the types of adverse events of suvortinib were similar to those of traditional EGFR-TKI, and were mainly
grade 1~2.
With its excellent efficacy and safety, suvortinib has become the first and only domestic innovative drug
in the field of lung cancer to obtain the "breakthrough therapy designation" in China and the United States.
With the advent of drugs such as suvortinib, mobotinib, and evantuumab, patients with EGFR ex20ins mutations will have more treatment options
.

The METSAVANNAH study [16] is a phase 2 single-arm trial evaluating patients with locally advanced or metastatic NSCLC with EGFR mutations with MET overexpression and/or MET amplification following progression of osimertinib therapy, Efficacy and safety
of sevotinib combined with osimertinib.
The results of the study presented at the 2022 WCLC Annual Meeting showed that in all patients, the ORR was 32% (95% CI, 26~39), the median DoR was 8.
3 months (95% CI, 6.
9~9.
7), and the median PFS was 5.
3 months (95% CI, 4.
2~5.
8).

。 Among patients who met the threshold for high MET abnormal levels, the ORR was 49% (95% CI, 39~59%), the median DoR was 9.
3 months (95% CI, 7.
6~10.
6), and the median PFS was 7.
1 months (95% CI, 5.
3~8.
0).

Consistent with the results of the earlier TATTON study, the results further confirm that MET amplification/overexpression is the mechanism of resistance in the treatment of third-generation EGFR-TKI osimertinib, and that the combination of sevotinib and osimertinib may offer hope
for this resistant population.

Antibody drug conjugates (ADCs) are generally specific monoclonal antibodies and highly killer cytotoxic drugs linked through specific connectors, the purpose of which is to "target" target tumor cells and transport small molecule cytotoxic drugs
more precisely.
It not only has the tumor killing characteristics of small molecule cytotoxic drugs, but also can selectively reduce the side effects of off-target drugs and exert the therapeutic effect of drugs more efficiently [17].

telisotuzumab vedotin (Teliso-V) is a novel ADC targeting the c-MET protein that delivers cytotoxic payloads (microtubule-associated inhibitors) into c-MET overexpressing tumor cells
.
Its phase 1/1b trial (NCT02099058) [18] explored the safety, pharmacokinetics and preliminary efficacy
of Teliso-V plus osimertinib in osimertinib in c-MET overexpression non-squamous NSCLC that failed osimertinib.
Data reported at the 2022 ASCO Annual Meeting showed that Teliso-V in combination with osimertinib was well tolerated and TR occurred during Teliso-V treatmentAE and grade ≥ 3 adverse events were 22 (88%) and 8 (32%)
, respectively.
Peripheral sensory neuropathy, nausea, and peripheral edema are the main toxicities associated with Teliso-V, and the overall safety profile is similar
to that of Teliso-V monotherapy.
Of the 25 enrolled patients, the ORR of 19 patients whose efficacy was evaluable was 58%, showing good efficacy
of combination therapy.

HER-2 trastuzumab-deruxtecan (DS-8201, T-DXd) is a popular HER2-targeting ADC drug, which is a combination of trastuzumab and esartecan derivatives through peptide chains for the treatment of HER2-mutated metastatic, recurrent or unresectable solid tumors
。 Previous DESTINY-Lung01 results show that T-DXd shows strong and robust tumor response in more than half of previously treated patients with HER2-mutant metastatic NSCLC
.
The ORR of T-DXd for late-line treatment of patients with HER2-mutant NSCLC was 55%, median PFS and median OS were 8.
2 and 17.
8 months, respectively, and median DoR was 8.
2 months
.

In March, the DESTINY-Lung02 study was published in the New England Journal of Medicine (NEJM
).
The study aims to evaluate the efficacy and safety
of T-DXd in the treatment of metastatic or unresectable NSCLC with HER2 mutations.
The results of the study showed that T-DXd for HER2-mutant NSCLC had an ORR of 55 percent, a median DoR of 9.
3 months, a median PFS of 8.
2 months, and a median OS of 17.
2 months [19].

