Background

Adding bevacizumab to erlotinib prolonged PFS in NEJ026 and CTONG 1509 trials, but limited data are available in non-Asian patients (pts). BEVERLY is an Italian no-profit, randomized, open-label, multicenter phase III trial of bevacizumab (BEV) plus erlotinib (E) vs E alone as first-line treatment for EGFR-mutated advanced NSCLC.

Methods

Eligible pts were randomized 1:1 to E (150mg daily) alone or combined with BEV (15mg/kg iv q3w) until disease progression or unacceptable toxicity. Center, ECOG PS and type of mutation (ex19 deletion vs ex21 L858R vs others) were stratification variables. Co-primary endpoints were investigator-assessed PFS (IA-PFS) and blinded-independent centrally-reviewed PFS (BICR-PFS). Secondary endpoints were OS, QoL, IA- and BICR- objective response rate (ORR) and safety; biomarker analyses are also planned. 126 events out of 160 randomized pts were required to detect a PFS prolongation with BEV from 10 to 16.7 mos (HR 0.60), with 2-sided α=0.05, 80% power.

Results

From Apr 11, 2016 to Feb 27, 2019, 160 pts were randomized to BEV+E (80) or E alone (80). Pts were mainly female (63.8%), never smokers (51.9%), ECOG PS 0-1 (98.1%), median age 66 (IQR 59-73); 55% of pts had ex19Del and 41% L858R mutation. At a median follow-up of 31 mos, 130/160 (81.3%) pts had a PFS event (progression or death) and 84/160 (52.5%) died. BEV+E significantly prolonged IA-PFS over E alone with a median of 15.4 vs 9.7 mos (HR 0.60; 95%CI 0.42-0.85, log-rank P=0.0039). Median OS was 28.4 vs 23.0 mos in BEV+E and E arms, respectively (HR 0.70; 95%CI 0.46-1.10, log-rank P=0.12). One toxic death was reported, due to intracranial hemorrhage with BEV+E. Hypertension (any grade: 49% vs 18%; grade≥3: 24% vs 5%), skin rash (grade≥3: 31% vs 14%), thromboembolic events (any grade: 11% vs 4%), and proteinuria (any grade: 23% vs 6%) were more frequent with the experimental combination treatment.

Conclusions

The addition of BEV to E significantly prolonged IA-PFS compared with E alone as first-line treatment in Italian EGFR-mutated NSCLC patients, with no unexpected safety issues. Blinded radiologic revision of PFS and ORR is ongoing and will be presented at the meeting.

Clinical trial identification

NCT02633189; EudraCT 2015-002235-17.

Legal entity responsible for the study

Clinical Trial Unit, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale.

Funding

Roche provided partial funding and experimental drugs.

Disclosure

M.C. Piccirillo: Financial Interests, Personal, Invited Speaker: Astellas; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Bayer. L. Bonanno: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim. L. Cavanna: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Sponsor/Funding: Pfizer; Financial Interests, Personal, Sponsor/Funding: Celgene; Financial Interests, Personal, Sponsor/Funding: Ipsen. F. Rosetti: Financial Interests, Personal, Sponsor/Funding: Roche. S. Rizzato: Financial Interests, Personal, Sponsor/Funding: Roche; Financial Interests, Personal, Sponsor/Funding: Amgen. R. Di Liello: Financial Interests, Personal, Invited Speaker: Astellas. F. Morgillo: Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Institutional, Research Grant: AstraZeneca. F. Ciardiello: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Amgen. All other authors have declared no conflicts of interest.

Background

Osimertinib (Osi) has been a standard treatment for untreated patients (pts) with non-small-cell lung cancer (NSCLC) harboring an EGFR mutation. Previous studies showed that the addition of anti-VEGF inhibitors to erlotinib prolonged progression-free survival (PFS) in EGFR mutated non-squamous NSCLC (Ns-NSCLC) pts. This phase II, open-label, randomized trial was conducted to compare Osi plus bevacizumab (Bev) with Osi monotherapy for untreated pts with advanced EGFR mutated Ns-NSCLC.

