ASCO first look | Targeting and immune complement each other, enriching early and mid-term NSCLC treatment options

*Only for medical professionals to read for reference.
Focus on ASCO and review the latest developments in NSCLC-assisted and neo-adjuvant treatments.

The 2021 American Society of Clinical Oncology (ASCO) will be held from June 4th to June 8th.
At present, the ASCO official website has published the summary information of a number of studies.

Among them, early and mid-term non-small cell lung cancer (NSCLC) neoadjuvant and adjuvant treatment research progress can be described as many bright spots, attracting attention.
Now the application of targeted and immunotherapy in early and mid-term NSCLC is sorted out as follows for readers.

Targeted therapy: EGFR-TKI neoadjuvant and adjuvant therapy are full of fire.
1 Neoadjuvant therapy: Osimertinib and other TKIs lead breakthroughs.
Osimertinib as a resectable stage II-IIIB EGFR-mutant lung adenocarcinoma Neoadjuvant therapy: RR is as high as 73.
3%, and DCR is as high as 100% (Abstract No.
8524).

NEOS is a prospective, multi-center, single-group study to evaluate the efficacy and safety of osimertinib as a neoadjuvant treatment for resectable EGFRm (19del/L858R) lung adenocarcinoma.

The ASCO reported that the interim analysis results of the study showed that in all 15 patients who completed the efficacy evaluation after the neoadjuvant treatment of osimertinib, the response rate (RR) was 73.
3% (11/15), and the disease control rate (DCR) ) Is 100% (15/15).

93.
3% (14/15) patients underwent R0 resection.

Pathological downgrade occurred in 53.
3% (8/15) of patients.

42.
9% (3/7) of patients diagnosed with N2 lymph nodes fell to stage N0 after receiving neoadjuvant therapy with osimertinib.

The final overall survival analysis of a randomized phase II trial (CTONG1103) of erlotinib compared with gemcitabine + cisplatin as neoadjuvant therapy for IIIA-N2 EGFR-mutant NSCLC: mOS was significantly prolonged (Abstract No.
8502).

The results of the CTONG1103 study published by ASCO showed that the median follow-up time was 62.
5 months.
Based on 47 (65.
3%) events in the overall ITT population, the median overall survival (mOS) was 42.
2 months.

The mOS in the erlotinib (E) group was 42.
2 m, and in the gemcitabine + cisplatin (GC) group was 36.
9 m (HR=0.
83, 95%CI 0.
47-1.
47, P=0.
513).

The 3-year and 5-year OS rates of the E group were 58.
6% and 40.
8%, respectively, and the GC group were 55.
9% and 27.
6% (p3-y=0.
819, p5-y=0.
252).

For all predefined subgroups (including age, gender, EGFR mutation type), there was no significant difference between the two groups.

Follow-up therapy (ST), especially targeted therapy, contributed the most to OS (HR=0.
35, 95%CI 0.
18-0.
70).

The mOS of patients receiving ST was 45.
8m (n=38), other treatments were 34.
6m (n=12), and without ST was 24.
6m (n=15).

The mOS of the E group was 46.
4m (n=15; targeted therapy), 42.
2m (n=8; others) and 24.
6m (n=9; none, P=0.
021), and the mOS of the GC group was 42.
6m ( n=23; targeted therapy), 30.
1m (n=4; others) and 24.
6m (n=6; none, P=0.
130).

The RR of EGFR-TKI re-treatment patients (n=15) in group E was 53.
3%, DCR was 93.
3%, mPFS was 10.
9 m, and mPPS was 21.
9 m.

No new unexpected SAEs were observed during the follow-up period.

2 Adjuvant treatment: the second generation is absent, the third generation of osimertinib is cost-effective, and the first-generation EVAN study ushered in data updates.
Cost evaluation of osimertinib for adjuvant treatment of EGFR-mutant NSCLC: the cost-effectiveness of different disease stages is significantly different.
Stage II patients have the lowest cost associated with outcomes (abstract number: 8525).

