A summary of the series of studies of atezolizumab (T drug) in lung cancer

Lung CancerAtezolizumab (T Drug) Series Research Summary (2021)

Atezumab ( Atezolizumab, Tecentriq) is a humanized monoclonal anti-PD-L1 antibody that inhibits PD-L1-PD-1 and PD-L1-B7-1 signaling and restores tumor-specific T Cellular immunity
.
The series of studies on atezolizumab in non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) have helped us to have a deeper understanding of PD-L1 Antibody—atezumab
.

Summary of the series of studies

Non-small cell lung cancer

Neoadjuvant immunotherapy

1.
LCMC3 study: EGFR/ALK(-), T drug, MPR of 21%

Adjunctive therapy

2.
IMpower010 study: phase III, chemotherapy + T drug vs chemotherapy + BSC, OS has a benefit trend

Late first-line therapy

Immunotherapy alone

3.
BIRCH&FIR: Two phase II studies with outstanding data

4.
IMpower110: immune monotherapy for high expression of PD-L1

Immunity + chemotherapy

5.
IMpower130: Approved for non-squamous cell carcinoma first-line

6.
IMpower132: non-squamous cell carcinoma, change chemotherapy regimen, OS is not statistically significant

7.
IMpower131: First-line failure of squamous cell carcinoma

Immunity + immunity

8.
CITYCYPE STUDY: TIRAGOLUMAB + T DRUG VS T DRUG, ORR 42% VS 23%

Immunity + chemotherapy + antivascular

9.
IMpower150: The "Deluxe" protocol was approved, the only immunization regimen available for patients with mutations

irAE - efficacy

10.
T drug summary analysis: first-line, irAE and OS prolongation occurred in the atezolizumab group (grade 1/2 prolongation was obvious)

Late second-line therapy

11.
POPLAR & OAK: WON THE INDICATIONS IN ONE FELL SWOOP, DOUBLING THE OS RATE IN 4 YEARS

Small cell lung cancer

12.
IFCT-1603: Failure of second-line therapy

13.
IMpower133: Rewriting the history of first-line treatment of ES-SCLC

14.
SKYSCRAPER-02 study: First-line, phase III, atezolizumab + chemotherapy ± Tiragolumab, missed the PFS endpoint TIGIT first taste failure

Non-small cell lung cancer

Neoadjuvant immunotherapy

LCMC3 study

At the 2020 WCLC Congress, researchers presented the results of the Phase II LCMC3 study to evaluate the efficacy and safety
of atezolizumab for neoadjuvant therapy in patients with treatment-naïve stage IB-IIIB resectable non-small cell lung cancer (NSCLC).

The LCMC3 study evaluated the effects of
treatment with Atezolizumab (anti-PD-L1) before surgery for untreated stage IB-IIIB resectable NSCLC.
LCMC3 is divided into two parts: the first group of patients receive Atezolizumab 1200 mg intravenously every 3 weeks for ≤ 2 cycles, followed by surgical resection (40±10 days); The second part is an exploratory study, and patients who benefit clinically in the first part can continue adjuvant therapy with the PD-L1 inhibitor Atezolizumab for ≤ 12 months
.

The primary endpoint was major pathologic remission (MPR, 10% surviving tumor cells at the time ≤of surgery) in patients without EGFR/ALK mutant NSCLC
.
Secondary endpoints included MPR, tumor mutational burden (TMB), and adverse events (AEs)
in patients with different PD-L1 levels.
Biomarker analysis includes multiplex immunofluorescence (mIF) image analysis, whole exome sequencing, RNA sequencing, and multiparameter flow cytometry
.

Study design

Patient baseline characteristics

This report analysed postoperative follow-up data (n=181)
for all enrolled and dosed NSCLC patients.
The baseline characteristics were: mean age 65.
1 years, female 51%, current smoker 19%, non-squamous NSCLC 62%, stage IB 16 cases, stage IIA 20 cases, stage IIB 60 cases, stage IIIA 71 cases, stage IIIB 14 cases
.

The results of the study: 1) In patients without EGFR/ALK mutations undergoing surgery, the MPR rate was 21% (30/144) and the pathologically complete response rate (pCR) was 7% (10/144; 95% CI: 3%-12%)
。 Phase-reduction was achieved in 43% (66/155) of patients receiving atezolizumab neoadjuvant monoclonalab, and pathological stage increased
in 19% (29/155) of patients.

MPR and pCR

Patient downgrade

2) After atezolizumab treatment, 12% (22/181) and 4% (7/159) of patients were found to be unresectable
before and during surgery, respectively.
Most patients (151/159) underwent anatomic resection and 101 patients underwent minimally invasive surgery, of which only 15% (15/101) underwent thoracotomy
.
Only 12% (19/159) of patients had surgery
outside the window period.
Only 3% (5/159) of patients had intraoperative complications
.
Complete resection (R0) was achieved in 92% (145/159)
of patients.