(Related reading: "NEJM-ESMO2021: ADC achieves good results in the treatment of HER2-mutated advanced non-small cell lung cancer| Zhou Caicun Review") Based on the positive results of the clinical trial DESTINY-Lung02, the US FDA announced in 2022 that the T-DXd expanded indication for the treatment of previously received a systemic treatment.
Patients
with unresectable or metastatic NSCLC with HER2 mutations.
T-DXd thus became the first drug to be used for HER2-mutant NSCLC [20].

At present, a phase 3 clinical trial DESTINY-Lung04 is being carried out internationally, aiming to explore the efficacy and safety
of T-DXd compared with immunotherapy in first-line therapy.
In addition, the DESTINY-Lung05 registration clinical study in China is trying to repeat the results of DESTINY-Lung01 and 02 in Chinese clusters to support the application of
T-DXd in Chinese clusters.

KRAS KRASmutations can have a mutation rate of up to 25% in the overall NSCLC [21,22].

The emergence of sotorazib (AMG510, sotorasib) has brought the dawn of NSCLC for targeted treatment of KRAS G12C mutations, thus opening the door to
targeted KRAS mutation therapy.
adagrasib (MRTX849) is a novel orally KRAS G12C mutationally highly selective irreversible inhibitor with a longer half-life (23 vs.
5 hours)
than sotolasib.

In June 2022, NEJM [23] published the results of the KRYSTAL-1 study, which evaluated the efficacy and safety of adagrasib in patients with solid tumors with KRAS G12C mutations (Related Reading: NEJM-ASCO: Novel KRAS targeted drugs to alleviate brain metastasis in non-small cell lung cancer
).
For the NSCLC cohort, the results showed that the ORR reached 42.
9%, the DCR was 79.
5%, the median PFS was 6.
5 months (95% CI, 4.
7~8.
4), and the median OS was 12.
6 months (95% CI, 9.
2~19.
2).

In terms of safety, the incidence of grade 3 and above adverse events reached 44.
8%, with gastrointestinal adverse events, abnormal liver and kidney function and fatigue being the most common
.
Considering that many patients with KRAS mutation NSCLC have brain metastases, and preclinical studies have confirmed that adagrasib has a good ability to enter CNS, the researchers retrospectively selected patients with central metastases in the cohort for subgroup analysis, and the results showed that the ORR of intracranial lesions could reach 33.
3%.
In patients with intracranial lesion remission, the median intracranial lesion DoR was up to 11.
2 months; in the entire cohort, the median intracranial lesion PFS was up to 5.
4 months
.

Compared with the results of the Phase 2 trial CodeBreak100, adagrasib and sotolasib monotherapy have similar efficacy in the back-line treatment of advanced inoperable KRAS G12C mutant NSCLC, and both can effectively inhibit tumor growth and benefit patients
。 In terms of adverse events, sotolazeb performed better
.
In the control of intracranial lesions, adagrasib showed a significant outperformance of sotolasib (ORR: 33.
3 versus 13%), suggesting the applicability of adagrasib for patients with CNS metastases [24].

The results of the Phase 1b dose exploration trial CodeBreak100/101 were released at the 2022 WCLC Annual Meeting [25] to explore the efficacy of
sotolacib combined with immunotherapy.
Based on the pre-safety data of targeted combination immunotherapy, low-dose sitolasib induction therapy followed by consolidation therapy was designed to reduce toxic side effects
.
The results showed that as an introduction therapy to immunotherapy, sotolasib showed durable clinical efficacy in patients with NSCLC with KRAS G12C mutation, and its OS with combined immunotherapy reached 15.
7 months
.
However, the hepatotoxicity of combination therapy cannot be ignored, and the incidence of TRAE, which is common in the study, is 59%.

Therefore, whether the combination therapy can ultimately achieve PFS and OS benefits remains to be disclosed
.

The efficacy and safety of ALK in ALK-TKI alactinib in ALK-TKI patients and related studies have been fully verified
by ALEX studies, J-ALEX studies and real-world clinical experience.
The ALESIA trial [26] is a study evaluating the efficacy of aletinib versus crizotinib in patients with ALK-positive advanced NSCLC in Asia, and previous preliminary analysis suggested that aletinib improves PFS in this group of patients, and investigators presented 5-year follow-up data
from the ALESIA trial at the 2022 ESMO Annual Meeting.