Methods

This study enrolled untreated pts with advanced Ns-NSCLC harboring an EGFR sensitizing mutation (Del19 or L858R), and without symptomatic brain metastases. 122 eligible pts were randomized in a 1:1 ratio to receive either Osi (80 mg, daily) plus Bev (15 mg/kg, every 3 weeks) (OB arm) or Osi monotherapy (O arm), and stratified according to sex, stage and EGFR mutation status. The primary endpoint was PFS, assessed by blinded, independent central radiologic reviewer (BICR). Assuming that the median PFS in the OB arm and the O arm were 27 and 18 months, planned sample size was 120 in total to give a power of 80% with a one-sided alpha of 20%, with an accrual period of 1.5 years and a follow-up period of 2 years.

Results

Between January 2018 and September 2018, 122 pts were enrolled (OB arm, 61 pts O arm, 61 pts). At a median follow-up of 19.8 months, median PFS by BICR was 22.1 months for OB arm and 20.2 months for O arm, with a hazard ratio (HR) of 0.862 (60% CI, 0.700–1.060; 95% CI, 0.531–1.397; one-sided stratified log-rank p=0.213). In subgroup analysis, ex-smoker (HR 0.481) and pts with 19del (HR 0.622) showed better trend of PFS in OB arm. Objective response rate was 82% in OB arm and 86% in O arm. Grade 3-4 adverse events were observed in 34 pts (56%) for OB arm and in 29 (48%) for O arm. Any grade paronychia, rash acneiform, hypertension, epistaxis and proteinuria were frequently observed in OB arm. Among them, 3% and 18% experienced any grade pneumonitis, and grade 3 pneumonitis in 1 pt for each arm.

Conclusions

This study failed to show the efficacy of OB arm for improving PFS in untreated pts with EGFR mutated Ns-NSCLC.

Clinical trial identification

UMIN000030206.

Legal entity responsible for the study

West Japan Oncology Group.

Funding

AstraZeneca.

Disclosure

H. Kenmotsu: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co, Ltd.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co, Ltd.; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly K.K; Financial Interests, Personal, Invited Speaker: Kyowa Hakko Kirin Co., Ltd.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis Pharma K.K.; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Invited Speaker: AstraZeneca K.K.; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Taiho Pharma; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical Co, Ltd.; Financial Interests, Institutional, Research Grant: Novartis Pharma K.K.; Financial Interests, Institutional, Research Grant: Daiichi Sankyo Co., Ltd.; Non-Financial Interests, Principal Investigator: AstraZeneca K.K.; Non-Financial Interests, Principal Investigator: Eli Lilly K.K; Non-Financial Interests, Principal Investigator: Boehringer Ingelheim. K. Wakuda: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly K.K.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Astrazeneca; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Astrazeneca; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: AbbVie. T. Kato: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Merck KGaA; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Merck KGaA; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Institutional, Funding: AbbVie; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Chugai; Financial Interests, Institutional, Funding: Eli Lilly; Financial Interests, Institutional, Funding: Merck biopharma; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Regeneron; Other, Personal, Other: Eli Lilly. S. Sugawara: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai Pharma; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical; Financial Interests, Personal, Invited Speaker: Nippon Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly and Company; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Personal, Invited Speaker: Kyowa Kirin; Financial Interests, Personal, Invited Speaker: Yakult Honsha. K. Kirita: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Personal, Funding: Chugai Pharmaceutical Co., Ltd. I. Okamoto: Financial Interests, Personal, Invited Speaker: AstraZenaca; Financial Interests, Institutional, Funding: AstraZenaca; Financial Interests, Personal, Advisory Board: AstraZenaca. K. Azuma: Financial Interests, Personal, Speaker’s Bureau: Astrazeneca; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Personal, Speaker’s Bureau: Ono Pharma; Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharm; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Nippon Kayaku. K. Nishino: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Merck Biopharma Co., Ltd; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Nippon Boehringer Ingelheim Co., Ltd.; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Shanghai Haihe Pharmaceutical Co., Ltd. S. Teraoka: Financial Interests, Personal, Invited Speaker: Chugai Pharma; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutica; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutica; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Eli Lilly. H. Hayashi: Financial Interests, Personal, Invited Speaker: AstraZeneca K.K.; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim Japan Inc.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb Co. Ltd.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co. Ltd.; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K; Financial Interests, Personal, Invited Speaker: Kyorin pharmaceutical co. ltd; Financial Interests, Personal, Invited Speaker: Merck Biopharma Co., Ltd.; Financial Interests, Personal, Invited Speaker: MSD K.K.; Financial Interests, Personal, Invited Speaker: Novartis pharmaceuticals K.K.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd.; Financial Interests, Personal, Invited Speaker: Shanghai Haihe Biopharm; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co. Ltd; Financial Interests, Personal, Invited Speaker: Takeda Pharmaceutical Company Limited; Financial Interests, Personal, Advisory Board: AstraZeneca K.K.; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim Japan Inc.; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb Co. Ltd.; Financial Interests, Personal, Advisory Board: Chugai Pharmaceutical Co. Ltd.; Financial Interests, Personal, Advisory Board: Eli Lilly Japan K.K; Financial Interests, Personal, Advisory Board: Pfizer Japan Inc.; Financial Interests, Personal, Advisory Board: Shanghai Haihe Biopharm; Financial Interests, Personal, Advisory Board: Takeda Pharmaceutical Company Limited; Financial Interests, Personal, Advisory Board: Merck Biopharma Co., Ltd.; Financial Interests, Institutional, Funding: AstraZeneca K.K.; Financial Interests, Institutional, Funding: Astellas Pharma Inc.; Financial Interests, Institutional, Funding: MSD K.K.; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: Nippon Boehringer Ingelheim Co.,Ltd; Financial Interests, Institutional, Funding: Novartis Pharma K.K.; Financial Interests, Institutional, Funding: Pfizer Japan Inc.; Financial Interests, Institutional, Funding: Bristol Myers Squibb Company; Financial Interests, Institutional, Funding: Eli Lilly Japan K.K.; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co.,Ltd; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd.,; Financial Interests, Institutional, Funding: Merck Serono Co., Ltd./ Merck Biopharma Co., Ltd.; Financial Interests, Institutional, Funding: Takeda Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: Taiho Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: SymBio Pharmaceuticals Limited.; Financial Interests, Institutional, Funding: AbbVie Inc; Financial Interests, Institutional, Funding: inVentiv Health Japan; Financial Interests, Institutional, Funding: ICON Japan K.K.; Financial Interests, Institutional, Funding: Gritstone Oncology Inc. Financial Interests, Institutional, Funding: Parexel International Corp.; Financial Interests, Institutional, Funding: Kissei Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: EPS Corporation.; Financial Interests, Institutional, Funding: Syneos Health.; Financial Interests, Institutional, Funding: Pfizer R&D Japan G.K.; Financial Interests, Institutional, Funding: A2 Healthcare Corp.; Financial Interests, Institutional, Funding: Quintiles Inc. / IQVIA Services Japan K.K.; Financial Interests, Institutional, Funding: EP-CRSU Co., Ltd.; Financial Interests, Institutional, Funding: Linical Co.,Ltd.; Financial Interests, Institutional, Funding: Eisai Co., Ltd.; Financial Interests, Institutional, Funding: CMIC Shift Zero K.K; Financial Interests, Institutional, Funding: Kyowa Hakko Kirin Co.,Ltd; Financial Interests, Institutional, Funding: Bayer Yakuhin, Ltd.; Financial Interests, Institutional, Funding: EPS International Co.,Ltd,; Financial Interests, Institutional, Funding: Otsuka