Surgical options and efficacy

TRAE、irAE

3) Safety: treatment-related adverse reactions (TRAEs) and immune-related adverse reactions (irAEs): preoperative and postoperative ≥ grade 3 TRAE were 6% and 14%, respectively; The incidence of grade 3 irAEs ≥ preoperative and postoperative was 2% and 9%.

Postoperative mortality at 30 and 30 to 90 days was 1 in 159 (0.
6%)
.

4) This part of the data is extracted from the abstract published on the official website: a.
MPR is related to PD-L1 status, and the MPR of TPS<1% patients is 16%, and the MPR of TPS≥1% patients is 29% (P=0.
117); The MPR was 14% at 50% TPS < and 37% at 50% TPS ≥ (P=0.
009).

b.
Biomarker analysis: (1) mIF image analysis showed that the treatment increased the ratio of CD3+/CD8+ and GZMB+/CD8+ T cells to CD3+/FOXP3+ cells, suggesting the transition of T cell activation; (2) MPR was not observed in known EGFR/ALK positive patients; (3) The median TMB was 7.
2 mutations/Mb (0.
8-43.
5) (n=53), and patients with high TMB had better pathological responses; (4) STK11/LKB1 and KEAP1 mutations are more common
in non-MPR patients.

Conclusions: 1) the study achieved the primary endpoint and obtained an MPR of 21%, comparable to neoadjuvant cisplatin therapy, with a pCR of 7%; 2) In resectable IB-IIIB stage NSCLC, Atezolizumab neoadjuvant therapy was well tolerated with no new safety signals; 3) After neoadjuvant treatment with Atezolizumab: a.
safe surgical resection and low perioperative morbidity and mortality; b.
rarely performed outside the treatment program window; c.
high rate of complete resection (92%)
.
The study provides additional supporting evidence
for the ongoing Phase III IMpower030 study.

The summary released by the 2020 WCLC, individual data is different from the published PPT

Adjunctive therapy

IMpower010 study

IMpower010 study: A multicenter, open-label, phase III randomized controlled study conducted at 227 sites
in 22 countries and territories 。 A total of 1280 patients with stage IB (tumor ≥4 cm) to stage IIIA NSCLC were enrolled after complete resection, and patients who received adjuvant platinum-based chemotherapy (1 to 4 cycles) were randomized (1:1) to receive adjuvant atezolizumab (1200 mg every 21 days) by block randomization (4 block sizes); 16 cycles or 1 year) or optimal supportive care (observation and regular monitoring for disease recurrence).

The primary endpoint of the study was investigator-assessed DFS and the secondary endpoint was overall survival (OS), and stratified analysis was performed: first a subgroup of patients with stage II-IIIA NSCLC with PD-L1 TC≥1% (SP263) was analyzed, then DFS was assessed for all randomized II-IIIA patients, and then DFS and final OS
were analyzed for all intention-to-treat (ITT) populations (IB-IIIA patients).
Efficacy assessments are based on randomized patients
.
Safety was performed
in assessable populations (patients who received ≥ 1 doses of atezolizumab or ≥ 1 post-baseline safety assessment in the BSC group).

In the first interim analysis of DFS (after a median follow-up of 32.
2 months), atezolizumab significantly prolongs disease-free survival
compared with optimal supportive care.
PD-L1 expression ≥1% of patients with stage II-IIIA: a 34% lower risk of disease progression or death (stratified HR 0.
66) and a higher 3-year disease-free survival rate (60% vs 48%)
.
All patients with stages II-IIIA: 21% lower risk of disease progression or death (stratified HR 0.
79) and higher 3-year disease-free survival (56% versus 49%)
.
The first pre-specified OS midterm analysis and safety analysis was announced at this meeting, with a median follow-up period of 45.
3 months and a data cut-off date of April 18
, 2022.

Study Design & Statistical Methods

Results of the results: The mid-phase analysis of OS showed that 1) in PD-L1≥1% of stage II~IIIA population, the median OS of atezolizumab group and BSC group did not reach (HR: 0.
71, 0.
49-1.
03), and the OS rate at 36 months and 60 months was 82.
1% vs 78.
9%, respectively ，76.
8% vs 67.
5%
。 2) In all randomized populations (phase II~IIIA), the median OS of atezolizumab group and BSC group did not reach (HR: 0.
95, 0.
74-1.
24).

3) In all intention-to-treat (ITT) populations (IB-IIIA patients), the median OS of atezolizumab in the atezolizumab group and the BSC group did not reach (HR: 0.
995, 0.
78-1.
28, P=0.
9661).

4) In addition, in PD-L1≥50% (stage II~IIIA, excluding EGFR/ALK+) population, the median OS of atezolizumab group and BSC group did not reach (HR: 0.
42, 0.
23-0.
78), and the OS rates at 36 months and 60 months were 89.
1% vs 77.
5% and 84.
8% vs 67.
5%,
respectively.

OS：PDL1≥50%

security

Similar to the evaluation results as of January 21, 2021, the incidence of treatment-related AEs in the atezolizumab group was 67.
9%, the incidence of treatment-related grade 3~4 AEs was 10.
7%, and the incidence of treatment-related grade 5 AEs was 0.
8%.

