The magazine's cutting-edge Chinese strong voice: Professor Zhou Caicun, Professor Wu Yilong, Professor Wang Jie led the research and won the JTO and JCO

Editor: Xiaoyuan

Medical pulse collation, please do not reprint
without authorization.

I The results of phase II RATIONALE-303, Ib/III "NCT04316364" and phase III CHOICE-01 were published
online on September 29, October 1 and October 7, respectively, in the internationally renowned oncology journals JTO, JTO and JCO.
From the announcement of the international oncology event to the official publication of journals and magazines, the research results have allowed us to witness the demeanor and glory
of Chinese scholars and Chinese drugs again and again.

RATIONALE-303 findings

Brief introduction to the study

The RATIONALE-303 study led by Professor Zhou Caicun of Shanghai Pulmonary Hospital has been presented at several oncology conferences
.
At the 2022 WCLC conference, RATIONALE-303 announced the final analysis results
.
Recently, the results of RATIONALE-303 were published
online in the JTO journal.
The phase III RATIONALE-303 trial explored the efficacy and safety
of tislelizumab versus docetaxel in patients with treated advanced non-small cell lung cancer (NSCLC).


Previous studies have shown that PD-1/PD-L1 monoclonal antibody improves median overall survival (OS) of patients with treated NSCLC by 3 to 4 months
compared with docetaxel.
At present, the median OS of patients with advanced NSCLC is about 9-13 months
.

Tislelizumab is a PD-1-targeting IgG4 monoclonal antibody with a high affinity for the PD-1 receptor and is structurally designed to reduce binding to the Fcɣ receptor and complement 1q (C1q), thereby avoiding possible resistance problems
.
Tislelizumab has shown strong efficacy and controllable safety in
multiple tumor types.
A total of 805 patients aged 18 years and older with locally advanced or metastatic squamous or non-squamous NSCLC were enrolled in the study and randomized to tislelizumab (200 mg) or docetaxel (75 mg/m2) every 3 weeks in a 2:1 ratio
.
The common primary endpoint is ITT and PD-L1 tumor cell (TC) expression ≥ OS
in 25% of the population.

Key results

At the time of pre-specified interim analysis (data cut-off of August 10, 2020), the study met the primary endpoint
of OS in the ITT population.
Compared with docetaxel, tislelizumab significantly improved OS, and the median OS of tislelizumab and docetaxel was 17.
2 and 11.
9 months, respectively (HR=0.
64, P<0.
0001).

。 At the time of final analysis on July 15, 2021, the study reached the primary endpoint of OS in 25% of the population with a PD-L1 TC ≥, and median OS of 19.
3 months and 11.
5 months in the tislelizumab and docetaxel groups, respectively; HR=0.
53; P <0.
0001), in the ITT population, the OS of the tislelizumab group was still significantly improved, and the median OS of the tislelizumab group and docetaxel group was 16.
9 months and 11.
9 months, respectively (HR=0.
66).

OS outcomes in the ITT population and PD-L1 TC ≥ 25% of the population

Results of the OS subgroup analysis in the ITT population

Progression-free survival (PFS) outcomes also improved significantly in the tislelizumab group, with PFS HR of 0.
63 and 0.
37
in the ITT population and PD-L1 ≥ 25% population, respectively.
In the ITT population, the objective response rate (ORR) was 22.
6% and 7.
1% (P<0.
0001)<b13> in the tislelizumab group and docetaxel group, respectively.
The median duration of response (DOR) was 13.
5 months and 6.
0 months
, respectively.
In the PD-L1 ≥ 25% population, the ORRs of the two groups were 37.
4% and 6.
9% (P<0.
0001), respectively, and the median DOR was 11.
9 months and 4.
2 months<b15>, respectively.

OS and PFS results stratified by NOTCH1 mutation

Biomarker analysis found that NOTCH1-4 mutations were associated with improved OS and PFS outcomes in tislelizumab, and no new safety events
were identified.

Discussion and conclusions

The study achieved a common OS double endpoint
between ITT and PD-L1 TC ≥25% of the population.
Regardless of PD-L1 expression, tislelizumab results in significant improvement
in OS in treated patients with advanced NSCLC compared with docetaxel.
The median OS in the tislelizumab group was more than 16 months
.
Compared with historical data (second-line and third-line), tislelizumab had a better survival benefit than docetaxel, with OS extended by 7.
8 and 5.
0 months
in PD-L1 TC ≥25% and ITT populations, respectively.

Adebrelimab was used for resectable perioperative NSCLC with a major pathologic response (MPR) of 51.
4%

Brief introduction to the study

The results of a Phase Ib study led by Professor Wu Yilong of Guangdong Provincial People's Hospital were presented at
this year's ELCC Conference.
Recently, the study was published
online in the journal JTO.

Neoadjuvant/adjuvant therapy is widely used for resectable disease, reducing the risk of recurrence and improving survival
.
Neoadjuvant/adjuvant chemotherapy has been the mainstay of therapy in patients with resectable NSCLC over the past decade, but chemotherapy has resulted in less benefit for resectable patients, with 5-year survival improving by only 4% to 6%.

In the past two years, great breakthroughs
have been made in the use of immunotherapy in neoadjuvant/adjuvant therapy.
The IMpower 010 and CheckMate 816 studies have shown additional benefits
for resectable NSCLC with adjuvant immunotherapy and neoadjuvant immunotherapy.


Adebrelimab (SHR-1316) is a humanized IgG4-type PD-L1 antibody that shows good antitumor activity
in solid tumors.
This phase Ib/III study evaluated the efficacy and safety
of adebrelimab + chemotherapy versus placebo + chemotherapy for the perioperative treatment of resectable NSCLC.
Eligible patients are resectable stage II and III (IIIA and T3N2M0 IIIB) without EGFR/ALK mutation NSCLC
.
Enrolled patients received 3 cycles of SHR-1316 neoadjuvant therapy (intravenous, 20 mg/kg on day 1), albumin-bound paclitaxel (100 mg/m2 on days 1, 8, and 15), and carboplatin (AUC5, 5 mg/ml/min on day 1), with 1 cycle on 21 days and sequential surgical resection
.
Subsequently, patients will receive a further 16 cycles of Adebrelimab adjuvant therapy
.
The primary endpoint was MPR
based on blinded independent pathology review (BIPR).

Key results

Between July 14, 2020 and May 12, 2021, a total of 54 patients were screened and 37 patients
were finally included.
As of the cut-off of data on 25 January 2022, all 37 patients had completed a 3-cycle adebrelimab combination chemotherapy regimen
.
Thirty-four patients (91.
9%) underwent surgery
.

After three preoperative cycles of treatment, 19 of the 37 patients achieved MPR (51.
4%), 11 (29.
7%, 95% CI 19.
1-49.
2) achieved pathopathological complete remission (pCR), and the R0 resection rate was 91.
9
%.

Tumor remission with neoadjuvant therapy

Of the 37 patients receiving neoadjuvant therapy, 26 (70.
3%, 95% CI 54.
2-82.
5) achieved objective response, with 1 achieving a complete response (CR) and 25 achieving a partial response (PR).

At the end of the data, the median follow-up was 12.
1 months, median EFS was not reached, 12-month event-free survival (EFS) was 77.
8%, the estimated 12-month disease-free survival (DFS) rate was 85.
6%, and the 12-month OS rate was 97.
3%.

Survival analysis

conclusion

Adebrelimab + albumin paclitaxel + carboplatin neoadjuvant therapy has shown a high MPR rate and a good safety profile in patients with resectable NSCLC, and a phase III study
will be carried out based on the results of phase Ib studies.

The Phase III CHOICE-01 study was awarded to the JCO

Brief introduction to the study

CHOICE-01 is a randomized, double-blind, placebo-controlled phase III study led by Professor Wang Jie of the Cancer Hospital of the Chinese Academy of Medical Sciences in 59 medical centers in China, aiming to evaluate the efficacy and safety
of teripulimab + chemotherapy versus placebo + chemotherapy in the first-line treatment of NSCLC without EGFR/ALK driver mutations.
Recently, the latest research results were published online in the journal
JCO.
Previous research results were selected for oral presentations at WCLC 2021 and ASCO 2022
.

Teripulimab is a humanized IgG4K monoclonal antibody
targeting PD-1.
Crystal structure analysis showed that teripulimab had different PD-1 domains
than nivolumab and pembrolizumab.
In one preclinical study, teripulimab promoted stronger antigen-specific interferon-γ
production compared with nivolumab.
Eligible patients are locally advanced (stage IIIB or IIIC) or metastatic NSCLC, or have completed neoadjuvant or adjuvant therapy ≥for 6 months
prior to enrollment.
Enrolled patients were randomized 2:1 to receive teripulimab (240 mg)/placebo plus chemotherapy
.
Treatment regimen for squamous NSCLC: albumin-bound paclitaxel (100 mg/m2) intravenously (IV) every 3 weeks + carboplatin (AUC 5), IV, every 3 weeks + teripulimab or placebo every 3 weeks, IV, 4-6 cycles of treatment, sequential teripulimab or placebo maintenance therapy
.
Treatment regimens for nonsquamous NSCLC: pemetrexed (500 mg/m2), IV + cisplatin (75 mg/m2), IV or carboplatin (AUC 5), IV, every 3 weeks + teripulimab or placebo, sequential pemetrexed + teripalimab or placebo maintenance therapy
.
The primary endpoint was investigator-assessed PFS
.

Key results

Interim PFS analysis and final PFS results

Between April 2, 2019 and August 5, 2020, a total of 835 patients were screened and 465 patients
were finally included.
As of interim analysis on 17 November 2020, the median follow-up was 7.
1 months and the event rate was 46.
9%.

The risk of disease progression or death was reduced by 42% in the teripulimab combination group compared with the placebo combination group (median PFS: 8.
3 vs 5.
6 months, HR=0.
58, P=0.
0001).

Efficacy analysis of ITT populations

The results of the interim analysis were further supported by the results of the final PFS analysis on October 31, 2021, which was 8.
4 months and 5.
6 months, respectively, in the combination group and the placebo group (HR = 0.
49, P<0.
0001), and the 1-year PFS rate in the two groups was 36.
7% and 17.
2%,<b11> respectively.

Final PFS analysis and subgroup analysis

OS results

At the time of the first interim analysis, the OS results were premature, and the median OS of either group could not be assessed
.
At the time of the second interim analysis, the median follow-up was 16.
2 months, the event rate was 45.
2%, and the median OS was not achieved in the combination group of teripulimab and 17.
1 months, respectively (HR=0.
69, P=0.
0099).

OS results and subgroup analysis

The ORRs of teripalimab and placebo were 65.
7% and 46.
2% (P<0.
0001<b11>), respectively.
The median DOR in the two groups was 8.
4 months and 4.
2 months, respectively (HR=0.
38).

Biomarker analysis

Genomic analysis
was performed using whole exome sequencing on tumor biopsy samples and paired peripheral blood mononuclear cells (PBMCs) from 394 patients.

In patients with higher TMB levels (TMB-H), the teripulimab group had a better ORR (72.
7 versus 46.
7 percent) than the placebo group, and the trend of efficacy was similar to that in the ITT population (65.
7 versus 46.
2 percent).

。 Compared with patients with lower TMB levels (median PFS: 8.
3 v 6.
5 months, HR=0.
62), the benefit of PFS in the teripulimab group (median PFS: 13.
1 v 5.
5 months, HR=0.
34, P=0.
026)
was more pronounced in patients with TMB-H.

Genome enrichment analysis was performed on genes with distinct interactions to identify representative signaling pathways
.
Interestingly, the researchers found that plaque adhesion (FA) or plaque-associated PI3K-Akt-mTOR signaling pathway and genetic mutations including COL3A1, COL6A3, FLT1, FLNC, HGF, IRS1, IRS2, ITGA4, ITGA8, and KDR appear to be among the
most commonly occurring signaling pathways associated with efficacy.
Compared with chemotherapy alone, patients with mutations associated with this signaling pathway had significantly improved PFS and OS (P≤ 0.
001) in combination immunotherapy
.
In addition, patients with mutations associated with the IL-7 signaling pathway downstream genes (HGF, IRS1, IRS2, and SMARCA4) or chromatin remodeling SWI/SNF complexes (SMARCA4, SMARCA2, and PBRM1) have good PFS
when receiving combination immunotherapy.

Correlated signal path analysis

conclusion

Regardless of PD-L1 expression, teripulimab in combination with chemotherapy significantly improves PFS and OS in patients with a manageable safety profile
compared with chemotherapy alone.
The study is the first to identify a signaling pathway associated with better efficacy of immunotherapy: FA-PI3K-Akt
.
Disruption of this pathway can increase immune surveillance and tumor sensitivity
to immunotherapy by overcoming fibrotic and immunosuppressive tumor microenvironments.

References:

1.
Zhou C, Huang D, Fan Y, et al.
Tislelizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer (RATIONALE-303): a phase 3, open-label, randomized controlled trial, Journal of Thoracic Oncology (2022), doi: https://doi.
org/10.
1016/j.
jtho.
2022.
09.
217.

2.
Yan W, Zhong W-Z, Liu Y-H, et al.
Adebrelimab (SHR-1316) in combination with chemotherapy as perioperative treatment in patients with resectable stage II-III NSCLC: an open-label, multicenter, phase 1b trial, Journal of Thoracic Oncology (2022), doi: https://doi.
org/10.
1016/j.
jtho.
2022.
09.
222.

3.
Wang Z, Wu L, Li B, et al.
Toripalimab Plus Chemotherapy for Patients With Treatment-Naive Advanced Non-Small-Cell Lung Cancer: A Multicenter Randomized Phase III Trial (CHOICE-01).
J Clin Oncol.
2022 Oct 7:JCO2200727.
doi: 10.
1200/JCO.
22.
00727.
Epub ahead of print.
PMID: 36206498.