The median PFS was 41.
6 months in the aletinib group and 11.
1 months in the crizotinib group, and the difference was statistically significant (HR, 0.
33; 95% CI, 0.
23~0.
49).

For patients with baseline CNS metastases, median PFS was 42.
3 and 9.
2 months in the aletinib and crizotinib groups, respectively, and 41.
6 and 12.
7 months
in the aletinib and crizotinib groups in patients without baseline CNS metastases.
For previously untreated Asian patients with III.
B/IV.
ALK-POSITIVE NSCLC, alectinib still has significant clinical benefit as first-line therapy, consistent with
the results of the global ALEX study.
In addition, alectinib can effectively control the progression of CNS in patients, and the safety profile is generally controllable, supporting alectinib as the standard first-line treatment
for Asian patients.

Envonalkib (TQ-B3139, Env) is a novel small molecule ALK/ROS1/c-Met inhibitor, with CNS permeability
.
Preclinical studies and phase 1 trials have shown that Env is well tolerated and has antitumor activity
in ALK-positive NSCLC patients.
The TQ-B3139-III.
-01 trial [27] was designed to evaluate the efficacy and safety
of Env versus crizotinib in patients with advanced ALK-positive NSCLC who have not received ALK inhibitors 。 The analysis of the primary endpoint reported at the 2022 ESMO Annual Meeting showed that the median PFS assessed by IRC was not reached in the Env group; In the crizotinib group, the median PFS assessed by IRC was 11.
89 months, with a statistically significant difference (HR, 0.
46; 95% CI, 0.
32-0.
66; P<0.
0001
).
Subgroup analysis of PFS by IRC showed that Env was superior to crizotinib
in each subgroup.

Safety analysis showed that the incidence of TRAE in Env group and crizotinib group was 99.
24% and 98.
5%, and the incidence of TRAE in grade ≥ 3 was 51.
91% and 40.
60%,
respectively.
The most common TRAE in the two groups included diarrhea, vomiting, elevated ALT and elevated AST, and the safety profile was generally controllable, and no new safety signals
were found.
For patients with advanced or metastatic NSCLC who are ALK-positive and have not been treated with ALK-TKI, Env can significantly improve PFS and ORR compared with crizotinib, and has outstanding performance in controlling CNS metastasis, and the safety of Env is controllable
.
Data from this study suggest that Env could be used as a new treatment for patients with advanced or metastatic NSCLC who are ALK-positive and not treated with ALK-TKI
.

At present, ALK-TKI is showing a positive trend
of "three generations in the same household" worldwide.
More efficient and low-toxicity next-generation ALK inhibitors and combination therapy models are expected to further improve the survival benefits
of ALK-positive patients.

As tumor treatment gradually enters the era of precision treatment, targeted therapy of NSCLC has always been a hot topic
that has attracted much attention 。 In 2022, targeted therapy for lung cancer has made some progress on the whole, but there are still many problems to be solved, including targeted therapy in the fields of KRAS G12C and EGFR ex20in is still in its infancy, and there is still a lot of room for improvement in targeted drugs; For standard treatment strategies after targeted drug resistance, although there is some evidence-based medical evidence, more data are still needed to support it, and further research
is needed.

Advanced NSCLC immunotherapy progresses
immunotherapy in combination with chemotherapy A growing number of clinical studies suggest that immunotherapy combined with chemotherapy can significantly improve efficacy and survival
in patients with advanced NSCLC.
However, in the real world, more than 40% of patients with NSCLC are poorly tolerated by combination therapy due to poor performance status (Eastern Cooperative Oncology Group (ECOG) performance status score ≥2
) or multiple complications.

The IPSOS study (NCT03191786) [28] was a phase 3 global multicenter randomized controlled trial to evaluate the efficacy, safety, and patient-reported outcomes
of atezolizumab versus monotherapy in patients who are not candidates for first-line platinum-dual therapy 。 The primary endpoint presented at the 2022 ESMO Annual Meeting showed that median OS was significantly better in the atezolizumab group than in the chemotherapy group (10.
3 vs.
9.
2 months; HR，0.
78；P=0.
028）
。 Health-related quality of life functional scores (EORTC QLQ-C30 and OLQ-LC13) remained stable in the atezolizumab group; Compared with chemotherapy, chest pain was significantly improved in the atezolizumab group (HR, 0.
51).