 Osimitinib is the first-line treatment of EGFR + advanced NSCLC (stage IB, Ⅱ, and ⅢA), and it also has significant clinical efficacy as a postoperative adjuvant treatment.

This ASCO report assesses the incremental cost-benefit and utility ratios of life years (LY) and quality-adjusted life years (QALY) obtained from adjuvant osimertinib treatment in basic case (BCA) and probability sensitivity analysis (PSA) (ICER/ICUR).

The results show that, with LY as the result, for stage IB, the disease-free survival (DFS) LY increment is 0.
40 (0.
39), the incremental cost is 500,782 US dollars (501,034 US dollars), and ICER/DFSLYG is approximately 1.
3 million US dollars (1.
2 million US dollars).
US dollars).

For Phase II, the incremental DFSLY is 0.
79 (0.
79), the incremental cost is US$503,144 (US$503,092), and ICER/DFSLYG is approximately US$636,913 (US$638,278).

For Phase IIIA, the increment of DFSLY is 0.
18 (0.
07), the incremental cost is US$322,356 (US$293,377), and ICER/DFSLYG is approximately US$1.
2 million (approximately US$1.
2 million).

QALY results in the same incremental cost.

Taking QALY as the result, for the 1B period, the DFSQALY increment is 0.
26 (0.
27), and the ICUR/DFSQALY is approximately $1.
9 million.

For Phase II, the DFSQALY increment is 0.
53 (0.
53), and the ICUR/DFSQALY is approximately US$950,616 (US$952,654).

For the ⅠC period, an increment of 0.
18 (0.
07) DFSQALY resulted in approximately US$1.
8 million (approximately US$3.
7 million) of ICUR/DFSQALY.

ICER and ICUR show that the cost-effectiveness of different disease stages is significantly different.

Phase II showed the lowest cost of outcome correlation.

The incremental benefit of osimertinib in stage IIb is more obvious than that of stage IB and IIIA.

Table 1.
BCA (PSA) results.
Cost-effectiveness modeling of osimertinib for adjuvant treatment of EGFR-mutant NSCLC patients: OS benefit of adjuvant treatment of osimertinib can be increased by 25%-30% compared with placebo.
The cost-benefit ratio (ICER) has been significantly improved (Abstract No.
8527).

 Based on the disease-free survival (DFS) benefit of the ADAURA trial, the indication for osimertinib for adjuvant treatment of EGFR-mutant non-small cell lung cancer (NSCLC) has been approved.

In this ASCO report, a Markov model was constructed using the digital DFS data from the ADAURA trial and the transition of health status after resection to compare the 3-year adjuvant treatment of osimertinib with placebo in patients with stage IB to IIIA NSCLC in the ADAURA trial.
Cost and quality adjusted life year (QALY) within 10 years.

The results showed that the incremental cost-effectiveness ratio (ICER) of adjuvant osimertinib was US$317,119.
90 per QALY.

The initial cost of osimertinib was higher in the first 3 years, but it was lower than the placebo group from the 4th year, and the cost after the 7th year was similar.

In the first 6.
5 years, the placebo group had higher costs due to disease progression (PD).

The average pre-peritoneal dialysis, post-peritoneal dialysis and total costs of the placebo group were US$2,388, US$379,047, and US$502,937, respectively, while the osimertinib group was US$505,775, US$255,638 and US$800,697, respectively.

The sensitivity analysis using incremental overall survival (OS) benefit reached a cost-effectiveness (CE) threshold of $195,000, and the OS benefit of osimertinib was 25%-30% higher than that of placebo.

Compared to the annual cost of osimertinib, the 50% discount resulted in an ICER of US$115,419.

The results suggest that if you are willing to pay an extra US$317,119 per QALY, adjuvant osimertinib for 3 years is more cost-effective than placebo, and most of the costs accumulate as drug costs in the first 3 years.