Summary: In the first pre-specified OS phase mid-phase analysis, the benefit trend
of OS could be seen in the atezolizumab group in PD-L1≥1% of stage II~IIIA patients.
However, no trend
of benefit for OS was shown in all randomized and ITT populations.
The security data is similar to before, with no new safety signals
.
Looking forward to the final DFS analysis of the IMpower010 study and subsequent OS analysis
.
（2022WCLC）

Late first-line therapy

Immunotherapy alone

BIRCH & FIR: Two phase II studies

The BILCH study [1] was conducted to examine the efficacy of atezolizumab in all lines of treatment of advanced non-small cell lung cancer and included at least 5% (TC2/3 or IC2/ 3) NSCLC patients without brain metastases, including first-line (cohort 1:n=139), second-line (cohort 2:n=268) and third-line and above (cohort 3:n=252).

The primary endpoints were ORR, secondary endpoint OS, PFS, etc
.
The ORRs for the three cohorts were 24%, 19%, and 19%,
respectively.
The ORRs of patients with high PD-L1 expression (TC3/IC3) were 32%, 25%, and 30%,
respectively.
The median OS for the first and second/third lines was 20.
1 months and 14.
7 months
, respectively.

The FIR study [2] was conducted to observe the clinical activity and safety of atezolizumab in patients with PD-L1-selective NSCLC and included a total of 138 patients with conditions similar to the BIRCH study.

The results showed that the ORR of first-line patients (n=31) was 32%, the ORR of treated patients with anencephaly metastases (n=93) was 21%, and the ORR of patients with treated brain metastases (n=13).
It's 23%.

TC3/IC3 patients have a higher
response rate.

IMpower110 study: immunological monotherapy for PD-L1 high expression

The IMpower110 study [3] was a single-agent atema (1200 mgq3w) versus platinum-based chemotherapy (pemetrexed + carboplatin/cisplatin for squamous cell carcinoma, gemcitabine for squamous cell carcinoma + carboplatin/cisplatin) for PD-L1 Positive metastasis Phase 3 study
of NSCLC.
A total of 572 patients with PD-L1≥1% (using SP142) squamous cell carcinoma and non-squamous cell carcinoma with TC or IC were included, and the primary endpoint of the study was exclusion of EGFR Patients with mutations or ALK translocations, and overall survival in populations selected according to PD-L1
.

Results of the study: In patients with high PD-L1 expression (TC3/IC3), atezolizumab was significantly more effective than chemotherapy, with median OS of 20.
2 months versus 13.
1 months (HR 0.
59, P=0.
01）
。 In patients with high or medium PD-L1 expression, OS did not cross the preset α cut-off (18.
2 months vs 14.
9 months, HR 0.
72, P = 0.
04), therefore, OS in any PD-L1 expression patient No formal inspection
has been performed.
Molecular marker analysis found that patients with a high tumor mutational burden on blood tests (TMB, bTMB≥16) had better PFS and OS, 6.
8 vs 4.
4 months, and 13.
9, respectively vs 8.
5 months
.
In terms of safety, the incidence of grade 3-4 AE was 30.
1% versus 52.
5%.

Overall survival in the atezolizumab and chemotherapy groups

Overall survival in patients with high PD-L1 expression

2020WCLC Announces Latest Results: Data as of February 4, 2020, with a median follow-up of 31.
3 months, in the WT group with high PD-L1 expression , 1) OS: median OS in atezolizumab group vs chemotherapy group was 20.
2 months (n=107) vs 14.
7 months (n=98); The 6-month OS rate was 76.
5% vs.
70.
4%, respectively; The 12-month OS rate was 66.
1% vs.
52.
3% (HR=0.
76; 95%CI:0.
54-1.
09)
。 2) PFS: the median PFS in the tirolizumab group versus chemotherapy group was 8.
2 vs 5.
0 months; The 6-month PFS rate was 60.
3% vs.
38.
3%, respectively; The 12-month PFS rate was 39.
2% vs.
19.
2%, respectively (HR=0.
59; 95%CI：0.
43-0.
81；P=0.
0010)
。 3) ORR/DOR: The confirmed ORR of atezolizumab group was 40.
2%, the chemotherapy group was 28.
6%, and the median DOR of the two groups was 38.
9 months vs.
8.
3 months
.

Safety: The updated safety analysis of the IMpower110 study was consistent with the results of the original analysis, and no new safety signals
of atezolizumab were observed at longer follow-up.
Grade 3 or 4 AEs were present in 33.
9% of patients in the atezolizumab group, compared with 53.
2% in the chemotherapy group, with 14.
3% and 44.
9% of grade 3 and 4 treatment-associated AEs (TRAEs) in both groups
.
The incidence of severe AEs was 31.
8% and 29.
3%, respectively, of which 9.
4% and 15.
6% were treatment-related.
Discontinued patients accounted for 7.
3% and 17.
1%,
respectively.