The proportion of patients with grade 3~4 TRAE in the atezolizumab group was lower (16.
3% vs.
33.
3%)
.
IPSOS is the first prospective study to show poor prognosis with atezolizumab first-line therapy and OS in an NSCLC population without EGFR and ALK changes (regardless of histological, PD-L1 status, and ECOG function score), providing data to support first-line use of immunity in this population
.

The KEYNOTE-189/407 study explored the efficacy and safety of pembrolizumab in combination with chemotherapy in patients with treatment-naïve non-squamous cell carcinoma or advanced squamous cell carcinoma NSCLC, and updated data from the five-year follow-up of both studies were presented at
the 2022 ESMO Annual Meeting.
The results of KEYNNOTE-189 (non-squamous cell carcinoma) studies [29] showed that the median OS was 22.
0 and 10.
6 months (HR, 0.
60) and 19.
4% and 11.
3% at 5 years compared with chemotherapy alone, respectively.
The median PFS was 9.
0 and 4.
9 months (HR, 0.
50), respectively, and the adverse event rates of grade 3 and above were 72.
8% and 67.
3%,
respectively.

The results of the KEYNOTE-407 (squamous cell carcinoma) study [30] showed that the median OS of ITT population was 17.
2 months and 11.
6 months (HR, 0.
71), the 5-year OS rate was 18.
4% and 9.
7%, and the adverse event rate of grade 3 and above was 74.
8% and 70.
0%, respectively
。 These data continue to support pembrolizumab plus platinum-containing dual therapy as first-line standard therapy
for patients with advanced NSCLC who are negative for driver mutations.

The Poseidon study [31] is a global multicenter phase 3 trial
exploring the safety and efficacy of duvalumab combination therapy in patients with advanced NSCLC.
The 4-year follow-up results presented at the 2022 ESMO Annual Meeting demonstrate the long-term survival advantages
of immunotherapy.
Duvalumab (D) + tremelimumab (T) + chemotherapy confers OS benefit with patients compared with chemotherapy (HR, 0.
75).

In post-hoc analysis, the confirmed ORR of D+T+ chemotherapy triple therapy was 38.
8% and the median DoR was 9.
5 months (95% CI, 7.
2 to unestimated).

ORRs were 41.
5% and 24.
4% in the D+ chemotherapy and chemotherapy alone groups, respectively, and the median DoR was 7.
0 and 5.
1 months
, respectively.

In the KEAP1 mutation cohort, the ORRs of the D+T+, D+, and chemotherapy alone groups were 45.
5%, 21.
7%, and 33.
3%, respectively, and the median DoR was 16.
4 months, not reached, and 4.
6 months
, respectively.
Among patients with KRAS mutations, the ORRs of patients in the D+T+ chemotherapy, D+ chemotherapy and chemotherapy alone groups were 55.
0%, 43.
3%, and 21.
2%, respectively.
The median DoR was NR, 12.
5 and 5.
4 months
, respectively.
This exploratory analysis demonstrates that the trend towards OS benefit in patients with STK11 mutations, KEAP1 mutations, or KRAS mutations, which typically have a poor prognosis and response to treatment, may be the treatment
option for this refractory subgroup.

The immuno-plus antivascular agent Lung-MAP S1800A was studied in patients with NSCLC who developed acquired resistance to immune checkpoint inhibitors, defined as at least 84 days of prior immune checkpoint inhibitor treatment, Disease progression
during or after treatment.
The aim of this study was to compare ramoximab + pembrolizumab (P+R) versus standard care (SOC) in patients with advanced NSCLC who had previously received immunotherapy
.

The results of the study[32] presented at the 2022 ASCO Annual Meeting showed a significant improvement in OS in the P+R group (14.
5 months vs.
11.
6 months; HR，0.
69；P=0.
05）
。 PFS was not significantly different between groups (4.
5 months vs.
5.
2 months; HR，0.
86）
。 There was also no difference in ORR between groups (22% vs.
28%)
.
The incidence of grade 3 TRAE was 42% in the P+R group ≥ 60%
in the SOC group.
Grade 3~5 immune-related adverse events
occurred in 9 patients (31%) in the P+R group.
Overall, pembrolizumab + ramoximumab improved OS in patients
with advanced NSCLC who had previously received chemotherapy and immunotherapy compared with SOC.
This is the first second-line exploration of treatment on a chemotherapy-free basis, and the combination regimen may have potential survival benefit
compared with existing standard care.