Pharmaceutical Co., Ltd. R. Toyozawa: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan; Financial Interests, Personal, Invited Speaker: Nippon Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Novartis Pharm; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Institutional, Funding: AbbVie; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: Daiichi Sankyo; Financial Interests, Institutional, Funding: Eli Lilly Japan; Financial Interests, Institutional, Funding: Pfizer Japan; Financial Interests, Institutional, Funding: Takeda Pharmaceutical. S. Miura: Financial Interests, Personal, Speaker’s Bureau: Chugai Pharma.; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharma; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: Boehringer-Ingelheim Japan; Financial Interests, Personal, Speaker’s Bureau: Ono Pharma.; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo. Y. Sato: Financial Interests, Personal, Invited Speaker: Chugai Pham; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical CO; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Nippon Kayaku; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Kyowa Kirin Co.,Ltd. K. Nakagawa: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Merck Biopharma Co., Ltd.; Financial Interests, Personal, Invited Speaker: Amgen Inc.; Financial Interests, Personal, Invited Speaker: Kyowa Kirin Co., Ltd.; Financial Interests, Personal, Invited Speaker: akeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: AstraZeneca K.K.; Financial Interests, Personal, Invited Speaker: 3H Clinical Trial Inc.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K.; Financial Interests, Personal, Invited Speaker: Medical Review Co., Ltd.; Financial Interests, Personal, Invited Speaker: MSD K.K.; Financial Interests, Personal, Invited Speaker: Medical Mobile Communications co., Ltd; Financial Interests, Personal, Invited Speaker: Pfizer Japan Inc.; Financial Interests, Personal, Invited Speaker: Nippon Boehringer Ingelheim Co., Ltd.; Financial Interests, Personal, Advisory Board: Eli Lilly Japan K.K.; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Parexel International Corp.; Financial Interests, Institutional, Funding: Eisai Co., Ltd.; Financial Interests, Institutional, Funding: PRA Health Sciences; Financial Interests, Institutional, Funding: AstraZeneca K.K.; Financial Interests, Institutional, Funding: EPS Corporation.; Financial Interests, Institutional, Funding: Mochida Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Kissei Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Covance Japan Inc; Financial Interests, Institutional, Funding: EPS International Co.,Ltd,.; Financial Interests, Institutional, Funding: Japan Clinical Research Operations; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Funding: Takeda Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: Taiho Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: GlaxoSmithKline K.K.; Financial Interests, Institutional, Funding: MSD K.K.; Financial Interests, Institutional, Funding: Sanofi K.K.; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Funding: PPD-SNBL K.K.; Financial Interests, Institutional, Funding: Nippon Boehringer Ingelheim Co.,Ltd.; Financial Interests, Institutional, Funding: SymBio Pharmaceuticals Limited.; Financial Interests, Institutional, Funding: Sysmex Corporation; Financial Interests, Institutional, Funding: IQVIA Services Japan K.K.; Financial Interests, Institutional, Funding: Medical Reserch Support; Financial Interests, Institutional, Funding: Syneos Health; Financial Interests, Institutional, Funding: /Eli Lilly Japan K.K. N. Yamamoto: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD K.K.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Thermo Fisher Scientific; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K.; Financial Interests, Personal, Invited Speaker: Boehringer-Ingelheim; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer Inc.; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Invited Speaker: Nippon Kayaku; Financial Interests, Personal, Invited Speaker: GlaxoSmithKline K.K.; Financial Interests, Personal, Invited Speaker: Sanofi K.K.; Financial Interests, Personal, Invited Speaker: Hisamitsu Pharmaceutical Co.Inc.; Financial Interests, Personal, Invited Speaker: Merk biopharma; Financial Interests, Personal, Invited Speaker: Guardant Health Japan; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: MSD K.K.; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Advisory Board: Eli Lilly Japan K.K.; Financial Interests, Personal, Advisory Board: Boehringer-Ingelheim; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer Inc.; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Nippon Kayaku; Financial Interests, Personal, Advisory Board: Life Technologies Japan Ltd.; Financial Interests, Personal, Advisory Board: Amgen Inc.; Financial Interests, Personal, Advisory Board: Guardant Health Japan; Financial Interests, Personal, Advisory Board: Janssen Pharmaceutical K.K.; Financial Interests, Personal, Research Grant: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Research Grant: Boehringer-Ingelheim; Financial Interests, Personal, Research Grant: Tosoh Life Science Research Laboratory; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Boehringer-Ingelheim; Financial Interests, Institutional, Funding: Otsuka Pharmaceutical CO., Ltd.; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Shionogi & Co., Ltd.; Financial Interests, Institutional, Funding: Daiichi Sankyo Co., Ltd.; Financial Interests, Institutional, Funding: Eli Lilly Japan K.K.; Financial Interests, Institutional, Funding: Tsumura & CO.; Financial Interests, Institutional, Funding: Nippon Kayaku; Financial Interests, Institutional, Funding: Asahi Kasei Pharma; Financial Interests, Institutional, Funding: Janssen Pharmaceutical K.K.; Financial Interests, Institutional, Funding: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Sanofi K.K.; Financial Interests, Institutional, Funding: Amgen Inc. T. Takahashi: Financial Interests, Personal, Invited Speaker: AstraZeneca K.K.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan K.K.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: MSD K.K.; Financial Interests, Personal, Invited Speaker: Pfizer Japan Inc.; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim Japan; Financial Interests, Personal, Invited Speaker: Roche Diagnostics K.K.; Financial Interests, Institutional, Funding: AstraZeneca K.K.; Financial Interests, Institutional, Funding: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: Eli Lilly Japan K.K; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Funding: MSD K.K.; Financial Interests, Institutional, Funding: Pfizer Japan Inc.; Financial Interests, Institutional, Funding: Amgen inc.; Financial Interests, Institutional, Funding: Boehringer Ingelheim Japan. All other authors have declared no conflicts of interest.