On May 18, 2020, the US FDA approved atezolizumab monotherapy for EGFR/ALK negative, PD-L1 high expression (TC≥ 50% or 50% based on the IMpower110 study ICs ≥10%) of patients
with metastatic NSCLC.

Remarks: PD-L1 high expression is defined as 50% ≥ PD-L1 expression in tumor cells (TC≥50%) or 10% expression ≥ PD-L1 in tumor-infiltrating immune cells (IC≥10%).

Immunity + chemotherapy

IMpower130 study: approved for non-squamous cell carcinoma first-line

IMpower130 is a multicenter, randomized, open-label phase III clinical study [4] comparing immunotherapy plus chemotherapy (atezolizumab + carboplatin + albumin paclitaxel) with chemotherapy alone (carboplatin + Albumin paclitaxel) efficacy in patients with advanced nonsquamous NSCLC
.
A total of 724 patients were included, including 451 patients in the immunotherapy group and 240 patients
in the chemotherapy group.
The common primary endpoints of the study were investigator-assessed PFS and OS in EGFR/ALK wild-type patients (n=679); Secondary endpoints included investigator-assessed PFS and OS in the intention-to-use population (ITT population
).

Results showed significant improvement in outcomes in the immunotherapy group versus chemotherapy, with a median PFS of 7.
0 months versus 5.
5 months (HR 0.
64) and a median OS of 18.
6 months vs 13.
9 months in both groups Month (HR 0.
79).

In the analysis of ITT population, atezolizumab still brought benefits, with PFS 7.
0 months vs 5.
6 months (HR 0.
65) and OS 18.
1 months vs 13.
9 months (HR 0.
80)
in both groups.
However, in subgroup analysis, there was no improvement in PFS and OS in EGFR/ALK gene changes (n=44), liver metastases, and non-smokers
.
The incidence of grade 3 to 4 AEs was 81 versus 71 percent in both groups, and immune-related AEs were 45 percent, mostly grade 1 to 2, with common AEs including rash, hypothyroidism, and hepatitis
.

<< Swipe to view the next image >>

In December 2019, based on this result, the FDA approved "atezolizumab + carboplatin + albumin paclitaxel" for the first-line treatment of patients with non-squamous cell carcinoma NSCLC without EGFR/ALK changes.

IMpower132: Non-squamous cell carcinoma, change in chemotherapy regimen, OS is not statistically significant

IMpower 132 study [5]: This is a comparison of Atezolizumab in combination with pemetrexeplatin (APP) with pemetrexeplatin (PP group) in late stage nonscale Efficacy
in patients with NSCLC.
The study enrolled 578 patients with EGFR/ALK wild-type treatment-naïve non-squamous NSCLC who were randomized 1:1 to receive Atezolizumab after completing 4-6 cycles of induction therapy Maintenance therapy
with pemetrexed or pemetrexed monotherapy.
The primary endpoints were investigator-assessed PFS and OS
.

<< Swipe to view the next image >>

The results published by WCLC in 2018 showed that PFS in the combination group was better than in the chemotherapy group, with a median PFS of 7.
6 months vs 5.
2 months (HR 0.
60), respectively, while the median OS of the two groups was different Interim analysis did not reach statistical significance, with median OS 18.
1 versus 13.
6 months (HR 0.
81,).
P=0.
0797）
。 The incidence of TRAE in grade 3 to 4 was 54% vs.
39%
in both groups.

The subgroup analysis of PFS, which showed that patients who received 4 cycles of chemotherapy benefited more from combination therapy with Atezolizumab than those who received 6 cycles of chemotherapy, is an interesting phenomenon, which also suggests that the number of cycles of immune combination chemotherapy needs to be explored; In addition, unlike previous studies, non-smokers also benefited more
from atezolizumab combination therapy.
Looking forward to the final study results
.

IMpower131: Squamous cell carcinoma first-line failure

IMpower 131 is a randomized controlled phase III clinical trial [6] that included 1021 patients with stage IV squamous NSCLC who had not previously received first-line chemotherapy (patients with EGFR or ALK gene mutations have received targeted therapy).

Among them, 343 patients received T drug + chemotherapy (carboplatin + albumin paclitaxel), and 340 patients in the control group received chemotherapy alone (carboplatin + albumin paclitaxel).

The dosing cycle is 4 or 6 cycles, and the drug is used until the disease progresses (PD).

<< Swipe to view the next image >>

The results showed that T drug + chemotherapy could significantly improve PFS compared with chemotherapy alone, and the median PFS of the two groups was 6.
3 months vs 5.
6 months (HR0.
71, P= 0.
0001）； Unfortunately, however, OS did not meet expectations, which was 14.
2 months vs 13.
5 months (HR 0.
88, P=0.
16).

However, in the TC3/IC3 group with high PD-L1 expression, the ACnP regimen benefited significantly, with the median PFS being 10.
1 months vs 5.
1 months (HR 0.
41), and the median OS being 10.
1 months, respectively 23.
4 months vs 10.
2 months (HR 0.
48).

SAFETY: THE INCIDENCE OF GRADE 3-4 AEs WAS 68.
0% VS 57.
5% IN BOTH GROUPS, AND THE INCIDENCE OF SEVERE AEs was 47.
9% VS 28.
7%.