The ORIENT-31 study [33] evaluated patients with advanced non-squamous cell NSCLC who carried EGFR mutations and progressed after initial treatment with EGFR-TKI, and evaluated combination therapy regimens against PD-1 antibody sindilimab, bevacizumab biosimilar (IBI305), Pemetrexed and cisplatin efficacy and safety
in this population.
Results showed significant improvement in PFS for the primary endpoint compared with chemotherapy alone in the sindilimab + IBI305+ chemotherapy group compared with chemotherapy alone at a median follow-up of 9.
8 months (6.
9 vs.
4.
3 months; HR, 0.
46; P <0.
0001), ORR (44% vs.
25%), and median DoR (8.
3 vs.
7.
0 months) also improved<b21> significantly.
The regimen was generally well tolerated with no new safety signals
.

This combination regimen is important
for patients with EGFR-mutant NSCLC.
Immunotherapy has generally been shown to be ineffective in these patients, but appears to achieve greater benefit
when combined with bevacizumab and chemotherapy.
The reason for this may be the immunomodulatory effects of VEGF inhibitors: these drugs reverse vascular endothelial growth factor-mediated immunosuppression, which may enhance the cancer cell killing ability
of immune checkpoint inhibitors mediated by T cells.
This study, along with other studies exploring immunotherapy, will help us improve the optimal treatment regimen
for EGFR-mutant TKI-resistant NSCLC.
"
Immunomodulation ADC At the 2022 WCLC Annual Meeting, preliminary results of the Phase 1b trial of TROPION-Lung02 were announced [34].

The study aimed to assess the efficacy and safety
of Dato-DXd+ pembrolizumab ± platinum-containing chemotherapy (two- or three-drug group).
Dato-DXd is an ADC
targeting Trop2.
It consists of three parts, namely Trop2-targeting human IgG1 monoclonal antibody datopotamab, a cleavable cysteine linker, and a DNA topoisomerase inhibitor DXd
.

The results of the study showed that Dato-DXd in combination with pembrolizumab, regardless of the addition of platinum-containing drugs, showed better efficacy and safety
in patients with advanced or metastatic NSCLC 。 In patients with advanced or metastatic NSCLC and no targetable gene variants, the ORR was 37% (median follow-up 6.
5 months) in patients treated with Dato-DXd + pembrolizumab (two-agent combination) and 41% (median follow-up 4.
4 months)
in patients with Dato-DXd + pembrolizumab + platinum-based chemotherapy (three-drug combination).
In all patients treated with both first- and second-line therapy, DCR was achieved in both two- and three-drug regimens
.

This is the first study
to report Dato-DXd+ pembrolizumab ± platinum-containing chemotherapy for metastatic NSCLC.
Based on the well-tolerated combination regimen and the encouraging antitumor activity shown in first-line therapy, the Phase 3 TROPION-Lung08 trial is
ongoing.
The study will explore the efficacy
of Dato-DXd+ pembrolizumab versus pembrolizumab for first-line treatment of PD-L1 TPS≥50% of patients with metastatic NSCLC.

Bispecific antibodies Bispecific antibodies, including T cell articulating biantibodies and dual antibodies
regulated by dual immune pathways based on anti-PD-1 or PD-L1.
The AK112-202 study [35] presented at the 2022 ASCO Annual Meeting aims to explore the efficacy and safety
of AK112 (ivonescimab, evoximab) monotherapy in the treatment of advanced NSCLC 。 AK112 is a humanized anti-PD-1/VEGF bispecific antibody with IgG1-ScFv structure, which uses immune synergistic anti-angiogenic strategy, acts on PD-1 and VEGF targets at the same time, restores the anti-tumor effect of the immune system with anti-PD-1, and synergistic anti-VEGF blocks the immunosuppressive and angiogenic effects of VEGF, and promotes the infiltration of T cells in tumor tissues, thereby improving the efficacy
.

The results showed that in patients who were treatment-naïve and PD-L1 expression positive (TPS≥1%), the ORR of patients receiving AK112 > 10 mg/kg once every three weeks was 60% and the DCR was 97.
1%.

Patients with high PD-L1 expression (TPS ≥50%) had an ORR of 76.
9% and a DCR of 100%.

It can be seen that AK112 shows good efficacy
in different PD-L1 expression patients.
The safety performance was good, and there were no adverse events
related to VEGF targets such as severe bleeding and perforation.
A Phase 3 clinical trial has been initiated, and bispecific antibodies are expected to provide first-line treatment options
for more NSCLC patients through this study.

Part IV: Summary and outlook

The field of lung cancer has seen many wonderful and important clinical studies
in 2022.
Clinical research on perioperative NSCLC-assisted immunotherapy and neoadjuvant immunotherapy has been initiated
.
In terms of targeted therapy, the research and development of drugs for rare and refractory targets continues to maintain its popularity, and the research and development of antibody drug conjugates is gradually hot, which is expected to open up a new track
for the diagnosis and treatment of lung cancer.
The diagnosis and treatment of rare targets of NSCLC has gradually entered the era
of precision and standardization.
In terms of immunotherapy in patients with advanced NSCLC, the new combination of immunization is expected to further improve the efficacy
.
In the new year, we should make tireless clinical explorations in many areas: screening immunotherapy biomarkers, developing new drugs to break through bottlenecks, pursuing more combination therapies such as dual immunotherapy, immune combined ADC, immune combination personalized vaccine, and establishing treatment methods
after immunotherapy resistance.

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Introduction by experts

Zhou Caicun, Chief Physician, PhD supervisor, second-level professor, Director of Cancer Institute of Tongji University, Director of
Department of Oncology, Shanghai Pulmonary Hospital Affiliated to Tongji University.
Committed to the clinical-translational-applied research
of lung cancer diagnosis and treatment.
At present, he has published more than 400 academic papers, including more than 300 SCI papers including Lancet Oncol, Lancet Res Med, JCO
, etc.
Global Board Member of the International Society for Lung Cancer Research, leader of the expert group of CSCO Primary Lung Cancer Diagnosis and Treatment Guidelines, Chairman of CSCO Non-small Cell Lung Cancer Committee, Chairman-elect of CSCO Translational Medicine Research Committee, National Committee Member of Oncology Branch of Chinese Medical Association, Standing Committee Member
of Oncology Branch of Chinese Medical Doctor Association.
The second prize of National Science and Technology Progress Award in 2019, the first prize of Shanghai Science and Technology Progress Award in 2018, the first prize of Science and Technology Award of China Anti-Cancer Association in 2017, and the first prize of Huaxia Medical Science and Technology Award in 2014
.
Su Chunxia, chief physician, professor, doctoral supervisor
.
Deputy Director of the Department of Oncology and Deputy Director of
the Department of Internal Medicine of Shanghai Pulmonary Hospital affiliated to Tongji University.
He has served as a youth committee member of the Oncology Branch of the Chinese Medical Association, a member of the Executive Committee of the USCACA, a vice chairman of the Patient Education Committee of the Chinese Clinical Cancer Society (CSCO), the deputy secretary-general of the CSCO Transformation Committee, and the vice chairman of the Youth Committee of the Shanghai Anti-Cancer Association
.
He is committed to lung cancer immunotherapy, precision targeted therapy, and drug resistance mechanisms and countermeasures
.
He has presided over 3 projects of the National Natural Science Foundation of China, Shanghai Municipal Science and Technology Commission and Shenkang Three-Year Action Plan
.
He has published 6 monographs and more than 50 SCI papers represented by Lancet Breathing, and many research results have been written into international and domestic guidelines and promoted and applied
.
He has won the honorary titles of Shanghai Excellent Academic Leader, Shanghai Outstanding Young Physician, National Famous Medical Outstanding Style, etc.
, and has been rated as an excellent model expert
in the field of lung cancer of "People's Good Doctor-Golden Camellia Project" for two consecutive years.
He has won the second prize of National Science and Technology Progress Award, the first prize of Shanghai Science and Technology Progress Award, the second prize of Shanghai Science and Technology Popularization Award, and the second prize of Shanghai Science Education Innovation Award
.

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