Background

HER2 mutations occur in ∼3% of NSCLC; there are no HER2-targeted therapies approved for pts with NSCLC, representing a high unmet need. DESTINY-Lung01 (NCT03505710) assessed the efficacy and safety of T-DXd, a HER2 antibody-drug conjugate, in pts with HER2m NSCLC.

Methods

In a multicenter, 2-cohort phase 2 trial, pts with HER2m NSCLC refractory to standard treatment received T-DXd 6.4 mg/kg. Primary endpoint was ORR per RECIST v1.1 by independent central review (ICR). Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Exploratory biomarkers of HER2 alterations were analyzed.

Results

Ninety-one pts with HER2m NSCLC were enrolled (data cutoff, May 3, 2021). Median follow-up was 13.1 mo. Median age was 60 years. 93.4% of pts had a HER2 kinase domain mutation; 36.3% had asymptomatic central nervous system (CNS) metastasis not requiring ongoing treatment. Median number of prior cancer therapies was 2 (range, 0-7), including platinum-based therapy (94.5%) and PD-1/PD-L1 therapy (65.9%). Centrally confirmed ORR was 54.9% (95% CI, 44.2-65.4). Efficacy was consistent across subgroups, including pts previously treated with a HER2 TKI or with CNS metastasis. Treatment-related adverse events (TRAEs) occurred in 96.7% pts. Adjudicated drug-related interstitial lung disease (ILD) occurred in 24 pts (3 grade 1, 15 grade 2, 4 grade 3, 2 grade 5). Additional biomarker analyses showed responses across different HER2m subtypes, as well as in pts with no detectable HER2 expression or HER2 gene amplification. Table: LBA45

Efficacy and safety of T-DXd in pts with HER2m NSCLC

Conclusions

T-DXd demonstrated robust and durable activity in pts with previously treated HER2m NSCLC, with a manageable safety profile consistent with previous studies. This study provides compelling evidence of positive benefit/risk balance for T-DXd and supports its establishment as a potential new treatment standard for this population.

Clinical trial identification

NCT03505710.

Editorial acknowledgement

Under the guidance of authors, medical writing and editorial support was provided by Cindy M. Rigby, PhD, and Charlene Rivera, PhD, of ApotheCom and was funded by Daiichi Sankyo, Inc.

Legal entity responsible for the study

Daiichi Sankyo, Inc., and AstraZeneca.

Funding

Daiichi Sankyo, Inc. and AstraZeneca.

Disclosure

B.T. Li: Non-Financial Interests, Personal, Advisory Role: Daiichi Sankyo, AstraZeneca, Amgen, Genentech, Boehringer Ingelheim, Lilly; Financial Interests, Institutional, Research Grant: Amgen, Genentech, AstraZeneca, Daiichi Sankyo, Lilly, Illumina, GRAIL, Guardant Health, Hengrui Therapeutics, MORE Health and Bolt Biotherapeutics; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Resolution Bioscience, MORE Health, and Jiangsu Hengrui Medicine; Financial Interests, Personal, Licensing Fees: Karger Publishers, Shanghai Jiao Tong University Press (intellectual property as book author). E.F.F. Smit: Financial Interests, Institutional, Advisory Role: AstraZeneca , Bristol Myers Squibb, Bayer, Cellgene, DSI, Eli Lilly, MSD, Merck, Novartis, Pfizer, Takeda, Regeneron, Roche Genentech, Roche Diagnostics; Financial Interests, Institutional, Research Grant: AstraZeneca , Bristol Myers Squibb, Merck, MSD, Roche Genentech. Y. Goto: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Ono Pharmaceutical, Taiho, Chugai, Novartis, Eli Lilly, Pfizer, Daiichi Sankyo, Bristol Myers Squibb, Merck, Thermo Fischer, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Eli Lilly, AstraZeneca, Chugai, Taiho, Boehringer Ingelheim, Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, MSD, Novartis, Daiichi Sankyo, Illumina, Guardant Health Inc.; Non-Financial Interests, Institutional, Research Grant: AbbVie, Eli Lilly, Bristol Myers Squibb, DaiichiSankyo, Prefered Network; Financial Interests, Personal and Institutional, Research Grant: Pfizer, Chugai, Novartis, . K. Nakagawa: Financial Interests, Personal, Other, Honoraria: Astellas Pharma Inc./Takeda Pharmaceutical Co.,Ltd./NANZANDO Co.,Ltd/AstraZeneca K.K./Chugai Pharmaceutical Co.,Ltd./Roche Diagnostics K.K./MSD K.K./Eli Lilly Japan K.K./Nippon Kayaku Co., Ltd./Ono Pharmaceutical Co.,Ltd./Merck Biopharma Co., Ltd./Bayer Y; Financial Interests, Personal, Advisory Role: Astellas Pharma Inc./Takeda Pharmaceutical Co.,Ltd./Eli Lilly Japan K.K./Pfizer Japan Inc./KYORIN Pharmaceutical Co., Ltd./Ono Pharmaceutical Co.,Ltd.; Financial Interests, Institutional, Research Grant: MSD K.K./AstraZeneca K.K./Pfizer Japan Inc./ICON Japan K.K./Astellas Pharma Inc./Bayer Yakuhin, Ltd/Takeda Pharmaceutical Co.,Ltd./Novartis Pharma K.K./Otsuka Pharmaceutical Co., Ltd./Eli Lilly Japan K.K./EPS International Co.,Ltd,./Bayer Yakuhin, Ltd/Bri. J. Mazieres: Financial Interests, Personal, Other, Honoraria: Roche, BMS, MSD, AstraZeneca, Takeda, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Roche, Pierre Fabre, AstraZeneca. M. Nagasaka: Financial Interests, Personal, Advisory Role: AstraZeneca, Caris, Daiichi Sankyo, Takeda, Novartis, EMD Serono, JNJ, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Blueprint Medicines; Financial Interests, Personal, Other, Travel expenses: An Heart Therapeutics. L. Bazhenova: Financial Interests, Institutional, Other, Honoraria: AstraZeneca, Takeda; Financial Interests, Personal, Advisory Role: Neuvogen, Janssen, Daichi Sankyo, Boehringer Ingelheim, Merck, Regeneron, Bristol Myers Squibb, Novartis; Financial Interests, Institutional, Research Grant: Beyondspring. A.N. Saltos: Financial Interests, Personal, Other, Honoraria: MJH Life Sciences; Financial Interests, Institutional, Research Grant: Novartis, Daiichi Sankyo, Lilly, Mersana, Genmab, AstraZeneca, Turning Point Therapeutics. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, Beigene, Boehringer-Ingelheim, BMS, Eli Lilly, F. Hoffman-La Roche, Glaxo Smith Kline, Janssen, Medical Trends, Merck Sharp and Dohme, Merck Serono, Peptomyc, Pfizer, Puma, Regeneron, Sanofi, Syneos Health, Takeda; Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, BMS, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Peervoice, Pfizer, Springer, Touch Medical. J.M. Pacheco: Financial Interests, Institutional, Other, Honoraria: Takeda, Genentech; Financial Interests, Personal, Advisory Role: AstraZeneca, Blueprint Medicines, Gerson Lehrman Group, Hengrui Pharmaceuticals, Jazz Pharmaceuticals, Novartis, Pfizer, Takeda, Research America; Financial Interests, Personal, Other, Travel/Accommodations/Expenses: Daiichi Sankyo, AstraZeneca, Novartis, Pfizer, Takeda; Financial Interests, Institutional, Research Grant: Pfizer. M. Pérol: Financial Interests, Personal, Other, Honoraria: Roche, Genentech, Eli Lilly, Pfizer, Boehringer-Ingelheim, Clovis Oncology, Merck Sharp & Dome, Bristol Myers Squibb, Novartis, Pierre Fabre, AstraZeneca, Takeda, Sanofi, GlaxoSmithKline, Gritstone; Financial Interests, Personal, Advisory Role: Roche, Genentech, Eli Lilly, Pfizer, Boehringer-Ingelheim, Clovis Oncology, Merck Sharp & Dome, Bristol Myers Squibb, Novartis, Pierre Fabre, AstraZeneca, Takeda, Sanofi, GlaxoSmithKline, Gritstone; Financial Interests, Personal, Speaker’s Bureau: Roche, AstraZeneca; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, Boehringer-Ingelheim, Takeda, Chugai; Financial Interests, Personal, Other, Travel/Accomodations/Expenses: Roche, Genentech, Eli Lilly, Pfizer, Boehringer-Ingelheim, Merck Sharp & Dome, Bristol Myers Squibb, AstraZeneca, Takeda. L. Paz-Ares: Financial Interests, Personal, Speaker’s Bureau: Roche, MSD, Merck Serono, BMS, AstraZeneca, Lilly, Pfizer, Pharmamar, Bayer, AbbVie, Amgen, Janssen, GSK, Novartis, Ipsen, Boerhinger, Takeda, Sanofi, Blueprint, Mirati; Financial Interests, Institutional, Research Grant: BMS, AstraZeneca, Pharmamar. K. Saxena: Financial Interests, Personal, Other, Full/Part-time employment: Daiichi Sankyo, Inc. R. Shiga: Financial Interests, Personal, Other, Full/Part-time employment: Daiichi Sankyo, Inc. Y. Cheng: Financial Interests, Personal, Other, Full/Part-time employment: Daiichi Sankyo, Inc. S. Acharyya: Financial Interests, Personal, Other, Full/Part-time employment: Daiichi Sankyo, Inc. J. Shahidi: Financial Interests, Personal, Other, Full/Part-time employment: Daiichi Sankyo, Inc. D. Planchard: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung; Financial Interests, Institutional, Other, Honoraria: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche, Samsung; Financial Interests, Personal, Other, Travel expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. P.A. Jänne: Financial Interests, Personal, Advisory Role: Pfizer, Boehringer Ingelheim, AstraZeneca, Merrimack, Chugai Pharma, Roche/Genentech, LOXO, Mirati Therapeutics, Araxes Pharma, Ignyta, Lilly, Takeda, Novartis, Biocartis, Voronoi Health Analytics, SFJ Pharmaceuticals Group, Sanofi, Biocartis, Daiichi San; Financial Interests, Personal, Stocks/Shares: Gatekeeper Pharmaceuticals, LOXO; Financial Interests, Personal, Research Grant: AstraZeneca, Astellas Pharma, Daiichi Sankyo, Lilly, Boehringer Ingelheim, Puma Biotechnology, Takeda, Revolution Medicines; Financial Interests, Personal, Royalties: I am a co-inventor of DFCI owned patent on EGFR mutations licensed to Lab Corp. I receive post-marketing royalties from this invention. All other authors have declared no conflicts of interest.