。

Immunity + immunity

CITYCYPE study: TIGIT target sensitizing immune + T drugs, doubling the efficacy, but relying on PD-L1 expression

CITYCYPE Study: A Phase II clinical study
to investigate the efficacy and safety of TIGIT monoclonal antibody Tiragolumab + atezolizumab and atezolizumab monotherapy for PD-L1-positive, locally advanced unresectable or metastatic NSCLC.
At the 2020 ASCO Annual Meeting, data were published to initially confirm the effectiveness of
the joint approach.
The 2020 WCLC conference was reported as a marker analysis
.
The value
of PD-L1 (22C3 and SP263 assays), TIGIT and PVR as predictive biomarkers for tira+atezo therapy was analysed exploratorily.
The results of the study are as follows:

(1) The efficacy of the combination regimen in different PD-L1 expression subgroups

1) The data showed that the proportion of patients in each subgroup of PD-L1 was comparable in the two immunohistochemical tests
.

2) The objective response rate (ORR) of 22C3 TPS≥1% of patients and SP263 TC≥1% of patients treated with tiragolumab combined with atezolizumab was better than that of the atezolizumab monotherapy group, and the results were consistent
.
Prolonged progression-free survival (PFS) in the combined group; In people with high PD-L1 expression, the PFS benefit of the combination group was more significant
.

The above results suggest that high PD-L1 expression may be an important predictive marker for the first-line treatment of metastatic NSCLC with tiragolumab in combination with atezolizumab
, whether evaluated by 22C3 or SP263 IHC.

(2) TIGIT and PVR expression were not significantly associated with PFS

On the other hand, in the TIGIT and PVR subgroups, PFS in the high- and low-expression subgroups was generally similar
.
No TIGIT or PVR high expression was found to be associated with
clinical outcomes.
However, given the small sample size analysed, the results
will be further confirmed in subsequent large studies.

PFS of TIGIT and PVP expression subgroups

Immunity + chemotherapy + antivascular

IMpower150: Luxury protocol approved, the only immunization regimen available for patients with mutations

The IMpower150 study is a randomized controlled phase III.
clinical trial exploring atezolizumab plus bevacizumab and carboplatin paclitaxel (ABCP) in the first-line treatment of advanced non-squamous NSCLC, with the main endpoint being progression-free survival in intention-to-treat wild-type (ITT-WT) patients and Teff-high WT patients (PFS), and OS
in ITT-WT populations.

Previous reported data [7, 8] showed that PFS was significantly longer in the ABCP group than in the BCP group in ITT-WT patients, at 8.
3 versus 6.
8 months, respectively (HR 0.
61 ， P<</b110>0.
001 OS 19.
2 vs 14.
7 HR 0.
78 P=0.
02Both the ORR and DoR the BCP ORR: 63.
5% vs.
48.
0%;D oR 9.
0 months vs.
5.
7

The overall survival results of each group in the IMpower150 study were updated at the 2020 AACR Annual Meeting [9], atezolizumab + bevacizumab + carboplatin + paclitaxel (ABCP group).
and atezolizumab + carboplatin + paclitaxel (ACP group) compared with bevacizumab + carboplatin + paclitaxel (BCP group) for first-line treatment of advanced non-squamous non-small cell lung cancer (NSCLC) The final overall survival time (OS) results were performed with subgroup analysis of EGFR-sensitive mutations, liver metastases, and PD-L1 expression status.

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The results showed that the median follow-up was about 40 months, and the OS benefit of the ABCP group compared with the BCP group was consistent with the interim analysis, and the median OS of the two groups was 19.
5, respectively months and 14.
7 months (HR 0.
80, P = 0.
01).

[At present, most immunotherapy-related studies have designed control regimens based on platinum-containing double-agent chemotherapy, in fact, BCP regimens are also the standard first-line treatment for advanced non-squamous NSCLC without driver gene mutations, and can benefit patients more
.
] Therefore, the IMpower150 study chose the BCP regimen as the control group, and the ABCP regimen still significantly improved the OS, suggesting ABCP The regimen is more clinically significant
.
】

The median OS in the ACP group was 4.
3 months longer in the ITT-WT group than in the BCP group, 19.
0 months vs.
14.
7 months (HR 0.
84, P=0.
05).

With longer follow-up, up to 46.
4% of patients in the BCP group received at least one immunotherapy during subsequent treatment, which may have prolonged OS
in the BCP group.

The study was also updated Median OS data
in patients with EGFR-sensitive mutations.
In patients with EGFR-susceptible mutations, median OS was improved by 11.
3 months, 29.
4 months vs.
18.
1 months, HR = 0.
6 (95% CI0.
31~1.
14)
。 The small number of participants and proportion between groups may have affected the statistical performance (26 cases in the ABCP group and 32 cases in the BCP group).

