Can targeted/immunotherapy become the "key" to the survival of stage III non-small cell lung cancer?

*Only for medical professionals to read and refer to the latest research progress of the speed to punch in! According to statistics from previous studies, about 22% of lung cancer patients are already in stage III when they are diagnosed, and stage III non-small cell lung cancer (NSCLC) is very heterogeneous (T1-T2N2, T3N1-2, T4N0-N3) Most patients have lost the chance of resection
.

Although the treatment goal of clinicians is to cure, it is sad that most patients cannot avoid recurrence, and the low long-term survival rate is a real problem facing all clinicians and patients
.

Neoadjuvant/adjuvant therapy came into being.
Research results show that neoadjuvant chemotherapy can improve the overall survival (OS), recurrence-free survival (RFS) and the time to distant metastasis in patients with stage III NSCLC by about 5% [ 1], adjuvant chemotherapy can improve OS, disease-free survival (DFS), and the absolute survival rate within 5 years by about 5% [2], but creating better survival for patients will not "stop here"
.

At the 2021 World Conference on Lung Cancer (WCLC), Professor Sonam Puri from The Huntsman Cancer Institute at the University of Utah explained in detail the neoadjuvant/adjuvant treatment methods for stage III NSCLC.
The medical oncology channel is hereby compiled for readers
.

Immunotherapy ■ NADIM study NADIM study is an open-label, multi-center, single-arm, phase II clinical study, which included histopathologically or cytopathologically confirmed, untreated, potentially resectable, and non-carrying EGFR Or patients with stage IIIA NSCLC with ALK gene mutation
.

The enrolled patients received nivolumab (fixed dose 360mg) combined with paclitaxel (200mg/m2) and carboplatin (AUC=5)
.

After receiving three cycles of treatment, the surgery is performed within 42-49 days after the last cycle of treatment ends
.

3-8 weeks after receiving surgical treatment, patients receive postoperative maintenance treatment with nivolumab, the upper limit is 1 year
.

The primary endpoint is the 24-month progression-free survival (PFS) rate
.

The results of the study showed that all patients underwent R0 resection, the 12-month PFS rate was 95.
7%, the 18-month PFS rate was 87%, and the 24-month PFS rate was 77.
1%.
From the perspective of safety, the entire group was grade III The incidence of adverse reactions and above is 30% [3]
.

■ SAK16/14 study SAK16/14 study is a phase II clinical trial that included untreated, potentially resectable stage IIIA NSCLC patients.
The enrolled patients received cisplatin 100 mg/m2 + docetaxel 85 mg/m2 After the treatment, he received a fixed dose of 750 mg duvalizumab, and then underwent surgery.
After the operation, he received a one-year adjuvant duvalizumab treatment
.

The results of the study showed that the one-year event-free survival rate (EFS) was 73%, and 88% of patients had grade III and above adverse reactions [4]
.

■ Neoadjuvant treatment plan of atilizumab combined with chemotherapy This open-label, multi-center, single-arm, phase II study included patients ≥18 years of age, stage IB-IIIA resectable NSCLC, and ECOG score of 0-1 Patient
.

The enrolled patients received intravenous atelizumab (1200 mg) and carboplatin (AUC 5; 5 mg/mL/min) on day 1, and albumin-paclitaxel (100 mg) on ​​day 1, 8, and 15 /m2) Neoadjuvant therapy is performed, and every 21 days is a cycle
.

The results of the study showed that 29 patients (97%) underwent surgery, and 26 patients (87%) successfully underwent R0 resection
.

57% (17/30) of patients achieved major pathological remission (MPR), and 33% (10/20) of patients achieved pathological complete remission (pCR) [5]
.

In addition, studies such as CheckMate-816 and IMpower010 have also continuously explored the value of immunotherapy in neoadjuvant/adjuvant therapy
.

At the same time, as researchers continue to explore and recognize the molecular typing of lung cancer, biomarkers such as circulating tumor DNA (ctDNA) have also been used in trials as the criteria for selecting individualized treatments
.

Targeted Therapy ■ ADAURA Study The ADAURA study is an international multi-center, double-blind, randomized controlled phase III clinical study, which aims to evaluate osimertinib as an adjuvant therapy in the IB-IIIB phase (T3N2, AJCC8) EGFR sensitive mutation positive , Efficacy and safety in NSCLC patients undergoing complete resection
.