Background

Treatment of non-small cell lung cancer (NSCLC) with EGFR and HER2 exon 20 mutations is an unmet medical need. We evaluated the efficacy and safety of poziotinib, a potent tyrosine kinase inhibitor (TKI) able to overcome the restricted binding pocket of exon 20 mutations, in newly diagnosed patients with NSCLC and HER2 exon 20 insertion mutations in a multinational, multi-cohort Phase 2 study.

Methods

ZENITH20 study enrolled pts with advanced NSCLC with exon 20 insertion mutations: previously treated EGFR, previously treated HER2, naïve EGFR and naïve HER2 in Cohorts 1, 2, 3, and 4 respectively as identified by genetic profiling of tumor tissue. Poziotinib (16 mg) was administered orally daily either as once (QD) or twice (BID), allowing dose interruptions/reductions for toxicity. The primary endpoint was objective response rate (ORR) evaluated centrally by an independent image review committee using RECIST 1.1 criteria. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and safety. Data from Cohort 4 is presented.

Results

48 received 16 mg QD and 23 received 8 mg BID in Cohort 4. QD data is presented; BID dosing group is currently enrolling. In QD group, 48 patients with a median age of 61 years (34-87) were treated and 4 patients are ongoing in the study. Majority were White (75%), female (54%), non-smokers (69%) with ECOG PS of 1 (65%). 88% patients had dose interruptions and 76% had reductions from 16 mg starting dose. 12% had AE related discontinuations. The most common treatment-related Grade ≥3 AEs were rash (35%), diarrhea (14%), stomatitis (20%) and paronychia (8%). Primary endpoint ORR was 44% (95% CI: 29.5 – 58.8%) in the 48 treated patients. 2 additional patients had response not confirmed (uORR=48%). DCR was 75%. Median DoR was 5.4 months (range: 2.8-19.1+) with 3 patients continuing treatment. Median PFS was 5.6 months (range: 0-20.2+).

Conclusions

Poziotinib demonstrated clinically meaningful efficacy in newly diagnosed NSCLC patients with HER2 exon 20 mutations with 16 mg QD dosing. Safety profile was similar to other second generation TKIs with manageable AEs. Study is ongoing with BID dosing currently.

Clinical trial identification

NCT03318939.

Legal entity responsible for the study

Spectrum Pharmaceuticals, inc.

Funding

Spectrum Pharmaceuticals.

Disclosure

L. Dreling: Financial Interests, Institutional, Full or part-time Employment: Spectrum Pharmaceuticals. G. Bhat: Financial Interests, Institutional, Full or part-time Employment: Spectrum Pharmaceuticals. F. Lebel: Financial Interests, Institutional, Full or part-time Employment: Spectrum Pharmaceuticals. All other authors have declared no conflicts of interest.