From the survival curves of the ABCP group and the BCP group, it can be clearly seen that the survival curves of the two groups have a clear separation in the early stage of treatment, suggesting a clear trend
of benefit.
In addition, in patients with EGFR-sensitive mutations, no OS benefit
was observed in the ACP group compared with the BCP group.

Subgroup analysis suggests that the IMpower150 study is currently the only randomized prospective phase III.
clinical trial in which immune combination therapy benefits OS in patients with NSCLC with EGFR-sensitive mutation subgroup
。 For late-line therapy that fails EGFR TKI, the combination of atezolizumab in addition to the standard therapy of bevacizumab + chemotherapy will become a new treatment option
.

Several studies in the IMpower series presuppose liver metastasis as a stratification factor
.
In the subgroup of liver metastases studied by IMpower150, OS was extended by 4.
1 months in the ABCP group compared with the BCP group by 13.
2 months and 9.
1 months, respectively (HR = 0.
67, 95% CI).
0.
45~1.
02)
。 From the survival curve, it can be observed that the two OS curves are clearly separated
at the beginning of treatment.
Compared with the BCP group, there was no significant difference in OS (9.
1 months vs 7.
7 months, HR=1.
01, 95%CI 0.
68~1.
51).

In In the ITT-WT population, the expression level of PD-L1 based on IHC detection was stratified and the ABCP group had different degrees of OS improvement
compared with the BCP group regardless of the patient's PD-L1 expression status.
The ABCP regimen in the IMpower150 study, namely atezolizumab plus bevacizumab and paclitaxel carboplatin, is now the standard of care for first-line nonsquamous NSCLC recommended by NCCN guidelines and has been approved for first-line treatment of non-squamous NSCLC in more than ten countries, including the United States What is
the expression status of PD-L1.

Also in patients with TC1/2/3 or IC1/2/3, ACP regimen versus BCP regimen also had a significant clinical benefit, 24.
4 months vs.
16.
0 months (HR = 0.
71, 95% CI0.
55~0.
91); While Patients with TC0/IC0 were treated with either the ACP regimen or the BCP regimen and there was no significant difference
in OS.
Suggesting that for patients with positive PD-L1 expression, atezolizumab plus paclitaxel carboplatin chemotherapy regimen is our new clinical treatment option
.
In patients with negative PD-L1 expression, bevacizumab plus chemotherapy remains the cornerstone of first-line nonsquamous NSCLC.

The IMpower150 study is the first and currently the only phase III study to demonstrate a significant benefit of immunotherapy combined with antiangiogenic agents and chemotherapy regimens in the first-line treatment of metastatic nonsquamous NSCLC with PFS and OS.

Atezolizumab combined with bevacizumab and paclitaxel carboplatin regimens for the first-line treatment of metastatic nonsquamous NSCLC showed varying degrees of improvement in OS regardless of the patient's PD-L1 expression status
.

For The ABCP regimen can also bring persistent OS in patients with EGFR-sensitive mutant NSCLC who have failed EGFR TKI therapy, and NSCLC patients with strong tumor aggressiveness, high tumor burden, or large tumor volume that urgently require disease remission (such as with liver metastases).
Benefit, and safely tolerated ABCP may become a new clinical treatment option for first-line non-squamous NSCLC patients.

In addition, for patients with PD-L1-positive non-squamous NSCLC, first-line atezolizumab combined with paclitaxel carboplatin also provides us with new treatment options
.
For patients with negative PD-L1 expression, bevacizumab plus chemotherapy regimen remains the current standard of care
.

It is currently being carried out in Chinese clusters The IMpower151 study was conducted to explore the efficacy and safety of atezolizumab in combination with bevacizumab and paclitaxel/pemetrexed carboplatin in patients with stage IV nonsquamous NSCLC who did not receive chemotherapy.

In patients aged ≥ 65 years, the safety profile of TIS was similar to that of patients of all ages ≥ 18 years.

T drug summary analysis

Pooled analysis: PD-L1/PD-1 inhibitors altered the treatment
of advanced NSCLC.
There is evidence that the development of irAE when these drugs are used predicts improved
outcomes for cancers such as NSCLC.
Phase III trials of IMpower130, IMpower132 and IMpower150 evaluated atezolizumab + chemotherapy ± bevacizumab as first-line treatment
for NSCLC.
The researchers explored the correlation between irAE and efficacy in these trials.

Study Methods: Each trial enrolled untreated patients
with stage IV non-squamous NSCLC.
Patients were randomly assigned to receive: carboplatin + albumin-binding paclitaxel monotherapy or in combination with atezolizumab in IMpower130; Carboplatin or cisplatin monotherapy or in combination atezolizumab in IMpower132; Atezolizumab (A) + bevacizumab (B) + carboplatin + paclitaxel (CP), ACP, or BCP
in IMpower150.
Aggregated data (data cut-off date: March 15, 2018 [IMpower130]; May 22, 2018 [IMpower132]; September 13, 2019 [IMpower150]), and analyzed
by treatment (containing atezolizumab vs control) and irAE status.
Immortal bias
was controlled using a time-dependent Cox model and marker analysis at 1, 3, 6 and 12 months.
The study protocol dictates that if ≥ grade 3 irAE (Gr) occurs, treatment with atezolizumab should be discontinued/discontinued
.

Results: 2503 patients were included in the analysis (atezolizumab, n=1577; control, n=926).

In both groups, baseline features were roughly balanced
between patients who developed irAE (atezolizumab, n=753; control, n=289) and those who did not develop irAE (atezolizumab, n=824; control, n=637).
Any GrirAE occurred in 48% (atezolizumab) and 32% (control) of patients; Grade 3-5 irAE
occurred in 11% (atezolizumab) and 5% (control).
The most common irAEs (atezolizumab versus control) were rash (28% vs.
18%), hepatitis (laboratory abnormalities; 15% vs.
10%) and hypothyroidism (12% vs.
4%)
.
The median time to first onset of irAE was 1.
7 months (atezolizumab group) vs.
1.
4 months (control group).

According to the time-dependent Cox model, the OS HR (95% CI) between patients with and without irAE was 0.
69 (0.
60, 0.
78) in the atezolizumab group and 0.
82 (0.
68, 0.
99) in the control group; After excluding rash (considered the least specific irAE), OS and HR (95% CI) were 0.
75 (0.
65, 0.
87) and 0.
90 (0.
71, 1.
12),
respectively.

Conclusions: In this exploratory pooled analysis, according to the time-dependent Cox model and landmark analysis, patients with irAE had a longer OS than those without irAE in the atezolizumab-containing and control groups.
After exclusion of rash, this trend persisted in the atezolizumab treatment group.

Boundary analysis showed that patients with grade 1/2 irAEs in the atezolizumab group had the longest OS and those who developed grade ≥ 3 irAEs had the shortest OS, possibly due to
treatment interruption/discontinuation.
（2021ASCO，9002）

Late second-line therapy

POPLAR & OAK: WINNING THE INDICATIONS IN ONE FELL SWOOP

The Phase 2 POPLAR study [10] enrolled a total of 287 patients with advanced NSCLC who had progressed after platinum-based chemotherapy and were randomized to atezolizumab or docetaxel, with the primary endpoint being intention-to-treat ( Intention-to-treat (ITT) and PD-L1-positive population Overall Survival.
OS）
。 In the ITT population, the median OS of the two groups was 12.
6 months vs 9.
7 months (HR = 0.
73, P = 0.
04) and progression-free survival (PFS).
There was no significant difference
from the Objective Response Rate (ORR).

Fifty-seven patients who continued atezolizumab after RECIST progression after atezolizumab treatment still benefited from OS 11.
1 months after progression compared with 8.
3 months with other treatments (n=3).
0）
。 The incidence of grade 3 to 4 adverse events (AEs) in studies was 40% versus 53%, and grade 3- to 4 treatment-related adverse events (TRAEs).
The incidence was 11 versus 39 percent
.

POPLAR is the first clinical study
to apply PD-L1 checkpoint inhibitors to patients with treated NSCLC.
Atezolizumab significantly increased survival in such patients compared to docetaxel, and this increase was associated with PD-L1 expression in tumor tissues, suggesting that patients with high PD-L1 expression received Atezolizumab Benefit more
.
In the safety evaluation, Atezolizumab showed better tolerability and better safety compared with chemotherapy drugs
.

A total of 1225 patients in the Phase 3 OAK study [11] were treated with second-line atezolizumab or docetaxel with a common primary endpoint of OS and PD-L1 positive in the ITT population OS
。 Among ITT population, the median OS was 13.
8 months vs 9.
6 months (HR 0.
73, P=0.
0003).

PFS is similar to ORR
.
Among PD-L1-positive people, the median OS was 15.
7 months vs 10.
3 months (HR 0.
74, P=0.
0102).

Grade 3-4 AEs occurred in 37% versus 54%, and immune-related adverse reactions (irAEs) included pneumonia (1%, grade 3<1%), hepatitis (<1%)<b28>, and colitis (<</b28>1%)
。

Marker analysis showed that the benefit of OAK studies correlated with PD-L1 expression (tumor cells/tumor-infiltrating immune cells [TC/IC]), with the greatest benefit in populations with the highest PD-L1 expression (TC3/ IC3), median OS 20.
5 months vs 8.
9 months; However, in patients with TC0/IC0, atezolizumab is still better than docetaxel, with a median OS of 12.
6 months versus 8.
9 months
.

Further analysis was performed for the efficacy of patients with different histologic types (squamous cell carcinoma vs.
non-squamous cell carcinoma), baseline brain metastases, smoking history, and EGFR mutation status, except for the EGFR mutation subgroup (HR=1.
24 [95% CI 0.
71–2.
18] ), the rest of the subtypes are more likely to start with Atezolizumab benefits from treatment
.

On May 18, 2016, based on the POPLAR and OAK studies, atezolizumab received FDA approval for NSCLC after the progression of platinum-based chemotherapy.

Later, the Chinese Food and Drug Administration (NMPA) also approved this indication for atezolizumab
.

Data presented at the 2020 ESMO meeting showed that the shortest follow-up time for the POPLAR and OAK studies was 53 and 45 months, respectively, and the 4-year survival rate of the POPLAR study: 14.
8% in the atezolizumab group , 8.
1%
in the docetaxa group.

The 4-year survival rate of the OAK study: 15.
5% in the atezolizumab group and 8.
7%
in the docetaxel group.
Long-term OS benefits from atezolizumab were observed in all histologic types and PD-L1 expression subgroups.

Small cell lung cancer

IFCT-1603: Failure of second-line therapy

The IFCT-1603 study [12] is a Phase 2 clinical trial evaluating the efficacy and safety of atezolizumab (1200 mg every 3 weeks) compared with chemotherapy (topotecan or the original regimen) after the first-line EP regimen has progressed.

Seventy-three patients were randomized 2:1 to receive atezolizumab or usual chemotherapy, with a primary endpoint of 6-week ORR
.

The results showed that the 6-week ORR of atezolizumab and chemotherapy group was 2.
3% and 10%, and the PFS was 4.
3 and 1.
4 months, respectively (HR=2.
26, 95% CI: 1.
3– 3.
93, P=0.
004), but there was no difference in OS between the two groups (9.
5 vs.
8.
7 months; HR=0.
84, 95% CI: 0.
45–1.
58, P=0.
6）
。

IMpower133: Rewriting the history of first-line treatment of ES-SCLC

The IMpower133 study [13] was a global phase I/III double-blind, randomized, placebo-controlled trial in which 403 patients with treatment-naïve extensive-stage SCLC were randomly and equally assigned to Atezolizumab+EP regimen for four cycles of induction chemotherapy.
Sequential Atezolizumab maintenance therapy (201 patients) or EP regimen + placebo (202 patients), sequential placebo maintenance therapy and follow-up until disease progression or intolerable adverse effects or no longer clinical benefit
。 The primary endpoint of the study was OS and investigator-assessed PFS
.

Results showed that Atezolizumab significantly increased OS (median OS, 12.
3 months vs.
10.
3 months) at a median follow-up of 13.
9 months , HR=0.
70, 95% CI0.
54~0.
91, P=0.
007), the median PFS of the two groups was 5.
2 months and 4.
3 months, respectively (HR=0.
77, 95%CI 0.
62~0.
96，P=0.
02)
。 In addition, the safety profile of the Atezolizumab combination is consistent with the reported safety profile of monotherapy, with no new findings
.

IMpower133 ended 30 years of progression-free treatment for ES-SCLC and can be called a milestone
in the history of ES-SCLC treatment.

Efficacy and safety of
adradramine + atezolizumab versus docetaxel in patients undergoing ICI and platinum-containing chemotherapy.

ASTRUM-005 study

The ASTRUM-005 study was a randomized, double-blind, international multicenter, phase III clinical study
comparing the efficacy and safety of serplulimab in combination with chemotherapy (carboplatin-etoposide) and placebo plus chemotherapy (carboplatin-etoposide) in patients with ES-SCLC who had not previously received treatment 。 The included patients were randomized to receive intravenous serplulimab infusion or placebo plus chemotherapy every three weeks in a 2:1 ratio until disease progression, death, toxic intolerance, withdrawal of informed consent, or other conditions specified in the protocol
, whichever occurs first.
The primary endpoint of the study was overall survival (OS).

Findings: As of October 22, 2021, a total of 585 eligible patients (serplulimab group, n=389; placebo group, n=196) were enrolled in this study, with a median follow-up of 12.
3 months
.
The median OS was 15.
4 months (95% CI 13.
3-NE) and 10.
9 months (95% CI 10.
0-14.
3) in the serplulimab and placebo groups, respectively, and the risk ratio (HR) was 0.
63 (95% CI 0.
49 to 0.
82; p<0.
001),
respectively.
The 24-month overall survival rates in both groups were 43.
1% and 7.
9%,
respectively.
The median PFS in the serplulimab and placebo groups as assessed by the Independent Imaging Evaluation Committee (IRRC) against RECIST v1.
1 were 5.
7 and 4.
3 months, respectively (HR 0.
48, 95% CI 0.
38 to 0.
59).

Improvement in ORR (80.
2% vs.
70.
4%) and DOR (median DOR, 5.
6 vs.
3.
2 months) as assessed by IRRC according to RECIST v1.
1 was also observed
.

In the two trial arms, 129 (33.
2%) and 54 (27.
6%) patients experienced tertiary or greater treatment-related adverse events (TRAEs)
associated with serplulimab or placebo.
The incidence of immune-related adverse events (irAEs) was higher in the serplulimab group than in the placebo group and similar
to the approved PD-1/PD-L1 monoclonal antibodies.

Summary: The results of the trial showed that serplulimab combined with carboplatin-etoposide could significantly improve OS in first-line ES-SCLC patients, and its safety was consistent
with the previous results.
Serplulimab is expected to become the world's first first-line anti-PD-1 monoclonal antibody product for the treatment of ES-SCLC, providing a new treatment option
for such patients.

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