The OS benefit of adjuvant osimertinib is 25%-30% higher than that of placebo.
The annual cost discount of osimertinib significantly improves ICER.
This strategy is cost-effective.

Table 2.
Model QALY Benefits and Costs Invested in Erlotinib (E) Compared with Vinorelbine + Cisplatin (NP) in a Randomized Phase II EVAN Study of Adjuvant Treatment for Chinese Patients with Stage IIIA EGFR-mutant NSCLC, Overall Survival and Exploration The updated results of the sexual analysis: mOS has been improved, and DFS is affected by co-mutation (abstract number: 8520).

 The Phase III EVAN study has reached its primary endpoint in the past.
The 2-year disease-free survival (DFS) rate of the E group was 81.
4% (95%CI 69.
6-93.
1), and the NP group was 44.
6% (95%CI 26.
9-62.
4) (HR =1.
823; 95%CI 1.
194-2.
784; P=0.
0054).

The ASCO reported the 5-year OS and exploratory results of the EVAN study: the median follow-up time of E was 54.
8 months, and the NP was 63.
9 months.

In the ITT population, E improved OS and 5-year survival rate compared with NP.

The median OS in group E was 84.
2 m (95%CI 78.
1-NE), and in group NP was 61.
1 m (95%CI 39.
6-82.
1) (HR=0.
318; 95%CI 0.
151-0.
670).

The 5-year survival rates were 84.
8% (95% CI 72.
0-97.
6) and 51.
1% (95% CI 34.
7-67.
5).

WES analysis showed that the most common genes that were co-mutated at baseline were TP53, MUC16, FAM104B, KMT5A, and DNAH9, as well as other EGFR mutations.
Regardless of the EGFR activating mutation subgroup, the prevalence of each mutation was similar.

Moreover, in erlotinib-treated patients, the SNP mutation of UBXN11 was associated with significantly worse DFS (P=0.
0111).

 Different exposure times of adjuvant therapy with icotinib in stage II-IIIA NSCLC patients with EGFR-positive mutations: A randomized, open-label Phase II study (ICOMPARE study): Prolonging TKI adjuvant therapy or prolonging DFS (Abstract No.
: 8521 ).

In the ICOMPARE study, patients with stage Ⅱ-ⅢA EGFR mutation-positive NSCLC after R0 resection were randomly assigned to receive adjuvant icotinib therapy for 1 year (group A) or 2 years (group B).

The primary endpoint is disease-free survival (DFS).

The results showed that the median follow-up time was 44.
1 months (95%CI 37.
1-49.
9), 31 out of 55 patients in the 1-year group (56%) and 25 out of 54 patients in the 2-year group (46%).
DFS event.

The median DFS of the 2-year group and the 1-year group were 48.
92 months (95%CI 33.
15-70.
11) and 32.
89 months (95%CI 26.
61-44.
78), respectively.

Two years of treatment with icotinib can significantly prolong DFS (HR=0.
521, 95%CI 0.
278-0.
976; P=0.
039).

OS events were observed in 20 patients, and OS is not yet mature.

32 patients with recurrence or metastasis were given first-line treatment with icotinib, and 66.
7% of the 30 patients with measurable lesions achieved objective remission.

Treatment-related adverse events were recorded in 41 (75%) of 55 patients in the 1-year group and 36 (67%) of 54 patients in the 2-year group, and 4 of 55 patients (7%) in the 1-year group Three (6%) of 54 patients in the two-year and two-year group had grade 3 or 4 treatment-related adverse events, respectively.

No treatment-related deaths or interstitial lung disease have been reported.

 A randomized phase III trial (IMPACT, WJOG6410L) of gefitinib and cisplatin/vinorelbine (cis/vin) for adjuvant treatment of EGFR-mutant stage II-III NSCLC: adjuvant treatment of gefitinib seems It can prevent early recurrence (Abstract No.
8501).

 The results of the IMPACT study published by ASCO showed that 2 patients in the gefitinib group withdrew their informed consent and were excluded from the ITT population.

No treatment-related deaths were observed in the gefitinib group, but 3 treatment-related deaths were reported in the cis/vin group.

The median follow-up time was 71 months.

The median DFS (36 months) in the gefitinib group was numerically longer than that in the cis/vin group (25.
2 months).

However, the Kaplan-Meier curves began to overlap around 5 years after surgery, there was no significant difference in DFS, and the hazard ratio (HR) was 0.
92 (95%CI 0.
67-1.
28; P=0.
63).

There was also no significant difference in overall survival (neither of the two groups reached the median).

The 5-year survival rates of the gefitinib group and the cis/vin group were 78.
0% and 74.
6%, respectively, and the death-related HR was 1.
03; 95% CI 0.
65-1.
65; P = 0.
89.

Exploratory subgroup analysis showed that the survival time of 70-year-old patients in the gefitinib group (G to cis/vin group n=19/27) was longer than that of the cis/vin group (HR=0.
31; 95%CI 0.
10-0.
98; P=0.
046).

  2.
Immunotherapy: PD-1/PD-L1 monoclonal antibody is still the highlight.
1 Neoadjuvant therapy: CheckMate 816 study, NeoTPD01 study show the limelight.
Nivolumab (NIVO) + platinum dual-drug chemotherapy (chemotherapy) comparison The surgical outcome of the Phase III CheckMate 816 study of chemotherapy alone as a neoadjuvant treatment for patients with resectable NSCLC: does not affect the feasibility, timing, and scope or completeness of resection (Abstract No.
: 8503).

 The CheckMate816 study has previously reached the primary endpoint of pathological complete remission (pCR).

The ASCO reported the key surgical outcome of the study: the baseline characteristics of the two groups were similar; 64% of patients (pts) were stage IIIA.

The definitive surgery rates in the NIVO+ chemotherapy group (n=149) and chemotherapy group (n=135) were 83% and 75%, respectively.

The reasons for the cancellation of surgery were disease progression (12 and 17 patients, respectively), AE (2 patients/group), or other conditions (14 and 19 patients, respectively; including patient refusal, unresectable, and poor lung function).

The rates of minimally invasive surgery in the NIVO+ chemotherapy group and chemotherapy group were 30% and 22%, respectively, and the rates of switching from minimally invasive surgery to open surgery were 11% and 16%, respectively.

The proportions of patients undergoing lobectomy in the two groups were 77% and 61%, respectively, and the proportions of patients undergoing pneumonectomy were 17% and 25%, respectively.

Six patients in the NIVO+ chemotherapy group and 9 patients in the chemotherapy group had AEs that caused delays in surgery.

In the two groups, 83% and 78% of patients achieved R0 resection, and the median residual viable tumor (RVT) cells in the primary tumor bed were 10% and 74%, respectively.

The median (Q1, Q3) operation duration and hospital stay of the two groups did not extend [184 (130, 252) vs 217 (150, 283) minutes, respectively; 10.
0 (7, 14) vs 10.
0 (7, 14) day].

The proportions of patients reporting any grade and grade 3-4 surgery-related AEs in the two groups were 41% vs 47% and 11% vs 15%, respectively.

Two and 0 patients in the two groups reported grade 5 surgery-related AEs; 0 and 3 patients died of treatment-related AEs, respectively.

 Phase II trial of teriprizumab combined with chemotherapy as a neoadjuvant treatment for resectable phase III NSCLC (NeoTPD01 study): The major pathological remission (MPR) was as high as 66.
7% (Abstract No.
: 8541).

The NeoTPD01 study aims to explore the activity and safety of teriprizumab combined with chemotherapy as a neoadjuvant therapy for resectable stage III NSCLC in Asian populations.

The results showed that 33 patients (median age: 61 years, IQR: 56-66; female: 6 cases, 18.
2%) were enrolled and received neoadjuvant therapy.