The results showed that in patients with stage II-IIIB (T3N2, AJCC8), the DFS of the osimertinib group was significantly prolonged compared with the placebo group, and the risk of disease recurrence or death was reduced by 83% (not reached vs.
19.
6 months, HR =0.
17, P＜0.
001)
.

Similar DFS benefits were also found in all populations [IB-IIIB (T3N2, AJCC8)], and the risk of disease recurrence or death was reduced by 80% (not reached vs.
27.
5 months, HR=0.
20, P<0.
001 ) [6]
.

Figure 1.
DFS for patients with stage II-IIIB (T3N2, AJCC8) Figure 2.
DFS for the overall population At present, the US Food and Drug Administration (FDA), the European Union and the China National Medical Products Administration (NMPA) have approved osimertinib As an indication for adjuvant therapy in adult NSCLC patients with EGFR-sensitive mutations after tumor resection, a new standard has been established for adjuvant therapy in EGFR-positive NSCLC patients after complete surgical resection
.

■ NeoADAURA study osimertinib neoadjuvant treatment phase II clinical study included resectable stage I-IIIA EGFR-mutant NSCLC patients
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After receiving 1-2 cycles of osimertinib neoadjuvant therapy, surgical resection was performed
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The results of the study showed that the MPR rate of 13 NSCLC patients with early EGFR mutations was 14%, and the pathological remission rate reached 69%
.

46% of patients had imaging partial remission (PR), and 4 of the 5 patients with positive lymph nodes detected before treatment achieved lymph node downstasis
.

■ CTONG 1103 study CTONG 1103 is a national multicenter randomized controlled study comparing the efficacy and safety of erlotinib and traditional platinum-containing dual drugs as neoadjuvant treatment for stage IIIA-N2 non-small cell lung cancer
.

The study included 72 patients with stage IIIA-N2 who had not received previous treatment, stage N2 confirmed by mediastinoscopy/EBUS/PET-CT, EGFR mutation-positive, ECOG 0-1, ≥18 years old, and EGFR mutation NSCLC patients
.

Patients were randomly divided into groups of 1:1 to receive erlotinib or GC (gemcitabine + cisplatin) treatment
.

The primary endpoint is the objective response rate (ORR), and the secondary endpoints include pathological lymph node downgrade rate, pCR, progression-free survival PFS, 3-year and 5-year OS rates, safety, and tolerability
.

The results of the study showed that in the overall population, erlotinib significantly prolonged the PFS of patients compared with the GC group, and the PFS of erlotinib vs.
GC group was 21.
5 months (95%CI 16.
6-26.
4) vs.
11.
4, respectively.
Month (95%CI 7.
1-15.
7; HR=0.
36; P<0.
001)
.

However, there was no significant difference in OS between the two groups.
The OS of erlotinib vs.
GC group was 42.
2 months (95%CI 29.
8-54.
6) vs.
36.
9 months (95%CI 25.
6-48.
1; HR=0.
83; P=0.
513), and the trial did not reach the primary endpoint ORR[8]
.

Professor Sonam Puri said that these new treatments have paved the way for new treatment strategies for potentially resectable stage III NSCLC patients.
The future treatment model is a combination of traditional radiotherapy and chemotherapy with new immune and targeted drugs, based on tumor gene analysis.
type, PD-L1 expression, mutation further stratified tumor load (TMB) and other biomarkers, individual treatment
.

Future treatment directions include: obtaining rapid perioperative molecular detection of tumor tissue; for pCR or MPR evaluation, the need for standardized pathological evaluation and specimen processing procedures; development and standardization of biomarkers for identifying high-risk patients; optimization of perioperative procedures The duration of treatment of the new therapies in the period; timely identification of treatment-related adverse events of the new therapies in the perioperative period to avoid delays in surgery; new therapies will be obtained after regulatory approval
.

References: [1]Pignon et al.
Lung adjuvant cisplatin evaluation:a pooled analysis by the LACE Collaborative Group.
J Clin Oncol.
2008 Jul 20;26(21):3552-9.
[2]NSCLC Meta analysis Colaborative Group.
The Lancet 2014.
383(9928);P1561-1571[3]Provencio et al.
ASCO 2018 abstract 8521,Provencio et al.
Lancet Oncology 2020[4]Rothschild et al.
ASCO 2020,Rothschild et al JCO 2021[5]Shu et al .
Lancet oncology 2020[6]Yi-Long Wu et al.
Osimertinib as adjuvant therapy in patients(pts) with stage IB–IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection,NEJM 2020.
[7]Zhong W,et al.
JCO 2019*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform