Background

CAN is a monoclonal antibody that inhibits proinflammatory IL-1β–driven pathways that may play a role in tumor growth in early-stage NSCLC. Preclinical data suggest targeting IL-1β could decrease inflammation and immunosuppression in the tumor microenvironment (TME).

Methods

CANOPY-N (NCT03968419) is a phase II, randomized, open-label study of neoadjuvant CAN, PEM or CAN+PEM in resectable NSCLC. Eligibility: Stage IB–IIIA NSCLC; treatment (tx) naive; ECOG PS 0–1; and eligible for planned resection 4–6 weeks after first dose. Pts were randomized 2:2:1 to the tx arms: CAN, CAN+PEM or PEM. CAN and PEM were both given as two 200 mg doses once every 3 weeks. Primary endpoint: major pathological response (MPR) rate based on central review. Key secondary endpoints: overall response rate (ORR), surgical feasibility rate, and safety. Changes in CD8⁺ T cell, tumor-associated macrophage (TAM) and regulatory T cell (Treg) levels, among others, were assessed in exploratory biomarker analyses.

Results

88 pts enrolled across 3 arms: CAN (n=35), CAN+PEM (n=35) and PEM (n=18). 87 pts completed planned neoadjuvant tx. Four pts did not have surgery: 3 due to disease progression (CAN) and 1 to pt decision (CAN+PEM). MPR rates were 2.9% (CAN), 17.1% (CAN+PEM) and 11.1% (PEM). ORRs were 0% (CAN), 8.6% (CAN+PEM) and 11.1% (PEM). Gr ≥3 AEs occurred in 37.1%, 28.6% and 22.2% of pts, of which 0%, 11.4% and 11.1% were tx related, in the CAN, CAN+PEM and PEM arms, respectively. Decreases in TAMs and Tregs were seen in CAN arms whereas increases in CD8⁺ T cells were seen in PEM arms. Modulations were more pronounced with CAN+PEM (Table). Table: LBA4

Biomarkers at screening (SCR) and surgery (SUR)

Conclusions

CANOPY-N did not meet the primary endpoint of MPR rate, with minimal clinical efficacy and no increase in CD8⁺ T cells with CAN alone. No new safety signals were seen. IL-1β inhibition impacted inflammation and immunosuppression in the TME.

Clinical trial identification

CACZ885V2201C / NCT03968419.

Editorial acknowledgement

Editorial assistance was provided by Ollie Butlin, MSc of Articulate Science Ltd., and was funded by Novartis Pharmaceuticals Corporation.

Legal entity responsible for the study

Novartis Pharmaceuticals Corporation.

Funding

Novartis Pharmaceuticals Corporation.

Disclosure

T.S.K. Mok: Financial Interests, Personal, Invited Speaker: AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Daiichi Sankyo, Fishawack Facilitate, InMed Medical Communication, Lunit USA, Inc., Merck Serono, MSD, Roche, MD Health, Medscape/WebMD, PeerVoice, Touch Medical Media, Permanyer SL, Prime Oncology, Research to Practice, Sanofi-Aventis, Takeda, PER, Daz Group, Lucence Health Inc., Janssen Pharmaceutical NV, Jiahui Holdings Co., LiangYiHui Healthcare, Merck Pharmaceuticals HK Ltd, MiRXES, Novartis, OrigiMed Co. Ltd., Pfizer, Shanghai BeBirds Translation & Consulting Co., Ltd., Taiho Pharmaceutical Co., Ltd, AstraZeneca; Financial Interests, Personal, Advisory Board: AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Blueprint Medicines, Berry Oncology, CStone Pharma, Daiichi Sankyo, Fishawack Facilitate, Eisai, Gritstone Oncology, Guardant Health, G1 Therapeutics, Hengrui, Ignyta, IQVIA, Incyte Corporation, Inivata, Janssen, Loxo Oncology, Qiming Dev., Lunit USA, Inc., Merck Serono, MSD, Roche, Mirati Therapeutics, MoreHealth, Novartis, OrigiMed, Puma Tech., Sanofi-Aventis, Takeda, Virtus Medical, Yuhan, Curio Science, Bayer Healthcare Pharmaceuticals Ltd., Covidien LP, C4 Therapeutics, Cirina Ltd., Da Volterrra, F. Hoffmann-La Roche Ltd / Genentech, Gilead Sciences, Lucence Health Inc., Medscape LLC / WebMD, MiRXES, OSE Immunotherapeutics, Pfizer, SFJ Pharmaceutical Ltd., Synergy Research, Tigermed, Vertex Pharmaceuticals, Berry Oncology, D3 Bio Ltd., Lakeshore Biotech; Financial Interests, Personal, Invited Speaker, Former known as Hutchison Chi-Med: HutchMed; Financial Interests, Personal, Officer, Chairman: ACT Genomics-Sanomics Group; Financial Interests, Personal, Stocks/Shares: Sanomics Ltd., Biolidics Ltd., Aurora Tele-Oncology, AstraZeneca; Financial Interests, Personal, Stocks/Shares, Former known as Hutchison Chi-Med: HutchMed; Financial Interests, Institutional, Funding, For clinical trials performed at CUHK: Merck Serono, AstraZeneca, BMS, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, XCovery, Takeda, G1 Therapeutics, Clovis Oncology; Non-Financial Interests, Personal, Advisory Role: geneDecode; Non-Financial Interests, Personal, Other, Invited Speaker: AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc., Sanomics Ltd.; Non-Financial Interests, Personal, Leadership Role, Term ended on 30 June 2022: American Society of Clinical Oncology (ASCO); Non-Financial Interests, Personal, Leadership Role: Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), St. Stephen’s College & Prep. School (Hong Kong); Non-Financial Interests, Personal, Leadership Role, Term ended: Chinese Society of Clinical Oncology (CSCO); Non-Financial Interests, Personal, Leadership Role, Term ended on 30 April 2019: International Association for the Study of Lung Cancer (IASLC). M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan; Financial Interests, Personal, Advisory Board, Lectures, Advisory boards: AstraZeneca KK, Chugai Pharmaceutical CO.,LTD, MSD; Financial Interests, Personal, Invited Speaker, Lectures: Eli Lilly Japan, Bristol Myers Squibb KK, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical CO.,LTD; Financial Interests, Personal, Advisory Board, Advisory boards: Novartis; Financial Interests, Personal, Invited Speaker: Daiichi-Sankyo company limited, MSD, AstraZeneca, Novartis; Financial Interests, Institutional, Research Grant: Beohringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical CO.,LTD, Bristol Myers Squibb KK, Novartis; Financial Interests, Institutional, Invited Speaker: Eli Lilly Japan. J.M. Lee: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Astrazeneca, Roche/Genentech, Novartis; Financial Interests, Personal, Invited Speaker, LCMC3, LCMC4, NAUTIKA-1: Roche/Genentech; Financial Interests, Personal, Invited Speaker, CANOPY-N, GEOMETRY-1: Novartis. E.S. Kim: Financial Interests, Personal, Other, Consulting/Research: Regeneron, Takeda, Novartis. J. Zhang: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Biodesix, Bristol Myers Squibb, Cardinal Health, Daiichi Sankyo, Hengrui Therapeutics, Eli Lilly, Mirati, Nexus Health, Novartis, Novocure, Sanofi, Takeda Oncology; Financial Interests, Personal, Invited Speaker: AstraZeneca, MJH Life Sciences, Regeneron, Sanofi; Financial Interests, Institutional, Research Grant, PI and Sponsor: AstraZeneca, Biodesix, Nilogen, Genentech; Financial Interests, Institutional, Invited Speaker: Hengrui Therapeutics, Mirati, Novartis, Abbvie, BeiGene, Merck; Financial Interests, Institutional, Research Grant, PI, basic science research: Mirati; Non-Financial Interests, Personal, Member, American Society of Clinical Oncology: ASCO; Non-Financial Interests, Personal, Member, American Association for Cancer Research: AACR; Non-Financial Interests, Personal, Member, International Association for the Study of Lung Cancer: IASLC; Non-Financial Interests, Personal, Member, Chinese American Hematologist and Oncologist Network: CAHON. J. Duan: Financial Interests, Personal, Stocks/Shares: Novartis Pharmaceuticals Corporation. C. Lobetti-Bodoni: Financial Interests, Personal, Full or part-time Employment, Clinical Development Medical Director: Novartis Oncology; Financial Interests, Personal, Stocks/Shares: Novartis Oncology; Other, Personal, Other, My husband is a Roche employer: Roche; Other, Personal, Other, My husband had consultancy in the last two years with these companies: Sanofi and Takeda; Other, Personal, Other, My husband ha honoraria in the last 2 years with these companies: Takeda, Jansenn-Cilag Ltd; Other, Personal, Other, My husband owns stock of this company: Harlock Helatcare Consulting Ltd. J.C. Brase: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. A. Savchenko: Financial Interests, Personal, Full or part-time Employment: Novartis; Financial Interests, Personal, Stocks/Shares: Novartis. P. Garrido Lopez: Financial Interests, Personal, Advisory Board: Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, sanofi; Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, MSD, Novartis, Pfizer, Roche, Takeda, Novartis, IO Biotech; Financial Interests, Personal, Advisory Board, Spouse: Boehringer Ingelheim, Gebro, Janssen, Nordic; Financial Interests, Personal, Invited Speaker, Spouse: Boehringer Ingelheim, Janssen; Financial Interests, Personal, Other, Data monitoring committee for a clinical trial in 2020: Novartis; Financial Interests, Personal, Other, Lung Cancer Medical Education TASC Committee 2021: Janssen; Financial Interests, Institutional, Invited Speaker: Novartis, Janssen, AstraZeneca, Pfizer, Blue print, Apollomics, Amgen, Array Biopharma; Financial Interests, Personal, Invited Speaker, study entitled JNJ-372: Janssen; Non-Financial Interests, Personal, Leadership Role, Council member as Women for Oncology Committee ChairFellowship and Award Committee and Press CommitteeFaculty for lung and other thoracic tumours: ESMO; Non-Financial Interests, Personal, Leadership Role, President of the Spanish Federation of Medical Societies (FACME): FACME; Other, Personal, Other, My son is working in the pharma company TEVA as an engineer. I do not have any kind of relationship with TEVA: TEVA; Non-Financial Interests, Personal, Leadership Role, Former President of Spanish Medical Oncology SocietyMember of the Spanish National Health Advisory Board: SEOM; Non-Financial Interests, Personal, Leadership Role, Member of the Scientific Committee of the Spanish Against Cancer Research Foundation (aecc) and also Borad member: AECC; Non-Financial Interests, Personal, Leadership Role, IASLC Women in Thoracic Oncology Working Group Member: IASLC. All other authors have declared no conflicts of interest.

Background

PD-L1 inhibitors have been approved for the first-line treatment of extensive-stage small-cell lung cancer (ES-SCLC) in combination with chemotherapy (chemo), marking a milestone in the management of this disease. Whether a PD-1 inhibitor provides similar or better benefits in the same patient population remains unclear. At 2022 ASCO Annual Meeting, we presented the results from the interim analysis of a phase 3 study of serplulimab, a novel anti-PD-1 antibody, in combination with chemo in previously untreated ES-SCLC patients. Here we report the updated results after another 7.5 months of follow-up, and the efficacy in subgroups.

Methods

In this randomised, double-blind, international, multicentre, phase 3 study (NCT04063163), patients with ES-SCLC who had not received prior systemic therapy were randomised 2:1 to receive serplulimab 4.5 mg/kg or placebo combined with carboplatin and etoposide intravenously every 3 weeks. The primary endpoint was OS. Secondary endpoints included PFS, ORR, DOR, and safety.

Results

Between Sept 12, 2019 and Apr 27, 2021, 585 patients were randomised (serplulimab group, n = 389; placebo group, n = 196). As of data cutoff (June 13, 2022), median follow-up duration was 19.7 months. Median OS was significantly improved in serplulimab group than that in placebo group (15.8 vs. 11.1 months; HR 0.62, 95% CI 0.50–0.76; P <0.001). Median PFS assessed by IRRC per RECIST v1.1 was also prolonged with the addition of serplulimab (5.8 vs. 4.3 months; HR 0.47, 95% CI 0.38–0.58). Subgroup analysis of OS by race showed similar trends to improved survival in Asians (HR 0.65, 95% CI 0.51–0.84) and non-Asians (HR 0.51, 95% CI 0.33–0.79). Grade ≥3 treatment-related adverse events (AEs) were reported in 75.6% and 75.5% patients in the respective groups. Five patients died from AEs related to serplulimab and one from AE related to placebo.

Conclusions

The promising efficacy and favourable safety of serplulimab plus chemo for untreated ES-SCLC were maintained. Subgroup analysis revealed consistent survival benefits. ASTRUM-005 supports the development of serplulimab as the first PD-1 inhibitor combined with chemo for untreated ES-SCLC.

Clinical trial identification

NCT04063163.

Editorial acknowledgement

Shiqi Zhong and Chen Hu of Shanghai Henlius Biotech, Inc.

Legal entity responsible for the study

Shanghai Henlius Biotech, Inc.

Funding

Shanghai Henlius Biotech, Inc.

Disclosure

W. Kang, Q. Wang, J. Zhu: Financial Interests, Personal, Full or part-time Employment: Shanghai Henlius Biotech, Inc. All other authors have declared no conflicts of interest.

Background

In patients (pts) with ALK+ NSCLC, resistance to the first-generation ALK TKI CRZ eventually develops, with CNS progression and/or ALK-acquired resistance mutations. ALC and BRG are CNS-active, next-generation ALK TKIs with differing selectivity vs these mutations. Single-arm post-CRZ trials with ALC reported median PFS (mPFS) <12 mo, while BRG showed mPFS >16 mo (16.3–16.7). ALTA-3 (NCT03596866) was designed to test whether BRG efficacy is superior to ALC in ALK+ NSCLC that progressed on CRZ. We report results of the preplanned interim analysis (IA).

Methods

ALTA-3 was a phase 3 trial in pts with advanced ALK+ NSCLC who progressed on CRZ. Treatment with ≤2 systemic regimens for advanced NSCLC was allowed, excluding CRZ, but no other ALK TKI. Pts were randomized 1:1 to BRG 180 mg QD (7-day lead-in at 90 mg) or ALC 600 mg BID and stratified by baseline brain metastases (BL BM; yes/no) and best CRZ response (CR/PR vs other). Primary endpoint: BIRC-assessed PFS (RECIST v1.1); secondary endpoints included OS, ORR by BIRC, and safety. An IA for efficacy and futility was conducted, planned after ∼115 (∼70%) of 164 expected events occurred.

Results

From May 2019 to Jun 2021, 248 pts were randomized (BRG/ALC, n=125/123); median age: 54/53 yr; BL BM: 64%/61%; best response CR/PR to prior CRZ: 67%/69%. At IA data cutoff (11 Feb 2022), median follow-up (BRG/ALC) was 15.9/16.9 mo, with 107 (43%; 50/57) BIRC PFS events. BRG BIRC mPFS was 19.3 mo vs ALC 19.2 mo (HR 0.97 [95% CI: 0.66–1.42]; 2-sided log-rank P=0.867). The study met futility criteria (BIRC PFS P>0.6948) at IA and is being discontinued. OS was immature (41 events [16.5%]). BIRC-confirmed ORR (BRG/ALC), 52%/61% (OR: 0.70 [0.42‒1.15]); in pts with measurable BL BM, iORR was 73%/68% (OR: 1.31 [0.44–3.84]). Most common TEAEs: BRG, increased CPK (71%), AST (56%), ALT (43%); ALC, increased AST (40%) and ALT (38%); anemia (37%); grade 3/4: BRG, increased CPK (26%) and lipase (7%); ALC, increased ALT (6%) and AST (5%). TEAEs led to dose interruption (BRG/ALC): 54%/26%; discontinuation: 9%/6%.

Conclusions

At the IA, BIRC PFS was numerically similar between arms. No new safety findings were observed, with safety profiles consistent with known BRG and ALC profiles.

Clinical trial identification

NCT03596866.

Editorial acknowledgement

Professional medical writing assistance was provided by Lauren Gallagher, RPh, PhD, of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, and funded by Millennium Pharmaceuticals, Inc.

Legal entity responsible for the study

Takeda Development Center Americas, Inc., Lexington, MA, USA.

Funding

Takeda Development Center Americas, Inc., Lexington, MA, USA.

Disclosure

J.C. Yang: Financial Interests, Personal, Other, Honoraria or advisory role: Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech/Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, Bristol Myers Squibb, Ono Pharmaceutical, Daiichi Sankyo, Takeda, AstraZeneca, Hansoh Pharmaceuticals. G. Liu: Financial Interests, Personal, Other, Honoraria: Takeda, Amgen, AstraZeneca, Roche, Novartis, Merck, Pfizer, Jazz Pharmaceuticals; Financial Interests, Institutional, Research Grant: Takeda, AstraZeneca, Amgen, Boehringer Ingelheim. S. Lu: Financial Interests, Personal, Other, Grants or contracts: AstraZeneca, Hutchison, Bristol Myers Squibb, Heng Rui, BeiGene, Roche, Hansoh; Financial Interests, Personal, Other, Consulting fees: Roche/Genetech, Hutchison MediPharma, ZaiLab, Novartis, AstraZeneca, GenomiCare, Yuhan Corporation, Menarini, Mirati Therapeutics Inc., Roche; Financial Interests, Personal, Other, Honoraria: Roche/Genentech, Hansoh, BeiGene, AstraZeneca. M. Burotto: Financial Interests, Personal, Other, Consulting fees: Roche/Genentech, Bristol Myers Squibb, MSD Oncology, Novartis, AstraZeneca; Financial Interests, Personal, Invited Speaker: Roche/Genentech, MSD Oncology, Bristol Myers Squib, AstraZeneca. S. Vincent, J. Yin, X. Ma: Financial Interests, Personal, Full or part-time Employment: Takeda. S. Popat: Other, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Janssen, Lily, Merk Serono, MSD, Novartis, Pfizer, Sanofi, Seattle Genetics, Takeda, Turning Point Therapeutics, X; Other, Personal, Invited Speaker: Medscape, Touch Medical, VJ Oncology; Other, Personal, Expert Testimony: Roche; Other, Personal, Other, Journal deputy editor: Elsevier; Financial Interests, Institutional, Other, Sub-investigator: Amgen, Blueprint, MSD, Seattle Genetics; Other, Personal, Other, Coordinating PI: Ariad, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Janssen, Lilly, Roche, Takeda, Turning Point Therapeutics; Other, Personal, Other, Local PI: AstraZeneca, GlaxoSmithKline, Roche, Trizel; Financial Interests, Institutional, Research Grant: Guardant Health; Other, Personal, Other, Advisory and leadership roles: ALK Positive UK, British Thoracic Oncology Group, European Society of Medical Oncology, European Thoracic Oncology Platform, International Association for the Study of Lung Cancer, Lung Cancer Europe, Mesothelioma Applied Research Foundation, Ruth Strauss. All other authors have declared no conflicts of interest.

Background

Befotertinib (D-0316), a novel highly selective oral third-generation EGFR-TKI, exhibited encouraging antitumor activity in a pivotal phase II study (NCT03861156) in EGFR T790M mutation-positive patients (pts). This phase III, open-label, randomized trial was conducted to compare the efficacy and safety of befotertinib versus icotinib as first-line treatment in pts with previously untreated, locally advanced or metastatic NSCLC with EGFR-sensitizing mutation (Del19 or L858R).

Methods

Eligible stage IIIB/IIIC/IV NSCLC pts with confirmed EGFR Del19 or L858R mutation were randomly assigned (1:1) to receive either befotertinib (75–100 mg once daily) or icotinib (125 mg thrice daily) as first-line therapy. The primary endpoint was progression free survival (PFS) assessed by independent central review (IRC). Second endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS) by IRC, and safety.

Results

Between Dec 24, 2019 and Dec 28, 2020, 362 pts were randomized to receive befotertinib (n=182) and icotinib (n=180). At a median follow-up of 20.6 months, median PFS by IRC was 22.1 months for befotertinib and 13.8 months for icotinib (HR 0.49 [95% CI 0.36-0.68]; p<0.0001). ORR was 75.8% and 78.3%, DCR was 94.5% and 98.3% for befotertinib and icotinib arms, respectively. Median DOR was 12.4 months for icotinib arm but not reached for befotertinib arm. OS data were immature in both treatment arms. Median treatment duration was 16.4 months with befotertinib versus 11.1 months with icotinib. Grade≥3 treatment-emergent adverse events (TEAEs) were observed in 86 pts (47.3%) for befotertinib arm and in 54 (30.0%) for icotinib arm. Drug-related deaths occurred in 2 (1.1%) versus 1 (0.6%) pts in the befotertinib versus icotinib arm.

Conclusions

Befotertinib demonstrated superior efficacy compared with icotinib in the first-line treatment for advance pts with EGFR mutation-positive NSCLC, with an acceptable safety profile.

Clinical trial identification

NCT04206072.

Editorial acknowledgement

Editorial assistance in the writing of the abstract that was provided by Betta Pharmaceuticals Co., Ltd., Hangzhou, China.

Legal entity responsible for the study

Betta Pharmaceuticals Co., Ltd., Hangzhou, China.

Funding

Betta Pharmaceuticals Co., Ltd., Hangzhou, China.

Disclosure

S. Lu: Financial Interests, Institutional, Invited Speaker: AstraZeneca, Hansoh, Hengrui, Roche; Financial Interests, Institutional, Advisory Board: AstraZeneca, Boehringer lngelheim, GenomiCare, Hutchison MediPharma, InventisBio Co.Ltd, Menarini, Prizer, Roche, Yuhan Corporation, ZaiLab; Non-Financial Interests, Personal, Research Grant: AstraZeneca, BeiGene, BMS, Hansoh, Hengrui, Hutchison, Lilly Suzhou Pharmaceutical Co., Ltd., Roche. L. Ding: Financial Interests, Personal, Stocks/Shares: Betta Pharmaceuticals Co., Ltd. All other authors have declared no conflicts of interest.

Background

Anlotinib（Catequentinib） is an oral multi-targeted tyrosine kinase inhibitor that effectively inhibits VEGFRs, FGFRs, PGFRs, c-kit and MET. This phase III study aims to evaluate the efficacy and safety of Anlotinib or placebo plus Gefitinib in patients (pts) with untreated EGFR-mutated metastatic NSCLC.

Methods

Eligible pts were aged 18∼75 years old, had stage IIIB or IV NSCLC, with an EGFR 19del or 21L858R mutation, an ECOG PS of 0 or 1, measurable lesion according to RECIST v1.1 and adequate organ function. We randomly assigned eligible pts in a 1:1 ratio to receive oral Gefitinib (250 mg QD) plus either Anlotinib (G+A group, 12 mg QD, days1-14, 21days per cycle) or matching placebo(G+P group) until progressive disease or unacceptable toxicity. The primary endpoint was PFS assessed by IRC. Secondary endpoints included OS、ORR、DCR、DoR and safety. Blood samples for ctDNA analysis were collected at baseline, first evaluation, and progression disease (PD) and analyzed with a 329-gene panel.

Results

From Apr. 2019 to Aug. 2021, 315 patients were assigned to the G+A (n=157) or G+P group (n=158). At data cutoff (Jul 31, 2022), the median follow-up was 17.3m in G+A and 18.8m in G+P. The mPFS by IRC was significantly longer in G+A than in G+P group (14.75m vs. 11.20m; HR 0.64, p = 0.0035). Confirmed ORR was 76.13% in G+A and 64.52% in G+P. Treatment with G+A was associated with more durable response (mDoR: 12.48m vs 9.46m, HR=0.56, p=0.0003) than G+P. OS data are immature. Grade ≥3 TEAEs occurred in 49.68% (G+A) vs. 30.97% (G+P). The most common Grade ≥3 TEAEs were hypertension (29.68 %) in G+A and increased ALT (12.26%) in G+P. We also exploratory analysis biomarker information and resistance mechanism based on dynamic ctDNA. The preliminary analysis of the ctDNA data of 289 pts showed that pts with TP53+EGFR CNV co-mutations had a better benefit from G+A than G+P (11.74 m vs 6.83m; HR=0.3). We will update the detailed biomarker data in congress.

Conclusions

Compared with G+P group, G+A group significantly prolonged PFS in pts with untreated metastatic EGFR-mutated NSCLC and the safety profiles were manageable.

Clinical trial identification

NCT04028778.

Legal entity responsible for the study

The authors.

Funding

1) Chia Tai-Tianqing Pharmaceutical Co., Ltd. 2) OrigiMed.

Disclosure

All authors have declared no conflicts of interest.