Eighteen patients (54.
5%) had squamous cell lung cancer, and 13 patients (39.
4%) had T3-4N2 stage IIIB disease.

Two cases refused surgery, and one case progressed after treatment.

Thirty patients (91.
9%) underwent resection (median time interval between neoadjuvant therapy and surgery: 36.
5 days, IQR 30-42.
5), except for one patient, all patients achieved R0 resection (29/30 , 96.
7%).

According to the protocol data analysis, 20 patients (20/30, 66.
7%) achieved major pathological remission (MPR), including 15 patients (15/30, 50.
0%) achieved pathological complete remission (pCR).

Surgical complications included 3 cases of arrhythmia, 1 case of persistent air leak, and 1 case of chylothorax.

Twenty-four patients (80.
0%) were pathologically downgraded after treatment, and 70.
0% (21/30) of the patients had complete lymph node clearance (ypN0).

The most common grade 3-4 treatment-related adverse event in the intention-to-treat population was anemia (2, [6.
0%]).

Severe treatment-related adverse events included grade 3 peripheral neuropathy (Guillain-Barré syndrome) in 1 patient (3.
0%), which resulted in the cancellation of surgery.

At the time of the data cutoff (February 7, 2021), the median follow-up time was 4.
13 months, and there were no treatment-related deaths.

2 Adjuvant treatment: The IMpower010 study reached the primary endpoint and became the hot spot of the conference.
After adjuvant chemotherapy, atezolizumab (atezo) and best supportive treatment (BSC) are used for resection of IB-IIIA NSCLC phase III global study IMpower010 Main results: Patients with stage II-IIIA DFS benefited significantly, especially in the subgroup of PD-L1TC≥1% (Abstract No.
8500).

 The results released by ASCO indicate that at the time of the data cut-off (January 21, 2021), the median follow-up time for the intent-to-treat (ITT) population was 32.
2 months.

The baseline characteristics between the two groups were basically balanced.

In the stage II-IIIA population with PD-L1 TC ≥ 1% and all randomized stage II-IIIA populations, atezo showed statistically different DFS benefits compared to BSC; the DFS of the ITT population did not exceed the threshold.

The OS data is immature and has not been formally tested.

The median number of administrations in the atezo group was 16 times (range, 1-16 times).

92.
7% (atezo) and 70.
7% (BSC) of patients had AEs of any grade; 21.
8% and 11.
5% of events were grade 3/4, respectively.

Grade 5 treatment-related AEs occurred in 0.
8% of patients in the atezo group, and 18.
2% of patients experienced AEs that led to the discontinuation of atezo.

Table 3.
Summary of DFS benefit results.
At present, in the field of NSCLC adjuvant and neoadjuvant therapy, both targeted and immunotherapy have performed well.
EGFR-TKI and PD-1/PD-L1 inhibitors represented by osimertinib have been More and more strides towards the field of early and mid-stage lung cancer.

In the future, it can be expected that whether it is early, mid-term or advanced lung cancer, targeted and immunotherapy will show a good trend, escorting more lung cancer patients throughout the process, and bringing hope.

Reviewer Prof.
Meiqing Xu, chief physician of the First Affiliated Hospital of the University of Science and Technology of China, and a postgraduate tutor, Chairman of the Thoracic Surgery Branch of the Anhui Medical Association Chairman of the Lung Cancer Professional Committee of the Anhui Anti-Cancer Association Chairman of the Thoracic and Cardiovascular Surgery Branch of the Chinese Medical Association Thoracoscopy Member of the Scientific Group Member of the Thoracic Surgery Professional Committee of the Chinese Medical Association Anhui Physician Branch Deputy Chairman of the Thoracic and Cardiovascular Surgery Professional Committee of the Anhui Minimally Invasive Medicine Association Member of the Thoracic Surgery Professional Committee of the Chinese Association of Research Hospitals Member of the Mirror Professional Committee Member of the Thoracic Surgery Branch of the China Association for the Promotion of International Healthcare Exchange